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Module 2.5 Clinical Overview
Module 2.5
Clinical Overview
Copyright 2012 ViiV Healthcare and the GlaxoSmithKline group of companies. All
rights reserved. Unauthorized copying or use of this information is prohibited.
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Module 2.5 Clinical Overview
TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................6
1.
PRODUCT DEVELOPMENT RATIONALE...............................................................9
1.1.
HIV Infection .................................................................................................9
1.2.
Current Therapies and its Unmet Clinical Need ............................................9
1.3.
Claimed Indication and Dosage .................................................................. 11
1.4.
Clinical Development Program.................................................................... 12
1.5.
Regulatory History ......................................................................................13
1.6.
Compliance with Good Clinical Practice (GCP)........................................... 13
2.
OVERVIEW OF BIOPHARMACEUTICS ................................................................13
2.1.
Biopharmaceutical Classification ................................................................13
2.2.
Formulation Development........................................................................... 13
2.3.
Analytical Methods......................................................................................14
2.4.
Biopharmaceutics Studies .......................................................................... 14
3.
OVERVIEW OF CLINICAL PHARMACOLOGY...................................................... 15
3.1.
Absorption, Distribution, Metabolism and Elimination of Dolutegravir.......... 15
3.1.1.
Absorption ................................................................................... 15
3.1.2.
Distribution................................................................................... 15
3.1.3.
Metabolism and Excretion............................................................16
3.1.4.
Elimination ................................................................................... 16
3.2.
Pharmacokinetics in Healthy Subjects and Target Patient
Populations................................................................................................. 17
3.2.1.
Summary of Dolutegravir PK Parameters .................................... 17
3.2.2.
Pharmacokinetics in Special Populations..................................... 19
3.2.2.1.
Children...................................................................... 19
3.2.2.2.
Elderly ........................................................................ 20
3.2.2.3.
Renal impairment .......................................................20
3.2.2.4.
Hepatic impairment..................................................... 20
3.2.2.5.
UGT1A1 Polymorphism.............................................. 21
3.2.2.6.
Co-infection with Hepatitis B or C ...............................21
3.2.2.7.
Population PK.............................................................21
3.3.
Drug-Drug Interactions................................................................................ 21
3.3.1.
Effect of Dolutegravir on the Pharmacokinetics of Other
Agents .........................................................................................21
3.3.2.
Effect of Other Agents on the Pharmacokinetics of
Dolutegravir and Dose Recommendations................................... 24
3.4.
Pharmacodynamics .................................................................................... 28
3.4.1.
Effect of DTG on Cardiac Conduction .......................................... 28
3.4.2.
Effect of DTG on Renal Function ................................................. 28
3.5.
Pharmacokinetic – Pharmacodynamic Relationships and Definition
of “No Effect Boundaries”............................................................................ 28
3.5.1.
PK/PD Relationship for Efficacy................................................... 28
3.5.1.1.
Short-Term Monotherapy............................................ 28
3.5.1.2.
Long-Term Combination Therapy ...............................29
3.5.2.
PK/PD Relationship for Safety ..................................................... 30
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3.5.3.
3.6.
Definition of No Effect Boundaries of Alteration in DTG
Exposure .....................................................................................30
Clinical Pharmacology Conclusions ............................................................31
4.
OVERVIEW OF EFFICACY ................................................................................... 32
4.1.
Non-clinical Virology ................................................................................... 32
4.2.
Selection of Patient Populations in Pivotal and Supportive Efficacy
Studies ....................................................................................................... 33
4.3.
Rationale for Dose Selection in Clinical Development................................. 33
4.3.1.
ART-Naïve/ART-Experienced (INI-Naïve) Subjects ..................... 33
4.3.2.
ART-Experienced (INI-Resistant) Subjects .................................. 34
4.4.
Clinical Trial Methodology and Design (Pivotal Efficacy Study
Designs) ..................................................................................................... 35
4.4.1.
Studies in INI-Naïve Subjects ...................................................... 35
4.4.2.
Studies in INI-Resistant Subjects................................................. 35
4.5.
Efficacy Endpoints and Statistical Considerations of Efficacy
Analyses ..................................................................................................... 39
4.5.1.
Primary and Secondary Efficacy Endpoints ................................. 39
4.5.2.
Statistical Considerations.............................................................40
4.6.
Efficacy Results in all Studies ..................................................................... 41
4.6.1.
Enrolment of Key Demographic Subpopulations in
ING113086, ING114467, and ING111762 ................................... 41
4.6.2.
ART-Naïve................................................................................... 43
4.6.2.1.
Demographics and Baseline Characteristics............... 43
4.6.2.2.
Key Efficacy Endpoints............................................... 43
4.6.2.3.
Comparison of Primary Efficacy Results in
Sub-populations .........................................................45
4.6.3.
ART-Experienced (INI-Naïve) Subjects........................................ 47
4.6.3.1.
Demographics and Baseline Characteristics............... 47
4.6.3.2.
Key Efficacy Endpoints............................................... 47
4.6.3.3.
Comparison of Principal Efficacy Results in
Sub-populations .........................................................49
4.6.4.
Treatment Emergent Resistance in INI-Naïve Subjects ............... 49
4.6.5.
ART-Experienced (INI-Resistant) Subjects .................................. 51
4.6.5.1.
Demographics and Baseline Characteristics............... 51
4.6.5.2.
Key Efficacy Endpoints............................................... 51
4.6.5.3.
Treatment Emergent Resistance in INIresistant Subjects .......................................................52
4.6.5.4.
Comparison of Primary Efficacy Results in
Sub-populations .........................................................53
4.6.5.5.
Antiviral Activity of DTG by Baseline
Resistance in INI-resistant Subjects in
ING112574................................................................. 53
4.7.
Efficacy Conclusions................................................................................... 55
5.
OVERVIEW OF SAFETY .......................................................................................56
5.1.
Introduction................................................................................................. 56
5.1.1.
Data Cut-off Dates ....................................................................... 56
5.2.
Non-Clinical Data Relevant to Human Safety.............................................. 57
5.3.
Exposure in the Clinical Development Program .......................................... 57
5.4.
Safety in Clinical Pharmacology Studies..................................................... 58
5.4.1.
Frequently Reported AEs.............................................................58
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5.4.2.
5.4.3.
5.4.4.
5.4.5.
5.5.
5.6.
5.7.
5.8.
5.9.
5.10.
5.11.
5.12.
5.13.
6.
Deaths .........................................................................................58
Non-Fatal Serious Adverse Events .............................................. 58
Adverse Events Leading to Withdrawal........................................ 59
Clinical Laboratory Evaluations and Vital Signs ...........................59
5.4.5.1.
Hepatobiliary Adverse Events..................................... 59
5.4.5.2.
Renal Adverse Events ................................................ 59
5.4.6.
Cardiac Evaluation....................................................................... 60
Safety in Pediatrics - ING112578 (P1093) .................................................. 60
Safety in Phase II and III Studies ................................................................61
5.6.1.
Safety Population for Phase II and III Studies ..............................61
5.6.2.
Common Adverse Events ............................................................62
5.6.2.1.
Frequently Reported Adverse Events .........................62
5.6.2.1.1. ART-Naïve Adult Subjects ...................... 63
5.6.2.1.2. ART-Experienced (INI-Naïve)
Adult Subjects......................................... 64
5.6.2.1.3. ART-Experienced (INI-Resistant)
Adult Subjects......................................... 64
5.6.2.2.
Labeling and Adverse Drug Reactions........................ 65
5.6.2.3.
Supportive PK/PD Safety Analyses ............................67
5.6.3.
Deaths .........................................................................................67
5.6.4.
Serious Adverse Events...............................................................67
5.6.4.1.
ART-Naïve Adult Subjects .......................................... 67
5.6.4.2.
ART-Experienced (INI-Naïve) Adult Subjects ............. 68
5.6.4.3.
ART-experienced (INI-Resistant) Adult
Subjects ..................................................................... 69
5.6.5.
Adverse Events Leading to Withdrawal........................................ 69
5.6.5.1.
ART-Naïve Adult Subjects .......................................... 69
5.6.5.2.
ART-Experienced (INI-Naïve) Adult Subjects ............. 70
5.6.5.3.
ART-Experienced (INI-Resistant) Adult
Subjects ..................................................................... 71
5.6.6.
AEs of Special Interest................................................................. 72
5.6.6.1.
Hypersensitivity and Rash .......................................... 72
5.6.6.2.
Hepatobiliary Disorders .............................................. 73
5.6.6.3.
Renal Function ...........................................................74
5.6.6.4.
Gastrointestinal (GI) Disorders ................................... 76
5.6.6.5.
Musculoskeletal Disorders.......................................... 76
5.6.6.6.
Immune Reconstitution Inflammatory
Syndrome (IRIS).........................................................77
5.6.6.7.
Other .......................................................................... 77
5.6.7.
Clinical Laboratory Evaluations.................................................... 77
5.6.7.1.
Clinical Chemistry.......................................................77
5.6.7.2.
Hematology ................................................................78
Vital Signs................................................................................................... 78
Electrocardiograms.....................................................................................78
Safety in Special Groups and Situations ..................................................... 78
Pregnancies................................................................................................79
Withdrawal Effects, Abuse Potential, Overdose .......................................... 79
Post-Marketing Experience......................................................................... 79
Safety Conclusions .....................................................................................79
BENEFITS AND RISKS CONCLUSIONS...............................................................81
6.1.
Benefits of Dolutegravir in the Treatment of HIV-1 Infection........................ 81
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6.2.
6.3.
6.4.
Risks of Dolutegravir in the Treatment of HIV-1 Infection............................84
Overall Dosing Recommendations..............................................................86
Overall Conclusions.................................................................................... 86
7.
REFERENCES....................................................................................................... 87
8.
APPENDICES ........................................................................................................ 91
Appendix Table 1
Explanation for Empty Submission Modules ............... 91
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ABBREVIATIONS
3TC
ABC
AE
AIDS
ALT
API
ATV
AST
ART
AUC
AUC(0-t)
AUC(0-)
AUC(0-)
AUC(0-24)
BID
C24
CL/F
Cmax
CMC
C0
C0_avg
C
c/mL
Cavg
CDC
CSF
CI
COBI
CPSR
CrCL
CSR
CYP
CV%
CVb
DNA
DRV
DTG
EFV
EMA
Emax
ERPF
ETR
lamivudine
abacavir
Adverse event
Acquired immunodeficiency syndrome
Alanine aminotransferase
Active pharmaceutical ingredients
atazanavir
Aspartate aminotransferase
Antiretroviral therapy
Area under the curve
Area under the concentration-time curve from time zero
(pre-dose) to the last time of quantifiable concentration
Area under the concentration-time curve over the dosing
interval
Area under the concentration-time curve from time zero
(pre-dose) extrapolated to infinite time
Area under the concentration-time curve from time zero
(pre-dose) to 24 hours post dose or over 24 hours
Twice daily
Concentration at 24 hours post dose
Apparent clearance following oral dosing
Maximum observed concentration
Chemistry, manufacturing and controls
Pre-dose concentration
Average of concentrations at time 0
Concentration at the end of the dosing period
copies per milliliter
Average of concentrations
Centers for Disease Control and Prevention
Cerebrospinal fluid
Confidence Interval
cobicistat
Clinical Pharmacology Study Report
Creatinine clearance
Clinical Study Report
Cytochrome P450
Coefficient of variance
Between-subject variability (or coefficient of variation)
Deoxyribonucleic acid
darunavir
dolutegravir, S/GSK1349572
efavirenz
European Medicines Agency
Maximum effect
Effective renal plasma flow
etravirine
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EVG
FC
FDA
FDC
FPV
FTC
GCP
GFR
GI
GSK
HBV
HCV
HIV
HIV-1
HIV-2
IC50
ICH
IN
IND
INI
ITT-E
LOCFDB
LPV
MAA
mg
mITT-E
mm3
MSDF
NDA
NDS
ng
NRTI
NNRTI
OBR
OCT2
OMP
OSS
PAH
PBMC
PDVF
PI
PK
PD
PP
PSS
elvitegravir
Fold change
(US) Food and Drug Administration
Fixed dose combination
fosamprenavir
emtricitabine
Good Clinical Practice
Glomerular filtration rate
Gastrointestinal
GlaxoSmithKline
Hepatitis B Virus
Hepatitis C Virus
Human Immunodeficiency Virus
Human Immunodeficiency Virus Type 1
Human Immunodeficiency Virus Type 2
Half-maximal inhibitory concentration
International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for
Human Use
Integrase
Investigational New Drug
Integrase inhibitor
Intent-to-Treat Exposed
Last observation carried forward (discontinuation equals
Baseline)
lopinavir
Marketing Authorization Application
Milligram
Modified Intent-to-Treat Exposed
Cubic millimeter
Missing, Switch or Discontinuation = Failure
New Drug Application
New Drug Submission
Nanogram
Nucleoside reverse transcriptase inhibitor
Non-nucleoside reverse transcriptase inhibitor
Optimized background regimen
Organic cation transporter 2
Omeprazole
Overall susceptibility score
Para-aminohippurate
Peripheral blood mononuclear cell
Protocol defined virologic failure
Protease inhibitor
Pharmacokinetic
Pharmacodynamic
Per-protocol
Phenotypic susceptibility score
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PGx
RAL
RIF
RNA
RTV
t1/2
TLOVR
TDF
TPV
UGT
UNAIDS
US
Vd/F
VL
Vz/F
Pharmacogenetics
raltegravir
Rifampin
Ribonucleic acid
ritonavir
Terminal phase half-life
Time to Loss of Virologic Response
tenofovir disoproxil fumarate
tipranavir
Uridine diphosphate glucuronyltransferase
Joint United Nations Programme on HIV/AIDS
United States
Apparent volume of distribution
Viral load
Apparent volume of distribution after extravascular (e.g.,
oral) administration at terminal phase
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV
Healthcare
EPZICOM
KIVEXA
Atripla
Isentress
Stribild
Truvada
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1.
PRODUCT DEVELOPMENT RATIONALE
1.1.
HIV Infection
An estimated 34.2 million adults and children worldwide, were living with Human
Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) in 2011
[UNAIDS, 2012a].
In 2011, the global adult (15 to 49 years) HIV prevalence rate was 0.8%
[UNAIDS, 2012b]. During that year, 2.5 million people were newly infected with HIV,
and there were 1.7 million deaths due to HIV/AIDS. Of newly infected people, an
estimated 1.2 million were women and girls, and 330,000 were children. As well,
3.4 million children younger than 15 years were living with HIV in 2011
[UNAIDS, 2012a]. In 2009, an estimated 370,000 children contracted HIV during the
perinatal and breastfeeding period. Overall, the epidemic appears to have stabilized in
most regions, although prevalence continues to increase in Eastern Europe and Central
Asia and in other parts of Asia due to a high rate of new HIV infections
[UNAIDS, 2010]. In 2011, Sub-Saharan Africa remained the most heavily affected
region, accounting for 68% (1.7 million) of all new HIV infections among adults and
children [UNAIDS, 2012b].
1.2.
Current Therapies and its Unmet Clinical Need
Combination antiviral therapy with HIV type-1 (HIV-1) protease and reverse
transcriptase inhibitors has significantly reduced AIDS-related morbidity and mortality.
However, emerging multi-class drug-resistant HIV strains and long-term toxicities
warrant development of new classes of antiretroviral therapies. Integrase inhibitors (INIs)
are a newer class of antiretroviral drugs designed to block the action of the integrase (IN)
viral enzyme, which catalyzes two key steps in the HIV life cycle and is responsible for
insertion of the viral genome into the deoxyribonucleic acid (DNA) of the host cell. Since
genome integration is a vital step in retroviral replication, it is an attractive target for HIV
therapy.
Dolutegravir (DTG, GSK1349572) is an INI owned by ViiV Healthcare, which is
working with GlaxoSmithKline (GSK) to develop the asset.
Raltegravir (RAL), the first marketed INI, and elvitegravir (EVG), which recently gained
United States (US) Food and Drug Administration (FDA) approval (in August 2012 in a
combination product), have demonstrated good antiviral activity in clinical trials,
confirming the INI class as a new option for constructing effective HIV-1 treatment
regimens. In the STARTMRK study, RAL demonstrated excellent antiviral activity as
first-line treatment and was shown to be non-inferior to an efavirenz (EFV)-containing
standard of care regimen [Lennox, 2010]. In this trial, a similar proportion of subjects
randomized to RAL versus EFV [both in combination with tenofovir disoproxil
fumarate/emtricitabine (TDF/FTC)] achieved undetectable HIV-1 ribonucleic acid
(RNA) (<50 copies/milliliter [c/mL]) at Week 48 (86% vs. 82%) and Week 96 (81% vs.
79%). Additionally, the time to achieve viral suppression was shorter for subjects on
RAL than on EFV (log rank test P<0.001).
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Similarly, in the GS-US-236-0102 study, EVG co-formulated with the cytochrome P450
(CYP) 3A4 inhibitor cobicistat (COBI), TDF, and FTC (now approved in the US as
Stribild), was shown to be non-inferior to the co-formulated standard of care regimen
EFV/TDF/FTC as a first-line treatment, with 87.6% versus 84.1% of patients,
respectively, achieving <50 c/mL HIV RNA at Week 48 [Sax, 2012].
Integrase inhibitors have also shown potent antiviral activity in treatment-experienced
patient populations. In the BENCHMRK study, patients with three-class antiretroviral
resistance (naïve to INIs) received RAL or placebo plus optimized background therapy;
62% of RAL subjects (versus 33% of placebo subjects) had HIV RNA <50 c/mL at
Week 48 [Steigbigel, 2008]. In Study 145, a study in INI-naïve, treatment-experienced
subjects with at least two-class resistance, EVG once daily was non-inferior to RAL
twice daily (BID), each administered with a background regimen that included a ritonavir
(RTV)-boosted protease inhibitor (PI) and a second antiretroviral agent. At Week 48 of
Study 145, 59% of the EVG group versus 58% of the RAL group achieved virologic
response (<50 c/mL) [Molina, 2012].
In addition to providing good virologic suppression in treatment-naïve and treatmentexperienced patients, the INIs have been well-tolerated in clinical trials. In STARTMRK,
there were fewer drug-related adverse events (AEs) reported for the RAL group
compared with the EFV group, and fewer subjects randomized to RAL discontinued from
the study due to AEs. In GS-US-236-0102, AEs were similar between the EVG and EFV
groups, with the exception of nausea (significantly higher in the EVG group), and
dizziness, abnormal dreams, and rash (significantly higher in the EFV group); similar
numbers of subjects in the two groups discontinued treatment because of AEs (4% versus
5%).
While these trials highlight the potent antiviral efficacy and promise of better long-term
tolerability with INI-based therapy, clinical resistance to both RAL and EVG has been
reported from Phase II studies in treatment-experienced subjects [Hazuda, 2007;
McColl, 2007], and also from Phase III studies in both treatment-experienced [Cooper,
2008; Molina, 2012] and treatment-naïve subjects [Lennox, 2010; Sax, 2012;
DeJesus, 2012]. In Study 145, comparing EVG- versus RAL-based therapy in treatmentexperienced subjects, among subjects who failed therapy, 16/60 (27%) and 15/72 (21%)
of patients who had IN genotype data available at the time of virologic failure developed
INI resistance mutations. In addition, phenotypic cross-resistance to both drugs was
typical, preventing sequencing from one drug to the other [Molina, 2012]. Therefore, the
development of new INIs with different resistance profiles is desirable; for many
treatment-experienced patients with clinical resistance to RAL and EVG, new agents are
essential for providing HIV-infected individuals an option for constructing an effective
antiretroviral regimen.
There are other properties of RAL and EVG that also provide room for improvement.
RAL requires BID dosing and is currently not available in a fixed dose combination
(FDC) regimen. EVG requires co-administration with a pharmacokinetic (PK) booster,
such as RTV or cobicistat (COBI) [German, 2010], and therefore, has the potential for
clinically-significant drug-drug interactions with drugs that depend on CYP3A4 for
clearance. Additionally, EVG-containing regimens had higher rates of gastrointestinal
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(GI) AEs than a RAL-containing regimen and Atripla in treatment-experienced and
treatment-naïve patients, respectively [Molina, 2012; Sax, 2012]; Stribild is also not
recommended for patients with creatinine clearance (CrCL) under 70 mL/min.
Finally, both RTV and COBI (one of which is required in conjunction with EVG; COBI
is a component of the FDC tablet that contains EVG/COBI/TDF/FTC) boost TDF
concentrations, which may increase TDF proximal tubular toxicity [FDA, 2012].
Dolutegravir is a potent, low nanomolar inhibitor of HIV IN, which offers once-daily
dosing without the requirement for pharmacokinetics boosters. Based on in vitro and
clinical data, DTG demonstrates the excellent antiviral activity and tolerability typical of
the INI class, with a higher barrier to resistance. Finally, most HIV isolates with
resistance to RAL and EVG remain susceptible to DTG, making DTG an important
option for many treatment-experienced patients with multi-class drug resistance.
1.3.
Claimed Indication and Dosage
The proposed product labeling for DTG includes the following key elements:
Dolutegravir is indicated for the treatment of HIV infection in combination with other
antiretroviral agents in adults and children 12 to 18 years of age.
Dolutegravir should be administered as presented below (with or without food):
Treatment-naïve Adults:
For patients initiating antiretroviral therapy for the first time (treatment-naïve), the
recommended dose of dolutegravir is 50 mg once daily.
Treatment-experienced, and integrase inhibitor-naïve Adults
For patients who are treatment experienced, and have not previously been treated with an
integrase inhibitor, the recommended dose of dolutegravir is 50 mg once daily.
Integrase inhibitor-resistant Adults
For patients with integrase inhibitor resistance, the recommended dose of dolutegravir is
50 mg twice daily.
Pediatric Patients
In pediatric patients (12 to less than 18 years of age and weighing greater than or equal to
40 kg) who have not previously been treated with an integrase inhibitor, the
recommended dose of dolutegravir is 50 mg once daily.
There are insufficient data to recommend a dose for dolutegravir in integrase inhibitor
resistant children and adolescents under 18 years of age.
There are insufficient safety and efficacy data available to recommend a dose for
dolutegravir in children below age 12 or weighing less than 40 kg.
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1.4.
Clinical Development Program
The Sponsor’s strategy for the development of DTG is to file for a New Drug Application
(NDA)/Marketing Authorization Application (MAA)/New Drug Submission (NDS) by
demonstrating significant improvements over the first marketed INI (RAL).
Improvements include activity in the presence of integrase resistant viruses and an
improved dosing regimen (unboosted once daily administration) with similar or improved
safety and efficacy. An additional study in treatment naïve subjects was conducted to
compare a regimen containing DTG plus the abacavir/lamivudine (ABC/3TC) FDC with
the co-formulated standard of care regimen EFV/TDF/FTC.
The clinical development program has been designed to achieve a broad initial indication
for the treatment of HIV-1 infection in combination with other antiretroviral agents in
adults and children over 12 years of age.
A full listing of studies included in this application is located in m5.2, Table of Studies.
The clinical program investigating DTG involves 30 Phase I, 4 Phase II, 7 Phase III/IIIb
clinical trials. In addition, there is an Investigational New Drug (IND)/Named Patient
Program and an Expanded Access Program currently providing DTG to a limited number
of subjects (see m5.3.5.4 ING114916 and m5.3.5.4 ING115502 Brief Written
Summaries).
To support the proposed indication, the submission includes a Clinical Pharmacology
package describing the PK and the PK/pharmacodynamic (PD) relationship of DTG in
both healthy volunteers and HIV-infected subjects. Additionally, a comprehensive
package of drug interaction studies has been completed to inform dosing of DTG with
other antiretroviral agents as well as key concomitant medications for HIV-infected
patients. PK studies in special populations, as well as PD studies to complement the
safety data from all clinical trials have been completed. Finally, a PK, safety and efficacy
study in HIV-infected children is ongoing and data to support dosing in children 12 to
<18 years of age is included. This package is described in detail in m2.7.2.
The supportive Phase II package (Studies ING111521, ING112276 and ING112961)
includes initial efficacy data as well as enabling dose-ranging data and longer-term
efficacy and safety data in antiretroviral therapy (ART)-naive, -experienced and INIresistant subjects. In these supportive efficacy studies, patients were treated with doses
of dolutegravir from 2 mg daily up to 100 mg daily, administered via once daily or BID
dosing.
The pivotal Phase III Studies, ING113086, ING111762, ING114467, and ING112574
assessed DTG in HIV-infected subjects with a broad range of treatment experience and
support an unrestricted indication for the treatment of HIV-infection. Studies
ING113086, ING111762, and ING114467 were international, multi-center, randomized,
double-blind studies, and each has the characteristics of an “adequate and well-controlled
clinical trial” as described in Title 21 of the US Code of Federal Regulations,
Section 314.126 and ICH Topic E 8 General Considerations for Clinical Trials. Study
ING112574 is an international, multicenter study with a single arm, reflecting ethical
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difficulties in randomizing subjects to a control arm in the multi-class resistant population
studied. There are additional Phase III/IIIb studies currently ongoing.
Longer term efficacy and safety data are available from ongoing Studies ING112276
(96 weeks) and ING112961 (Cohort I 96 weeks, Cohort II 48 weeks) where up to 206
subjects received DTG. Studies ING113086, ING111762, ING114467, and ING1112574
are ongoing and will continue, pending the outcome of regulatory evaluation of the
marketing applications.
1.5.
Regulatory History
The development program for DTG has been formally discussed with key regulatory
agencies at various milestones throughout the development program (See m2.2).
1.6.
Compliance with Good Clinical Practice (GCP)
All studies were undertaken in accordance with standard operating procedures of the
GlaxoSmithKline Group of Companies, which comply with the principles of Good
Clinical Practice. All studies were conducted with the approval of Ethics Committees or
Institutional Review Boards. Informed consent was obtained for all subjects, and the
studies were performed in accordance with the version of the Declaration of Helsinki that
applied at the time the studies were conducted. Where required, regulatory approval was
obtained from the relevant health authority.
2.
OVERVIEW OF BIOPHARMACEUTICS
Data from clinical biopharmaceutics Studies ING111322, ING112941, ING113068, and
ING113674, along with chemistry, manufacturing and controls (CMC) and bioanalytical
methods data, form the basis of the biopharmaceutical evaluation of DTG in this
submission. These studies are described in m2.7.1 (Summary of Biopharmaceutic Studies
and Associated Analytical Methods); critical aspects of the results are discussed below.
2.1.
Biopharmaceutical Classification
DTG sodium, Form 1, is a non-hygroscopic, crystalline solid with suitable solid state
stability and oral bioavailability. DTG sodium has a solubility of 3.2 mg/ml in water at
25C; in buffered solutions across the physiological pH range 1 to 7, the solubility is
significantly lower (at or below 50 g/ml). The measured permeability is approximately
3x10-4 cm/sec. The combination of low solubility with high predicted permeability puts
dolutegravir in Biopharmaceutics Classification System Class II (m2.7.2, Section 1.1).
2.2.
Formulation Development
Dolutegravir was administered as dolutegravir sodium in all clinical studies.
Initial Phase I studies utilized a powder for reconstitution consisting of DTG sodium,
hypromellose and sodium lauryl sulphate. Doses of up to 250 mg DTG were
administered in Phase I studies using this formulation.
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Module 2.5 Clinical Overview
Tablet formulations were then developed to provide 1 mg, 10 mg and 25 mg dose
strengths for Phase II studies. These tablets contained: d-mannitol and microcrystalline
cellulose as diluents, povidone as a binder, croscarmellose sodium as a disintegrant, and
sodium stearyl fumarate as a lubricant. These tablets were used in Phase II studies.
Based on ING112276, a dose ranging study in treatment-naive HIV-infected subjects, a
dose of 50 mg dolutegravir once daily was selected for Phase III studies.
During Phase II, sodium starch glycolate was identified as a more optimal disintegrant for
long-term stability compared to the croscarmellose sodium used in the Phase II tablet
formulation. Two variations of the new formulation (both 25 mg tablets) were assessed
against the Phase II tablet formulation (25 mg tablet) in a relative bio-availability study
(ING113674).
Both 25 mg tablet variations were bioequivalent with the Phase II 25 mg tablet
formulation. The variant with the lower overall tablet weight was selected to progress
into Phase III with the tablet core compression weight set to deliver 50 mg of
dolutegravir in a single tablet.
Micronized API is utilized in dolutegravir tablets, 50 mg. The particle size for this API
to be used in the commercial formulation is supported by data obtained in Study
ING113068 (m2.7.1, Section 2.1.2).
The commercial formulation is identical to the clinical trial tablet formulation used in all
Phase III/IIIb studies and pediatric study, differing only in the film coat color and the
degree of concavity of the tooling used to produce the tablets (m2.7.1, Section 1.3.2).
2.3.
Analytical Methods
The bioanalytical methods used to measure concentrations of DTG in human plasma
were sensitive, selective, accurate and reproducible. Stability of the analyte was
demonstrated during sample processing and long-term storage (m2.7.1, Section 1.4).
2.4.
Biopharmaceutics Studies
The key results from biopharmaceutic studies for consideration in clinical use and
detailed in m2.7.1 are as follows:

The oral bioavailability of the tablet was less than that of a suspension, with mean
AUC(0-t) decreased by 30% following administration of the tablet compared to the
suspension formulation under the fasted condition. The rate of absorption of the
drug from tablet was slower than suspension.

Changes in particle size did not have a significant impact on exposure. A formulation
of un-micronized particles demonstrated similar exposure to the current tablet
formulation (with micronized particles). These data support the particle size
specification for the micronized API.

For DTG tablets, a 25 mg tablet with the Phase III formulation composition met the
bioequivalence criteria with the 25 mg tablet used in the Phase II studies.
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Module 2.5 Clinical Overview

A higher strength tablet of this formulation (50 mg tablet) was manufactured at the
commercial site for use in Phase III clinical trials. This 50 mg tablet has the same %
weight/weight composition but made at double the tablet weight of the 25 mg tablets
used to establish bioequivalence to the Phase II product. The in-vitro dissolution
profiles (3 media used) of the 50 mg tablets (Phase III formulation) compare closely
to the profiles of two 25 mg tablets (Phase III composition) tested per dissolution
vessel (i.e. total dose level = 50 mg).

Administration with food increases the exposure of DTG. Plasma DTG AUC(0-)
increased by 33%, 41%, and 66% when DTG was administered with low fat,
moderate fat and high fat food, respectively. DTG can be taken with or without food
based on the accumulated safety data in Phase IIb and III studies, which permitted
DTG dosing without restriction to food or food content.
3.
OVERVIEW OF CLINICAL PHARMACOLOGY
Critical findings from the clinical pharmacology studies conducted with DTG are
discussed below. These studies are described in detail in m2.7.2 (Summary of Clinical
Pharmacology).
3.1.
Absorption, Distribution, Metabolism and Elimination of
Dolutegravir
3.1.1.
Absorption
DTG is rapidly absorbed following oral administration of tablet formulations, with no
absorption lag time and a median tmax of 2 to 3 hours post dose. DTG concentration
declines mono-exponentially with an average terminal half life of approximately 14 hours
(m2.7.2, Section 2, Study ING111207).
DTG absorption is increased with co-administration of food (m2.7.1, Section 2.3). The
moderate food effect is not considered clinically significant; therefore DTG can be taken
without regard to food (m2.7.1, Section 2.3). Dosing separation is needed when DTG is
to be given together with antacids (e.g. Maalox), due to chelation with polyvalent cations
that decrease DTG exposure, (m2.7.2, Section2, Study ING111602); DTG should be
taken 2 hours before or 6 hours after antacid dose. DTG can be dosed with multivitamins
without dosing separation (m2.7.2, Section 2, Study ING111602).
The linearity of DTG pharmacokinetics is dependent on dose. Following oral
administration of tablet formulations, in general, DTG exhibited nonlinear
pharmacokinetics with less than dose-proportional increases in plasma exposure from 2
to 100 mg; however the increase in DTG exposure appears dose proportional from 25 mg
to 50 mg.
3.1.2.
Distribution
DTG is highly bound (approximately 99.3%) to human plasma proteins based on in vitro
data. The apparent volume of distribution (Vd/F, following oral administration of
suspension formulation) is estimated at 12.5 L (m2.7.2, Section 2, Study ING111853).
15
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Module 2.5 Clinical Overview
DTG appears to primarily bind to albumin rather than 1-acid glycoprotein (AAG) in
plasma (m2.7.2 Section 3.1.4). Binding of DTG to plasma proteins was independent of
DTG concentrations over the therapeutic range. Total blood and plasma drug-related
radioactivity concentration ratios averaged 0.441 to 0.535, indicating minimal association
of radioactivity with blood cellular components. Free fraction of DTG in plasma is
estimated at ~0.23% to 1.10% in healthy subjects, ~0.4 to 0.5% in subjects with moderate
hepatic impairment, 0.84 to 1.01% in subjects with severe renal impairment, and 0.49%
in HIV-positive subjects (m2.7.2, Section 2, Studies ING113097, ING113125, and
ING116070).
DTG is present in cerebrospinal fluid (CSF). In 12 treatment-naïve subjects receiving a
regimen of DTG plus abacavir (ABC)/lamivudine (3TC) for two weeks, DTG
concentration in CSF averaged 18 ng/mL, ranging from 3.97 to 23.2 ng/mL (comparable
to unbound plasma concentration, and above the 50% inhibitory concentration [IC50] in
all subjects); CSF:plasma concentration ratio of DTG ranged from 0.11 to 0.66%. A
rapid and significant decrease in HIV-1 RNA in CSF was observed after two weeks of
DTG therapy (when administered with ABC/3TC) (m5.3.4.2, ING116070 Week 2
Synoptic Clinical Study Report [CSR]).
DTG is present in the female and male genital tract. DTG exposure (expressed as AUC)
in cervicovaginal fluid, cervical tissue, and vaginal tissue was 6%, 10%, and 9%,
respectively, of that in corresponding plasma at steady state. DTG exposure (also
expressed as AUC) in seminal fluid and rectal mucosal tissue was 7% and 17%,
respectively, of that in corresponding plasma at steady state (m2.7.2, Section 2, Study
ING115465 and Study ING116195).
3.1.3.
Metabolism and Excretion
Following oral administration in humans, unchanged DTG is primarily eliminated
through metabolism, and renal elimination of unchanged DTG represents less than 1% of
the total dose administered. DTG is primarily metabolized via UGT1A1 with CYP3A4
as a secondary metabolic pathway (approximately 10% in a human mass balance study).
DTG is the predominant circulating compound in plasma, representing 97% of plasma
total radiocarbon. Fifty-three percent of total oral dose is excreted as unchanged DTG in
the feces, but it is unknown if all or part of this is due to unabsorbed drug or biliary
excretion of the glucuronide conjugate which can be further degraded to form the parent
compound in the gut lumen. Thirty-one percent of the total oral dose is excreted in the
urine, represented by ether glucuronide of DTG (18.9% of total dose), N-dealkylation
metabolite (3.6% of total dose), a metabolite formed by oxidation at the benzylic carbon
(3.0% of total dose), and other minor metabolites (m2.7.2, Section 2, Study ING111853).
3.1.4.
Elimination
DTG has a terminal half-life of ~14 hours and a low apparent clearance (CL/F) of
0.56 L/hr (m2.7.2, Section 2, Study ING111853). The apparent clearance represents <2%
of liver plasma flow, therefore the hepatic extraction ratio of DTG is low (lower than
2%). As CYP3A4 is only a secondary route of elimination of DTG, the first-pass
metabolism of DTG following oral dosing is expected to be very low.
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Module 2.5 Clinical Overview
3.2.
Pharmacokinetics in Healthy Subjects and Target Patient
Populations
3.2.1.
Summary of Dolutegravir PK Parameters
The pharmacokinetics of DTG in healthy subjects and target patient populations has been
evaluated after single and repeat doses given orally. The plasma pharmacokinetic
parameters estimates of DTG are summarized in Table 1. Based on accumulated data,
there appears to be no significant difference in pharmacokinetics between healthy and
HIV-infected subjects.
Table 1
Population
Summary of Key DTG Pharmacokinetic Parameters following Single
Dose 50 mg Tablet Administration in Healthy and HIV-infected
Subjects
DTG
Dose
50 mg
Data Source
Cmax
C24
CL/F
Vz/F
AUC (0-)
(L/h)
(L/h)
(g/ml)
(g/mL)
(g.h/mL)
Healthy
Phase 1
2.20
43.7
0.65
1.14
23.3
Meta-analysis
(43)
(45)
(49)
(45)
(45)
HIV-1
50 mg
ING111521
2.46
40.5
0.59
1.23
ND
infected
(32)
(33)
(31)
(33)
Data Source: m5.3.4.2 ING111521 Clinical Pharmacology Study Report (CPSR); m5.3.5.3 CPM Table 3.3
Note: Data presented are geometric mean (CV%).
ND: not determined.
Likely underestimated as based on 24-hour sampling window
17
t½
(h)
14.4
(19)
11.2
(29)a
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Module 2.5 Clinical Overview
Table 2
Population
Healthy
Healthy
Summary of Key DTG Pharmacokinetic Parameters following 50 mg
Once Daily and BID Dosing in Healthy and HIV-infected Subjects
DTG Dosing
Regimen
50 mg
once daily
(overall)
50 mg
once daily
(fasted)
50 mg
once daily
(fed)
50 mg BID
(overall)
50 mg BID
(fasted)
50 mg BID
(fed)
HIV-1
infected
Data Source
Phase 1
Meta-analysis
(m5.3.5.3)
Phase 1
Meta-analysis
(m5.3.5.3)
Phase 1
Meta-analysis
(m5.3.5.3)
Phase 1
Meta-analysis
(m5.3.5.3)
Phase 1
Meta-analysis
(m5.3.5.3)
Phase 1
Meta-analysis
(m5.3.5.3)
Population PK
(m5.3.3.5)
Cmax
(g/ml)
3.62
(35)
AUC (0-)
(g.h/mL)
49.1
(41)
AUC (0-24)
(g.h/mL)
49.1
(41)
C
(g/mL)
1.05
(56)
2.90
(34)
38.4
(40)
38.4
(40)
0.79
(59)
4.21
(27)
58.2
(30)
58.2
(30)
1.28
(41)
6.00
(39)
53.0
(42)
106
(42)
3.02
(52)
5.33
(38)
47.1
(42)
94.3
(42)
2.66
(53)
7.77
(23)
68.6
(27)
137
(27)
4.00
(36)
50 mg
3.67
53.6
53.6
1.11
once daily
(20)
(27)
(27)
(46)
(no food
restriction)
HIV-1
50 mg BID
Population PK
4.15
37.5
75.1
2.12
infecteda
(no food
(m5.3.3.5)
(29)
(35)
(35)
(47)
restriction)
Data Source: m5.3.5.3 CPM Table 3.2, m5.3.3.5 Population PK in ART-naïve; m5.3.3.5 Population PK in ART
experienced
Note: Data presented are geometric mean (CV%).
a. DTG PK exposure from 50 mg twice daily dosing is lower in HIV-1 infected subjects (treatment-experienced) than
healthy subjects and this is considered to be due to the wide use of inducers, e.g. DRV/RTV, in the background
regimen in the treatment-experienced HIV-1 infected subjects.
Following repeat dose administration, DTG achieved steady state after approximately 5
days of dosing, consistent with the estimated t½ of approximately 14 hours, and showed
time-invariant PK. Accumulation ratios for DTG 50 mg once daily dosing were 1.43,
1.36, and 1.42 for AUC(0-τ), Cmax, and Cτ, respectively.
In Phase I studies in healthy subjects, the PK variability of DTG is low to moderate with
between-subject (CVb%) for AUC and Cmax of 20 to 40% and for C of 30 to 65%
across studies. The PK variability of DTG is slightly higher in HIV-infected subjects than
healthy subjects, with CVb% of C0 (pre-dose concentration at steady state) ranging from
55% to 140% across studies. Intra-subject variability (CVw%) is lower than inter-subject
variability: CVw% ranged from 8 to 20% for DTG PK parameters in Phase I studies
conducted in healthy subjects and ranged from 17 to 29% in HIV-infected subjects based
on population PK modeling.
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Module 2.5 Clinical Overview
3.2.2.
Pharmacokinetics in Special Populations
3.2.2.1.
Children
The pharmacokinetics of DTG in 10 antiretroviral treatment-experienced, INI-naive HIV1 infected pediatric subjects 12 to <18 years of age was assessed in an ongoing study in
children (P1093, ING112578) based on weight band dosing of ~1 mg/kg. In 9 children
weighing at least 40 kg, DTG 50 mg once daily dosage resulted in DTG exposure in
pediatric subjects comparable to predefined target range based on data in adults receiving
DTG 50 mg once daily: 37 to 67 µg.h/mL for AUC(0-) and 0.77 to 2.26 µg/mL for
geometric mean of C. One additional subject weighing 37 kg received DTG 35 mg once
daily and also demonstrated PK similar to adults receiving DTG 50 mg once daily.
Table 3
Age/weight
Pediatric pharmacokinetic parameters
Dolutegravir Dose
Dolutegravir Pharmacokinetic Parameter Estimates
Geometric Mean (CV%)
AUC(0-24)
Cmax
C24
g.hr/mL
g/mL
g/mL
46 (43)
3.49 (38)
0.90 (59)
50 mg once daily a
12 to 18 yrs, 40 kg a
Data Source: m5.3.5.2. ING112578 CSR Table 14
a. One subject weighing 37 kg received 35 mg once daily.
A secondary objective of this study was an assessment of efficacy. Eight of 10 subjects
achieved virologic suppression (HIV-1 RNA <400 c/mL) at Week 24, with 7 of 10
subjects achieving HIV-1 RNA <50 c/mL. The efficacy data further support the validity
of the dosing strategy for adolescent (12 to <18 years of age), HIV-infected patients
(weighing at least 40 kg) of DTG 50 mg once daily.
Safety data for this study is summarized in Section 5.5. Overall, DTG was demonstrated
to be safe and well-tolerated in children 12 to <18 years of age.
Although only treatment-experienced children were enrolled in this age cohort of
ING112578 (Cohort I), the primary objective of this study was the assessment of PK and
safety, which would be expected to be similar in treatment-naïve patients. Consistent
with adult data for DTG 50 mg once daily, variability in AUC and C24h were 43% and
59%, respectively, using an adult tablet formulation administered under modified fasting
conditions in adolescents of 12 to <18 years. The Geometric Mean AUC24 for these 10
children in Cohort I was 46 g*h/mL and the C24h was 0.902 g/mL, meeting the predefined targeted PK exposure from adults receiving DTG 50 mg once daily (AUC0-24 37
to 67 µg*h/ml and C24h 0.77 to 2.26 µg/ml). These DTG exposures have shown to be
efficacious in both treatment-naïve and treatment-experienced (INI-naïve) adults in
ING113086 and ING111762, respectively, and support the use of DTG 50 mg once daily
in treatment-naïve and treatment-experienced (INI-naïve) 12 to <18 year olds weighing at
least 40 kg.
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Module 2.5 Clinical Overview
The virologic and immunologic principles underlying the use of ART are considered to
be similar in adults and children. With the use of antiretroviral agents, the course of HIV
infection is similar in children compared to adults [Gortmaker, 2001; Doerholt, 2006].
Therefore, efficacy data and exposure-response relationship from adult studies should be
relevant for the prediction of antiviral response in HIV infected children. As HIV
integrase is a viral target, not a host target, it is expected that the PK/PD relationship
between DTG drug exposure and antiviral activity is similar between adults and pediatric
populations. The guiding principles of disease management in children is similar to
adults with the same goals of therapy, i.e., complete suppression of viral replication as
measured by plasma HIV-1 RNA and restoration of the immune system.
Therefore, the PK data from ING112578 in adolescents aged 12 to <18 years are
sufficiently similar to adults to permit extrapolation of efficacy data from
pharmacokinetic correlation, which is in line with the International Conference on
Harmonization guidance for medicinal products in the pediatric population
[European Medicines Agency (EMA), 2011].
3.2.2.2.
Elderly
Pharmacokinetic DTG data in subjects of >65 years old are limited (n=12). However,
population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults
showed no clinically relevant effect of age on the PK profile of DTG (m2.7.2,
Section 1.3.5.3).
3.2.2.3.
Renal impairment
Renal clearance of unchanged drug is a minor pathway of elimination for DTG. A study
of the pharmacokinetics of DTG was performed in subjects with severe renal impairment
(CLcr <30 mL/min, not on dialysis) with matched healthy adult controls. No clinically
important pharmacokinetic differences between subjects with severe renal impairment
(CLcr <30 mL/min) and matching healthy subjects were observed. No dosage
adjustment is necessary for patients with mild, moderate, and severe renal impairment.
DTG has not been studied in patients on hemodialysis. Due to high protein-binding in
plasma (>99%), it is unlikely DTG PK is affected by hemodialysis.
3.2.2.4.
Hepatic impairment
DTG is primarily metabolized and eliminated by the liver. In a pharmacokinetic study
comparing subjects with moderate hepatic impairment (Child-Pugh Grade B) to matched
healthy adult controls, the single dose exposure of DTG was similar between the two
groups. No dosage adjustment is necessary for patients with mild to moderate hepatic
impairment (Child Pugh grade A or B). The effect of severe hepatic impairment on the
pharmacokinetics of DTG has not been studied.
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Module 2.5 Clinical Overview
3.2.2.5.
UGT1A1 Polymorphism
There is no evidence that common UGT1A1 polymorphisms alter DTG
pharmacokinetics. In a meta-analysis using pharmacogenetics (PGx) samples collected in
clinical studies in healthy subjects (n=89 in total), subjects with genotypes associated
with low (n=7) or reduced (n=40) activity of UGT1A1 had similar DTG exposure to
subjects (n=41) with wild-type genotype. One subject had a genotype with metabolizer
status as unknown. No dose adjustment for DTG is needed in subjects with genotypes
conferring poor metabolizer status of UGT1A1 (*28/*28; *28/*37; *37/*37).
3.2.2.6.
Co-infection with Hepatitis B or C
Population pharmacokinetic analysis indicated that hepatitis C virus (HCV) co-infection
had no clinically relevant effect on the exposure to DTG. There are limited PK data in
subjects with hepatitis B co-infection. There are no demonstrated or suspected drug
interactions between DTG and commonly used drugs for the treatment of hepatitis B
virus (HBV) and HCV.
3.2.2.7.
Population PK
Population PK analyses using pooled pharmacokinetic data from Phase II and Phase III
adult trials in HIV-infected subjects identified weight, age, gender, albumin levels, and
smoking status as statistically significant covariates of DTG clearance, volume, or
bioavailability. These factors resulted in changes in DTG PK parameters of <30% and are
not considered clinically significant. Other factors demonstrating no significant effect
were race/ethnicity, HCV co-infection, Centers for Disease Control and Prevention
(CDC) classification, mild to moderate renal impairment, creatinine clearance, alanine
aminotransferase (ALT), and aspartate aminotransferase (AST). No dose adjustment in
DTG is required based on demographic or laboratory factors, smoking status, and disease
status (CDC classification of HIV infection).
3.3.
Drug-Drug Interactions
The drug-drug interaction studies are described in m2.7.2, Section 2.1.3 and Section 3.
3.3.1.
Effect of Dolutegravir on the Pharmacokinetics of Other Agents
In vitro, DTG demonstrated little or no direct inhibition (IC50 values >50 M) in vitro on
the transporters BCRP, multi-drug resistance protein (MRP) 2, organic anion transporting
polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, and Pgp, or the
enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,
CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7. In vitro,
DTG did not induce CYP1A2, CYP2B6 or CYP3A4. In vitro, DTG was noted to have
little or no inductive effects on the human Pregnane X Receptor (PXR), or on CYP1A2,
2B6 or 3A4 mRNA. DTG glucuronide, GSK2832500, did not inhibit MRP2, thus
inhibition of biliary clearance of bilirubin glucuronides or glucuronide conjugates of coadministered drugs is not expected. Based on these data, DTG is not expected to affect
the pharmacokinetics of drugs that are substrates of these enzymes or transporters.
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Module 2.5 Clinical Overview
In vitro, DTG inhibited the renal organic cation transporter 2 (OCT2, IC50=1.9 M or
0.82 g/mL). Based on this observation, DTG may increase plasma concentrations of
drugs for which excretion is dependent upon OCT2, such as dofetilide and metformin.
Co-administration of DTG and dofetilide (which has a narrow therapeutic index) is
therefore contraindicated. Metformin concentrations may be increased by DTG; subjects
should be monitored during therapy and a dose adjustment of metformin may be required.
Results from studies evaluating the effect of DTG on co-administered drugs are shown in
Table 4. In vivo drug interaction studies also demonstrated that DTG did not affect the
PK of EFV, LPV/RTV, DRV/RTV, ATV, ETR, FPV, RPV, and TVR, by comparing PK
data of these agents observed when co-administered with DTG to historical data.
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Module 2.5 Clinical Overview
Table 4
Effect of DTG on Concomitant Medications
Concomitant Concomitant drug dose
drug
MDZ
3 mg SD
TDF
Methadone
DTG dose
N
Study
Conclusion
Co-ad drug +DTG / co-ad drug alone
10
300 mg once daily
20 mg once daily
(suspension)
50 mg once daily
Individualized dose
50 mg BID
11
15
Oral
norgestimate 0.25 mg
Contraceptive and
(Ortho-Cyclen) ethinyl estradiol 0.035 mg
50 mg BID
15
RPV
50 mg once daily
16
25 mg once daily
GM Ratio (90% CI)
C24/C
NA
AUC
Cmax
0.95
(0.82, 1.10)
1.12
(1.01-1.24)
NA
ING111322
No effect on MDZ
1.09
(0.97-1.23)
ING111604
No TDF dose adjustment
ING115698
No methadone dose adjustment
0.98
(0.91, 1.06)
1.00
(0.94, 1.06)
R-methadone
0.95
(0.89, 1.02)
0.95
(0.89, 1.02)
0.97
(0.91, 1.03)
S-methadone
1.02
(0.93, 1.12)
0.93
(0.85, 1.03)
1.02
(0.93, 1.11)
1.21
(1.07, 1.38)
1.01
(0.93, 1.09)
0.98
(0.91, 1.04)
1.03
(0.96, 1.11)
1.06
(0.98, 1.16)
1.03
(0.97, 1.10)
0.89
(0.82, 0.97)
0.99
(0.91, 1.08)
1.10
(0.99, 1.22)
ING111855
No OC dose adjustment
LAI116181
No RPV dose adjustment
1.19
(1.04-1.35)
Total methadone
0.99
(0.91, 1.07)
Data Source: m2.7.2, Table 55
Note: MDZ: midazolam; OC: oral contraceptive; RPV: rilpivirine.
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Module 2.5 Clinical Overview
3.3.2.
Effect of Other Agents on the Pharmacokinetics of Dolutegravir
and Dose Recommendations
DTG is eliminated mainly through metabolism by UGT1A1with CYP3A4 as a minor
route. DTG is also a substrate of UGT1A3, UGT1A9, Pgp, and BCRP; therefore drugs
that affect UGT1A1, UGT3, UGT1A9, CYP3A4, Pgp, and/or BCRP may theoretically
affect DTG plasma concentration.
Moderate to strong inducers of UGT1A1 and/or CYP3A4 such as etravirine (ETR),
efavirenz (EFV), rifampicin (RIF), and tipranavir/ritonavir (TPV/RTV) reduced the
plasma concentrations of DTG significantly; for C, reductions of75% or more were
observed, which overlap with or are outside of the lower bound of the “no effect
boundaries” (Section 3.5.3). Phase III Study ING111762 demonstrated that subjects
receiving DTG 50mg once daily in combination with TPV/RTV and EFV had lower
virologic responses (m2.7.2, Section 2.3.8 and Section 3.4.3.2), therefore DTG 50 mg
twice daily dosing is recommended in INI-naïve subjects (treatment-naïve or treatmentexperienced) receiving DTG in combination with these agents. As RIF reduced DTG
exposure to a similar extent as TPV/RTV and EFV, DTG 50 mg twice daily is also
recommended for subjects who require RIF therapy for treatment of TB infection.
TPV/RTV, EFV, and RIF may also be given with DTG 50 mg twice daily dose in INIresistant subjects with caution.
Although not formally assessed in a study, co-administration with nevirapine has the
potential to decrease dolutegravir plasma concentration to the extent similar to or less
than EFV due to enzyme induction. Therefore, DTG dose adjustment to 50 mg twice
daily is recommended when co-administration with nevirapine is needed. Caution is
warranted and clinical monitoring is recommended when the combination is given in INIresistant patients.
Etravirine reduced DTG C by more than 80%, however the effect of ETR was mitigated
by co-administration of lopinavir/ritonavir (LPV/RTV) and darunavir/ritonavir
(DRV/RTV). The co-administration of DTG 50 mg once daily with ETR is not
recommended unless the regimen includes the patient is also receiving concomitant
atazanavir/ritonavir (ATV/RTV), LPV/RTV or DRV/RTV.
DRV/RTV 600 mg/100 mg twice daily reduced DTG AUC, Cmax, and C by 22%, 11%,
and 38%, respectively, based on Phase I study; such effect is not considered clinically
significant. The effect of once daily dosing of DRV/RTV (800 mg/100 mg) was
evaluated in Phase III Study ING111762, which showed that subjects receiving DTG
50 mg once daily and DRV/RTV 800 mg/100mg once daily had similar DTG exposures
and similar virologic responses when compared to subjects receiving DTG 50 mg once
daily and DRV/RTV 600 mg/100 mg twice daily. DTG can be dosed with DRV/RTV
(once or twice daily) without dose adjustment.
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Module 2.5 Clinical Overview
The UGT1A1 inhibitor, ATV (or ATV/RTV) increased DTG AUC by 62% to 91%. Such
effect is not considered clinically significant based on accumulated toxicity data in
preclinical studies and accumulated safety and tolerability data in humans receiving DTG
to date. No dose adjustment is necessary when DTG is co-administered with ATV/RTV
or ATV.
Results from studies evaluating the effects of co-administered drugs on the
pharmacokinetics of DTG are summarized in the Table 5.
25
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Module 2.5 Clinical Overview
Table 5
Effect of Concomitant Medications on DTG Pharmacokinetics and Dose Recommendation
Coadministered
Drug
Co-administered
Drug Dose
DTG Dose
N
TDF
300 mg once daily
15
DRV/RTV
600/100 mg BID
LPV/RTV
400/100 mg BID
ETR
200 mg BID
ETR/LPV/RTV
Multivitamins
200/400/
100 mg BID
200/600/
100 mg BID
One-a-Day
50 mg
once daily
30 mg
once daily
30 mg
once daily
50 mg
once daily
50 mg
once daily
50 mg
once daily
50 mg SD
Maalox
20 mL
50 mg SD
16
Maalox 2 hrs
after
ATV/RTV
20 mL
50 mg SD
16
OMP
40 mg once daily
30 mg
once daily
30 mg
once daily
50 mg SD
12
ATV
300/100 mg
once daily
400 mg once daily
TPV/RTV
500/200 mg BID
14
EFV
600 mg
once daily
700/100 mg BID
50 mg
once daily
50 mg
once daily
50 mg
once daily
ETR/DRV/RTV
FPV/RTV
15
15
15
8
9
16
12
12
12
12
Geometric Mean Ratio (90% CI) of DTG PK
Parameters with/without Co-administered Drugs
No Effect = 1.00
AUC
Cmax
C or C24
0.920
1.005
0.969
(0.816-1.036)
(0.908-1.113)
(0.867-1.083)
0.620
0.782
0.892
(0.555-0.694)
(0.722-0.848)
(0.825-0.965)
0.944
0.973
1.000
(0.848-1.052)
(0.911-1.039)
(0.937-1.066)
0.121
0.294
0.484
(0.093-0.157)
(0.257-0.337)
(0.433-0.542)
1.278
1.105
1.072
(1.130-1.445)
(1.017-1.201)
(1.020-1.128)
0.629
0.750
0.882
(0.523-0.758)
(0.691-0.814)
(0.781-0.997)
0.679
0.668
0.646
(0.560-0.824)
(0.553-0.806)
(0.540-0.774)
0.256
0.264
0.276
(0.211-0.311)
(0.218-0.318)
(0.231-0.331)
0.703
0.743
0.821
(0.579-0.853)
(0.615-0.897)
(0.686-0.984)
2.206
1.617
1.336
(1.972-2.468)
(1.500-1.743)
(1.254-1.423)
2.802
1.911
1.495
(2.523-3.113)
(1.802-2.026)
(1.404-1.591)
0.954
0.971
0.915
(0.752-1.209)
(0.783-1.203)
(0.754-1.111)
0.239
0.409
0.535
(0.212-0.270)
(0.379-0.443)
(0.500-0.572)
0.245
0.431
0.608
(0.179-0.336)
(0.346-0.536)
(0.506-0.730)
0.510
0.651
0.763
(0.413-0.629)
(0.542-0.782)
(0.632-0.921)
26
Study
DTG Dose Recommendation
ING111604
No dose adjustment
ING111405
No dose adjustment
ING111405
No dose adjustment
ING111603
Not recommended
ING112934
No dose adjustment
ING112934
No dose adjustment
ING111602
No dose adjustment
ING111602
DTG should be taken 2 hours
before or 6 hours after antacid
ING111602
ING111854
No dose adjustment
ING111854
No dose adjustment
ING112941
No dose adjustment
ING113096
DTG 50 mg BIDc
ING114005
DTG 50 mg BIDc
ING113068
No dose adjustment
CONFIDENTIAL
Module 2.5 Clinical Overview
Coadministered
Drug
Co-administered
Drug Dose
DTG Dose
N
RIF
600 mg once daily
50 mg
BIDa
50 mg
BIDb
50 mg
once daily
50 mg
once daily
50 mg
once daily
50 mg
once daily
50 mg
once daily
11
RFB
300 mg once daily
Prednisone
60 mg once daily
BCV
800 mg q8h
TVR
750 mg q8h
RPV
250 mg once daily
11
9
12
13
15
16
Geometric Mean Ratio (90% CI) of DTG PK
Parameters with/without Co-administered Drugs
No Effect = 1.00
AUC
Cmax
C or C24
1.220
1.327
1.184
(1.005, 1.480) (1.152, 1.529)
(1.026, 1.366)
0.277
0.460
0.565
(0.228, 0.336) (0.384, 0.552)
(0.489, 0.652)
0.700
0.947
1.156
(0.566, 0.866) (0.816, 1.098)
(0.978, 1.365)
1.167
1.111
1.062
(1.062, 1.281) (1.030, 1.198)
(0.991, 1.139)
1.080
1.068
1.052
(0.911, 1.281) (0.948, 1.203)
(0.960, 1.153)
1.368
1.253
1.185
(1.290, 1.450) (1.196, 1.314)
(1.111, 1.264)
1.223
1.121
1.130
(1.149, 1.302) (1.053, 1.194)
(1.055, 1.210)
Data Source: m2.7.2, Table 56
Note: OMP: omeprazole; FPV/RTV: fosamprenavir/ritonavir; RFB: rifabutin; BCV: bocepravir; TVR: telaprevir;
a. Comparison was between DTG 50 mg BID + RIF(test treatment) vs DTG 50 mg once daily (reference treatment).
b. Comparison was between DTG 50 mg BID + RIF(test treatment) vs DTG 50 mg BID (reference treatment)
c. Caution should be given to INI-resistant subjects.
27
Study
DTG Dose Recommendation
ING113099
DTG 50 mg BIDc
ING113099
No dose adjustment
ING115696
No dose adjustment
ING115697
No dose adjustment
ING115697
No dose adjustment
LAI116681
No dose adjustment
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Module 2.5 Clinical Overview
3.4.
Pharmacodynamics
The pharmacodynamic studies are described in m2.7.2, Section 2.2.
3.4.1.
Effect of DTG on Cardiac Conduction
In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single
dose oral administrations of placebo, a supratherapeutic dose of DTG at 250 mg as
suspension (exposures approximately 2-3-fold of the 50 mg twice daily dose at steady
state), and moxifloxacin (400 mg, active control) in random sequence. DTG did not
prolong the QTc interval for 24 hours post dose. After baseline and placebo adjustment,
the maximum mean QTc change based on Fridericia correction method (QTcF) was
1.99 msec (1-sided 95% upper CI: 4.53 msec).
3.4.2.
Effect of DTG on Renal Function
The effect of DTG on serum creatinine clearance (CrCL), glomerular filtration rate
(GFR) using iohexol as the probe, and effective renal plasma flow (ERPF) using paraaminohippurate (PAH) as the probe was evaluated in an open-label, randomized, 3 arm,
parallel, placebo-controlled study in 37 healthy subjects, who were administered DTG
50 mg once daily (n=12), 50 mg twice daily (n=13) or placebo once daily (n=12) for 14
days. A modest decrease (about 10%) in CrCL was observed with DTG within the first
week of treatment, consistent with that seen in clinical studies. DTG at both doses had no
significant effect on actual GFR or ERPF. These data support in vitro studies which
suggest that the small increases in creatinine observed in clinical studies are due to the
likely benign inhibition of the organic cation transporter 2 (OCT2) in the proximal renal
tubules, which mediates the tubular secretion of creatinine.
3.5.
Pharmacokinetic – Pharmacodynamic Relationships and
Definition of “No Effect Boundaries”
3.5.1.
PK/PD Relationship for Efficacy
3.5.1.1.
Short-Term Monotherapy
In a 10-day monotherapy study, ING111521, in HIV-infected ART-naïve subjects, a
strong dose-response relationship and exposure-response relationship were observed. A
mean decrease from Baseline on Day 11 in plasma HIV-1 RNA of 1.51 to
2.46 log10 c/mL was observed with DTG doses of 2 to 50 mg compared with placebo
(0.05 log10 c/mL increase). Antiviral responses were maintained for 3 to 4 days after the
last dose in the 50 mg group. Greater antiviral activity was associated with higher DTG
plasma exposure. Such relationship was best described by an Emax model, with
pharmacokinetic parameter C identified as the best predictor for antiviral activity
(Figure 1). DTG exposure from 10 mg once daily dose approximated or exceeded EC90
and DTG exposure from 50 mg once daily are well upon the plateau of curve.
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Module 2.5 Clinical Overview
Plasma HIV-1 RNA Change from Baseline to Day 11 (log10 Copies/mL)
Figure 1
Relationship between Reduction in Log10 c/mL Plasma HIV-1 RNA
from Baseline to Day 11 and Day 10 C, Best Model in ING111521
3.0
2.5
2.0
1.5
1.0
0.5
Emax = 2.60 log10
EC50 = 35.68 ng/mL
0.0
0
200
400
600
800
1000
1200
Ctau on Day 10 (ng/mL)
Note: Lines represent the best fitted line (solid) and 95% CI (dashed).
Data source: m5.3.4.2 ING111521 CPSR, in-text Figure 1.
3.5.1.2.
Long-Term Combination Therapy
Treatment-Naïve Subjects
In HIV-infected ART-naïve subjects where DTG was given in combination with
nucleoside reverse transcriptase inhibitors (NRTIs), no relationship between DTG dose or
pharmacokinetic exposure and antiviral response was observed at doses ranging from 10
to 50 mg once daily. The lack of dose-response or exposure-response relationship is
likely due to the potency of combination therapy, resulting in 79%, 78%, and 88%
achieving HIV-1 RNA values <50 c/mL at Week 96 across DTG 10, 25, and 50 mg doses
(respectively) in the Phase IIb study ING112276 and an 88% response rate on DTG
50 mg once daily observed at Week 48 in the Phase III study ING113086. Such findings
indicate that DTG doses of 10 to 50 mg once daily in combination with dual NRTIs
achieved maximum virological suppression in this population.
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Module 2.5 Clinical Overview
Treatment-Experienced and INI-Naïve Subjects
In HIV-infected, ART -experienced, INI-naive subjects where DTG was given in
combination with at least 1 active agent in the background regimen, average DTG trough
concentration(C0_avg) was a statistically significant predictor of antiviral response at
Week 24 when using all available data.
The use of moderate-strong inducers (TPV/RTV and EFV) in the background therapy
was associated with reduced C0_avg and reduced virologic efficacy. Additional PK/PD
analyses were thus performed, excluding subjects who were receiving these agents and
those with clear evidence of noncompliance (defined as non-detectable DTG
concentration observed at one or more PK visits). The results from this additional
analysis showed that DTG C0_avg was no longer a predictor of virological response,
suggesting that a sufficiently high DTG exposure was achieved for robust virological
responses for the rest of the population. Coupled with the statistically significantly
greater responses in subjects treated with DTG vs. RAL (plus background regimen), these
PK/PD results support the selection of DTG 50 mg once daily for the majority of
treatment-experienced, INI-naïve subjects. DTG at a dose of 50 mg BID is
recommended for subjects who require co-administration with TPV/RTV and EFV to
ensure optimal responses.
INI-Resistant Subjects
In HIV-infected, INI-resistant subjects in the Phase III study ING112574, DTG trough
concentration (C) was not statistically significantly correlated with antiviral activity
observed at Day 8 and Week 24. These data suggested that DTG 50 mg twice daily may
be at the plateau of the dose-response curve for the drug effect in INI-resistant subjects.
These data support the selection of DTG 50 mg twice daily in the INI-resistant
population.
3.5.2.
PK/PD Relationship for Safety
Plasma DTG exposure was not correlated with the presence of the most frequent AEs
including diarrhea, nausea, and headache or with most clinical laboratory tests of interest.
There was a statistical correlation between DTG exposure and change from Baseline in
total bilirubin (likely due to competition with UGT1A1) and serum creatinine (due to
known OCT2 inhibition). However, such relationship is not considered clinically
significant due to the small, non-progressive changes in these clinical chemistries.
3.5.3.
Definition of No Effect Boundaries of Alteration in DTG Exposure
The PK/PD relationship for efficacy defines the lower bound and the PK/PD relationship
for safety defines the upper bound. These “no effect boundaries” were used as
justification for recommendations on whether dose adjustment was needed for drug
interactions or the impact of other intrinsic or extrinsic factors on DTG PK. The lower
boundary is proposed to be 25% of DTG C observed at the recommended doses (or 75%
reduction in C), and currently the upper boundary cannot be determined due to good
safety and tolerability profiles of DTG.
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Module 2.5 Clinical Overview
The definition of the lower bound of the “no effect boundaries” was based on the finding
of no dose-response or PK/PD relationship for antiviral activity at DTG doses from
10 mg to 50 mg once daily in combination with NRTI backbones in Phase IIb treatmentnaive trial (ING112276). DTG exposure observed at 10 mg once daily (0.30 g/mL for
C) is considered as the lower bound of the “no effect boundaries”, which is 25% of C
observed at 50 mg once daily (1.20 g/mL). Reduction in DTG C by less than 75%
(whilst also accounting for variability) caused by any intrinsic or extrinsic factor is not
considered clinically significant and thus does not require DTG dose adjustment.
3.6.
Clinical Pharmacology Conclusions
Overall, pharmacokinetics, pharmacodynamics, PK/PD relationship in various patient
populations, and drug interaction profiles of DTG support the following dose
recommendation:
Treatment-naïve adults: DTG 50 mg once daily.
Treatment-experienced but integrase inhibitor-naïve adults: DTG 50 mg once daily.
Integrase inhibitor resistant adults: DTG 50 mg twice daily.
Integrase inhibitor-naïve children of 12 to <18 years of age and weighing greater
than or equal to 40 kg: DTG 50 mg once daily.
No DTG dose adjustment is necessary based on age, gender, race/ethnicity, weight,
smoking, CDC classification of HIV infection, HBV/HCV co-infection, UGT1A1
polymorphisms, in subjects with mild to moderate hepatic impairment (Child Pugh grade
A or B), and in subjects with mild, moderate, or severe (CrCL<30 mL /min, not on
dialysis) renal impairment. DTG can be co-administered with most ART or non-ART
drugs without dose adjustment except for the following:

Moderate/strong metabolic inducers: DTG 50 mg twice daily is recommended when
co-administered with TPV/RTV, EFV, and RIF. The co-administration of DTG
50 mg once daily with ETR is not recommended unless the regimen includes
concomitant ATV/RTV, LPV/RTV or DRV/RTV.

Polyvalent metal cation-containing antacids: DTG should be dosed 2 hours prior to
or 6 hours after antacids.
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Module 2.5 Clinical Overview
4.
OVERVIEW OF EFFICACY
Efficacy has been demonstrated for dolutegravir in four Phase III studies (ING113086,
ING111762, ING114467, and ING112574) in ART-naive and experienced subjects with
HIV infection. Additional efficacy data is provided by longer term supportive studies
ING112276 and ING112961.
The following ongoing studies did not contribute to the summary of efficacy: ING112578
(P1093), ING116070 (CSF), ING114915 (FLAMINGO), ING114916 (Expanded Access
Program) and ING115502 (Named Patient Program).
Module 2.7.3 (Clinical Summary of Efficacy) provides details on the individual efficacy
results from the clinical program.
4.1.
Non-clinical Virology
A summary of non-clinical and clinical virology can be found in m2.7.2.4 (Special
Studies). DTG inhibits HIV integrase by binding to the integrase active site and blocking
the strand transfer step of retroviral DNA integration which is essential for the HIV
replication cycle. Key non-clinical virology is as follows:

Dolutegravir has low nM activity against wild type HIV-1 and HIV-1 in a variety of
cells lines, regardless of subtype. Human serum causes approximately 75-fold
increase in DTG IC50. Dolutegravir trough concentration for a single 50 mg dose in
integrase inhibitor naïve subjects was 1.20 mcg/mL, 19 times higher than the
estimated protein adjusted 90% inhibitory concentration (PA-IC90).

In a viral integrase susceptibility assay using the integrase coding region from 13
clinically diverse clade B isolates, dolutegravir demonstrated antiviral potency
similar to that seen with laboratory strains, with a mean IC50 of 0.52 nM. When
tested in peripheral blood mononuclear cell (PBMC) assays against a panel
consisting of 24 HIV-1 clinical isolates (group M [clade A, B, C, D, E, F and G] and
group O) and 3 HIV-2 clinical isolates, the geometric mean IC50 was 0.20 nM and
IC50 values ranged from 0.02 to 2.14 nM for HIV-1, while the geometric mean IC50
was 0.18 nM and IC50 values ranged from 0.09 to 0.61 nM for HIV-2 isolates.

DTG is additive or synergistic when assayed in combination with other antiretroviral
agents.

Comparative susceptibilities to DTG and RAL were obtained from 60 RAL resistant,
site directed HIV-1 mutants and 6 site directed HIV-2 mutants. DTG retained
activity against a vast majority of these mutants. Additionally, susceptibilities to
DTG and RAL were determined for over 700 RAL resistant clinical isolates, with
DTG retaining significant antiviral activity (<10 FC) against >90% of them.

The dissociation of DTG, RAL, and EVG from wild type and mutant IN proteins
complexed with DNA was investigated to obtain a better understanding of INI
dissociation kinetics. DTG demonstrated slower dissociation from all IN-DNA
complexes tested, including those with single, double, and up to four residue IN
substitutions.
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Module 2.5 Clinical Overview
4.2.
Selection of Patient Populations in Pivotal and Supportive
Efficacy Studies
The registrational studies in adults supporting this submission recruited HIV-1 infected
subjects aged 18 years and older who were able to provide written informed consent.
Women of child-bearing potential were eligible for enrolment if using a reliable method
of contraception as permitted by labeling of comparator agents. Subjects were excluded
on the basis of medical history (e.g. active CDC Category C disease with certain
exceptions, moderate to severe hepatic impairment, gastrointestinal bleeding, allergy to
study drugs, history of malignancies), concomitant or recent medical therapy (e.g. HIV-1
vaccines, treatments with activity against HIV-1 that are not licensed for that purpose,
radiation therapy, immunomodulators, cytotoxic chemotherapeutic agents or recent use of
experimental drugs) or screening laboratory values (e.g. any verified Grade 4 lab
abnormalities, or liver chemistries above specified thresholds). The specific criteria
applied during each phase of development reflected DTG data available at that time, and
are therefore slightly different for the Phase IIb studies compared to the Phase III studies.
Additionally, there are some differences amongst the Phase III studies based on the
patient population enrolled or the background regimens administered. Notwithstanding
the minimum inclusion and exclusion criteria defined in each protocol, investigators were
also required to follow any existing country specific guidelines when making decisions
about subjects who are eligible for study participation.
4.3.
Rationale for Dose Selection in Clinical Development
Section 4 of m2.7.3 describes in more detail the data relevant to dose selection decisions
made with DTG, and concludes with the data supporting the selected dose in ART -naive
adults, ART-experienced (INI-naïve) adults and adolescents (of 12 to <18 years old and
at least 40 kg of weight), and ART-experienced (INI-resistant) adults with HIV-1
infection.
4.3.1.
ART-Naïve/ART-Experienced (INI-Naïve) Subjects
The 50 mg once daily dose for DTG in ART-naïve/ART-experienced (INI-naïve)
subjects was selected based on the following:

Results from ING111521, 10-day monotherapy study in treatment-naive or
treatment-experienced and INI-naive subjects demonstrate that once daily dosing of
DTG achieved viral load declines for 2 mg, 10 mg and 50 mg of 1.54, 2.04, and
2.48 log10 c/mL, respectively. The 50 mg once daily dose achieved an inhibitory
quotient (observed DTG concentration at the end of the dosing interval [C]/fold
above PA-IC90) of 19, demonstrating considerable coverage above the in vitro
protein adjusted target concentration of 0.064 ng/ml.

A PK/PD analysis from ING111521 evaluated the relationship between C and
change in HIV RNA from Baseline. The data were fit to a maximum effect model
and demonstrated that the 50 mg dose was on the plateau of the concentrationresponse curve after monotherapy.
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Module 2.5 Clinical Overview

In ING112276, a Phase IIb dose-ranging study in treatment-naive subjects that
evaluated DTG at doses of 10 mg, 25 mg and 50 mg once daily with 2 NRTIs vs.
EFV plus 2 NRTIs. DTG was well tolerated across all doses studied. A good safety
and tolerability profile with a low discontinuation rate due to AEs was observed in
all three arms with no significant dose-dependent trends in safety parameters. All
three doses showed similar robust antiviral responses and no apparent dose-response
relationship was observed, suggesting DTG doses from 10 mg to 50 mg once daily in
combination with 2 NRTIs achieved maximum virologic suppression. Therefore, the
highest dose, DTG 50 mg once daily, was selected as the dose for the Phase III
studies in INI-naive population. Selection of 50 mg once daily dose was also to
accommodate decreases in DTG in light of drug interactions, poor absorption,
imperfect adherence, or other cause.
Efavirenz, TPV/RTV, and FPV/RTV decrease the C of DTG by 75%, 76%, and 49%,
respectively (m2.7.2, Section 3.4.3). The resulting C values remain 3.4 to 5.5-fold above
the protein adjusted IC90 for wild type HIV. In addition, the C values with enzyme
inducers range from 0.22 to 0.35 g/mL (see m2.7.2, Section 2.3.3). Despite decreases in
DTG exposures with these interactions, the DTG exposure is still comparable to or higher
than those demonstrated with 10 mg once daily dosing in ING112276, supporting the
selection of DTG 50 mg once daily for use in ING111762.
In summary, a dose of 50 mg once daily demonstrated safety and efficacy while
providing a significant coverage in plasma exposure to account for reductions due to drug
interactions or other events that could decrease concentrations. This dose was selected
for Phase III studies in ART-naive and ART-experienced (INI-naïve) adult subjects.
4.3.2.
ART-Experienced (INI-Resistant) Subjects
The 50 mg BID dose selection for DTG in ART-experienced (INI-resistant) subjects was
based on the following:

ING112961 Cohort I evaluated 50 mg once daily in subjects with resistance to RAL,
but a sub-optimal anti-viral response that was observed in some subjects harboring
virus with higher fold change (FC) to DTG prompted the evaluation of an increased
dose of DTG in a second cohort of subjects.

PK/PD modeling predicted that increasing the DTG dosage from 50 mg once daily to
100 mg daily dose in populations of raltegravir-resistant subjects would yield
substantive improvements in treatment response.

A dose of 100 mg once daily was initially considered for evaluation, however data
from healthy subjects in ING114005 demonstrated that plasma DTG exposures
increase less-than-dose-proportionally from 50 mg to 100 mg. In addition, one-third
of subjects did not have any appreciable increase in C between 50 mg and 100 mg
doses. These data demonstrated that a 50 mg twice daily dose would provide more
consistent exposures than a dose of 100 mg once daily.
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Module 2.5 Clinical Overview

ING112961 Cohort II evaluated DTG 50 mg twice daily in a similar population of
subjects as Cohort I, but those enrolled had more limited high-level resistance to
DTG. Comparison of the primary end-point (proportion of subjects with Day 11
plasma HIV-1 RNA <400 c/mL or at least 0.7 log10 c/mL below their Baseline
values) between Cohort I and Cohort II suggested a higher response rate may be
achieved with 50 mg twice daily of DTG.

Analyses of data through Week 24 for Cohort II (and Week 72 for Cohort I) in
ING112961 confirmed the continued benefit of the 50 mg DTG twice daily regimen
without overt increase of clinical or laboratory AEs compared to the 50 mg once
daily regimen.
In summary, the short term antiviral response rates, pharmacokinetics, and data through
Week 24 of Cohort II (and Week 72 in Cohort I) of ING112961 suggested additional
benefit would be realized with DTG 50 mg twice daily compared to the DTG 50 mg once
daily dose in this population harboring INI-resistant virus. Therefore the DTG 50 mg
twice daily dose was selected for Phase III evaluation in this population.
4.4.
Clinical Trial Methodology and Design (Pivotal Efficacy
Study Designs)
The study designs details including the objectives, treatment regimens and number of
patients enrolled/ randomized for pivotal and supportive efficacy studies are presented in
m2.7.3, Section 1.6.
4.4.1.
Studies in INI-Naïve Subjects
Pivotal efficacy studies ING113086, ING114467, and ING111762 are Phase III,
international, multicenter, parallel-group randomized, double-blind, active-controlled,
double-dummy studies conducted in ART-naïve (ING113086 and ING114467) and ARTexperienced (INI-naïve) subjects (ING111762). Supportive study ING112276 is a
Phase IIb international, multicenter, parallel group randomized partially blinded active
controlled dose-ranging study conducted in ART-naïve subjects (Table 6).
4.4.2.
Studies in INI-Resistant Subjects
Pivotal efficacy study ING112574 is an international, multicenter, open-label, single-arm,
Phase III study to demonstrate the antiviral activity and safety of dolutegravir in HIV-1
infected adult subjects with integrase inhibitor resistance. Supportive study ING112961
is a Phase IIb international, multicenter, open-label single-arm sequential cohort pilot
study in ART-experienced (INI-resistant) subjects (Table 6).
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Module 2.5 Clinical Overview
Table 6
Summary of Studies Supporting Clinical Efficacy of Dolutegravir in the Treatment of HIV-1 Infection
Study
Number
Phase
Pivotal Efficacy Studies
ING113086
(SPRING-2)
ING114467
(SINGLE)
ING111762
(SAILING)
III
III
III
Study Design
Multicentre randomized, double
blind, double-dummy, activecontrolled, parallel group, fullypowered non-inferiority study.
Screening viral load (VL) >1000
c/mL,
<10 days prior ART.
No evidence of resistance at
screening.
Randomized, double-blind,
double-dummy, active-controlled,
multicentre, parallel group, fullypowered non-inferiority study.
Screening VL >1000 c/mL,
HLA-B*5701 negative,
<10 days prior ART,
No evidence of resistance at
screening
Multicentre randomized, doubleblind, active-controlled, parallel
group, non-inferiority study.
2 Screening VL>400 c/mL or 1
Screening VL >1000 c/mL,
at least 2-class resistance,
Potential for 1 fully active agent
in background regimen (BR), No
INI experience
Primary Objectives
Durationa
To assess safety and
efficacy of DTG 50 mg once
daily compared to RAL
400 mg BID both
administered with fixed-dose
dual NRTI therapy
48 weeks
To assess safety and
efficacy of DTG plus
ABC/3TC fixed-dose
combination therapy
administered once daily
compared to Atripla
48 weeks
To evaluate safety and
efficacy of DTG 50 mg once
daily vs. RAL 400 mg BID,
both administered with an
investigator-selected
background regimen
24 weeks
Regimens
DTG 50 mg once daily; oral tablet or
RAL 400 mg once daily; oral tablet
+ ABC/3TC 600 mg/ 300 mg once daily; oral
tablet or
+ TDF/ FTC 300 mg/ 200 mg once daily; oral
tablet
DTG 50 mg once daily; oral tablet + ABC/3TC
600/300 mg once daily; oral tablet
EFV/TDF/FTC 600/200/300 mg once daily;
oral tablet
Number of
Patientsb
DTG:
413 Randomized
364 Ongoing
0 Completed
RAL:
414 Randomized
355 Ongoing
0 Completed
DTG + ABC/3TC:
422 Randomized
363 Ongoing
0 Completed
EFV/TDF/FTC:
422 Randomized
363 Ongoing
0 Completed
36
DTG 50 mg once daily; oral tablet
RAL 400 mg BID; oral tablet
+ Investigator-selected background regimen
DTG
354 Randomized
305 Ongoing
1 Completedc
RAL
361 Randomized
189 Ongoing
111 Completed
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Module 2.5 Clinical Overview
Study
Number
ING112574
(VIKING-3)
Phase
III
Study Design
Multicentre, open-label, single
arm.
Screening VL >500 c/mL,
Documented virologic failure on
RAL or ELV,
Documented resistance to RAL or
ELV,
At least 3-class resistance
(including INIs),
Potential for 1 fully active agent
in optimized background regimen
(OBR)
Primary Objectives
To assess the antiviral
activity of DTG administered
with failing background
therapy to Day 8 and
thereafter with optimized
background ART
37
Durationa
24 weeks
Regimens
DTG 50 mg BID; oral tablet
Number of
Patientsb
DTG
183 Enrolled
155 Ongoing
0 Completed
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Module 2.5 Clinical Overview
Study
Number
Phase
Study Design
Supportive Efficacy Studies
ING112276
IIb
Randomized, multicentre, parallel
(SPRING-1)
group, dose-ranging.
Screening VL >1000 c/mL,
Screening CD4 >200 cells/mm3,
<10 days prior ART,
No evidence of resistance at
screening
Primary Objectives
To select a once daily oral
dose of DTG administered
with either ABC/3TC or
TDF/FTC and to evaluate
antiviral activity, safety and
PK over time
Durationa
96 weeks
Regimens
DTG 10 mg once daily; oral tablet
DTG 25 mg once daily; oral tablet
DTG 50 mg once daily; oral tablet
EFV 600 mg once daily; oral tablet
+ ABC/3TC 600 mg/ 300 mg once daily; oral
tablet
or
+ TDF/ FTC 300 mg/ 200 mg once daily; oral
tablet
[At the Week 96 visit, all DTG subjects were
switched to the selected dose of 50 mg once
daily]
ING112961
(VIKING)
a.
b.
c.
d.
IIb
Multicentre, open-label, single
arm, sequential cohort, pilot
study.
To assess the antiviral
activity of DTG containing
regimen
Cohort I:
96 weeks
Cohort II:
48 weeks
DTG 50 mg once daily; oral tablet
DTG 50 mg BID; oral tablet
Screening VL >1000 c/mL,
RAL resistance at Screening,
At least 3-class resistance
(including INIs),
Potential for 1 fully active agent
in OBR (BID Cohort only)
Weeks for evaluation of efficacy in this submission.
For ongoing studies, the number of subjects reported as of data cutoff date (~
or data cutoff date in respective CSR).
One subject who completed the DTG treatment decided they did not want to participate in the open label phase.
DTG 10 mg and 25 mg subjects are currently ongoing on DTG 50 mg.
38
Number of
Patientsb
DTG 10 mg
53 Randomized
47 Ongoingd
DTG 25 mg
51 Randomized
45 Ongoingd
DTG 50 mg
51 Randomized
46 Ongoing
EFV
50 Randomized
41 Completed
DTG 50 mg once
daily
27 Enrolled
13 Ongoing
0 Completed
DTG 50 mg BID
24 Enrolled
19 Ongoing
0 Completed
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Module 2.5 Clinical Overview
Estimated timings for the completion of study reports following the initial submission are
presented in Table 7.
Table 7
Study
Identifier
Data Availability for Ongoing Studies
Length of Study
ING113086
48 weeks, with up to 3year follow-up
96 weeks (primary
endpoint at Week 16)
96 weeks
ING112574
24 and 48 weeks
ING112578
ING116070
ING116529
ING111762
ING114915
ING114467
7 days double-blind
phase and 48 weeks
open-label phase.
48 weeks
96 weeks
144 weeks
Data Available at Initial
Submission
10 subjects (Stage 1) from
Cohort 1 through 24 weeks
Estimated Completion
of Study Report
/ Week 24 Analysis
(Cohort 1, Stages 1 & 2)
All subjects through 2 weeks
All subjects through 48 weeks
All subjects through Day 8,
114/183 subjects through 24
weeks
/ Week 16 Analysis
/ Week 96 Analysis
/ Week 24 (all)/
Week 48 (first 114 subjects) Analysis
No efficacy data
/ Day 8 Analysis
All subjects through 24 weeks
No efficacy data
All subjects through 48 weeks
/ Week 48 Analysis
/ Week 48 Analysis
/ Week 96 Analysis
4.5.
Efficacy Endpoints and Statistical Considerations of
Efficacy Analyses
4.5.1.
Primary and Secondary Efficacy Endpoints
The primary endpoint for pivotal studies ING113086, ING114467, and ING111762 was
analyzed using a Missing, Switch or Discontinuation = Failure (MSDF) algorithm as
codified by the FDA’s “snapshot” algorithm (m2.7.3, Section 1.8).
The primary endpoints for pivotal and supportive studies are listed in Table 8. Secondary
endpoints are provided in m2.7.3, Section 1.8.2.
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Module 2.5 Clinical Overview
Table 8
Primary Efficacy Endpoints in Pivotal and Supportive Studies
Pivotal Studies
Proportion of subjects with HIV-1 RNA <50 c/mL through
Week 48 (MSDF)a
Mean change from Baseline in plasma HIV-1 RNA
(log10 c/mL) at Day 8 (LOCFDB) (for hypothesis testing)b
Proportion of subjects with plasma HIV-1 RNA <50 c/mL at
Week 24 (MSDF)a
ING113086
X
ING114467
X
ING111762
X
ING112574
X
X
Supportive Studies
ING112961 ING112276 ING111521
Proportion of subjects with Day 11 plasma HIV-1 RNA <400 c/mL or at
X
least 0.7 log10 c/mL below Baseline
Proportion of subjects with HIV-1 RNA <50 c/mL through Week 16
X
(TLOVR) c
Change from Baseline in plasma HIV-1 RNA to Day 11
X
DTG PK parameters following dose administration on Day 1
X
a. Analyzed using the Missing, Switch or Discontinuation = Failure (MSDF) algorithm as codified by the FDA’s
“snapshot” algorithm.
b. Analyzed using a last observation carried forward (discontinuation equals baseline) (LOCFDB) dataset.
c. Analyzed using to Time to Loss of Virological Response (TLOVR) algorithm
4.5.2.
Statistical Considerations
Details of the statistical methodology are described in m2.7.3, Section 1.9.3.
Assumptions underlying the determination of study sample size requirements, varied
across the pivotal and supportive trials:

ING113086: Assuming a 75% response rate in the RAL arm, the study required 394
evaluable subjects per arm to have 90% power with a 10% non-inferiority margin
and a one-sided 2.5% significance level. The selection of a 10% non-inferiority
margin has been well described [Hill, 2008]. The study was stratified on the
following factors: Screening HIV-1 RNA (100,000 vs. >100,000 c/mL) and
investigator-selected NRTI backbone (ABC/ 3TC vs. TDF/FTC).

ING114467: Assuming a 75% response rate in the TDF/FTC/EFV arm, the study
required 394 evaluable subjects per arm to have 90% power with a 10% noninferiority margin and a one-sided 2.5% significance level. The study was stratified
on the following factors: Screening HIV-1 RNA (100,000 vs. >100,000 c/mL) and
CD4+ cell count (200 vs. >200 cells/mm3).

ING111762: Assuming a 65% response rate in the RAL arm, the study required 333
subjects per arm to have 90% power with a 12% non-inferiority margin and a onesided 2.5% significance level. Recruitment of subjects with fully PI/r susceptible
virus who received DRV/RTV was capped at 170 subjects in order to help achieve at
least 80% power to detect non-inferiority in the “added sensitivity (AS)” population
(defined in ING111762 CSR Section 4.8.3). Assuming a response rate of 65% in
that population, and a non-inferiority margin of 12%, this requires at least 249
subjects per arm. The study was stratified on the following factors: Screening HIV-1
RNA (50,000 vs. >50,000 c/mL), use of DRV/RTV with or without primary PI
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Module 2.5 Clinical Overview
mutations (yes vs. either no DRV/RTV use or presence of primary PI mutations), and
number of fully active background agents (2 vs. <2).

ING112574: Assuming a standard deviation of 0.5 log10 c/mL for the change from
Baseline in plasma HIV-1 RNA at Day 8, this study required fewer than 20 subjects
to be powered at 90% on the primary hypothesis test. However, the minimal sample
size was expanded to 150 to 200 subjects to allow a comprehensive assessment of
the safety, antiviral activity and PK of DTG in this study, acknowledging constraints
on the availability of the study patient population. The primary endpoint at Week 24
is the proportion of subjects with plasma HIV-1 RNA <50 c/mL. A single arm study
with 100 subjects will provide a precision (i.e. standard error) of four percentage
points, which translates to a 95% confidence interval (CI) of 72% to 88% for an
assumed response rate of 80% (% <50 c/mL at Week 24).
Across the pivotal and supportive studies the analysis populations upon which the
efficacy analyses were based are defined in m2.7.3 Section 1.9.2.
The Intent-to-Treat Exposed population consisted of all randomized subjects who
received at least one dose of investigational product. The Modified Intent-to-Treat
Exposed population for the ING111762 study consisted of all randomized subjects who
received at least one dose of investigational product, and who were not at one study site
(Site # 083523, Investigator ID=096536, n=4 subjects enrolled) in Russia that was closed
early after the sponsor became aware of GCP noncompliance issues in another ViiV
Healthcare-sponsored study. The ITT-E (ING113086, ING114467, ING112574,
ING112961, ING112276, and ING111521) and mITT-E (ING111762) are the primary
populations for efficacy analyses.
4.6.
Efficacy Results in all Studies
Due to differences in study designs and comparator arms, data from the studies was not
combined and therefore, are presented in a side-by-side format for comparative purposes.
4.6.1.
Enrolment of Key Demographic Subpopulations in ING113086,
ING114467, and ING111762
In Studies ING113086 and ING114467 about 15% of treatment-naïve subjects enrolled
were women (Table 9). In Study ING114467, a limiting factor to enrolment of women
was use of a blinded comparator with pregnancy warnings for women (Atripla).
However, due to the size (>800 subjects each study) of the treatment-naïve studies, a total
of 130 women were treated on DTG-containing regimens in these two studies. In
contrast, a higher percentage of women was enrolled in ING111762 (32%), which may
be due in part to the country distribution (the study enrolled subjects in Argentina, Brazil,
and South Africa). Overall, women were well-represented across the clinical program to
allow for an assessment of the efficacy and safety of DTG in this key subpopulation of
HIV-infected patients.
Across treatment-naïve studies, ING113086 and ING114467, 285 subjects (9 to 24%)
enrolled were of African American/African heritage (Table 9). In contrast, a higher
percentage of African American/African heritage subjects were enrolled into ING111762
(42%), which was likely due in part to the inclusion of South Africa in this study.
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Module 2.5 Clinical Overview
Overall, the racial diversity (especially African American/African heritage patients) of
the HIV population was well-represented across the clinical program to allow for an
assessment of the efficacy and safety of DTG in this key subpopulation of HIV-infected
patients.
Enrolment of geriatric subjects (65) ranged from about 1 to 2% across treatment-naïve
studies. In ING113086, one subject in the DTG treatment arm was 68 years and 5
subjects in the RAL treatment arm were >65 years of age. In ING114467, one subject on
DTG + ABC/3TC and 6 subjects (1%) on Atripla were 65 years old. Enrolment of
subjects 50 years ranged from 10 to 24% (Table 9). In the treatment-experienced (INInaïve) study, ING111762, 24% of subjects were 50 years including 12 subjects who
were 65 years old (6 DTG and 6 RAL) (Table 9, ING111762 Week 24 CSR Table 7.8).
Other key populations, such as severly immunosuppressed and viral hepatitis co-infected
patients, were adequately represented across the clinical program to allow for a robust
assessment of DTG efficacy and safety.
Table 9
Subgroup of
Interest
Proportion of Demographic Sub-populations in ING113086,
ING114467, and ING111762
ART-Naïve, INI-Naive
ING113086
ING114467
DTG
RAL
DTG 50 mg
EFV/TDF/FTC
50 mg
400 mg
+ ABC/3TC
once daily
once daily
BID
once daily
+ 2 NRTI
+ 2 NRTI
N=411
N=411
N=414
N=419
n (%)
n (%)
n (%)
n (%)
63 (15)
56 (14)
67 (16)
63 (15)
49 (12)
39 (9)
98 (24)
99 (24)
ART-Experienced, INI-Naive
ING111762
DTG 50 mg
RAL 400 mg
once daily
BID + BR
+ BR
N=354
n (%)
107 (30)
143 (41)
Females
African American/
African Heritage
Hepatitis C virus
41 (10)
35 (9)
27 (7)
29 (7)
32 (9)
(HCV)
Hepatitis B virus
7 (2)
8 (2)
1 (<1)
1 (<1)
18 (5)
(HBV)
CD4+ <50
8 (2)
6 (1)
11 (3)
14 (3)
62 (18)
cells/mm3
CD4+ <200
55 (13)
50 (12)
56 (14)
54 (13)
173 (49)
cells/mm3
CDC Category C
9 (2)
9 (2)
18 (4)
17 (4)
173 (49)
41
(10)
46
(12)
53
(13)
44
(11)
85 (24)
Age 50 years
Data Source:
ING113086 Week 48 CSR Table 6.9, Table 6.10, Table 6.12, Table 6.13, Table 6.21, ISE Table 1.1
ING114467 Week 48 CSR Table 6.10, Table 6.11, Table 6.13, Table 6.14, Table 6.22, ISE Table 1.2
ING111762 Week 24 CSR Table 6.10, Table 6.13, Table 6.14 and Table 7.8.
42
N=361
n (%)
123 (34)
160 (44)
49 (14)
17 (5)
59 (16)
184 (51)
158 (44)
84 (23)
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Module 2.5 Clinical Overview
4.6.2.
ART-Naïve
4.6.2.1.
Demographics and Baseline Characteristics
Overall, enrolment into ING113086 and ING114467 reflects the demographic
characteristic of the general ART-naïve population with HIV infection. Median age was
35 years, ~15% were female and ~20% were African American/ African Heritage
(Table 9).
Other Baseline characteristics were well-distributed across the studies and treatment
arms. Median Baseline HIV-1 RNA ranged from 4.52 to 4.70 log10 c/mL, and median
Baseline CD4 cell count ranged from 335 to 362 cells/mm3, which likely reflects current
guidelines and clinical practice for early treatment initiation (m2.7.3, Section 3.1).
4.6.2.2.
Key Efficacy Endpoints
In treatment-naïve subjects, DTG administered once daily with two NRTIs demonstrated
non-inferiority to RAL at Week 48 (ING113086: Adjusted Treatment Difference [95%
CI] +2.5% [-2.2%, +7.1%]) and co-administered with ABC/3TC demonstrated
superiority compared to Atripla (ING114467: Adjusted Treatment Difference [95% CI]
+7.4% [+2.5%, +12.3%], p=0.003). Consistent response rates (i.e., HIV-1 RNA
<50 c/mL; 88% for both studies) were observed across the two studies for the DTG
treatment regimens. Per protocol and other sensitivity analyses in both studies support
the primary endpoint in each study. The statistically significant difference in response
rates noted in ING114467 was primarily due to lower discontinuations due to AEs on the
DTG regimen (m2.7.3 Section 3.2.1.1).
Consistent with prior studies of INIs, rapid virologic responses were observed on DTGbased and RAL-based regimens (Figure 2 and Figure 3). The time to virologic
suppression was significantly faster on DTG + ABC/3TC (28 days) when compared to
TDF/FTC/EFV (84 days), hazard ratio: 2.32 [2.00, 2.68], p<0.001. This analysis was prespecified and adjusted for multiplicity.
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Module 2.5 Clinical Overview
Figure 2
ING113086 Week 48, Proportion (95% CI) of Subjects with Plasma
HIV-1 RNA <50 c/mL (Snapshot) by Visit
Data Source: ING113086 Week 48 CSR Figure 7.1
Figure 3
ING114467 Week 48 Proportion of Subjects with Plasma HIV-1 RNA
<50 c/mL Snapshot Analysis by Visit
Note: confidence intervals are derived using the normal approximation. (Triangles: DTG+ABC/3TC once daily,
Squares: Atripla once daily
Data Source: ING114467 48 Week CSR Figure 7.1
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Module 2.5 Clinical Overview
The rapid and significant viral load reductions seen with DTG containing regimens were
associated with substantial and sustained CD4 increases over 24 to 48 weeks. At
Week 48 the median CD4 increases were comparable with RAL (+230 cell/mm3; both
arms, ING113086) (m2.7.3, Table 43).
In Study ING114467, using the Repeated Measures Mixed Model Analysis,
DTG+ABC/3TC was statistically superior to Atripla with respect to change from
Baseline in CD4 in Week 48 (Adjusted mean change from Baseline: DTG+ ABC/3TC
267 cells/mm3 and Atripla 208 cells/mm3, difference 58.9 [33.4, 84.4] p <0.001).
Differences in CD4 cell counts were seen as early as Week 4 and persisted through
Week 48. This analysis was pre-specified and adjusted for multiplicity.
HIV-associated conditions in subjects treated with DTG compared to RAL and Atripla
were assessed over time by summaries of the incidence of post-Baseline HIV conditions,
and by the proportion of subjects with disease progression. Across treatment-naïve
studies, there was a similar low incidence of HIV associated conditions (1 to 3% across
all treatment-naive studies; Data Source: ING113086 Week 48 CSR and ING114467
Week 48 CSR), and in the number of subjects with HIV disease progression (m2.7.3,
Table 44).
4.6.2.3.
Comparison of Primary Efficacy Results in Sub-populations
Results of various subgroup analyses supported the findings of the primary analysis
(m2.7.3, Section 3.3.1). To assess the generalizability of the primary analysis results,
consistency of the treatment difference was explored within subgroups. Homogeneity of
the treatment difference was formally tested within each strata related to randomization in
pre-specified analyses. Other subgroups were explored based on summaries of the
treatment differences within the group to identify any potential interaction.
In the treatment-naïve studies ING113086 and ING114467, there was no clinically
meaningful difference between the proportion of subjects aged <50 years or 50 years in
the DTG treatment groups who achieved HIV-1 RNA <50 c/mL by Week 48
(m2.7.3, Section 3.3.1.1, Table 60). These studies showed similar responses in the DTG
treatment groups for the primary efficacy endpoint in other categories including gender
and race (m2.7.3, Section 3.3.1.1, Table 60).
Across treatment-naive studies, the DTG response rate was comparable to or better than
comparator for subjects whose Baseline HIV-1 RNA was >100,000 c/mL and for subjects
whose Baseline HIV-RNA was ≤100,000 c/mL (m2.7.3, Section 3.3.1.2, Table 61). In
ING114467, an identical 7% response difference in favor of the DTG-containing arm was
observed in each of these strata. As seen in prior studies with other antiretrovirals,
responses in general were higher in subjects with Baseline HIV-1 RNA 100,000 c/mL
when compared to subjects whose Baseline HIV-1 RNA was >100,000 c/mL (m2.7.3,
Section 3.3.1.2, Table 61).
Analysis according to Baseline HIV-1 RNA level supports the conclusion that treatment
effects are not heterogeneous across the predefined strata in ING113086 and ING114467
(ING113086 Week 48 CSR Section 6.2.1, ING114467 Week 48 CSR Section 6.2.2).
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Module 2.5 Clinical Overview
Good treatment responses were also observed across Baseline CD4+ cell count categories
(Table 10). In subjects with <200 CD4+ cells at Baseline, the DTG arm showed a bigger
treatment difference in ING113086 and a smaller treatment difference in ING114467.
These differences were not statistically significant, and are likely attributable to the low
number of subjects with low CD4+ cell counts. In addition, in ING114467, higher
response rates were maintained in the DTG + ABC/3TC in subjects with 200 cells at
Baseline (Table 10).
Finally, in ING113086, no significant differences in response were observed according to
investigator-selected NRTI backbones, providing further support for the non-inferiority
of DTG vs. RAL in treatment-naïve subjects (Table 10).
Table 10
Treatment Response based on Stratification Factors: HIV-1 RNA
<50 c/mL by Baseline HIV-1 RNA, CD4+ cell count, Background NRTI
in ART-Naïve Subjects
Response <50 c/mL
ING113086a,b
Week 48/ Snapshot
DTG 50 mg
RAL 400 mg
once daily
BID + 2 NRTI
+ 2 NRTI
N=411
N=411
ING114467a,c
Week 48/ Snapshot
DTG 50 mg
EFV/TDF/FTC
+ ABC/3TC
once daily
once daily
N=414
N=419
Baseline HIV-1 RNA
≤100,000 c/mL
267/297 (90)
264/295 (89)
253/280 (90)
238/288 (83)
>100,000 c/mL
94/114 (82)
87/116 (75)
111/134 (83)
100/131 (76)
Baseline CD4+ cell count
43/55 (78)
34/50 (68)
45/57 (79)
48/62 (77)
<200 cells/mm3
318/356 (89)
317/361 (88)
319/357 (89)
290/357 (81)
200 cells/mm3
Background NRTI
ABC/3TC
145/169 (86)
142/164 (87)
TDF/FTC
216/242 (89)
209/247 (85)
Other
Data Source:
ING113086 Week 48 CSR Table 7.5, Table 7.6 and Table 7.7;
ING114467 Week 48 CSR Table 7.10.
a. Baseline HIV-1 RNA: The lower ends of the 95% CIs for the treatment differences are above -10%. The test for
evidence against homogeneity of the treatment difference across high and low Baseline HIV-1 RNA was not
statistically significant.
b. Background NRTI: The lower ends of the 95% CIs for the treatment differences are above -10%. The test for
evidence against homogeneity of the treatment different across NRTI backbones was not statistically significant.
In this study, investigators chose the dual NRTI backbone of either ABC/3TC or TDF/FTC for each subject.
Overall, 41% of subjects received ABC/3TC, and 59% of subjects received TDF/FTC (m5.3.5.1, ING113086
Week 48 CSR Table 6.26).
c. Baselines CD4: The test for evidence against homogeneity of the treatment different across high and low Baseline
CD4 was not statistically significant
Notes:
ABC/3TC = ABC 600 mg and 3TC 300 mg in the form of EPZICOM/KIVEXA
EFV/TDF/FTC = EFV 600 mg, TDF 300 mg, FTC 200 mg in the form of Atripla.
N = Number of subjects in each treatment group.
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Among subjects with low viral load (100,000 c/mL) receiving ABC/3TC, response rates
were similar between the DTG and RAL treatment groups (DTG 87%, RAL 88%)
(m2.7.3, Section 3.3.1.2, Table 62). Among subjects with low viral load
(100,000 c/mL) and receiving the TDF/FTC NRTI, response rates between the DTG and
RAL treatment groups again were similar (DTG 92%, RAL 91%).
Among subjects with high viral load (>100,000 c/mL) receiving ABC/3TC, response
rates were similar between the DTG and RAL treatment groups (DTG 81%, RAL 82%).
For subjects with viral load >100,000 c/mL receiving TDF/FTC, response rates were
more disparate (DTG 83%, RAL 71%) (m2.7.3, Section 3.3.1.2).
4.6.3.
ART-Experienced (INI-Naïve) Subjects
4.6.3.1.
Demographics and Baseline Characteristics
The study population was very diverse in both race and gender, with 42% African
American / African heritage and 32% female subjects. Of the 230 women entered in the
study, 138 (60%) were enrolled in countries outside of North America and Europe (Data
Source: ING111762 Week 24 CSR Table 6.23). The majority of non-white subjects were
enrolled in North America (44%) and non-European countries (52%). The median age of
the mITT-E population was 43.0 years (m2.7.3, Section 3.1.2).
Baseline characteristics were well balanced across the treatment groups. Study subjects
had relatively advanced HIV-1 disease with a median Baseline CD4 cell count of
200 cells/mm3 and almost half of the study population having CDC Category C
Classification at entry. Subjects predominantly had HIV-1 subtype B (68%), but subjects
with a variety of subtypes were enrolled, including A1, AB, AE, AG, BF, C, CD,
complex, F, F1, and G (Data Source: ING111762 Week 24 CSR, Section 5.4).
Overall, subjects enrolled in this study had prior treatment with and resistance to a broad
range of ART (m2.7.3, Section 3.1.2, Table 30 and Table 31): 47% of subjects had
previously been exposed to drugs in three or more ART classes. Baseline resistance
testing indicated that overall, similar proportions of subjects had 2-class resistance
(364/715; 51%) versus resistance to three or more classes (351/715; 49%).
4.6.3.2.
Key Efficacy Endpoints
In ING111762 study, virologic suppression (HIV-1 RNA <50 c/mL) in the DTG arm
(79%) was statistically superior to the RAL arm (70%), based on the Week 24
prespecified analysis of outcomes of the FDA Snapshot (MSDF) algorithm (mITT-E
Population). This treatment difference was statistically significant in favor of DTG
(adjusted difference and 95% CI, +9.7% [+3.4%, +15.9%], p=0.003). This result is
supported by the Per-Protocol analysis where 81% and 72% of DTG and RAL subjects,
respectively, achieved plasma HIV-1 RNA <50 c/mL at Week 24 (treatment difference
and 95% CI +9.3% [+3.0%, +15.7%], Data Source: ING111762 Week 24 CSR
Table 7.2).
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There were fewer virologic nonresponders using the Snapshot (MSDF) algorithm through
Week 24 in the DTG group compared to the RAL group (DTG: 15%; RAL: 24%)
(m2.7.3, Section 3.2.2.1, Table 46).
The proportion of subjects with plasma HIV-1 RNA <50 c/mL using Snapshot (MSDF)
analysis for the mITT-E Population increased steeply in both treatment groups from
Baseline to Week 4, then tended to plateau starting at Week 8 through Week 24
(Figure 4).
Figure 4
ING111762 Week 24, Proportion (95% CI) of Subjects with Plasma
HIV-1 RNA <50 c/mL by Visit – Snapshot (MSDF) Analysis (mITT-E
Population)
Data Source: ING111762 Week 24 CSR Figure 7.1
Note: confidence intervals are derived using the normal approximation.
Mean and median CD4+ cell counts increased from Baseline to Week 24 in the DTG and
RAL groups. The mean changes in CD4+ cell count from Baseline were
+113.9 cells/mm3 in the DTG group and +105.8 cells/mm3 in the RAL group at 24 weeks
(m2.7.3, Section 3.2.2.2, Table 47).
HIV-associated conditions in subjects treated with DTG compared to RAL were assessed
over time by summaries of the incidence of post-Baseline HIV conditions, and by the
proportion of subjects with disease progression. There was a similar low incidence of
HIV associated conditions, excluding recurrences (DTG: 3%; RAL: 5%; Data Source:
ING111762 Week 24 CSR, Section 6.4). The number of subjects with HIV disease
progression was low (n=8 or 2% in each arm progressed to CDC Class C or death)
(m2.7.3, Section 3.2.2.2, Table 48). RAL had cases of progressions from a lower class to
Class C (n=3) and had 2 cases of progression to death; whereas the only progressions to
Class C for DTG were from Class C to New Class C.
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4.6.3.3.
Comparison of Principal Efficacy Results in Sub-populations
Higher response rates in the DTG vs. RAL arm were consistent across subgroups defined
by almost all clinical characteristics. The exceptions were age (50 years) and the use of
boosted darunavir, where RAL responses were comparable to DTG (m2.7.3,
Section 3.3.2).
Across stratification factors, the treatment difference between DTG and RAL was
maintained, with the exception of DRV use without primary PI mutations. In the RAL
arm, virologic response rates were higher in subjects who used DRV/RTV without
primary PI mutations (81% by Week 24) than in those who either did not use DRV/RTV
or used DRV/RTV in the setting of primary PI mutations. The difference in virologic
response rates between DTG and RAL were thus diminished in those subjects receiving
DRV/RTV without primary PI mutations. The treatment difference between DTG and
RAL were otherwise maintained across stratification factors including Baseline HIV-1
RNA ( and >50 000 c/mL) and by the number of fully active background agents as
measured by Baselins PSS (2 and <2) (m2.7.3, Section 3.3.2.2., Table 64). The treatment
differences in favor of DTG over RAL were maintained across key demographic
subgroups (including race and gender), with the exception of age (m2.7.3,
Section 3.3.2.1, Table 63). In subjects aged 50 years, the RAL virologic response rate
was comparable to the DTG treatment group (m2.7.3, Section 3.3.2, Table 63). The
treatment differences favoring DTG were consistent by HIV subtype as well (Clade B vs.
Clade C vs. Other).
4.6.4.
Treatment Emergent Resistance in INI-Naïve Subjects
A lower rate of confirmed virological failure with development of resistance mutations or
decreased susceptibility to any drugs in the regimen was observed in the DTG treatment
arms compared to EFV in ING114467 and RAL in ING113086 and ING111762.
Protocol defined virologic failure (PDVF) rates in ING113086 and ING114467 were low
and consistent for the DTG-containing regimens (5% and 4%, respectively), despite
stringent PDVF criteria (confirmed HIV-1 RNA 50 c/mL at or after Week 24).
In the ING111762 Week 24 analysis, treatment-experienced (INI-naive) subjects
receiving DTG were less likely to have genotypic or phenotypic evidence of treatmentemergent resistance at PDVF (confirmed plasma HIV-1 RNA levels ≥400 c/mL on or
after Week 24; full definition in ING111762 Week 24 CSR, Section 7.1). In a prespecified analysis, there was a statistically significant difference in favor of DTG for the
proportion of mITT-E subjects harboring virus with evidence of INI Resistance by
Week 24 (DTG: 2/354 (0.6%); RAL: 10/361(2.8%); p=0.016).
Across the treatment-naive studies, no subjects on DTG treatment arms developed
clinically relevant INI resistance mutations, but subjects on comparator agents (RAL,
EFV) developed clinically relevant resistance mutations to these third agents. In
ING111762, there were two subjects in the DTG arm with emergent integrase-defined
substitutions. Both had experienced virologic rebound instead of non-response, had no
defined integrase resistance substitutions at Baseline, and acquired a substitution at R263
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Module 2.5 Clinical Overview
in the integrase open reading frame. In each case the DTG fold change was <2, as was
the maximum RAL fold change. Neither of these subjects with emergent substitutions at
R263 had RAL-associated secondary mutations at Baseline.
Furthermore, no mutations were noted to background NRTI (ART-naive studies) with
50 mg DTG-based regimens in comparison to Atripla or RAL-based regimens in
treatment-naïve subjects (Table 11). There were few examples of emergent resistance to
the background regimen at PDVF in the RAL arm (6/361) or the DTG arm (3/354) in
ART-experienced subjects (m2.7.2.4).
Table 11
Number of Protocol-Defined Virologic Failures (+/- Resistance to
integrase, NNRTI, BR) in ART-Naïve and ART-experienced Subjects
Protocol-defined Virologic Failure, n (%)
Genotype/phenotype Determinable, n (%)
INI-r Mutations Present
NNRTI-r Mutations Present
NRTI-r Mutations Present
ART-Naïve Adults
ING113086
ING114467
Week 48
Week 48
DTG 50 mg
RAL 400 mg
DTG 50 mg
EFV/TDF/FTC
once daily
BID
+ ABC/3TC
once daily
+ 2 NRTI
+ 2 NRTI
once daily
N=411
N=411
N=414
N=419
20 (5)
28 (7)
18 (4)
17 (4)
0
0
1/18 (6)a
0c
0
b
4/19 (21)
0
ART-Experienced Adults
ING111762
Week 24
DTG 50 mg
RAL 400 mg
once daily + BR
BID + BR
N=354
N=361
14 (4)
34 (9)
0
4 (24)d
1 (6)e
Protocol-defined Virologic Failure
Genotype/phenotype Determinable
INI Mutations Present
2/9 (22%)f
9/27 (33)
Data Source:
ING113086 Week 48 CSR Table 7.22, Table 12.2, Table 12.4, and Listing 43;
ING114467 Week 48 CSR Table 7.7, Table 12.2, Table 12.4, and Listing 47;
ING111762 Week 24 CSR Table 12.2 and Table 7.10.
R=resistance to integrase, NNRTI and BR
a. T97T/A, E138E/D, V151V/I, N155H
b. A62A/V (n=2), K65K/R, K70K/E, M184M/I, M184M/V, M184V
c. IN Substitution (n=1) E157Q/P at Week 24. DTG FC = 1.13; RAL FC = 1.26
d. K101E, K101K/N, K103N, G190G/A (2)
e. K65K/R
f. DTG (n=2): R263R/K FC=1.12 and R263K FC=1.93.
Supporting the Phase III finding in treatment-naïve subjects, in ING112276, no subjects
receiving the Phase III selected dose of DTG 50 mg once daily had a confirmed PDVF
(400 c/mL) through Week 96, and no virologic resistance was observed in this treatment
group. A low rate of confirmed PDVF was observed in the DTG 10 mg and 25 mg
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Module 2.5 Clinical Overview
treatment groups and the EFV treatment group. No subjects demonstrated integrase or
non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance at PDVF. The only
demonstrated virologic resistance mutation was a single case of M184V, consistent with
3TC/FTC resistance, in a subject receiving TDF/FTC and DTG 10 mg once daily
(m2.7.2.4).
4.6.5.
ART-Experienced (INI-Resistant) Subjects
4.6.5.1.
Demographics and Baseline Characteristics
Overall, in Studies ING112961 and ING112574 there was a good representation of
female (23% to 25%) and African heritage (21% to 27%) subjects in the study
population. There was no clinically meaningful difference between studies with respect to
gender or age; median age was about 47 years.
Subjects enrolled in Studies ING112961 and ING112574 had advanced HIV-1 disease,
were highly antiretroviral treatment experienced, with extensive multi-class viral drug
resistance at Baseline (m2.7.3, Table 38). There was a good representation of all major
integrase resistance pathways (m2.7.3, Table 40).
4.6.5.2.
Key Efficacy Endpoints
The primary efficacy endpoint in ING112574 comprised the change from Baseline in
plasma HIV-1 RNA at Day 8 and an assessment of the proportion of subjects with
<50 c/mL HIV-1 RNA at Week 24. Assessing all subjects who had the opportunity to
reach Week 24 before the data cut-off, 63% of this Week 24 ITT-E population (N=114)
achieved viral suppression to <50 c/mL based on the Snapshot algorithm (Data Source:
ING112574 Week 24 CSR Table 7.21). A comparable proportion (66/101, 65%) was
observed in this analysis for the Per Protocol population (Data Source: ING112574
Week 24 CSR Table 7.4). Additionally, a significant mean reduction of 1.43 log10 c/mL
HIV-1 RNA at Day 8 compared to Baseline was observed for the ITT-E population with
an equivalent reduction observed for the Per Protocol population (Table 12).
The primary endpoint in ING112961 was the proportion of subjects with Day 11 plasma
HIV-1 RNA <400 c/mL or reduced by at least 0.7 log10 c/mL compared to Baseline.
Twenty-three of 24 (96%, CI: 79%, 100%) subjects in Cohort II (those receiving the
50 mg BID dose chosen to be carried into Phase III studies) achieved the primary
endpoint (Data Source: ING112961 Cohort II Week 48 CSR Table 7.1).
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Table 12
ING112574: Mean Change from Baseline in Plasma HIV-1 RNA
log10c/mL at Day 8
(LOCFDB, ITT-E)
Baseline
Change from Baseline Day 8
(LOCFDB, Day 8 PP population)
Baseline
Change from Baseline Day 8
N
183
182b
Mean (SD)
4.26 (0.93)
-1.43 (0.61)
N
173
173
Mean (SD)
4.26 (0.93)
-1.43 (0.60)
95% CI
p-value a
(-1.52,-1.34)
<0.001
95% CI
p-value a
(-1.52,-1.34)
<0.001
Data Source: ING112574 Week 24 CSR Table 7.1 and Table 7.2
a. p-value is derived by testing the hypothesis of no change from Baseline at the two-sided 5%
significance level using Student's t-test.
b. One subject at no Day 8 visit
Note: Proportion of CFB 0.5 log10 c/mL or <400 c/mL at Day 8: 169/183 (92%).
There were similar increases in CD4+ cell counts over time across in these INI-resistant
subjects in ING112961 and ING112574. The median change from Baseline to Week 24
in CD4+ cells ranged from +65 to +79 cells/mm3 across both studies. At Week 48, the
median change from Baseline in CD4 cells was 100 cells/mm3 in ING112961.
Across the INI-resistant subjects in ING112961 and ING112574, there was a similar low
incidence of HIV-associated conditions (5% to 8% Data Source: ING112961 Cohort II
Week 48 CSR, Section 6.5: ING112574 Week 24 CSR, Section 6.5). Little disease
progression to CDC category C or death was observed in this salvage population, aligned
with the overall immune recovery (m2.7.3, Section 3.2.4.2, Table 55).
In ING112574, few subjects had non-Clade B virus [Clade A (n=1), AG (n=1), Complex
(n=2), D (n=2), G (n=1)]. Nevertheless, all 7 subjects harboring non-B clade viruses
experienced significant response to DTG, with a change from Baseline in plasma HIV-1
RNA at Day 8 ranging from -1.41 log10 c/mL to -2.30 log10 c/mL.
4.6.5.3.
Treatment Emergent Resistance in INI-resistant Subjects
In Cohort II of ING112961, 5/24 (21%) subjects met the definition for PDVF (confirmed
plasma HIV-1 RNA levels ≥400 c/mL on or after Week 16; full definition in ING112961
Cohort I Week 48/Cohort II Week 96 CSR, Section 4.5.1) through Week 24. No new
PDVFs were identified through Week 48, except for one subject with unconfirmed
suspected failure at Week 40 who withdrew from the study at Week 40 due to protocol
violation (non-compliance to Investigational Product). Of the 5 subjects with PDVF, no
subjects harboring viruses with the Y143 (n=1) or N155 (n=1) pathway at Baseline
experienced PDVF with treatment-emergent resistance. The remaining 3 subjects
harboring virus with Q148 +1 additional IN resistance associated mutations at Baseline
had further evolution in integrase, resulting in a virus with Q148H + >3 additional INI
associated resistance mutations; significant increases in DTG FC were observed for these
three subjects. At Day 11 and Week 24, no novel mutations were identified (all have
previously been described as RAL and/or EVG resistance-associated mutations).
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In ING112574, the PDVF (confirmed plasma HIV-1 RNA levels ≥400 c/mL on or after
Week 24; full definition in ING112574 Week 24 CSR, Section 4.9.6.6) rate through
Week 24 (26/114, 23%) was similar to ING112961. For these 26 subjects, 16 (62%) had
Q148 plus associated mutations detected in the Baseline IN genotype. Of the remaining
10 subjects, 2 subjects had N155H and 8 subjects did not have primary resistance
detected at Baseline. Thirteen subjects (50%) had treatment-emergent IN resistance at
the time point of virological failure. For 11/13 subjects with treatment-emergent IN
resistance detected at PDVF, a mutation at Q148 (along with associated mutations) was
seen at Baseline or was present on historical testing. The only mutations that were
identified have been previously described for the integrase class.
4.6.5.4.
Comparison of Primary Efficacy Results in Sub-populations
Data were not pooled from ING112961 and ING112574. Very few subjects in
ING112961 harbored virus with higher levels of resistance to DTG (n=3 in the Q148+2
group and n=0 for DTG FC 10). Therefore, pooling the studies would not add
substantially to the ability of data from ING112574 to identify subgroups at risk of nonresponse.
In ING112574, multivariate analyses of factors impacting response indicated Baseline
resistance to be the strongest predictor of response at both Day 8 and Week 24 (m2.7.3,
Section 3.3.3.1). At Day 8, both Baseline DTG FC and pre-specified IN mutation
category models fitted the Day 8 response equally well (m2.7.3, ING112574 Week 24
CSR, Section 6.2.1.2). However at Week 24 the lowest AIC value and best model fitness
was determined for the pre-specified IN mutation categories model (m2.7.3, ING112574
Week 24 CSR, Section 6.3.2.2). This indicated that Baseline integrase genotypic
resistance would be a better predictor of response to DTG than phenotypic DTG FC. In
addition to these multivariate analyses, formal analyses of antiviral response by Baseline
resistance (phenotypic or genotypic) to DTG was performed in an attempt to determine a
clinical phenotypic cut-off and a genotypic guidance for use of DTG in INI-resistant
adults individuals. These analyses are summarized below (m5.3.5.4 ING112574
Genotypic/Phenotypic Cut off Analysis Written Summary).
4.6.5.5.
Antiviral Activity of DTG by Baseline Resistance in INI-resistant
Subjects in ING112574
As per the FDA Guidance for Industry and the EMA guideline, analyses of antiviral
activity of DTG observed in ING112574 were conducted according to genotypic and/or
phenotypic resistance [FDA, 2007; EMA, 2009]. In this analysis, no precise phenotypic
FC cut-off could be defined to effectively predict antiviral activity at both Day 8 and
Week 24. Three integrase mutation groups could be derived and were found to correlate
with antiviral response: ‘No Q148 mutation’ (Y143, N155H, T66, and E92Q mutations or
historical evidence of INI resistance), ‘Q148+1’ (Q148H/K/R with one secondary
mutation [G140A/C/S, L74I, E138A/K/T]), and ‘Q148+2’ (Q148H/K/R with two or
three secondary mutations [G140A/C/S, L74I, E138A/K/T]).
More than 90% of subjects achieved full response (>1 log10 c/ml decline in HIV-1 RNA
or <50 c/mL HIV-1 RNA) at Day 8 in the group of subjects with 155/143/66/no primary
mutation detected. In subjects with Q148 mutations, virologic response at Day 8
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Module 2.5 Clinical Overview
decreased with increasing number of secondary mutations, however approximately half
of subjects with Q148+2 secondary mutations still achieved full response at Day 8
(Table 13).
Table 13
Virologic Response (Plasma HIV-1 RNA) at Day 8 by Derived
Baseline IN Resistance Mutation Group (Day 8 Virologic Outcome
Population, N=177)
INI Mutations at Baseline
Number of
Mean CFB (SD)c at Day 8
% >1 log10 Decline or
Subjects
<50 c/mL at Day 8
No Q148H/K/R mutationsa
122
-1.59 (0.51)
92%
Q148 + 1 secondary mutationb
35
-1.18 (0.52)
71%
20
-0.92 (0.81)
45%
Q148 + 2 secondary mutationsb
Data Source: m5.3.5.4 ING112574 Geno/Pheno Cut-Off Analyses for Annex B Table 12.106 and Table 12.110
a. CFB: Change from Baseline; SD: Standard deviation.
b. Includes Baseline primary IN resistance mutations N155H, Y143C/H/R, T66A, E92Q and primary mutation not
detected at Baseline.
c. G140A/C/S, E138A/K/T, L74I.
After the monotherapy phase (i.e., Day 8 visit), subjects were able to optimize their
background regimen, where possible; per protocol, subjects needed to have at least one
fully active agent to combine with DTG 50mg BID. Of the 114 subjects who completed
24 weeks on study or discontinued before data cutoff, 72 (63%) had <50 c/mL RNA at
Week 24 (Snapshot algorithm). In subjects with Q148 mutations, virologic response at
Week 24 decreased with increasing number of secondary mutations. Background overall
susceptibility score (OSS) was not associated with Week 24 response (Table 14),
highlighting the independent activity of DTG in driving sustained virologic responses in
this INI-resistant population.
Table 14
Number and % of Subjects with HIV-1 RNA <50 c/mL at Week 24 by
OSS of OBR and Derived IN Resistance Mutation Group (Snapshot)
(Week 24 Virologic Outcome Population, N=101)
Derived IN Mutation Group
OSS=0
OSS=1
OSS=2
OSS>2
Total
No Q148H/K/R mutationsa
2/2 (100%) 24/29 (83%) 21/28 (75%) 10/13 (77%) 57 (79%)
Q148 + 1 secondary mutationb
2/2 (100%)
3/7 (43%)
4/11 (36%)
9 (45%)
b
1/2
(50%)
0/7
1 (11%)
Q148 + 2 secondary mutations
Data Source: ING112574 Geno/Pheno Cut-Off Analyses for Annex B Table 12.107
a. Includes Baseline primary IN resistance mutations N155H, Y143C/H/R, T66A, and primary mutation not detected.
b. G140A/C/S, E138A/K/T, L74I.
Although reduced virologic responses were observed, HIV-1 infected adults harboring
viruses with Q148+ 2 secondary integrase inhibitor resistance mutations and/or high
level of DTG FC in IC50, this subgroup of subjects with INI resistance is small. In the
Screening population of ING112574, 26/269 (10%) of subjects harbored viruses with
Q148+ 2 secondary integrase inhibitor resistance mutations (ING112574 Week 24 CSR,
Table 96). In a separate analysis of approximately 700 unrelated clinical isolates with
raltegravir resistance, viruses with Q148+ 2 secondary integrase inhibitor resistance
mutations represented only 13% of the population and those with DTG FC >10
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Module 2.5 Clinical Overview
represented only 6% of the population (m2.7.2.4, Section 4.1.12.3.2). Additionally,
evaluation of ~1000 RAL- resistant isolates from
to
demonstrated a
decreasing proportion of Q148+≥2 pathway isolates over time (m2.7.2.4,
Section 4.1.12.3.3). Therefore, it is anticipated that a minority of patients will harbor
virus with Q148+2 and thus, DTG dosed at 50 mg twice daily will be efficacious in the
majority of the viral population in INI-resistant patients.
4.7.
Efficacy Conclusions
In treatment-naïve, HIV-infected adult subjects, DTG 50 mg once daily was shown to be
an efficacious dose, and non-inferior to RAL in combination with a background regimen
with dual NRTIs. When used in combination with ABC/3TC, DTG was shown to be
superior to Atripla (EFV/TDF/FTC), a result driven by better tolerability of the DTGbased regimen.
In treatment-experienced, HIV-infected adult subjects naïve to INIs, DTG 50 mg once
daily was shown to be efficacious, and was associated with a statistically greater response
rate when compared to RAL in combination with up to a 2-drug, investigator-selected
background regimen.
In treatment-experienced, INI-resistant adult subjects, DTG 50 mg twice daily was shown
to have antiviral activity in short-term functional monotherapy in 2 studies (one Phase IIb
and one Phase III) and was shown to be efficacious to 24 weeks in combination with
investigator-selected optimized background regimen, despite the limited activity of
available OBR. This supports the use of this dose in combination with other
antiretroviral therapy in treatment-experienced, INI-resistant adults.
DTG 50 mg once daily has a higher barrier to resistance in INI-naive patients, as
demonstrated in the treatment-experienced (INI-naive) study ING111762 where
significantly fewer virologic failures and significantly fewer subjects with INI resistance
were observed when compared with RAL. Data from two studies (ING113086 and
ING114467) including over 1600 treatment-naive patients are also supportive of DTG’s
higher barrier to resistance, given that no subjects on the DTG regimen developed
resistance to either the INI or the background NRTIs, whereas resistance to both the third
agent and the background NRTIs was observed in both the RAL and EFV-based
comparator arms.
Increases in CD4+ cell counts were observed for subjects receiving DTG-containing
regimens across all patient populations that were evaluated in the Phase II and III
program. These CD4 cell count increases were similar in comparison with RAL in
treatment-naïve and treatment-experienced subjects and were greater than those observed
with EFV-containing regimens in treatment-naïve subjects.
There was no evidence of a diminished response to DTG in specific patient subgroups,
such as gender, age (< or 50 years), race, level of immunosuppression (low CD4 cell
counts or CDC Category C). However, there are limited data in INI-naïve subjects aged
65 (n=27).
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As shown in in vitro studies, DTG was highly active with broad activity against all HIV-1
and HIV-2 isolates tested. No difference in virologic response by HIV-1 Clade (or
isolate) was observed in a large, international Phase III study (ING111762) in treatmentexperienced subjects. A limited number of non-B clade viruses were included in the
other Phase III studies, but no differences in protocol-defined virologic failure were noted
in subjects harboring non-B viruses in the treatment-naïve and INI-resistant studies.
5.
OVERVIEW OF SAFETY
5.1.
Introduction
Safety data supporting the use of DTG in the treatment of HIV infection has been
collected from 30 Phase I, 4 Phase II, 7 Phase III/ IIIb clinical trials, as well as a
compassionate use and an expanded access program. A full listing of individual studies
and study descriptions are provided in m2.7.4, Sections 1.1.3 and 1.1.4.
Within this safety section, the study results are presented in the following groupings, and
are also analyzed and presented in the same groupings within the Integrated Safety
Summary (m5.3.5.3) and the Clinical Summary of Safety (m2.7.4):

Completed clinical pharmacology studies: includes Phase I studies in healthy adult
volunteers and a Phase IIa study in ART-naïve HIV- infected adults (collective
safety data are presented in Section 5.4).

Pediatric subjects (INI-naïve): ING112578 (P1093)

ART-naïve adult subjects: ING112276, ING113086, and ING114467

ART-experienced (INI-naïve) adult subjects: ING111762

ART-experienced (INI-resistant) adult subjects: ING112961 and ING112574
No additional safety issues have been identified in ongoing studies. Additional detail
related to safety results of ongoing studies is presented in m2.7.4.
5.1.1.
Data Cut-off Dates
For the majority of the Phase IIb and IIIa/b studies, the safety data cut-off occurred prior
to the end of
with the exception of ING111762 (data cut-off:
).
Details of individual study cut-off dates are provided in m2.7.4, Section 1.1.2.
An additional cut-off date of
for deaths, other SAEs, and pregnancies
was applied to all ongoing studies for complete disclosure of safety information. These
data were not integrated, but are reported separately as listings in m5.3.5.3 and are
described under corresponding sections of the m2.7.4 as applicable.
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5.2.
Non-Clinical Data Relevant to Human Safety
The safety of DTG has been well characterized in a comprehensive battery of nonclinical
studies (m2.4, Nonclinical Overview). The overall nonclinical safety data are supportive
of the clinical use of DTG in the treatment of ART-naïve and ART-experienced (INInaïve) adults, and in INI-naïve children 12 to <18 years at the recommended dose of
1mg/kg once daily. For ART-experienced adults with INI resistance, the recommended
dose is 50 mg BID, also supported by the overall nonclinical safety data.
The effect of daily treatment with high doses of DTG has been evaluated in repeat oral
dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 39 weeks). The
primary effect of dolutegravir was gastrointestinal intolerance or irritation in rats and
monkeys at doses that produce systemic exposures approximately 32 and 1.2 times the 50
mg human clinical exposure based on AUC, respectively. Because GI intolerance is
considered to be due to local drug administration, mg/kg or mg/m2 metrics are
appropriate determinates of safety cover for this toxicity. GI intolerance in monkeys
occurred at 30 times the human mg/kg equivalent dose (based on 50 kg human), and 10.5
times the human mg/m2 equivalent dose for a total daily clinical dose of 50 mg.
The overall nonclinical reproductive and developmental toxicity profile for DTG in rats
and rabbits suggests that DTG is not teratogenic and has a low potential for fetal risk.
DTG showed no genotoxic risk as assessed in a standard battery of in vitro and in vivo
genotoxicity studies. An assessment of the route of synthesis showed no impurities,
intermediates, solvents or other agents that may suggest a genotoxic risk. Overall, there
is not believed to be a genotoxicity risk with DTG drug substance.
DTG has also shown no carcinogenic potential in two carcinogenicity studies (standard 2year mouse and rat studies).
In summary, the toxic potential of DTG has been well characterized in a comprehensive
nonclinical development program. These data are considered adequate to support the
proposed clinical use as a treatment of HIV.
5.3.
Exposure in the Clinical Development Program
See m2.7.4, Section 1.2 for full presentation of exposure data.
As of the
analysis cut-off date, a total of 2663 subjects (2026
HIV-infected and 637 healthy) have been exposed to at least one dose of DTG in the
entire clinical development program for this product. This total comprises:

526 healthy subjects and HIV-infected subjects from the Integrated Clinical
Pharmacology Studies Analysis (Data Source: CPM Table 1)

1,571 HIV-infected subjects from the Phase IIb and Phase III studies (Data Source:
ISO Table 2.501, Table 2.502, and Table 2.503)
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
139 adult healthy subjects from the five additional Phase I studies that were ongoing
at data cut-off date for the Integrated Clinical Pharmacology Studies Analysis (i.e.,
ING113125, ING115697, ING115465, ING116915, and ING114580)

284 HIV-infected subjects who received at least one dose of DTG as part of ongoing
Phase IIIb clinical trials (ING114915, ING116070 and ING116529), which were all
fully enrolled by

110 HIV-infected adult subjects received DTG up to
through the
ongoing compassionate use program (ING115502 and ING114916), which is still
enrolling patients

33 adolescents and children in the ongoing pediatric study ING112578 (P1093) have
been exposed to DTG to the same data lock point; this study is also still enrolling
patients.
5.4.
Safety in Clinical Pharmacology Studies
Data is presented in this safety summary using three “dosing periods”, in which treatment
is combined regardless of dose and duration: Placebo, DTG alone, and DTG with
combination drug. As such, subjects who may have been exposed to both PBO and DTG
could have AEs in both dosing periods.
5.4.1.
Frequently Reported AEs
Overall there were relatively fewer AEs reported from the clinical pharmacology studies
than the Phase IIb/III studies (m2.7.4, Section 5.6.2, Table 79). The most frequently
reported AEs from healthy subjects receiving DTG in the clinical pharmacology studies
were headache (n=75 [14%]), nausea (n=32 [6%]), dizziness (n=22 [4%]) and diarrhea
(21 [4%]), which were similar to observations from the Phase IIb/III studies in HIVinfected adults (m2.7.4, Section 2.1.1.1.1 and Section 2.1.1.1.2).
While not frequent, reports of dizziness were observed in the DTG treatment groups and
not for placebo. There were 11 subjects who experienced ocular icterus in the “all DTG”
group. All 11 of these events were in the atazanavir drug interaction study (ING111854).
None of the subjects experienced this event while on DTG alone. Of the most common
AEs reported in at least 5% in any analysis group, only headache (14% vs. 3%) and
nausea (6% vs. 3%) were reported more frequently in subjects dosed with DTG than
those receiving placebo (m2.7.4, Section 5.6.2, Table 79).
5.4.2.
Deaths
No deaths were reported in any of the completed clinical pharmacology studies.
5.4.3.
Non-Fatal Serious Adverse Events
There were two SAEs reported from the clinical pharmacology studies (m2.7.4,
Section 2.1.3.4). One subject had a manic episode which was considered unrelated to
DTG in ING112941, and another subject in ING113099 had a suspected rifamycin
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hypersensitivity syndrome while receiving rifabutin and DTG (event was considered
related to study drugs).
5.4.4.
Adverse Events Leading to Withdrawal
Based on the clinical pharmacology integrated analysis, there were 12 subjects (12/559,
2%) who had AEs that led to discontinuation of study drug. There were no safety trends
noted leading to discontinuation across the clinical pharmacology studies.
Study ING113096 was the only study that had more than two subjects who withdrew due
to an AE. This was a drug interaction study with tipranavir/ritonavir, and 4/18 subjects
developed alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
elevations that resulted in the permanent discontinuation of investigational product and
withdrawal from the study. These elevations occurred in subjects receiving TPV/RTV
500/200 mg or DTG 50 mg + TPV/RTV 500/200 mg. In all four subjects, the increase in
ALT and AST began during dosing of TPV/RTV alone (Period 2), though 2 subjects
were withdrawn after the ALT continued to increase early in Period 3 (DTG +
TPV/RTV).
5.4.5.
Clinical Laboratory Evaluations and Vital Signs
No trends were noted during the conduct of the Phase I/IIa studies to suggest DTG has a
clinically significant effect on clinical chemistries (the exception of creatinine noted
below), hematological parameters, or vital signs.
5.4.5.1.
Hepatobiliary Adverse Events
No subject in the clinical pharmacology studies met criteria for drug induced liver injury
(DILI) defined as ALT and/or AST >3 times ULN and total bilirubin >1.5 times the
ULN.
Analysis of liver chemistries (Alkaline phosphatase, ALT, AST, total and direct bilirubin)
demonstrated no pattern of difference from placebo subjects and those receiving DTG
(alone or with other drugs), with the exception of increased rates of increased bilirubin
seen in the DTG and atazanavir drug interaction study during ATV administration and
increased rates of liver enzyme elevations in the DTG and TPV/RTV drug interaction
study in subjects during TPV/RTV administration (see m2.7.4, Section 5.6.7).
5.4.5.2.
Renal Adverse Events
A small, reversible increase in creatinine of approximately 0.11 mg/dL for subjects
receiving DTG was observed; this was approximately a 10% increase (versus a zero
increase in the placebo subjects). Occasional increases in both DTG and placebo subjects
were observed for trace proteinuria, with few subjects on DTG increasing one level (from
trace to 1+). There were no AEs of renal disorders reported in the integrated analysis of
safety in clinical pharmacology studies. Equivalent data from Phase IIb/III in HIV
infected patients are presented, and the clinical implications are discussed, in
Section 5.6.6.3.
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Study ING114819 was a dedicated study to assess the effect of DTG on renal plasma
flow and glomerular filtration rate (GFR). The results indicated that serum creatinine
increased, and hence, calculated creatinine clearance decreased in subjects receiving
DTG 50 mg once daily and twice daily. DTG at 50 mg once daily and 50 mg BID had no
significant effect on GFR compared to placebo over 14 days based on iohexol clearance.
In addition, neither treatment significantly changed para-aminohippurate (PAH)
clearance clearance (See m2.7.2 Section 2.1.5.3 for details).
5.4.6.
Cardiac Evaluation
In study ING111856, a single supra-therapeutic dose of DTG (250 mg) had no significant
effect on cardiac repolarization in a population of 42 healthy subjects, when compared to
moxifloxacin (400 mg; active control) or placebo. In this study, with demonstrated
ability to detect small effects, the upper bound of the two-sided 90% confidence interval
for the largest placebo adjusted, baseline-corrected QTcF was below 10 ms, the threshold
for regulatory concern. Since the study had adequate sensitivity to detect a positive QT
effect with moxifloxacin, it is concluded that this study was valid (See m2.7.4
Section 2.1.5.6.3 for details).
More generally in the 26 completed clinical pharmacology studies, there were only
singular reports of arrhythmia and supraventricular tachycardia in the subjects receiving
DTG alone. No significant ECG findings were reported. No syncope was reported.
5.5.
Safety in Pediatrics - ING112578 (P1093)
Limited safety data are available from an ongoing study in the pediatric population and
are described herein from 10 adolescent (12 to <18 years of age) subjects receiving at
least 24 weeks of DTG once daily in combination with an investigator-selected,
optimized background regimen in ING112578. Nine of 10 subjects in the pediatric
population received a DTG 50 mg once daily dose, and 1 pediatric subject, weighing
<40 kg, received DTG 35 mg once daily (~1 mg/kg dosing).
Nine of 10 subjects reported a clinical AE; the AEs reported in more than 1 subject
included cough, lymphadenopathy, and sinus congestion. All AEs were reported as
Grade 1 or 2 (mild or moderate) in intensity. No AEs were deemed related to study drug
by the reporting investigators. No deaths, non-fatal SAEs, or withdrawals due to AEs
have been reported to date in this ongoing pediatric study. Adverse events of special
interest for the DTG development program (as defined in m2.7.4 Section 2.1.5), were
rarely reported from this cohort of subjects, with only single episodes of rash, diarrhea
and nausea reported.
Clinical chemistry abnormalities were reported by 9/10 (90%) subjects. Minimal
absolute changes from Baseline were observed; none were serious, deemed clinically
significant, or considered related to DTG by the investigator. No hematology
abnormalities were reported.
No subjects met liver stopping criteria, nor did any subjects have ALT elevations 3X
ULN. One Grade 3 asymptomatic elevated lipase was reported at Day 344 (Week 48)
which was not considered related to DTG. One subject had a Grade 1 increase in CPK.
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Similar to observations in adult subjects, adolescent subjects had small increases in
creatinine that appeared at Week 2 and remained stable to Week 24, when an increase in
the mean, but not the range, was observed. Only 1 subject had a treatment-emergent
change in urine dipstick protein analysis, with trace amounts present at Week 24 (with
negative protein at Baseline).
No clinically significant changes in diastolic or systolic blood pressure, respiratory or
pulse rates, or temperature were noted.
5.6.
Safety in Phase II and III Studies
5.6.1.
Safety Population for Phase II and III Studies
The Safety population used for the safety analyses consists of all subjects who received at
least one dose of investigational product. This population is described in m2.7.4,
Section 1.1.4.
For the pivotal studies, 2557 subjects are included: 1182 subjects received DTG once
daily, 183 subjects received DTG twice daily and 1192 subjects received comparator
drug.
A total of 980 subjects in the ART-naïve population (ING112276, ING113086, and
ING114467) and 357 subjects in the adult ART-experienced (INI-naïve) population
(ING111762) received a DTG-containing regimen (DTG once daily, DTG 50 mg once
daily + ABC/3TC). The majority of these subjects were still ongoing at the time of this
analysis (87%). In the Phase III studies, patient populations with a broad set of Baseline
characteristics were enrolled as follows:

In ING113086, 822 HIV-1 infected, ART-naïve adults were randomized and
received at least one dose of either DTG 50 mg once daily or RAL 400 mg twice
daily. At Baseline, median patient age was 36 years, 14% were female, 15% nonwhite, 12% had hepatitis B and/or C co-infection and <1% were CDC Class C, these
characteristics were similar between treatment groups.
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
In ING114467, 833 HIV-1 infected, ART-naive adults were randomized and
received at least one dose of DTG 50 mg once daily + ABC/3TC or EFV/TDF/FTC.
At Baseline, median patient age was 35 years, 16% were female, 32% non-white, 7%
had hepatitis C co-infection and 4% were CDC Class C, these characteristics were
similar between treatment groups.

In ING111762, 724 HIV-1 infected, ART-experienced (INI-naïve) adults were
randomized to receive either DTG 50 mg once daily or RAL 400 mg twice daily. At
Baseline, median age was 43 years, 32% were female, 51% non-white, 17% had
hepatitis B and/or C co-infection and 44% were CDC Class C.
A total of 234 ART-experienced (INI-resistant) subjects from ING112961 and
ING112574 received a DTG-containing regimen (DTG 50 mg once daily or DTG 50 mg
twice daily). Eighty-three percent of subjects were still ongoing at the time of this
analysis.

In ING112574, 183 subjects enrolled. At Baseline, median age was 48 years, 23%
were female, 29% non-white, and 20% had hepatitis B and/or C co-infection.
Median Baseline CD4 cell count was 140 cells/mm3, median duration of prior ART
was 13 years, and 56% were CDC Class C.
5.6.2.
Common Adverse Events
For ART-naïve and ART-experienced (INI-naïve) patients, the safety profile for DTG
50 mg once daily was comparable to RAL and generally favorable to Atripla and EFV.
The most frequently observed AEs across patient populations were diarrhea, nausea, and
headache, which were typically Grade 1 or 2 in severity, and typically did not lead to
discontinuation from studies. Gastrointestinal (GI) tolerability was comparable to RALand EFV-containing regimens. Few cases of hypersensitivity reaction and/or severe rash
were seen, and the rates of these events were comparable to or lower than RAL- and
EFV-containing regimens, respectively. No subjects were reported to have the most
serious forms of rash, such as Stevens-Johnson syndrome (SJS), toxic epidermal
necrolysis (TEN), or erythema multiforme (EM). The incidence of mild to moderate skin
reactions with DTG were comparable to or lower than observed with RAL- or EFVcontaining regimens, respectively. Finally, psychiatric and nervous system disorders
with DTG were comparable to RAL and favorable to both Atripla and EFV, in terms of
reporting rates, nature and severity. Overall, the AE profile was generally similar to RAL
and improved when compared with an EFV-containing regimen.
Treatment-experienced (INI-resistant) subjects were treated with DTG 50 mg twice daily
to ensure durable efficacy in subjects with baseline DTG resistance. As a group, this
population had more advanced HIV disease and received more concomitant ART.
Nevertheless, the AE profile was similar to that reported for treatment-naïve and
treatment-experienced (INI-naïve) subjects receiving DTG 50 mg once daily.
5.6.2.1.
Frequently Reported Adverse Events
Details of frequently reported AEs are provided in m2.7.4, Section 2.1.1.
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5.6.2.1.1.
ART-Naïve Adult Subjects
Diarrhea, nasopharyngitis, nausea, headache, and fatigue were the most commonly
reported clinical AEs and occurred at similar rates across the treatment groups (see ISO
Table 2.17 for a full listing of AEs). Insomnia was observed at a significantly higher
frequency with DTG in ING114467. However, the incidence was lower than EFV in
ING112276 and similar to RAL in ING113086. In ING114467, insomnia events were
generally mild in intensity, with only one subject discontinuing on the DTG+ABC/3TC
arm (vs. two subjects discontinuing on the EFV/TDF/FTC arm). Data on insomnia are
further described in m2.7.4, Section 2.1.5.8.2. AE rates between DTG and RAL were
generally similar, and AEs such as dizziness, rash, and abnormal dreams occurred at
higher frequencies in the EFV and/or Atripla treatment groups. The majority of events
reported in DTG and comparator groups were considered Grade 1 or Grade 2 in intensity,
with few Grade 3 or Grade 4 AEs reported.
Table 15
Summary of Common Adverse Events by Frequency (in at Least 5%
of Subjects in the Combined DTG Group) – ART-Naïve Population
Preferred term
ING112276
DTG
EFV
once
600 mg
daily
once
+ 2 NRTI
daily
+ 2 NRTI
N=50
N=155
n (%)a
142 (92)
25 (16)
23 (15)
22 (14)
22 (14)
13 (8)
7 (5)
11 (7)
n (%)a
46 (92)
7 (14)
7 (14)
5 (10)
3 (6)
6 (12)
6 (12)
1 (2)
ING113086
DTG
RAL
50 mg
400 mg BID
once daily
+ 2 NRTI
+ 2 NRTI
ING114467
DTG 50 mg EFV/TDF/FTC
+ ABC/3TC
once daily
once daily
TOTAL
DTG
once
daily
N=411
N=411
N=414
N=419
n (%)a
343 (83)
49 (12)
60 (15)
53 (13)
53 (13)
22 (5)
20 (5)
29 (7)
n (%)a
346 (84)
51 (12)
54 (13)
54 (13)
49 (12)
18 (4)
19 (5)
26 (6)
n (%)a
369 (89)
72 (17)
59 (14)
62 (15)
55 (13)
64 (15)
54 (13)
36 (9)
n (%)a
387 (92)
75 (18)
57 (14)
60 (14)
56 (13)
43 (10)
50 (12)
43 (10)
N=980
n (%)a
854 (87)
146 (15)
142 (14)
137 (14)
130 (13)
99 (10)
81 (8)
76 (8)
24 (6)
18 (4)
18 (4)
22 (5)
8 (2)
37 (9)
24 (6)
23 (6)
23 (6)
30 (7)
148 (35)
29 (7)
26 (6)
22 (5)
72 (17)
68 (7)
59 (6)
55 (6)
55 (6)
45 (5)
18 (4)
20 (5)
20 (5)
23 (6)
15 (4)
17 (4)
51 (5)
46 (5)
Any event
Diarrhea
Nausea
Nasopharyngitis
Headache
Insomnia
Fatigue
Upper
respiratory tract
infection
Dizziness
8 (5)
11 (22)
23 (6)
Cough
15 (10)
2 (4)
20 (5)
Depression
11 (7)
6 (12)
21 (5)
Pyrexia
11 (7)
4 (8)
21 (5)
Abnormal
3 (2)
4 (8)
12 (3)
dreams
Bronchitis
9 (6)
5 (10)
22 (5)
Back pain
7 (5)
4 (8)
16 (4)
a. Number and percent of subjects with adverse event.
Data Source: ISO Table 2.17
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5.6.2.1.2.
ART-Experienced (INI-Naïve) Adult Subjects
The most commonly reported individual AEs among subjects receiving DTG were
diarrhea, upper respiratory tract infection, headache, nausea and cough, with no
appreciable difference between treatment groups (m2.7.4, Table 18). Overall, individual
AE rates between DTG and RAL were generally similar.
Table 16
Summary of Common Adverse Events by Frequency (in at least 5%
of Subjects in any Treatment Group– ART-Experienced, INI-Naïve
Population
Preferred term
Any event
Diarrhea
Upper respiratory tract infection
Headache
Nausea
Cough
Urinary tract infection
Influenza
Nasopharyngitis
Fatigue
Vomiting
Rash
Data Source: ISO Table 2.524
a. Number and percent of subjects with adverse event.
5.6.2.1.3.
DTG 50 mg
once daily + BR
N=357
n (%)a
265 (74)
72 (20)
38 (11)
31 (9)
26 (7)
29 (8)
26 (7)
21 (6)
21 (6)
15 (4)
17 (5)
18 (5)
RAL 400 mg
BID + BR
N=362
n (%)a
281 (78)
62 (17)
29 (8)
29 (8)
28 (8)
23 (6)
18 (5)
21 (6)
18 (5)
23 (6)
20 (6)
17 (5)
ART-Experienced (INI-Resistant) Adult Subjects
The most commonly reported individual AEs were diarrhea, bronchitis, nausea, headache
and pyrexia (Table 17). Diarrhea, nausea, and headache are further described under
m2.7.4, Section 2.1.5.5.3 and Section 2.1.5.7.3. The majority of events reported were
considered Grade 1 or Grade 2 in intensity, with few Grade 3 or Grade 4 AEs. In the
ART-experienced, (INI-resistant) studies, more Grade 3 events were reported (m2.7.4,
Section 2.1.1.1.3), but this patient population had more advanced HIV (m2.7.4,
Section 1.3.2.2.3) and a wide variety of concomitant antiretrovirals and other
concomitant medications, which likely contributed to this finding.
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Table 17
Summary of Common Adverse Events by Frequency (in at Least 5%
of Subjects in the Combined DTG Group) – INI-Resistant Population
Preferred term
ING112961
Cohort I
Cohort II
DTG 50 mg once daily DTG 50 mg BID
N=27a
N=24a
Any event
26 (96)
23 (96)
Diarrhea
5 (19)
9 (38)
Bronchitis
4 (15)
6 (25)
Headache
4 (15)
2 (8)
Pyrexia
4 (15)
5 (21)
Nausea
2 (7)
2 (8)
Cough
3 (11)
4 (17)
Fatigue
1 (4)
4 (17)
Insomnia
5 (19)
1 (4)
Nasopharyngitis
2 (7)
1 (4)
Asthenia
5 (19)
2 (8)
Injection site reaction
1 (4)
2 (8)
Upper respiratory tract infection
1 (4)
2 (8)
Rash
0
1 (4)
a. Number and percent of subjects with adverse event.
Data Source: ISO Table 2.18
5.6.2.2.
ING112574
DTG 50 mg
BID
N=183a
147 (80)
25 (14)
13 (7)
16 (9)
13 (7)
17 (9)
13 (7)
12 (7)
9 (5)
10 (5)
5 (3)
9 (5)
9 (5)
10 (5)
TOTAL
DTG
BID
N=207a
170 (82)
34 (16)
19 (9)
18 (9)
18 (9)
19 (9)
17 (8)
16 (8)
10 (5)
11 (5)
7 (3)
11 (5)
11 (5)
11 (5)
Labeling and Adverse Drug Reactions
Adverse reactions listed in the Company Reference Safety Information (RSI) and Local
Country Labeling include events that have been assessed as being at least possibly
causally related to dolutegravir.
Sponsor causality was by evaluation of the frequency and severity of AEs that were
considered by investigators to be related to DTG treatment. Study investigators were
obligated to assess the relationship between investigational product (IP) and the
occurrence of each AE/SAE. A ‘reasonable possibility’ of relatedness to IP is meant to
convey that there are facts/evidence or arguments to suggest a causal relationship, rather
than a relationship cannot be ruled out. The investigator was instructed to use clinical
judgment to determine the relationship. Alternative causes, such as natural history of the
underlying diseases, concomitant therapy, other risk factors, and the temporal
relationship of the event to the investigational product were to be considered and
investigated. The investigator is also instructed to consult the Investigator Brochure (IB)
and/or Product Information (for marketed products, which may be comparators or
included in a treatment regimen) in the determination of his/her assessment. For the
company RSI, and where it is required in Local Country Labeling that adverse events are
presented by System Organ Class and frequency, adverse events judged by the
investigator to be reasonably attributable to DTG, with a frequency of at least 1% in the
combined database of all DTG subjects (n=1571), were selected for inclusion in the label
and are presented below (Table 18).
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Table 18
Drug Related Adverse events with a frequency of 1% in Integrated
Safety Database
Preferred term
Total DTG
N=1571
n (%)
508 (32)
124 (8)
93 (6)
68 (4)
48 (3)
54 (3)
43 (3)
37 (2)
32 (2)
22 (1)
18 (1)
22 (1)
19 (1)
Any event
Nausea
Diarrhea
Headache
Dizziness
Insomnia
Fatigue
Abnormal dreams
Vomiting
Flatulence
Abdominal pain upper
Rash
Pruritus
Data Source: ISO Table 2.511
Events that occurred below the 1% threshold but where there was a reasonable possibility
of causal relationship to DTG treatment, including events that were indicative of typical
severe drug-induced adverse reactions (e.g., Hypersensitivity, hepatitis) were considered
for inclusion, independent of the incidence. Hypersensitivity and hepatitis were
considered possibly related and added to the Company RSI/Local Country Labeling.
Those events (e.g., abdominal pain and discomfort) related to an event of higher
frequency (e.g., upper abdominal pain) were also selected for inclusion.
Class label statements such as immune reconstitution syndrome were also included.
The frequency categories of events for the label were derived from the frequency of all
adverse events in the total DTG population (regardless of causality; Data Source: ISO
Table 2.508), not just the frequency of events considered to be at least possibly related by
the investigator (Table 18). These categories are defined according to MedDRA
convention, as follows:
Very common:
Common:
Uncommon:
1/10
1/100 to <1/10
1/1000 to <1/100.
Where adverse events are to be presented as a subset of data from clinical trials (e.g. US
Prescribing Information), events for inclusion were assessed by evaluation of the
frequency and severity of each AE considered by investigators to be related to DTG in
the four pivotal Phase III clinical trials. A cut-off was applied to Grade 2 to 4 events with
a frequency of 2% of subjects in any treatment arm within these four studies.
Laboratory abnormalities with a worsening grade from baseline in 2% (for Grades 3 to 4
combined) were provided where required.
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5.6.2.3.
Supportive PK/PD Safety Analyses
A summary of the exposure response relationship for safety endpoints from the
treatment-naïve and treatment-experienced populations is provided in m2.7.2,
Section 3.4.4. No association was observed between DTG exposure and the most
frequently reported AEs or specific lab abnormalities (e.g., ALT). However, correlations
between DTG C0 and change from Baseline in total bilirubin and serum creatinine were
observed, which were likely due to competition between DTG and unconjugated bilirubin
for UGT1A1 and an expected effect of DTG due to inhibition of OCT2, respectively.
5.6.3.
Deaths
A complete discussion concerning deaths in the dolutegravir clinical development
program can be found in m2.7.4, Section 2.1.2.
As of the
submission cut-off date, there were 16 deaths reported across
the DTG clinical studies and compassionate use program. Six deaths were reported in the
pivotal and supporting clinical trials investigating the ART-naïve population (3 on DTG
50 mg once daily, 1 on RAL and 2 on Atripla) and two in the ART-experienced (INI
naïve) population (both on RAL). Four deaths (2 receiving DTG 50 mg once daily and 2
receiving DTG 50 mg BID) were reported in the pivotal and supporting clinical trials
investigating the ART-experienced (INI-resistant) population. Four deaths were reported
in other ongoing studies (ING116529) and the compassionate use program (ING115502)
in subjects receiving DTG 50 mg BID.
None of the deaths on DTG were considered related to study drug. Deaths were
generally due to comorbidities seen in HIV-infected patients.
5.6.4.
Serious Adverse Events
No trends in SAEs were noted across the patient populations assessed in the clinical
program. The only SAEs reported consistently across the clinical program were
pneumonia and suicidal ideation or attempt, but these events were reported in both DTG
and comparator treatments and are more frequently observed in HIV-infected patients
than in the general population. Suicide is discussed further in m2.7.4 Section 2.1.5.8
[Jia, 2012]. The definition of a Serious Adverse Event and details of the reported SAEs
are provided in m2.7.4, Section 2.1.3.
5.6.4.1.
ART-Naïve Adult Subjects
The rate of subjects developing at least one SAE at the time of data cut-off for this
analysis was low and similar between treatment groups (Table 19).
With the exception of suicide attempt, depression, and neurosyphilis in the EFV group
(which were reported in 1 subject each in ING112276), all other individually reported
SAE preferred terms had a reporting rate of <1% across all treatment groups.
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Table 19
Preferred term
Summary of Serious Adverse Events in at Least Two Subjects in the
Combined DTG Group – ART-Naive Population
ING112276
DTG
EFV
once
600 mg
daily + 2
once
NRTI
daily + 2
NRTI
N=155
N=50
Any event
16 (10)
7 (14)
Suicide attempt
0
1 (2)
Drug hypersensitivity
0
0
Pneumonia
1 (<1)
0
Appendicitis
0
0
Neurosyphilis
0
1 (2)
Syphilis
0
0
Foot fracture
1 (<1)
0
Intentional overdose
0
0
Humerus fracture
1 (<1)
0
Road traffic accident
1 (<1)
0
Pyrexia
1 (<1)
0
Osteoarthritis
0
0
Data Source: ISO Table 2.39
ING113086
DTG
RAL
50 mg
400 mg
once daily
BID
+ 2 NRTI
+ 2 NRTI
N=411
33 (8)
2 (<1)
3 (<1)
0
1 (<1)
1 (<1)
0
0
0
0
0
0
1 (<1)
ING114467
DTG 50 mg EFV/TDF/FTC
+ ABC/3TC
once daily
once daily
N=411
36 (9)
3 (<1)
0
2 (<1)
3 (<1)
0
0
0
1 (<1)
0
0
1 (<1)
0
N=414
37 (9)
2 (<1)
1 (<1)
2 (<1)
1 (<1)
1 (<1)
2 (<1)
1 (<1)
2 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
N=419
35 (8)
1 (<1)
0
2 (<1)
0
0
0
1 (<1)
0
0
0
0
0
TOTAL
DTG
once
daily
N=980
86 (9)
4 (<1)
4 (<1)
3 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
Few SAEs were considered reasonably attributable to IP by reporting investigators across
treatment groups, with no emerging trends apparent for DTG from these data.
5.6.4.2.
ART-Experienced (INI-Naïve) Adult Subjects
No patterns were observed as all SAEs were reported in 1% of subjects in each
treatment group (Table 20).
Table 20
Summary of Serious Adverse Events in at least Two Subjects in any
treatment group – ART-Experienced, INI- Naïve Population
Preferred term
DTG 50 mg
once daily + BR
N=357
n (%)
28 (8)
2 (<1)
0
3 (<1)
2 (<1)
2 (<1)
2 (<1)
0
0
0
Any event
Pneumonia
Post operative wound
Suicidal ideation
Alcohol withdrawal syndrome
Depression
Pancreatitis
Anemia
Dehydration
Cerebrovascular accident
Data Source: ING111762 Week 24 CSR Table 8.13
68
RAL 400 mg
BID + BR
N=362
n (%)
41 (11)
4 (1)
2 (<1)
1 (<1)
0
0
1 (<1)
2 (<1)
2 (<1)
2 (<1)
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Module 2.5 Clinical Overview
5.6.4.3.
ART-experienced (INI-Resistant) Adult Subjects
The reporting rate of subjects developing at least one SAE at the time of data cut-off for
this analysis was low for this treatment population with advanced HIV disease
(Table 21).
Table 21
Summary of Serious Adverse Events in at least Two Subjects in the
Combined DTG Group – INI-Resistant Population
Preferred term
Any event
Pneumonia
Gastroenteritis viral
Progressive multifocal leukoencephalopathy
Pyrexia
Dehydration
Pleural effusion
Coronary artery disease
Data Source: ISO Table 2.40
ING112961
Cohort I
Cohort II
DTG 50 mg
DTG 50 mg BID
once daily
N=27
N=24
6 (22)
8 (33)
0
0
0
1 (4)
0
0
0
0
0
0
0
0
0
2 (8)
ING112574
DTG 50 mg
BID
TOTAL
DTG
BID
N=183
27 (15)
4 (2)
1 (<1)
2 (1)
2 (1)
2 (1)
2 (1)
0
N=207
35 (17)
4 (2)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
2 (<1)
The most frequent individually reported SAE is pneumonia, otherwise all other SAEs had
a reporting rate of <1% across the two studies.
5.6.5.
Adverse Events Leading to Withdrawal
Few subjects receiving DTG developed AEs resulting in the permanent discontinuation
of IP and withdrawal from the study. There were no discernible trends for AEs leading to
withdrawal for the DTG or comparator treatment groups, as most of these events were
isolated cases in individual studies. However, withdrawals due to liver stopping criteria
were noted on DTG and comparator arms across the Phase IIb and III studies. For the
various study treatment populations, these events were frequently confounded by
concomitant medications, co-infection with hepatitis B or C virus, concomitant alcohol or
drug misuse, or a combination thereof.
Details of AEs leading to withdrawal are provided in m2.7.4, Section 2.1.4.1.
5.6.5.1.
ART-Naïve Adult Subjects
AEs leading to permanent discontinuation of IP and withdrawal from the study were
more commonly reported for the Atripla and EFV treatment groups, compared to DTG
and similar between the DTG and RAL treatment groups.
Subjects in Atripla and EFV treatment groups more frequently developed psychiatric
disorders resulting in withdrawal, and subjects receiving Atripla more frequently
developed nervous system disorders resulting in withdrawal, compared to other treatment
groups.
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Module 2.5 Clinical Overview
Table 22
Summary of Adverse Events Leading to Withdrawal/Permanent
Discontinuation of Investigational Product by System Organ Class –
ART-Naïve Population
System organ class
Preferred term
Any event
Skin and subcutaneous tissue
disorders
Psychiatric disorders
Immune system disorders
Infections and infestations
Injury, poisoning and procedural
complications
Gastrointestinal disorders
Investigations
Nervous system disorders
General disorders and
administration site conditions
Renal and urinary disorders
Hepatobiliary disorders
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps)
Cardiac disorders
Social circumstances
Metabolism and nutrition
disorders
Musculoskeletal and connective
tissue disorders
Respiratory, thoracic and
mediastinal disorders
Blood and lymphatic system
disorders
Ear and labyrinth disorders
Data Source: ISO Table 2.43
ING112276
DTG
EFV
once
600 mg
daily +
once
2 NRTI
daily+
2 NRTI
N=155
N=50
4 (3)
5 (10)
1 (<1)
0
ING113086
DTG
RAL
50 mg 400 mg
Once
BID + 2
Daily +
NRTI
2 NRTI
N=411
N=411
10 (2)
9 (2)
1 (<1)
1 (<1)
ING114467
DTG
EFV/TDF/FTC
50 mg +
Once Daily
ABC/3TC
Once
Daily
N=414
N=419
10 (2)
42 (10)
2 (<1)
8 (2)
0
0
0
1 (<1)
3 (6)
1 (2)
0
0
1 (<1)
1 (<1)
2 (<1)
0
2 (<1)
1 (<1)
3 (<1)
1 (<1)
2 (<1)
2 (<1)
1 (<1)
2 (<1)
15 (4)
3 (<1)
2 (<1)
0
3 (<1)
3 (<1)
3 (<1)
3 (<1)
1 (<1)
0
0
0
0
0
0
2 (4)
1 (<1)
2 (<1)
1 (<1)
1 (<1)
2 (<1)
2 (<1)
1 (<1)
0
0
0
0
0
8 (2)
1 (<1)
13 (3)
7 (2)
2 (<1)
2 (<1)
1 (<1)
1 (<1)
0
0
1 (<1)
0
0
0
0
1 (<1)
0
0
1 (<1)
0
1 (<1)
0
0
2 (<1)
0
1 (<1)
1 (<1)
1 (<1)
1 (<1)
0
0
0
0
0
0
1 (<1)
1 (<1)
0
0
0
0
0
0
0
0
0
2 (<1)
1 (<1)
1 (<1)
0
0
0
0
1 (<1)
0
1 (<1)
0
0
0
0
0
0
2 (<1)
0
0
0
0
1 (<1)
0
2 (<1)
0
0
0
0
0
0
3 (<1)
0
TOTAL
DTG
once
daily
N=980
24 (2)
4 (<1)
With the exception of suicide attempt, neurosyphilis and depression in the ING112276
EFV group, all other individually reported AE preferred terms resulting in withdrawal
had a reporting rate of <1% across all treatment groups.
5.6.5.2.
ART-Experienced (INI-Naïve) Adult Subjects
There were few AEs leading to discontinuation of investigational product in either group
and there were no discernible patterns of events (Table 23).
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Module 2.5 Clinical Overview
Table 23
Summary of Adverse Events Leading to Withdrawal/Permanent
Discontinuation of Investigational Product by System Organ Class –
ART-Experienced (INI- Naïve) Population
System organ class
Any event
Hepatobiliary disorders
Infections and infestations
Gastrointestinal disorders
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Renal and urinary disorders
Investigations
Blood and lymphatic system disorders
Immune system disorders
Metabolism and nutrition disorders
Musculoskeletal and connective tissue disorders
Psychiatric disorders
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Data Source: ING111762 Week 24 CSR Table 8.15
5.6.5.3.
DTG 50 mg
Once Daily + BR
N=357
n (%)
6 (2)
2 (<1)
1 (<1)
0
0
2 (<1)
1 (<1)
0
1 (<1)
0
1 (<1)
0
0
0
RAL 400 mg
BID + BR
N=362
n (%)
13 (4)
3 (<1)
4 (1)
4 (1)
3 (<1)
1 (<1)
1 (<1)
1 (<1)
0
1 (<1)
0
1 (<1)
1 (<1)
1 (<1)
ART-Experienced (INI-Resistant) Adult Subjects
Few subjects developed AEs resulting in the permanent discontinuation of IP and
withdrawal from the study. All individually reported AEs resulting in the permanent
discontinuation of IP and withdrawal from the study had a rate of <1%.
Table 24
Summary of Adverse Events Leading to Withdrawal/Permanent
Discontinuation of Investigational Product in at least Two Subjects
in any Treatment Group – ART-Experienced (INI-Resistant)
Population
System organ class
Preferred term
Any event
Investigations
Skin and subcutaneous tissue disorders
Blood and lymphatic system disorders
Nervous system disorders
Hepatobiliary disorders
Metabolism and nutrition disorders
Psychiatric disorders
Data Source: ISO Table 2.44
ING112961
Cohort I
Cohort II
DTG 50 mg
DTG 50 mg
Once Daily + BR
BID + BR
N=27
N=24
2 (7)
2 (8)
0
0
0
0
1 (4)
1 (4)
1 (4)
0
0
0
0
1 (4)
0
1 (4)
71
ING112574
DTG 50 mg
BID + BR
TOTAL
DTG 50 mg
BID
N=183
5 (3)
2 (1)
2 (1)
0
1 (<1)
1 (<1)
0
0
N=207
7 (3)
2 (<1)
2 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
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Module 2.5 Clinical Overview
5.6.6.
AEs of Special Interest
The AEs of Special Interest (AESI) have been determined for DTG based on pre-clinical
and/or clinical safety data for DTG, labeling and/or regulatory authority interest for
approved integrase inhibitors and/or the INI class, and/or regulatory authority
requirements. Details on the AEs of Special Interest section are included in m2.7.4,
Section 2.1.5.
5.6.6.1.
Hypersensitivity and Rash
Severe, potentially life-threatening, and fatal skin reactions, including cases of SJS and
TEN, and hypersensitivity reactions are listed events in the Local Country Prescribing
Information for the first marketed INI, RAL [Isentress US Package Insert, revised April
2012, Isentress EU Summary of Product Characteristics, 2012].
The ABC (600 mg)/3TC (300 mg) once daily FDC tablet was used in all of the three
supportive/pivotal Phase IIb/III clinical trials in ART-naïve subjects, either as:
randomized study medication (ING114467) or investigator-selected dual NRTI backbone
(ING112276 and ING113086). The most important risk associated with the ABC
component of the FDC is a well characterized drug-related hypersensitivity reaction
(HSR), which is generally manageable. HLA-B*5701 has been shown to be highly
associated with ABC HSR, and the practice of pre-therapy screening for and exclusion of
patients with HLA-B*5701 reduces the risk of HSR [EPZICOM US Prescribing
Information, 2012; KIVEXA EU Summary of Product Characteristics, 2011]. Thus,
screening for and exclusion of subjects with HLA-B*5701 was required for all subjects in
the DTG program who received (or had the potential to receive due to blinding) ABCcontaining products.
Drug hypersensitivity is about 100 times more common in HIV-1-infected patients than
in the general population [Carr, 2000] and skin rash is associated with many
antiretrovirals [NIA, 2012].
In the DTG clinical program, reporting rates for “Rash” of any grade were low for DTG,
comparable with RAL, and lower than observed for EFV/Atripla. Cases of HSR and/or
severe skin reactions with or without systemic involvement were rarely seen for DTG.
Reporting rates were comparable to RAL and less than observed for EFV/Atripla. Cases
reported for DTG and RAL were generally confounded by co-suspect medications that
were considered to have contributed to the event. With the exception of the Atripla
treatment group in ING114467, rash or hypersensitivity events leading to discontinuation
of IP and withdrawal of subjects from study have been infrequent.
No episodes of serious rash such as SJS, TEN or erythema multiforme have been
reported for the DTG development program to date.
There is no evidence for increased risk of rash with or without systemic symptoms with
either DTG 50 mg once daily in INI-naïve subjects or DTG 50 mg twice daily in INIresistant subjects. Due to identification of a case of HSR with organ dysfunction in a
treatment-naïve subject in ING113086 and additional confounded cases identified in
treatment-experienced subjects, labeling for DTG is proposed to reflect a warning about
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Module 2.5 Clinical Overview
hypersensitivity reactions, including monitoring for liver enzymes if HSR is observed for
a patient on DTG.
5.6.6.2.
Hepatobiliary Disorders
Non-clinical data suggested a possible, albeit low, risk for hepatobiliary toxicity with
DTG. Due to comorbidities (e.g., hepatitis B and C co-infection) and co-administered
medications (e.g., antiretrovirals) in HIV-infected patients, it is recommended to monitor
liver chemistries in the clinical setting; hepatitis has been described for other
antiretrovirals.
For treatment-naïve subjects, Week 48 data from ING113086 indicated that, overall, the
incidence of treatment emergent liver chemistry toxicities was similar between DTG and
RAL. Eleven subjects met liver stopping criteria, 7 for DTG (2%) and four for RAL
(<1%). Most of these cases were confounded by underlying diseases or concomitant
medications that are considered more likely than study drug to have caused these events.
From the ING114467 48 Week data, the incidence of treatment emergent liver chemistry
toxicities for DTG+ABC/3TC was lower than observed for the Atripla comparator arm,
and lower when compared to both the DTG and RAL treatment groups in ING113086.
For treatment-experienced subjects, safety data suggests no excess risk of hepatic toxicity
for DTG. In ING111762, excluding observations for HBV and/or HCV co-infected
subjects (described below), the incidence of liver chemistry elevations on DTG were
comparable to RAL, and in an advanced HIV population receiving multiple concomitant
medications in ING112574, the incidence of treatment emergent liver chemistry toxicities
for DTG 50 mg BID was comparable to DTG 50 mg once daily in ING111762 (less HBV
and/or HCV co-infected subjects).
In most cases where liver abnormalities have been noted across the development
program, the following circumstances have been present: the co-administered
antiretroviral treatment included drugs with well-described bilirubin or liver enzyme
elevations; and/or hepatitis virus co-infection was evident; and/or subjects had a medical
history of alcohol abuse.
For subjects with hepatitis B and/or C co-infection, immune reconstitution as a result of
HIV virologic and immunologic responses, along with inadequate therapy for hepatitis B
co-infected subjects, likely contributed to significant elevations in liver chemistries. As
several ART-experienced subjects were allowed to restart DTG or continued DTG
without progression of liver enzyme elevations, drug-induced liver injury in this setting
seems less likely in this patient population.
Eight subjects were identified across the program who were hepatitis B co-infected and
with clinically significant flares of liver chemistries and/or HBV IRIS: 2 subjects in
ING113086 (DTG: 1, RAL: 1), 1 subject in ING112574, and 5 subjects in ING111762.
(DTG: 5, RAL: 0). Of the cases identified on DTG, 5/7 were not on HBV active therapy
at the time of liver chemistry elevation and 5/7 had HBV active therapy discontinued at
the start of DTG therapy. All subjects had HIV virologic and immunologic responses to
DTG.
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Module 2.5 Clinical Overview
Subjects who were treatment-naive were not eligible to re-start study drugs due to wide
availability of other therapeutic options. Subjects who were treatment-experienced could
be considered for restart of DTG, after careful review of each case with the ViiV
Healthcare Safety and Labeling Committee. Three subjects (1 in ING112574, 2 in
ING111762) restarted or continued DTG after or in conjunction with the start of HBV
active therapy (e.g., TDF/FTC or entecavir). For all 3 of these cases, liver chemistries
have remained within normal limits after restart (or continuation of DTG). Therefore, if
subjects are not receiving HBV active therapy at the start of potent HIV therapy, there is
an increased risk for HBV IRIS or flare in the setting of HIV viral decline and
immunologic improvement. The improved efficacy noted for DTG for the entire
population in ING111762 may be contributing to higher rates of HBV-related IRIS in the
hepatitis co-infected population in this study.
For hepatitis C virus co-infected subjects, the risk for significant liver chemistry increases
in the setting of HIV virologic and immunologic responses does not appear as profound
as that identified for HBV, but HCV IRIS may also contribute to the findings across the
clinical program. Across all studies and patient populations, comparable rates of liver
chemistry elevations were noted in HCV co-infected subjects across treatment groups.
Across all patient populations, safety data supports the administration of DTG in HIVinfected patients co-infected with hepatitis B and/or hepatitis C, with awareness of the
need for appropriate HBV therapy and the possibility of HBV/HCV flares or IRIS after
the start of DTG therapy. The sponsor plans to include recommended measures to
manage the risk of HBV/HCV IRIS in the Warnings and Precautions Section in the
proposed labeling.
5.6.6.3.
Renal Function
Mild elevations of serum creatinine have been observed with DTG. These are related to a
likely benign effect on creatinine secretion via blockade of the OCT2 receptor, which is
responsible for tubular secretion of creatinine. In a Phase I study to assess renal
pharmacodynamic effects, DTG at 50 mg once daily and 50 mg BID had no significant
effect on GFR compared to placebo over 14 days based on iohexol clearance. In
addition, neither treatment significantly changed PAH clearance, a measure of effective
renal plasma flow.
Small increases in serum creatinine were observed on the DTG arms in each of the
Phase IIb and III studies (range 9.66 mol/L at Week 48 for the combined 50 mg once
daily dose in the ART naïve treatment population to 11.57 mol/L at Week 24 for the
combined 50 mg twice daily dose in ART- experienced [INI-naïve] treatment
population). These were evident from Week 1 but plateaued with no evidence of
subsequent increase. Smaller mean increases in serum creatinine (range 4.66 to
6.5 mol/L) were noted on RAL treatment arms in ING113086 and ING111762, and
declines in mean change from baseline values for creatinine (range -2.36 to -0.7 mol/L)
were observed on EFV-containing treatment regimens.
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Module 2.5 Clinical Overview
A low incidence of graded creatinine elevations has been observed on DTG, and no
Grade 3 to 4 toxicities have been observed in the 48 Week data from either ING113086
or ING114467. There were few subjects who developed acute renal failure accompanied
by Grade 3 or 4 creatinine elevations. These subjects participated in ING111762 or
ING112574 receiving DTG or RAL (ING111762 only), and all had confounding medical
conditions or medications that likely caused or contributed to the events.
Transient increases in urine protein by dipstick in a minority of subjects were noted in the
Phase IIb studies, prompting quantitative measures of urine albumin in Phase IIb and III
studies (albumin is the protein detected by the dipstick test). These changes were not
progressive in nature, were not associated with clinically significant changes for
individual subjects with respect to AEs, graded lab abnormalities or withdrawals, and
were not supported by more reliable, quantitative measures of albuminuria. Median
increases in spot urine albumin/creatinine values were comparable between DTG and
comparator treatment groups (RAL or EFV-containing regimens) and between DTG 50
mg BID and 50 mg once daily in the Phase III clinical studies. Importantly, tubular and
glomerular urine protein was evaluated in the Phase I study assessing the renal safety of
DTG, and no association between DTG dosing at 50 mg once daily or BID and
proteinuria was observed in this study.
Finally, DTG is unlikely to potentiate nephrotoxicity observed with tenofovir. DTG does
not increase serum concentrations of tenofovir, an antiretroviral known to be associated
with renal tubular toxicity. Importantly, the in vitro and in vivo evidence to date suggests
that DTG does not impact renal tubule transporters responsible for tenofovir elimination.
DTG’s effect on creatinine secretion is via OCT2, which affects cation transport into the
renal tubule. DTG has not been shown to affect the transport of anions. OAT1 (organic
anion transporter) and OAT3 are responsible for anion (e.g., tenofovir) transport into the
renal tubule. As serum tenofovir concentrations are not increased with co-administration
with DTG, OAT inhibition by DTG is highly unlikely. MRP2 and MRP4 are anion
transporters responsible for the transport of anions (e.g., tenofovir) from the renal tubule
to the urine, and DTG has been shown not to inhibit MRP2, which also makes inhibition
of MRP4 by DTG unlikely. Polymorphic MRP4 that decreases tenofovir renal clearance
by 15% also increases plasma tenofovir concentrations by 32% [Kiser, 2008], which was
not observed in the drug interaction study assessing the impact of DTG on tenofovir PK.
Based on these data, an interaction with tenofovir at the renal tubule is considered
unlikely.
In review of creatinine changes by NRTI backbone across the treatment-naïve studies, the
median and interquartile ranges of change over time were similar, with no evidence of
deterioration in the renal tolerability of DTG due to concomitant tenofovir (m2.7.4,
Section 2.1.5.3). Additionally, 6/346 (2%) of subjects receiving DTG + TDF/FTC and
20/634 (3%) of subjects receiving DTG + ABC/3TC had treatment-emergent Grade 1 or
2 creatinine elevations, and no subjects had treatment-emergent Grade 3 or 4 elevations
in creatinine on either NRTI backbone co-administered with DTG. Therefore, there is
currently no clinical evidence that DTG potentiates the nephrotoxicity observed with
tenofovir.
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5.6.6.4.
Gastrointestinal (GI) Disorders
As noted in Section 5.2, the primary effect of dolutegravir in nonclinical studies was
gastrointestinal intolerance or irritation. Additionally, gastrointestinal symptoms are
frequent adverse events with antiretroviral medications [DHHS, 2012]. As noted in
Section 5.6.2 diarrhea and nausea were some of the most frequently observed AEs across
patient populations, which were typically Grade 1 or 2 in severity and typically did not
lead to discontinuation from studies. Events indicative of general GI intolerance (i.e.,
diarrhea, nausea, vomiting, and abdominal pain AE preferred terms only and no
derivatives) with DTG 50 mg once daily were comparable to RAL- and EFV-containing
regimens in treatment-naïve and –experienced subjects. Additionally, the general GI
intolerance adverse event rate was comparable for INI-resistant subjects receiving DTG
50 mg BID and subjects receiving DTG 50 mg once daily.
Few cases of gastric or peptic ulcer disease were reported in treatment-naïve and INIresistant subjects and were typically related to concomitant medications (e.g., aspirin) or
medical conditions (Non-Hodgkin’s lymphoma). No cases of gastric ulcer or peptic ulcer
disease were reported in ART-experienced (INI-naïve) subjects. Adverse events
considered potentially indicative of GI ulcerative lesion as identified by Sponsor medical
review were rarely reported in any of the patient populations. Hemoglobin
concentrations also increased over time on DTG regimen, as would be expected from the
positive effects of ART.
Nonclinical evidence for GI toxicity with DTG thus did not translate into significant
findings in double blinded randomized clinical trials; a similar rate and nature of GI
events were reported for DTG compared to RAL and EFV, and there was no evidence for
an increased risk of GI ulcerative lesions.
5.6.6.5.
Musculoskeletal Disorders
CPK elevations in subjects receiving DTG in the ART-naïve population were comparable
to RAL and EFV-containing regimens. Most CPK elevations were asymptomatic and
investigators were able to confirm high degrees of physical activity preceding the CPK
elevations in the majority of cases. In the ART-experienced (INI-naïve) population, more
subjects receiving RAL reported musculoskeletal disorders versus those receiving DTG,
with fewer subjects on DTG experiencing Grade 3 or 4 events. The incidence of events
reported for the ART-experienced (INI-resistant) population was lower than in the INInaïve (ART-naïve and ART-experienced) population, despite the higher daily dose of
DTG. Finally, no cases of drug-related rhabdomyolysis have been reported on DTG
across the clinical program.
Therefore, no increased risk for clinically significant or serious musculoskeletal disorders
has been identified for DTG.
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Module 2.5 Clinical Overview
5.6.6.6.
Immune Reconstitution Inflammatory Syndrome (IRIS)
As detailed in m2.7.4, Section 2.1.5.9, for the Phase III clinical trials, potential IRIS cases
were reviewed and adjudicated by senior ViiV Healthcare physicians (ING113086) or the
Independent Data Monitoring Committee (IDMC; ING114467, ING111762,
ING112574). For the ART-naïve and INI-resistant patient populations, few cases of IRIS
were identified and incidence rates were similar between DTG 50 mg once daily and
comparator treatments or DTG 50 mg BID.
Based on medical adjudication of IRIS-like events in the ART-experienced (INI-naïve)
patient population in ING111762, subjects with hepatitis B or C co-infection receiving
DTG were at greater risk for HBV or HCV IRIS than those receiving RAL. For other
medical conditions frequently implicated in IRIS events, there was a low rate of IRIS
cases for both DTG and RAL.
5.6.6.7.
Other
No clinically significant safety findings were identified in the following AEs of special
interest (discussed in more detail in m2.7.4 Section 2.1.5):

Torsades de Pointe

Nervous System Disorders

Psychiatric Disorders Including Suicidality

Neoplasms, Benign, Malignant, and Unspecified (including Cysts and Polyps)

Cardiovascular Disorders
5.6.7.
Clinical Laboratory Evaluations
See m2.7.4, Section 3 for details of laboratory data.
5.6.7.1.
Clinical Chemistry
Details of Clinical Chemistry safety findings can be found in m2.7.4, Section 3.1.
ART-naïve adult subjects: The majority of subjects (80% to 94%) across all studies
and individual comparative arms had treatment emergent Graded clinical chemistry
toxicities. A small proportion, 12 to 15%, had Grade 3 to 4 toxicities and the incidence
was similar in all treatment groups across all the studies.
ART-experienced (INI-naïve) adult subjects: Similar to ART-naïve subjects, the
majority of DTG (82%) and RAL (86%) subjects had treatment-emergent graded
abnormalities. A small proportion (DTG: 15%, RAL: 16%) had Grade 3 to 4 toxicities.
ART-experienced (INI-resistant) adult subjects: Although a high proportion of
subjects (85%) had a post-Baseline graded change in clinical chemistry, the majority
were Grade 1 and Grade 2 with few Grade 3 to 4 events.
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Liver and renal findings are discussed in Section 5.6.6.1 and Section 5.6.6.3, and are
detailed in m2.7.4, Section 3.1.1, and Section 3.1.2, respectively. CPK results are
discussed in detail in m2.7.4, Section 3.1.3.
There was no evidence of a clinically significant impairment of the lipid profile by DTG
treatment in the Phase III studies. Changes in lipid parameters were generally small in
both treatment and comparator groups in INI-naïve study populations, and did not appear
to be adversely affected by the larger DTG 50 mg BID dose in the INI- resistant
populations.
5.6.7.2.
Hematology
Details of Hematology safety results can be found in m2.7.4, Section 3.2. There were no
clinically significant trends in treatment emergent hematology abnormalities across all
populations.
5.7.
Vital Signs
There were no clinically significant patterns of changes in vital signs (weight, heart rate,
systolic and diastolic blood pressure) across the studies (Phase I, II, and III).
5.8.
Electrocardiograms
No subjects had a QTcF >500 msec, and few subjects had change from Baseline in QTcF
or QTcB 60 msec. Additionally, few clinically significant ECG abnormalities were
reported, and no trends were observed in these abnormalities. ECGs are discussed in
Section 4.2 of m2.7.4.
In study ING111856 (m2.7.4, Section 2.1.5.6.3), DTG had no significant effect on
cardiac repolarization.
5.9.
Safety in Special Groups and Situations
The effect of intrinsic factors (i.e., gender, age, race, and hepatitis co-infection) and
extrinsic factors associated with the patient environment (i.e., the effect of food) are
discussed in m2.7.4 Sections 5.1 and 5.2, respectively, including the outcome of
applicable PK analyses.
In general, gender, age, and race did not significantly impact rates of AEs or laboratory
abnormalities reported across treatment groups. The representation of special groups
(i.e., women, African American/African heritage, age 50) allowed an analysis of safety
in these groups. Minor exceptions for gender were noted, such as a higher incidence of
vomiting in treatment-naïve women receiving DTG, and differences in laboratory
abnormalities in men and women, including more anemia in women and more ALT and
CPK increases in men. Minor exceptions were also noted for race, with more African
heritage, treatment-naïve subjects experiencing neutropenia; this is likely related to lower
neutrophil counts in this racial group. These differences were not considered treatmentlimiting.
Overall, the safety profile was similar across gender, age and race.
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5.10.
Pregnancies
No studies have been conducted with DTG in pregnant women, and pregnant women
were excluded from the DTG clinical studies. Pregnancy outcomes from female subjects
who became pregnant during the conduct of the Phase I to IIIb clinical studies and the
compassionate use program conducted with DTG to date, are presented in m2.7.4,
Section 5.4.
As of the
submission cut-off date, there were 27 pregnancies reported
across the DTG clinical studies and compassionate use program. Adverse outcomes have
been reported for four of these cases; one was ectopic (Atripla) and three (one each for
DTG, RAL and Atripla) resulted in spontaneous abortion (all between 5 and 12 weeks
gestation).
Reproductive toxicity is not considered to be a risk for DTG based on the non-clinical
and clinical findings to date.
5.11.
Withdrawal Effects, Abuse Potential, Overdose
No studies to investigate the potential for withdrawal and rebound effects, or the potential
for abuse or dependency with DTG have been performed. There is currently limited
experience with DTG overdose (i.e., any dose above 50 mg once daily in INI-naïve
adults; 50 mg BID in INI-resistant adults; and 1 mg/kg once daily with a maximum daily
dose of 50 mg in INI-naïve pediatric patients). Single daily doses up to 250 mg have
been administered orally to healthy subjects in clinical pharmacology study ING111856;
with no unexpected adverse effects reported. The INI class of compounds has no known
drug abuse potential. There are no data suggesting that DTG has the potential to imply
illicit use, abuse, or dependency on DTG. In nonclinical studies, no effects related to
DTG administration on central and peripheral nervous system or body temperature were
noted following dosing withdrawal. There is no clinical evidence to suggest withdrawal
or rebound effects of DTG. There have been no studies to investigate the effect of DTG
on driving performance or the ability to operate machinery.
5.12.
Post-Marketing Experience
Dolutegravir is not marketed in any country in the world. All safety data included in this
submission are from clinical studies conducted with dolutegravir.
5.13.
Safety Conclusions
Overall the safety profile for DTG, combined with the efficacy and virology profile,
supports a favorable risk/benefit compared to other ARVs.
Based on limited available data in children and adolescents (12 to less than 18 years of
age), there were no additional types of adverse reactions beyond those observed in the
adult population.
The safety profile for DTG 50 mg once daily in INI-naïve subjects was comparable to
RAL and generally favorable compared to Atripla and EFV.
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DTG dosed 50 mg twice daily in highly ART-experienced (INI-resistant) subjects with
advanced HIV disease resulted in a safety profile comparable to DTG 50 mg once daily
in both ART-naïve and ART-experienced (INI-naïve) subjects, despite the advanced
stage of disease and multiple concomitant medications.
Hypersensitivity is an uncommon but recognized risk for ART containing DTG
regardless of dose or treatment population.
Cumulative data suggests a hepatic safety profile for DTG that is comparable to RAL or
EFV.
Safety and pharmacokinetic data supports the administration of DTG in HIV-infected
patients co-infected with hepatitis B virus and/or hepatitis C virus.

ART-experienced subjects with HBV co-infection receiving DTG were noted to have
significant liver chemistry elevations in the setting of HIV virologic and immunologic
responses to DTG and withdrawal (or lack of) HBV active therapy. The pattern of
injury is likely consistent with IRIS and/or inadequate HBV therapy rather than direct
liver injury due to DTG. Treatment-experienced subjects with hepatitis C virus coinfection may be at greater risk of HCV IRIS with DTG due to improved HIV
virologic responses versus RAL.
Overall, the renal profile of DTG is comparable to comparators in Phase III studies (i.e.,
RAL and EFV). Mild elevations of creatinine on DTG are related to a likely benign
effect on creatinine secretion via blockade of the OCT2 receptor, do not progress on
continued treatment with DTG, and revert towards Baseline after DTG discontinuation.
The gastrointestinal profile for DTG 50 mg once daily was comparable to RAL and
Atripla, was similar for the DTG 50 mg once daily and twice daily dose, and did not
indicate an increased risk for peptic ulcers or serious erosions, as was seen in animal
toxicity studies.
The musculoskeletal profile for DTG was generally comparable to that observed for RAL
and Atripla treatment groups in INI-naive subjects, and there was no evidence of excess
risk of musculoskeletal disorders for DTG 50 mg BID in INI-resistant subjects.
Despite the rapid decline in HIV-1 RNA observed on DTG, IRIS cases were generally
infrequent on DTG, and the rates of IRIS on DTG were comparable to those observed on
RAL and EFV.

ART-experienced (INI-naïve) subjects with hepatitis B and/or C virus co-infection
receiving DTG may be at greater risk for IRIS than those receiving RAL, due to
improved HIV virologic and immunologic responses with DTG compared to RAL,
and withdrawal (or lack of) HBV active therapy in HIV/HBV co-infected subjects.
Particular diligence should be applied in initiating or maintaining effective hepatitis
B therapy (referring to treatment guidelines) when starting dolutegravir-based
therapy in hepatitis B virus co-infected patients.
There was no evidence of a clinically significant impairment of the lipid profile by DTG
treatment in the Phase III studies.
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No effect of gender, age, or race on safety profile of DTG has been observed (beyond
what might be expected for each subgroup).
6.
BENEFITS AND RISKS CONCLUSIONS
HIV remains a serious and life-threatening infection for millions of patients around the
world. HIV infection is characterized by deterioration in immune function. If left
untreated or suboptimally treated, the subsequent occurrence of opportunistic infections
and malignancies ultimately results in death. The treatment of HIV-1 disease has been
significantly advanced by the availability of highly active antiretroviral therapy
(HAART), which initially is based upon therapy with two NRTIs and a third agent such a
NNRTI, boosted PI, or INI. However, each of these third agents has limitations that
require accommodation, whether due to tolerability concerns, potency in patients with
high viral loads, food restrictions, dosing complexity, or significant drug interactions that
preclude co-administration with other ART. New antivirals that are effective for multidrug resistant HIV are also critical for those patients who have no other options.
Dolutegravir given once daily has demonstrated advantages over RAL (the first marketed
INI) which is given twice daily in both treatment-naïve and treatment-experienced
patients. In treatment-experienced (INI-naïve) patients, a statistically higher proportion
of patients receiving DTG plus background therapy achieved virologic success when
compared to RAL plus background therapy through 24 weeks. DTG + ABC/3TC also
demonstrated superior efficacy with improved tolerability over EFV/TDF/FTC in
treatment-naïve patients. Importantly, DTG given twice daily has also demonstrated
robust antiviral activity and a favorable safety profile in patients with the greatest medical
need—extensively treatment-experienced patients with resistance to integrase inhibitors.
6.1.
Benefits of Dolutegravir in the Treatment of HIV-1 Infection
Novel safe and effective drugs are needed for all sectors of the HIV population, including
adults who are initiating ART for the first time, treatment-experienced adults (INI-naïve
and INI-resistant), and pediatric patients. Dolutegravir is being developed as a treatment
for all of these populations, and has distinct advantages over the most widely used
therapies as follows:

Significantly improved efficacy for treatment-naïve patients over EFV-based
regimen

Significant increase in efficacy for treatment-experienced (INI-naïve) patients over
RAL

Efficacious in treatment-experienced (INI-resistant) patients, where no satisfactory
alternative exists

Improved tolerability versus current preferred regimen with substantial reduction of
treatment-limiting adverse drug reactions

High barrier to resistance, with no INI or NRTI resistance seen to date in treatmentnaives on DTG regimen, and significantly lower resistance versus RAL in treatmentexperienced subjects
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
Convenient once daily dosing (treatment-naïve and treatment-experienced, INI
naïve), without need for pharmacokinetic booster

A new treatment option for adolescent (12 to <18 years) HIV-infected, INI-naïve
patients
The results from four pivotal studies (Studies ING113086, ING112574, ING111762, and
ING114467) provide substantial evidence of effectiveness for dolutegravir as a treatment
for HIV-1 infection in combination with other antiretroviral agents.
DTG with two NRTIs was highly effective in ART-naïve subjects. High rates of virologic
suppression [HIV-1 RNA <50 c/mL]) were observed in both studies of ART-naïve
subjects; consistent responses were demonstrated in important subgroups as defined by
Baseline HIV-1 RNA, NRTI backbone, CD4 cell count, gender, race, and age. DTG +
NRTI backbone demonstrated comparable efficacy to RAL + NRTI backbone at
Week 48. DTG + ABC/3TC achieved a statistically superior response through 48 weeks
against the preferred FDC tablet Atripla (tenofovir/emtricitabine/efavirenz) in a HLAB*5701 negative population, a result that was driven in large part by improved
tolerability of the DTG-containing regimen.
In ING111762, virologic suppression (HIV-1 RNA <50 c/mL) in the dolutegravir arm
(79%) was statistically superior to the raltegravir arm (70%), based on the Week 24
prespecified analysis (p=0.003), in this treatment-experienced, INI-naïve patient
population. The difference in virologic response rate was driven by better overall
virologic efficacy with DTG.
DTG 50 mg twice daily was effective for patients with resistance to INIs and associated
extensive antiretroviral resistance to other agents, with efficacy rates comparable to or
better than other antiretroviral agents utilized for within-class resistance in historical
studies. Virologic responses in ING112574 were not clearly associated with the activity
of the background antiviral agents but were best correlated with baseline DTG resistance
(as determined by baseline genotype).
With regards to safety and tolerability, the DTG-containing regimen (DTG+ABC/3TC) in
ING114467 was associated with significantly fewer withdrawals due to AEs in
comparison with Atripla in a HLA-B*5701 negative population. In addition, subjects
receiving Atripla were significantly less likely to develop dizziness, abnormal dreams,
rash, anxiety and somnolence (i.e., relative risk values and 95% confidence intervals were
<1), with statistically significant differences also observed in predefined neuropsychiatric
rates compared to DTG in a pre-specified, exploratory analysis conducted as part of
ING114467. Additionally, the safety profile for DTG was comparable to RAL in 2
treatment populations – treatment-naïve and treatment-experienced (INI-naïve). Finally,
an advanced HIV population on a wide variety of concomitant antiretrovirals and other
concomitant medications had a similar safety profile with a higher daily dose of DTG
(50 mg BID).
Another important benefit of DTG is the different virologic profile versus other available
INIs. Overall, the structural and electronic characteristics of DTG’s metal-binding
scaffold, along with its binding position within the integrase catalytic pocket, may
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contribute to slower dissociation kinetics, which have been observed for DTG compared
with RAL and EVG, both for wildtype and INI-resistant integrase protein. The
prolonged DTG binding to mutant integrase protein is associated with its distinct
resistance profile; since prolonged binding is observed with mutant integrase protein, this
may decrease the opportunity for resistance to develop, and would be consistent with a
higher barrier to resistance.
Confirming these in vitro attributes, DTG-based regimens had a higher barrier to
resistance in ART-experienced (INI-naïve patients), as demonstrated in ING111762
where significantly fewer virologic failures with INI resistance were observed when
compared with RAL. Data from ING113086 and ING114467 were also supportive, as no
subjects on the DTG regimens developed resistance to either the INI or the background
NRTIs, whereas resistance to both the third agent and the background NRTIs was
observed in both the RAL and EFV-based comparator arms.
In the setting of INI-resistance, DTG had efficacy across a broad range of mutational
patterns, with robust virologic responses across the viral populations which represent the
majority of INI-resistant viruses. Additionally, the most prevalent treatment-emergent
mutations detected were IN resistance-associated secondary mutations that were added to
a viral genotype with IN primary mutations present. All treatment-emergent mutations
detected in the setting of pre-existing INI resistance were well characterized RAL and/or
EVG resistance associated mutations.
Dolutegravir offers once-daily dosing in patients without INI resistance, no requirement
for pharmacokinetic boosters and few dose adjustments for drug interactions. DTG can
also be dosed without regard to meals, as there is no significant food effect. DTG also
exhibits less PK variability, with more predictable exposures and lower risk of achieving
inadequate or toxic exposures.
No clinically significant effect of age, weight, gender, race, ethnicity, smoking,
HBV/HCV co-infection, disease status (CDC classification of HIV infection), and
polymorphism of drug-metabolizing enzymes was observed on DTG concentrations,
therefore no dose adjustment of DTG is needed in subjects based on these patient
characteristics. Furthermore, no dose adjustment for DTG is needed in subjects with
mild to moderate hepatic impairment (Child Pugh grade A or B) or in subjects with mild,
moderate, or severe (CrCL<30 mL/min, not on dialysis) renal impairment. DTG can be
used in HBV or HCV-co-infected subjects, as no clinically significant differences in
DTG PK nor drug interactions with concomitant viral hepatitis therapy were observed or
expected.
Finally, DTG represents a new option for therapy of adolescents with HIV infection.
DTG PK in adolescents of at least 40 kg of body weight is similar to adults, and although
data is limited, the safety profile is comparable to adults. Therefore, INI-naïve pediatric
subjects can take the adult dose of 50 mg once daily.
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6.2.
Risks of Dolutegravir in the Treatment of HIV-1 Infection
The most common AEs seen in the dolutegravir clinical development program were
diarrhea, nausea, and headache. These events occurred at similar rates across the
treatment groups, were generally mild in intensity, and were typically not treatment
limiting. In the treatment-naïve subjects, the only AE observed at significantly higher
frequency with DTG+ABC/3TC versus Atripla was insomnia, with event rate differences
observed in ING114467only. In all other studies, rates of insomnia were generally low
and were comparable between DTG and RAL. Insomnia was not treatment limiting in
the clinical program. Neuropsychiatric events otherwise occurred at a comparable rate
for subjects on DTG versus RAL, in a pre-specified, exploratory analysis conducted as
part of ING114467, and at a statistically significantly lower rate compared with Atripla.
As observed with RAL, HSR, characterized by rash, constitutional findings, and in few
cases, organ dysfunction including liver injury have been observed in the DTG clinical
studies. This risk will be highlighted as a Warning and Precaution in the label and patient
information, including a recommendation to immediately discontinue DTG if HSR
develops. Clinical status including liver enzymes should be monitored and appropriate
therapy initiated in these patients. Other serious rash conditions, such as StevensJohnson syndrome, erythema multiforme and toxic epidermal necrolysis have not been
observed across the DTG clinical program.
The hepatic safety of DTG appears generally comparable to the widely prescribed
comparators, RAL and TDF/FTC/EFV in treatment-naïve patients, including those coinfected with HBV or HCV. For the overall population, a similar hepatic profile was
observed in treatment-experienced patients, taking into account concomitant
antiretrovirals and higher rates of hepatitis B and C co-infection.
Immune reconstitution syndrome is a labeled risk for other antiretrovirals. Data from this
clinical program indicates that the overall risk for immune reconstitution with DTGbased therapy is not in excess of comparator agents, with the possible exception of HBV
and HCV IRIS with initiation of DTG-based therapy. Treatment-naïve and -experienced
patients were identified across the program who were hepatitis B co-infected and had
clinically significant flares of liver chemistries and/or HBV IRIS. In
treatment-experienced, HBV co-infected patients, the significant liver inflammation was
associated with discontinuation of HBV active therapy and HIV virologic and
immunologic responses to DTG. Recurrence of this liver inflammation has not been
observed in those ART-experienced patients allowed to restart or continue DTG in
conjunction with initiating hepatitis B therapy, thus supporting the view that these cases
are related to hepatitis B flares or IRIS. Additionally, liver chemistry elevations were
noted in hepatitis C co-infected patients but were generally balanced across treatment
arms and, in most cases, were non-progressive or treatment-limiting. Instead, they were
also associated with HIV virologic and immunologic responses across treatment groups.
This view was confirmed by review of cases by the Independent Data Monitoring
Committee. The sponsor intends to describe the risk for immune reconstitution syndrome
in general (and in particular for patients co-infected with HBV/HCV) and appropriate
measures to manage this risk in the prescribing information and patient information
leaflet.
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Non-clinical GI findings did not result in higher rates of GI events (including nausea and
diarrhea events) versus comparators. GI erosions noted in nonclinical studies did not
translate into increased risk for GI ulcers or related conditions on DTG in the clinical
setting. Hemoglobin concentrations also increased over time on DTG regimen, as would
be expected from the positive effects of ART. PK-AE analyses did not show any
relationship between DTG exposure and the occurrence of nausea or diarrhea across the
patient populations.
Non-clinical data suggest that there are no specific risks to the fetus from dolutegravir
treatment. There are limited clinical data on the effect of dolutegravir on the developing
human fetus. It is the intent of the sponsor that women who become pregnant while on
DTG therapy will be encouraged to participate in the North American and European
pregnancy registries, to assess the presence or absence of teratogenic effects of DTG.
In vitro, DTG inhibited the renal organic cation transporter (OCT2) and may increase
plasma concentrations of drugs dependent on OCT2 for clearance (dofetilide and
metformin). The co-administration of DTG and dofetilide is contraindicated. Careful
monitoring is recommended when starting the combination of DTG with metformin, and
metformin dose adjustments may be required.
Although patients 65 years of age were eligible for enrolment into the clinical studies,
few did so. Consequently there are insufficient data to determine a meaningful
benefit/risk assessment in this population. However, the safety profile of DTG in patients
50 years of age appeared comparable to those <50 years of age, and the
pharmacokinetics of DTG were not affected in patients with moderate declines in liver
function or severe declines in renal function. Population pharmacokinetic analysis of
dolutegravir also showed that there was no clinically significant effect of age on
dolutegravir exposure.
Thus far the clinical development program for dolutegravir has treated a limited number
of pediatric patients. However, the PK of DTG in adolescents treated with 50 mg once
daily was consistent with PK in adults, and the tolerability and efficacy of DTG-based
therapy has been favorable to date. ING112578 (P1093) has completed enrolment of
adolescents to support the safety and efficacy of DTG in subjects 12 to <18 years of age;
the study plans to enroll sequential groups of subjects in descending age-based cohorts in
order to support updated DTG dose recommendations for children as young as 4 weeks of
age.
All medications have AE profiles which must be assessed prior to use, allowing for an
appropriate risk/benefit assessment. Relative to other current treatment options, DTG has
an acceptable safety profile in patients with HIV who have not been treated before with
INIs, and it has the potential to provide significant benefit with optimized background
therapy in most adults with multi-drug resistance that includes resistance to the currently
marketed INIs.
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6.3.
Overall Dosing Recommendations
The data collected in the clinical program suggests that in INI-naïve (treatment-naïve or
treatment-experienced) adults patients, dolutegravir therapy with 50 mg once daily is safe
and effective in combination therapy. The same 50 mg once daily dose is recommended
for INI-naïve adolescents 12 to 18 years of age and weighing at least 40 kg. In
INI-resistant adults, the recommended dose of DTG is 50 mg twice daily, in combination
with other antiretrovirals.
6.4.
Overall Conclusions
There remains a significant need for new antiretrovirals that can treat multi-drug resistant
strains of HIV. Moreover, patients and their physicians would benefit from antiretroviral
agents that deliver the combination of potent antiviral efficacy, good tolerability, and ease
of use (once daily administration without regards to food or major drug interactions).
Dolutegravir has been shown to be a highly effective treatment option, having
demonstrated statistically improved responses when compared to standard of care
regimen (EFV/TDF/FTC in treatment-naives, and RAL plus optimized background
therapy for treatment experienced patients who have not been treated with INIs
previously). DTG-based regimens have also demonstrated a higher barrier to resistance
in INI-naïve patients, as demonstrated in ING111762 where fewer virologic failures and
statistically significantly fewer subjects with INI resistance were observed when
compared with RAL through Week 24. Finally, DTG-based regimens have also
demonstrated excellent tolerability, evidenced by the low rate of discontinuations due to
AEs across the clinical program.
Identified risks for DTG-based therapy include hypersensitivity reactions, hepatitis,
immune reconstitution syndrome (including in the setting of HBV/HCV co-infection),
and a potentially serious drug interaction with dofetilide. Appropriate labeling and risk
management activities, tailored to the geographic regions where DTG will be marketed,
are described in this application. Dolutegravir compares well with other antiretroviral
agents, in both efficacy and tolerability. There are a substantial number of patients who
are in need of new agents to treat drug-resistant HIV, and that offer the unique
combination of efficacy and tolerability that encourage life-long adherence for this
chronic infection. Dolutegravir has been developed to provide much needed
improvements in the control of HIV disease.
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8.
APPENDICES
Appendix Table 1 Explanation for Empty Submission Modules
Module
5.3.1.1
Title
BA study reports
5.3.1.3
In-vitro/In-vivo Correlation Study reports
5.3.2.1
Plasma Protein Binding SR
5.3.2.2
Reports of Hepatic Metabolism and Drug
Interaction Studies
5.3.2.3
5.3.3.2
Reports of studies using other human
biomaterials
Patient PK & Initial Tolerability Report
5.3.6
Reports of post-marketing studies
5.3.7
Case Report Forms and Individual
Patient Listings
91
Explanation
The absolute bioavailability of DTG has not been
established. The low solubility of DTG in buffered
solutions and its non-specific binding present significant
challenges to an IV formulation for DTG even at very low
doses, as explained in m2.7.1. Comparative BA and BE
study reports for ING113674, ING114556 and
ING114581 can be found in m5.3.1.2
The development of an in-vitro/in-vivo correlation is not
considered necessary and has not been progressed.
This is described in m2.7.1 and based on ING113068,
which demonstrated similar exposure with tablets
containing different particle sizes.
Studies on the binding of dolutegravir to human plasma
protein are contained in m4.2.2.3.
Hepatic metabolism was examined in ING111853
(m5.3.3.1). Drug interaction studies are listed under
Extrinsic Factor PK Study Reports in m5.3.3.4.
Specific studies to examine the effect of other human
biomaterials on PK were not conducted.
The tolerability of dolutegravir was first tested in healthy
volunteers using an oral suspension in ING111207
(m5.3.3.1). The tolerability of the dolutegravir tablet was
first tested in the repeat dose study testing for relative
bioavailability in ING111322 (m5.3.3.1).
There is no information on post-marketing experience
since dolutegravir is not a marketed product.
Available upon request