Download IMPAACT P1093: Phase I/II, Multi-Center, Open

IMPAACT P1093
Phase I/II, Multi-Center, Open-Label Pharmacokinetic,
Safety, Tolerability and Antiviral Activity of Dolutegravir
(GSK1349572), a Novel Integrase Inhibitor, in Combination
Regimens in HIV-1 Infected Infants, Children and
Adolescents
IMPAACT P1093
Introduction and Overview
• Rationale: Unmet ARV needs remain in pediatric populations, especially
those with extensive resistance, drug intolerance or toxicity. Results from
P1093 will support regulatory filing for dolutegravir (GSK1349572) use in
pediatrics
• Hypothesis: Dolutegravir (GSK1349572), a novel integrase inhibitor, will be
well tolerated with acceptable safety profile and ARV activity when used
with an optimized background regimen in HIV infected pediatric
populations
Primary Objectives
• To select a dolutegravir dose for chronic dosing in infants, children and
adolescents that achieves similar exposure to the dolutegravir adult dose
selected from the Phase IIb clinical trial in ART-naïve adult subjects
• To determine the short term and long term safety and tolerability of
dolutegravir in HIV-1 infected infants, children and adolescents at 24 and
48 weeks
• To evaluate the steady-state pharmacokinetics of dolutegravir in
combination with other antiretrovirals (OBT) in treatment-experienced
and naïve HIV-1 infected infants, children and adolescents and to
determine the dose of GSK1349572 that achieves a targeted AUC24
(primary PK endpoint) and C24h (secondary PK endpoint) in this population
Secondary Objectives
• To evaluate the antiviral activity of dolutegravir in combination with an
OBT by measuring virologic response in infants, children and adolescents
at weeks 24 and 48
• To evaluate the effect on immunologic response from baseline to weeks
24 and 48
• To assess changes in HIV-1 genotype and phenotype to dolutegravir and
other components of the OBT in subjects experiencing virologic failure
• To determine the extended long term ( ≥ 48 weeks) safety and tolerability
of dolutegravir in HIV-1 infected infants, children and adolescents
IMPAACT P1093
• DESIGN: Phase I/II, multi-center, open-label, non-comparative study
• SITES: International and US
• SAMPLE SIZE: Approximately 160 infants, children and adolescents to
provide 100 evaluable subjects
• POPULATION: HIV-1 infected children and adolescents ages ≥4 weeks to
<18 years of age
• TREATMENT DURATION: 48 weeks plus long term safety follow-up (with
drug provided) until available, no benefit, patient endpoint or
discontinuation of dolutegravir development
• Two stages per cohort
– Stage I: At least 10 subjects in each age cohort
– Stage II: Opens after dose/safety criteria met in Stage I;
12 subjects per cohort (except cohort IIB)
Age Cohorts
•
•
•
•
•
•
Cohort I: Adolescents ≥12 to <18 years of age
(Tablets: COMPLETED)
Cohort IIA: Children ≥6 to <12 years of age
(Tablets: Stage I COMPLETED) Stage II is ongoing
Cohort IIB: Children ≥6 to <12 years of age
(Pediatric formulation: oral suspension)
Cohort III: Children ≥2 to <6 years of age
(Pediatric formulation: oral suspension)
Cohort IV: Children ≥6 months to <2 years
(Pediatric formulation: oral suspension)
Cohort V: Infants >4 weeks to <6 months
(Pediatric formulation: oral suspension)
Inclusion Criteria
– RNA ≥ 1,000 copies/ml at screening
– ARV treatment experienced (includes those who have received therapy
to interrupt maternal-infant transmission) subjects currently on no ART:
• Must be off treatment ≥ 4 weeks AND
• Must have HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening
– ARV treatment experienced subjects currently on ART:
• Must be on an unchanged, failing therapeutic regimen for within 8 to 12 weeks prior
to screening (≤1 log drop in HIV-1 RNA within the previous 8 to 12 weeks of screening)
AND
• Must have HIV-1RNA viral load greater than 1,000 copies/mL of plasma at screening
– Able to swallow assigned study medication (do to crush or dissolve)
– OBT: > 2 ARVs, one must be active (according to genotype)
– Female of childbearing potential, must be on 2 birth control methods
while on study and for 2 weeks after stopping study drug
Exclusion Criteria
• Active AIDS defining opportunistic infection
• Known ≥ Grade 3 of laboratory toxicities, 30 days prior to entry; Hb,
neutrophil count, platelets, AST, ALT, lipase, creatinine
• Known ≥ 4 laboratory toxicity, 30 days prior to entry
• Liver toxicity; ALT> 3 x ULN & Direct bilirubin > 2 x ULN
• History of malignancy
• Clinical evidence of pancreatitis
• Use of disallowed medications at the time of screening (section 4.32)
• Integrase inhibitor experienced (incl mother prior to delivery)
• Pregnancy
• Active TB /disease and/or requirement for treatment that includes
rifampin at the time of the screening visit. However, subjects who need
rifampin treatment while on dolutegravir will be allowed to continue in
P1093 provided the dolutegravir dose is adjusted according to protocol
section 6.18.
Dolutegravir Background
Dolutegravir: Key Characteristics
• Only once daily, unboosted INI
– Long plasma half life (~15 hours)
– Consistent pharmacokinetics
– Clear and predictable exposure-response relationship
• Favorable drug interaction profile
– Primarily metabolized via glucuronidation with minor CYP3A4 component
• Virology: High potency in a low mg,
– 10 day monotherapy: Decrease VL=2.5 log copies/ml; 7/10 with VL<50
– ≥88% undetectable at Week 48 (vs. 82% with EFV) in SPRING-1
– Limited cross resistance to RAL in vitro and in vivo (VIKING)
– Promise for higher barrier to resistance
• Excellent tolerability through 48 weeks in trt-naïve (SPRING-1) and 24 weeks in
trt-exp (VIKING) populations
SPRING-1: Rapid and Robust Antiviral Activity:
Week 48 Efficacy Analysis (%<50 copies/mL)
Proportion (%) <50 copies/mL (TLOVR)
91%
90%
88%
82%
GSK572 10mg
GSK572 25mg
GSK572 50mg
EFV 600mg
11
SPRING-1 Common Adverse Events
Preferred Term
12
GSK572
10mg
(N=53)
GSK572
25mg
(N=51)
GSK572
50mg
(N=51)
GSK572
Subtotal
(N=155)
EFV
600mg
(N=50)
Nausea
Diarrhea
Nasopharyngitis
10 (19%)
5 (9%)
7 (13%)
7 (14%)
6 (12%)
5 (10%)
6 (12%)
7 (14%)
6 (12%)
23 (15%)
18 (12%)
18 (12%)
5 (10%)
7 (14%)
5 (10%)
Headache
6 (11%)
7 (14%)
7 (14%)
20 (13%)
1 (2%)
Dizziness
2 (4%)
2 (4%)
3 (6%)
7 (5%)
11 (22%)
Insomnia
0
5 (10%)
5 (10%)
10 (6%)
5 (10%)
Pyrexia
Cough
Influenza
Rash
Bronchitis
Fatigue
Back pain
Sinusitis
Depression
Respiratory tract infection
5 (9%)
4 (8%)
2 (4%)
4 (8%)
4 (8%)
2 (4%)
2 (4%)
1 (2%)
2 (4%)
3 (6%)
3 (6%)
3 (6%)
5 (10%)
2 (4%)
2 (4%)
3 (6%)
2 (4%)
1 (2%)
3 (6%)
1 (2%)
2 (4%)
4 (8%)
3 (6%)
1 (2%)
2 (4%)
1 (2%)
2 (4%)
3 (6%)
1 (2%)
2 (4%)
10 (6%)
11 (7%)
10 (6%)
7 (5%)
8 (5%)
6 (4%)
6 (4%)
5 (3%)
6 (4%)
6 (4%)
4 (8%)
2 (4%)
2 (4%)
5 (10%)
3 (6%)
5 (10%)
3 (6%)
4 (8%)
2 (4%)
2 (4%)
Upper respiratory tract infection
Abdominal pain
1 (2%)
3 (6%)
1 (2%)
1 (2%)
5 (10%)
2 (4%)
7 (5%)
6 (4%)
1 (2%)
1 (2%)
Abdominal pain upper
Abnormal dreams
4 (8%)
1 (2%)
2 (4%)
2 (4%)
0
0
6 (4%)
3 (2%)
1 (2%)
4 (8%)
Asthenia
3 (6%)
3 (6%)
1 (2%)
7 (5%)
0
Vomiting
Dyspepsia
Pharyngitis
Vertigo
3 (6%)
0
2 (4%)
2 (4%)
3 (6%)
2 (4%)
2 (4%)
0
0
2 (4%)
0
2 (4%)
6 (4%)
4 (3%)
4 (3%)
4 (3%)
1 (2%)
2 (4%)
2 (4%)
2 (4%)
SPRING-1: Creatinine, CRT Clearance
GSK572
10mg
(N=53)
GSK572
25mg
(N=51)
GSK572
50mg
(N=51)
GSK572
Subtotal
(N=155)
EFV
600mg
(N=50)
CRT Maximum Treatment Emergent Toxicity
Grade 1
Grade 2
0
0
3 (6%)
1 (2%)
0
0
3 (2%)
1 (<1%)
0
0
Creatinine (µmol/L)
Baseline
Week 1 Change from Baseline (SD)
Week 16 Change from Baseline (SD)
Week 24 Change from Baseline (SD)
Week 48 Change from Baseline (SD)
82.0
8.5 (8.04)
8.1 (8.83)
4.4 (9.15)
2.7 (9.16)
88.1
9.0 (8.85)
7.0 (9.77)
5.1 (11.91)
1.1 (11.38)
82.2
11.9 (6.79)
12.4 (9.39)
10.6 (7.75)
6.3 (7.67)
84.1
9.8 (8.04)
9.1 (9.55)*
6.6 (10.08)**
3.4 (9.69)***
79.5
1.1 (7.79)
0.8 (6.99)
-2.0 (10.08)
-6.0 (10.19)
Creatinine Clearance - Cockcroft-Gault (mL/min)
Baseline
Week 24 Change from Baseline (SD)
Week 48 Change from Baseline (SD)
116.0
-5.0 (13.55)
-2.5 (13.62)
115.8
-4.5 (16.77)
-1.3 (14.31)
118.6
-11.2 (9.42)
-8.0 (10.54)
* p<0.001 vs. EFV;
** p<0.001 vs. EFV;
***p<0.001 vs. EFV;
13
by NRTI:
TVD: p<0.001 vs. EFV
TVD: p<0.001 vs. EFV
TVD: p<0.001 vs. EFV
KVX: p=0.021 vs. EFV
KVX: p=0.115 vs. EFV
KVX: p=0.128 vs. EFV
118.5
4.7 (16.25)
13.7 (28.02)
SPRING 1: Safety Summary
• Dolutegravir was well-tolerated across all doses studied.
• No significant dose-dependent trends in safety parameters.
• More cases of headache were reported across the DTG treatment groups
(13%) than in the EFV control (2%); nausea – DTG (15%), EFV (10%).
• Small, non-progressive increases in serum creatinine have been observed
across the dolutegravir doses in this study. In vitro data supports OCT2
inhibition; iohexol study in healthy subjects shows no effect on GFR or
renal plasma blood flow
• Urine protein changes noted on DTG – not time or dose-dependent,
resolve independently, confounded by other conditions
– Direct assessments in peds and ph3 studies
Dolutegravir
Pharmacokinetics
Predictable PK/PD Relationship
C (μg/mL)
Day 11 log10 VL Change from Baseline
0.0
-3.5
0.2
0.4
0.6
0.8
1.0
1.2
1.4
-3
-2.5
-2
-1.5
-1
Placebo
-0.5
2mg QD
0
10mg QD
0.5
50mg QD
Model Fit, Emax= -2.6, EC50= 0.036μg/mL
1
Song I, et al. IAS 2009, Cape Town, abstract WEPEB250.
Well characterized
relationship between
trough concentration
and viral load
decrease in 10-day
monotherapy
observed
Drug-drug Interactions
• Dolutegravir can be given with most ART agents without dose
adjustment or contraindication
• Dolutegravir can be given without food restrictions
• Exceptions (due to significant reduction in dolutegravir exposure)
– Disallowed concurrent medications:
• Etravirine (without PI/r)
• Rilpivirine
– Concurrent medications with caution:
• GSK1349572 should be taken 2 hours before or 6 hours after antacid products
containing divalent cations (e.g., Tums, Maalox)
Please refer to Section 4.3 in the protocol for complete list of
precautionary and disallowed medications at various stages of the
study
Mean (SD) plasma DTG concentration (ng/mL)
PK Result: DTG Exposure in Cohort 1
(12 to <18 y) is Similar to Adults IAC 2012
5000
PK parameter,
mean (CV%)
4500
Cohort 1
AUC(0-24)
4000
46.0 µg*h/mL (43%)
C24
0.90 µg/mL (58%)
3500
3000
P1093 Cohort 1 Stage 1
2500
2000
Adult
1500
1000
500
0
0
5
10 Time (h) 15
20
25
DTG exposure in Cohort 1 (12 to <18 y) achieved target exposure for both AUC(0-24)
(37-67 µg*h/mL) and C24 (0.77-2.26 µg/mL)
Adult profile is based on pooled data from Study ING111521 and SPRING-1: Min et al. AIDS. 2011; 25(14): 1737-45. Stellbrink et al.
CROI 2012; Seattle, WA. Abstract K-1002. van Lunzen et al. Lancet Infect Dis. 2012;12(2):111-118.
PK Result: DTG Exposure in Cohort IIA
(6 to <12 years) CROI 2014
PK
Parameter
Geometric
Mean (CV %)
AUC24
50.46 µg*h/mL (63%)
C24
0.92 µg/mL (89%)
Data From P1093 – CROI 2014
Dose and Safety at Week 48
•
Dose
n=23
•
50 mg for ≥ 40 kg
19 (82.6%)
•
35 mg for 30-< 40 kg
4 (17.4%)
• DTG was generally well tolerated
– No discontinuations due to adverse events
– No DTG-related AE
– Two participants with unrelated grade 3 laboratory abnormality
• Unconjugated bilirubin elevation associated with atazanavir
• Asymptomatic lipase elevation
– No trends in lab abnormalities
P1093: Efficacy: Percent of Patients (95% CI) with
HIV RNA<400 c/mL or ≥1 Log10 Decline from
Baseline (Cohort I - All Treated): ITT Approach
74%
Efficacy: Percent of Patients (95% CI) with
HIV RNA<400 c/mL or ≥1 Log10 Decline from
Baseline (Cohort IIA - All Treated): ITT Approach
82%
P1093: CD4+ Counts Median Changes (IQR)
from Baseline through Week 48
(Cohort I): As-treated Approach
P1093 Study Visits
Age Cohorts
•
Cohort I: Adolescents ≥12 to <18 years of age
(Tablets: COMPLETED)
•
Cohort IIA: Children ≥6 to <12 years of age
(Tablets: Stage IA COMPLETED)
Cohort IIB: Children ≥6 to <12 years of age
(Pediatric formulation: oral suspension)
Cohort III: Children ≥2 to <6 years of age
(Pediatric formulation: oral suspension)
Cohort IV: Children ≥6 months to <2 years
(Pediatric formulation: oral suspension)
Cohort V: Infants >4 weeks to <6 months
(Pediatric formulation: oral suspension)
•
•
•
•
P1093 Study Cohorts (similar to P1066)
•
Stage I: Mini-cohort: n=4
– Objective: Screen for enrolling full cohort and subsequent mini-cohort
– Add dolutegravir to stable, failing regimen or start as monotherapy if not
on ARV
– Intensive PK (day 5-10)
– Optimized background regimen (>2 ARV, one active) to be initiated after
PK (see Table 8 for excluded ARVs)
• One active ARV by genotype at screen
• Agents chosen based upon ARV history, prior genotype/pheno)
• Send proposed OBT to Team for approval
– Team evaluation: Intensive PK and 4 week safety and tolerability
– If acceptable, then enroll Full Cohort and start enrollment of
subsequent mini-cohort
– If not, new mini-cohort at adjusted dose
– Original mini-cohort dose adjusted, too
P1093: Full Cohort, Stage I
•
Stage I: Full Cohort (finish enrollment of 10)
– Team Evaluation: 4 week PK and safety
– If safety/PK results not acceptable, start a new mini-cohort at adjusted
dose
•
Case by case individualized dose adjustment for participants with PK
extremes for safety reason (Stage 1 only)
– Need to have repeat PKs 5-14 days post dose mod
– if refuse to have PKs, must discontinue 572
P1093: Stage II
• Stage II
– Objective: Long term safety, tolerability, efficacy of dolutegravir
with optimized background
– Dose employed, for each cohort, will be chosen from cohort data
from Stage I
– No Intensive PK
– Population PKs
– See Table 8 for permissible optimized background regimen
Disallowed ARVs (Table 9)
(to minimize effect of drug:drug interaction)
•
•
•
Stage I: Prior to Intensive PK
– Efavirenz
– Nevirapine
– Etravirine
Include use in any fixed-dose combination
– Atazanavir: unboosted and boosted
– Fosamprenavir: unboosted and boosted
– Tipranavir/ritonavir
– Rilpivirine (includes Complera)
Stage I: Before or After Intensive PK and all Stage II participants
– Etravarine
– Raltegravir
– Elvitegravir
– Rilpivirine (includes Complera)
See list of other disallowed medications
– Short course of corticosteroids allowed
Screening Highlights (Appendix I)
see Manual of Procedures (MOPS)
•
•
•
•
•
•
•
Must contact team for permission to screen
Real time HLA B*5701 for those using abacavir in OBR-minimize
hypersensitivity reactions
Entry within 30 days of screening
HIV-1 RNA PCR: Abbott platform
Specimen shipping: See Clarification memo
Pregnancy testing-screen and q visit
– urine or blood
Real time genotyping
– Must have one fully sensitive ARV to add to OBR
Intensive PKs
P1093
•
•
•
•
•
Day 5-10, 24 hr PK
Dosing: observed, as close to 24 hrs post last dose
Prior
– Document 2 doses prior to intensive PK
– Fast: 6 hrs but substantial liquids OK until 4 hrs prior to dosing (water
OK throughout)
Cancellation/rescheduling: complete within 7 days
– Missed dose within 72 hrs
– Missed 20-28 hr window after last dose
– Vomiting within 4 hrs post dose
– Not fasting
– Notify team
SHIP REAL TIME
Non-Intensive PKs
P1093
• Population PKs
– Study visit windows
• Weeks 4,8,12,16: one week window
• Weeks 24, 32, 40, 48: two week window
– Week 24: 2 samples between 12-26 hrs post dose
• Liver toxicity resulting in study drug interruption
– Request to collect 2 ml specimen within 72 hrs after last dose
Virologic Criteria
• Virologic Rebound
– Confirmed >1.0 log in RNA over nadir level on 2 consecutive
measurements (1-4 weeks after 1st suspect specimen)
• Virologic Failure
– Confirmed decrease of HIV RNA <1.0 log at, or after, wk 12
OR
– Confirmed RNA >400 at >24 weeks on 2 consecutive
measurements (1-4 weeks after 1st suspect specimen)
Participant Management
Virologic
•
•
•
•
Notify Team
See Appendix I for schedule of events
Send specimen for resistance testing
Participant options:
– Take off study drug, best available treatment
• Long Term Follow-up for subjects who discontinue study
medication: Appendix IF
– Optimize background regimen + dolutegravir
• Need approval of P1093 team
– Continue regimen without changes
*** Timing of which sample to send for resistance testing determined by
above option chosen (see MOPS)
Pharmacy Considerations
IMPAACT P1093
Thucuma Sise, Pharm.D., BCPS
Pharmacist
Pharmaceutical Affairs Branch
DAIDS/NIAID/NIH
Study Drugs: Formulations
• Dolutegravir 10 mg study drug tablet
• Dolutegravir 25 mg study drug tablet
• Dolutegravir 50 mg study drug tablet
• Dolutegravir Pediatric Formulation – oral suspension
– Granules must be reconstituted by the site pharmacist
Study Drugs: Duration of Therapy
• Stage I: Minimum of 48 weeks
Long Term Safety Follow-up: see Section 5.11 of the protocol.
• Stage II: 48 weeks
Long Term Safety follow-up: see Section 5.11 of the protocol.
Study Drugs: Dispensing and Storage
• Dolutegravir tablets are to be dispensed by the site pharmacist in
the original manufacturer’s container, which contains a
desiccant. The desiccant should remain in the container.
• Dolutegravir pediatric granules are to be reconstituted by the site
pharmacist and must remain in the same amber glass bottle in
which the granules were mixed with water.
• Please refer to Section 5.1 “preparation of oral suspension”.
• Dolutegravir study drugs must be stored between 15°C–30°C
(59°F–86°F)
Study Drug: Administration of Tablets
•
Dolutegravir - study drug - must be administered orally once daily or as
twice daily if administered with efavirenz or ritonavir boosted fosamprenavir
or tipranavir***
•
Dolutegravir tablets must be swallowed whole and may not be crushed or
dissolved before administration
•
Dolutegravir - study drug - can be taken with or without food
•
Dolutegravir - study drug - should be administered 2 hours before or 6
hours after taking antacid products containing divalent cat ions (e.g.
aluminum and magnesium) or iron supplements
Please refer to Section 4.3 in the protocol for complete list of precautionary
and disallowed medications at various stages of the study
***If EFV, NVP, FPV/r or TPV/r are part of OBR after the intensive PK the dose of
dolutegravir should be given TWICE daily as directed in LOA #2 and per FDA
guidance
Study Drugs: Administration of Suspension
•
The site pharmacist will dispense the pediatric suspension reconstituted
from granules
•
EVERY reconstituted bottle must be shaken EVERY day
•
Dolutegravir - study drug - must be administered orally once daily***
•
Dolutegravir - study drug - can be taken with or without food
•
Dolutegravir - study drug - should be administered 2 hours before or 6 hours
after taking antacid products containing divalent cat ions (e.g. aluminum and
magnesium) or iron supplements
Disperse directly to the mouth
Dosing instructions and an oral dispenser to measure the child’s dose will
be provided by the pharmacist (See Appendix IV for directions for parent or
caregiver)
•
•
***If EFV, NVP, FPV/r or TPV/r are part of OBR after the intensive PK the dose of
dolutegravir should be given TWICE daily as directed in LOA #2 and per FDA
guidance
Study Drug: Ordering and Shipping
•
Site Protocol Registered
•
Ordering instructions will be sent to the site pharmacist from the Clinical
Research Products Management Center (CRPMC)
•
Upon confirmation of site protocol registration
•
Receipt of order at the CRPMC
•
Study product packaged and shipped to the site pharmacist
•
Site pharmacists will receive study product shipped at appropriate
temperature
Study Drugs: Management and
Accountability
•
Accountability records must be kept by the Pharmacist
•
All unused study product must be handled as outlined in the manual
“Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks”
at study completion or termination.
Communication Among Site Study Staff
• A completed prescription signed by an authorized prescriber should
include pertinent information including the subject’s weight (kg),
Cohort, target mg/kg, Specific Dosing Table in Appendix 3 of the
protocol to use for initial dosing.
• A new prescription must be provided to the site pharmacist for
adjusted dosing.
P1093 AE Reporting
P1093
Adverse Event Reporting
• Serious Adverse Events (SAE) is the reporting
category to be used for this study.
• The study agent for which expedited reporting are
required is dolutegravir
SAE Definition
• Results in Death,
• Is life-threatening,
• Requires inpatient hospitalization or prolongation of
existing hospitalization,
• Results in persistent or significant disability or
incapacity,
• Is a congenital anomaly/ birth defect,
• Is an important medical event that may not be
immediately life threatening or result in death or
hospitalization but may jeopardize the patient or may
require intervention to prevent one of the other
outcomes listed in the definition above
P1093 SAE Reporting
• In addition to SAE, this protocol also requires reporting of the
following in an expedited manner:
– ALL GRADE 4 toxicities
– All Pregnancies
– Hy’s law liver toxicities
– Abacavir (ABC) hypersensitivity (HSR)
– All pregnancy complications, elective terminations and
spontaneous abortions
Abacavir Hypersensitivity Reactions
• ALL cases of Abacavir Hypersensitivity
reactions, MUST be reported as an EAE.
• In addition, the ABC HSR CRF must be
completed and submitted to the DMC within
one week of the onset of the hypersensitivity
reaction.
Liver Toxicities
• HY’s law, (section 6.13)
• If any of the liver chemistry stopping criteria are
met:
– Immediately withhold study drug
– Report to study team by email within 24 hours of
learning of the event to
– [email protected]
– Report Hy’s law liver toxicity to RSC as an EAE
– Complete and submit the liver toxicity CRFs within 1
week to the DMC.
Assessment
• AEs are assessed for:
–
–
–
–
Seriousness
Relationship
Expectedness
Severity
• Site Level: Study physician listed on
the 1572/IoR (Investigator of
Record) Agreement is responsible
for the assessment of AEs
• Sponsor Level: DAIDS MOs provide
secondary review
50
Serious versus Severe
Seriousness is NOT the same as Severity
Seriousness
Severity
Based on outcome of the AE
and is a factor in determining
reportability (regulatory
definition)
Based on the intensity of the
AE and is not a factor in
determining reportability
(clinical descriptor)
Determined using the SAE
criteria
Determined using the DAIDS
grading table
51
Site Investigator Signature
• A site physician investigator or sub-investigator listed
on the 1572 or the IoR Agreement must:
– Review and verify the completed report for accuracy and
completeness and
– Sign the report
• This physician makes the site’s final assessment of the
relationship to study agent(s)
52
P1093
CRFs / Data Management
The EVW0302 is being updated to allow patients who are taking TABLETS to skip
over the SUSPENSION questions. Until the update is released, please enter (-1) in
the questions collecting suspension feel and ease to swallow?
Propose the Logical Check in RESOLVE and the DMC will approve the check.
GSK1349572 (Dolutegravir) modifications are reported in question #1.
Modifications to the background ARV regimen are reported in question #2.
Modifications to non-ARVs are reported in question #4 along with the
reason for the modification.
P1093
LABORATORY TESTS
LPC
SHIPPING
Evaluation
DMC Test
Code
Hematology
N/A
CBC (to include platelet and differential)
PE6811
Chemistry
N/A
Chemistry-Electrolytes (sodium, potassium, HCO3),
glucose, creatinine, lipase, phosphorus, and LFTs (total
bilirubin, indirect bilirubin, direct bilirubin, alkaline
phosphatase, AST, , and albumin.)
PE6816
Lipid Profile
N/A
Lipid profile- triglycerides, cholesterol, HDL, LDL
PE6816
Urinalysis
N/A
Urinalysis (dipstick only)
PE0811
Tests
CRF #
Section 3: Specimen Processing & Shipping Instructions
Evaluation
Tube
Type
Special
Collection Notes
CRF #
DMC Test
Code
Abbott Real Time
HIV1
3mL
EDTA
Can be
performed at any
local CLIA/VQA
approved lab.
F3006 (and
F3109 if
results are
not reported
through
LDMS)
RNAHIVRU
Processing
Spin blood at 800xg
for 10 mins; remove
plasma and respin at
800xg for 10 min.
Freeze ≥ 2 x 0.8 ml
aliquots at –70°C or
lower.
Shipping
To be updated
2mL
EDTA
N/A
F3006
GENOHIV
Resistance testing
(Genotyping)
BASELINE
Resistance Testing
(Phenotyping)
4mL
EDTA
N/A
F3006
PHENOHIV
NOTE: To be
collected only if
sufficient blood
volume
Resistance Testing
(genotyping)
Virologic Failure
2ml
EDTA
N/A
F3006
GENOHIV
Spin blood at 800xg for 10
mins; remove plasma and
respin at 800xg for 10 min.
Save all plasma in one aliquot
and freeze at –70°C or lower.
Specimens should be shipped
in Real Time..
Spin blood at 800xg for 10
mins; remove plasma and
respin at 800xg for 10 min.
Save all plasma in two aliquots
and freeze at –70°C or lower.
US sites: Store locally and
ship to Monogram
Biosciences when requested.
Spin blood at 800xg for 10
mins; remove plasma and
respin at 800xg for 10 min.
Save all plasma in one aliquot
and freeze at –70°C or lower.
Specimens should be shipped
in Real Time..
US Sites: Ship to UNC.
Thailand – PHPT lab, Chiang
Mai, Thailand; Africa sites:
ship to Contract Lab Services,
Johannesburg, SA; South
America Sites: FioCruz,
Brazil.
International sites store locally
and ship to BRI when
requested. (NOTE:
Specimens to be forwarded
from BRI to Monogram)
US Sites: Ship to UNC.
International Sites:
Specimens should be shipped
in real time to BRI.
(Specimens to be forwarded
from BRI to UNC.)
HLA B-5701 Typing
NOTE: Sample ONLY
should be drawn on
subjects whose physician
plans to start ABC as part
of their OBR, and where
ABC hypersensitivity
screening is not done as
part of standard of care.
1mL
EDTA
M/C Ratio Assay
Microalbumin/creatinine
ratio (mcg/mg creatinine
4 mL
Urine
N/A
F3006
HLAIPCR
N/A
SPW0427
Spin blood at 800xg
for 10 mins; remove
plasma and re-spin
at 800xg for 10 min.
Save all plasma in
one aliquot and
freeze at –70°C or
lower.
Ship real time to BRI
as pass through.
(NOTE: BRI will
forward all samples
real time to final
destination, Quest.)
Aliquot urine into 2
aliquots at 2.0mL
each.
South Africa sites to
ship to CLS
Freeze at –20°C or
lower.
Lymphocyte subsetsCD3/CD4, CD3/CD8 cell
counts and percentages
1mL
EDTA
PBMCs/Plasma for
storage for future
studies.
4.5mL
EDTA
Send to local IQA
or CLIA certified
(or equivalent)
lab, ambient. The
same lab must
be used
throughout the
study
Send to
IMPAACT
processing lab
ambient
LBW0054
None
CD4CD8
Dual platform labs
only must also have
a WBC and diff.
F3006
Spin blood at 400xg
for 10 mins; remove
plasma and respin
at 800xg for 10 min.
Freeze 2x1 ml
aliquots at –70°C or
lower
STORVIR
Freeze all PBMCs
viably in 5X106
aliquots.
N/A
NIAID Sites: Ship to
BRI as directed.
NICHD Sites: Ship to
Fisher as directed.
Intensive
Pharmacokinetics
2mL EDTA
per time
point for
Cohorts I, II
and II
1 mL
EDTA per
time point
for
Cohorts IV
and V.
Population
Pharmacokinetics
1mL
EDTA per
time point
Subjects must be fasted
for 6 hours prior to
dosing (see Appendix I
footnote #11 for
additional info.)
Time points: Pre-dose,
1, 2, 3, 4, 6, 8,and 24
hours post dosing.
PKW0290 Centrifuge blood
within one hour of
PKINT
collection at 1000 x g
Transfer all plasma to
one pre-labeled 2 ml
cryovial, and freeze
immediately after
processing at -70C or
lower for 10 minutes
at 0-5oC.
International sites ship
to BRI real time as
pass through to UAB.
(NOTE: BRI will
forward all samples
real time to UAB.)
Send to local IMPAACT
processing lab on ice.
4 Weeks: Two samples PKW0291 Centrifuge blood
collected at pre-dose
PKPOP within one hour of
and 2-4 hours post dose.
collection at 1000 x g
for 10 minutes at 012 Weeks: One sample
5C.
at any time post dose.
Transfer all plasma to
24 Weeks: Two samples
between 12 and 26
hours post dose.
Send to local IMPAACT
processing lab on ice.
one pre-labeled 2 ml
cryovial and freeze
immediately after
processing at -70C or
lower.
International sites
store locally and ship
in batches to BRI
when requested as
pass through to UAB
(NOTE: BRI to
forward to UAB as
requested.)
Questions?