Download PROTOCOL DEVELOPMENT IMPAACT ICAB MEETING OCTOBER

IMPAACT P1090
A PHASE I/II, OPEN-LABEL TRIAL TO EVALUATE SAFETY, TOLERABILITY,
PHARMACOKINETICS AND ANTIVIRAL ACTIVITY OF ETRAVIRINE (ETR) IN ARV
TREATMENT-EXPERIENCED HIV-1 INFECTED INFANTS AND CHILDREN,
AGED ≥2 MONTHS TO <6 YEARS
Protocol Chair:
Protocol Vice Chairs:
NIAID Medical Officer:
NICHD Medical Officer:
Clinical Trials Specialist:
Statisticians:
Pharmacologists:
Laboratory Technologist:
Data Manager:
Richard Rutstein
Rolando Viani, Andrew Wiznia, Rami Yogev
Ellen Townley
George Siberry
Megan Valentine and Kathryn Lypen
Terry Fenton and Carmelita Alvero
Jennifer Kiser and Joseph Rower
Bill Kabat
Bobbie Graham
1
Background/Rationale
 Single or multi-dose NVP results in significant % of pts with NNRTI resistance
mutations (as high as 40-80%).
 In p1060, 12% of 6 to 36month old infected infants had NNRTI-R, 15/18 with Y181C,
3/18 K103N.
 New recommendations for prolonged use of NVP for breast fed infants, and
continued use of NVP as first line rx in some areas, will lead to increased R to
NVP/EFV.
 ETR is a 2nd generation NNRTI with a higher genetic barrier to HIV drug resistance,
and generally retains activity in pts with only K103N mutation; the Y181C mutation




may itself lower sensitivity to the drug.
Pill formulation is dispersible in liquid.
In adult studies, approx 4-19% of those failing NNRTI regimens have R to ETR
(usually requiring at least 2 or more ETR RAMs).
Safety and efficacy of ETR demonstrated in DUET studies. Note that no ETR pk
parameters were associated with virologic success in these adult studies.
In light of continued use of NVP for PMTCT prenatal/postnatal programs, and need
for alternate first and second line HAART (besides lopinavir/r), new agents are
needed for use in HIV-infected infants and children.
2
Objectives
Primary Objectives:
 To evaluate the steady state pharmacokinetics of ETR in combination
with an OBR in HIV-infected children aged ≥ 2 months to < 6 years.
 To determine the safety and tolerability of ETR in combination with
an OBR in children aged ≥ 2 months to < 6 years, through 48 weeks of
therapy.
 To determine the appropriate dose of ETR in combination with an
OBR for children aged >2 months to <6 years.
Secondary Objectives:





To assess the antiretroviral activity of ETR containing regimens through 48 weeks of therapy.
To determine the immunological changes (change in CD4 percent and absolute count; CD4/CD8
ratio and percent) through 48 weeks of ETR therapy in combination with an OBR.
To determine changes in viral drug resistance during 48 weeks of ETR therapy in combination with
an OBR.
To assess the relationship between ETR pharmacokinetics and the antiviral activity and safety of
ETR containing regimens.
To explore the relationship between subject-specific gene CYP profile and pharmacokinetics of ETR.
3
Schema/Study Design
DESIGN:
Phase I/II, multi-center, domestic and international open-label, pk and safety
study. Age and regimen based cohorts open sequentially. Intensive pk on
day 14 (+/-4) with individual dose adjustments as needed, and cohort dose
adjustment as needed. Mini-cohort of 6; if passes safety and pk rules, enroll
12 in that cohort, and at same time, open the next oldest cohort.
SAMPLE SIZE: Approximately 50 subjects will be accrued, to yield a minimum
of 36 evaluable subjects, 12/cohort.
Evaluable: Subjects who began study at final cohort dose.
POPULATION: ARV-experienced children aged ≥ 2 months to < 6 years of age,
VL >500cpm and with ETR pheno assay of <10 fold sensitivity (cohorts
I,II,III)
Stratified by age into 3 cohorts:
Cohort I:
≥2 year to <6 years who are treatment experienced*
Cohort II:
≥1 year to <2 years who are treatment experienced*
Cohort III:
≥2 months to <1 year who are treatment experienced*
* Treatment experienced children on a failing combination antiretroviral regimen (containing at least 3 ARVs) for at least 8 weeks
OR Treatment experienced children on a treatment interruption of at least 4 weeks with a history of virologic failure while on a
combination antiretroviral regimen (containing at least 3 ARVs)
4
Inclusion/Exclusion Criteria
Cohorts I, II, III:
 Ages 2 months-6yrs
 Failing HAART, VL >500 copies/ml (2 failed results)
 Sensitive to 2 NRTIs and boosted PI (Lopinavir or Atazanavir at
any age, Darunavir for age 3 and older)
 No grade >3 labs at screening (other than bilirubin, if on
atazanavir)
 No grade >3 QTc or PR on screening ECG
Disallowed Medications:
Rifampin, phenobarbital, chronic oral or inhaled steroids
5
Stratification and Cohorts
STRATIFICATION: By age, as follows:
Cohort I: ≥2 year to <6 years who are ARV treatment experienced
Cohort II: ≥1 year to <2 years who are ARV treatment experienced
Cohort III: ≥2 months to <1 year who are ARV treatment experienced
REGIMEN:
ETR + 2NRTI +boosted PI
Only boosted PIs allowed at this time are lopinavir, atazanavir and
darunavir
STUDY DURATION: Minimum of 48 weeks.
Follow up thru P1090 until drug is available locally
6
Dosing and PK assessment
changes between V3.0 and V4.0
 Original starting dose of 5.2mg/kg bid based on DUET and
PIANO studies. For first 4 subjects, dose was well tolerated,
but failed AUC12 criteria. New dose now weight band based
(Appendix III)
 Target: Original was geom mean AUC12 between 80-130% of
adult AUC12 in DUET -now adjusted to 60-150%.
 Individual: AUC12 >10% of adult exposure (2350 ng.mh/ml, at
200mg bid). Individual dose adjustments for low/high AUCs,
repeat pk in 7-14 days.
 Mini-cohort: First 6 must have acceptable geom mean AUC ,
and safety. For full cohort, the geometric mean AUC must be
within the 60-150% AUC12 in adults.
7
Description of Cohorts
Anticipated Accrual
To
Total
Mini
complete a cohor
Cohort
full cohort
t size
Cohort
Description of Subject
Drug
Regimen
Phenotyping /
Genotyping
Information
Comments
I
≥2 year to <6 years who are
treatment experienced
ETR
+ OBR
(1 active
boosted
PI+ at least 1
other active
drug)
HIV genotype and
phenotype assays should
be performed in real time
and results available prior
to starting study drug
Subjects will be enrolled providing
the phenotypic assay results indicate
a <10fold change in sensitivity to ETR
6
6
12
II
≥1 year to <2 years who are
treatment experienced
ETR
+ OBR
(1 active
boosted
PI+ at least 1
other active
drug)
HIV genotype and
phenotype assays should
be performed in real time
and results available prior
to starting study drug
Subjects will be enrolled providing
the phenotypic assay results indicate
a <10 fold change in sensitivity to ETR
6
6
12
III
≥2 months to <1 year who
are treatment
experienced
ETR
+ OBR
(1 active
boosted
PI+ at least 1
other active
drug)
HIV genotype and
phenotype assays
should be performed in
real time and results
available prior to
starting study drug
Subjects will be enrolled
providing the phenotypic assay
results indicate a <10 fold change
in sensitivity to ETR
6
6
12
8
Study Drug Supply
 Darunavir 100 mg/ml suspension, darunavir 75 mg tablets,
and darunavir 150 mg tablets will be available from the
CRPMC and supplied through the study for OBR purposes if
not reasonably available locally.
NOTE: Darunavir may only be used in children ≥3 years.
9
Algorithm for Cohort Management
10
Safety
 Less neuropsych symptoms than reported for EFV
 Rash noted in 10-20% of adults on study, 9% grade 2-3, 1.5%
grade 3, no grade 4 rash. Rare instances of SJS/TEN, <0.01%
each. Rash occurs in 2nd week of rx. Protocol requires derm
visit within 24-48 hrs for grade 2 or higher rash; may continue
meds for grade 2 rash. All sites so far have noted availability of
in-person derm consultation within 24-48hrs.
 GI AEs: grade 2-4: 5.2% in adults studies, no change from
placebo regimen (in DUET).
 Baseline/week 1-2 EKGs required (per EMEA), though no
increased % of cardiac conduction effects noted
11
Endpoints/Data Analysis
 PK parameters as noted
 Safety
 Virologic failure rules:
o VL <0.5 log drop at wk 8 (EMEA and Tibotec based)
o VL <1 log drop at, or after, wk 12 (unless <400 cp/ml)
o VL >400cpm at wk 24
o VL rebound: VL >1,000 cp/ml for those <400 cp/ml data analysis will
also look at those not <400cp/ml at wk 24 but have >2 log drop from
baseline
 CD4 and CD4/CD8 responses
 Also will look at CYP genotype vs. PK of ETR
12
Screening
 Request screening slot- if approved, must screen within




two weeks
Screening requires real time geno- and phenotype assays
ECG also required (via eRT)
OBR must be approved prior to enrollment
Possible screen failures:



ETR sensitivity >10 fold (cohorts I,II, III)
Grade 3 or higher AE, including ECG
Not sensitive to 2 NRTI or booster PI (lopinavir, atazanavir,
darunavir)
13
DAIDS
P1090
eResearchTechnology, Inc. (ERT)
Centralized Digital 12-Lead ECG Services
My Study Portal
Creating an account
 Access My Study Portal and
click on create account
 Enter contact details of Site
Qualification entry contact
 Carefully enter the
Qualification PIN. This is a 10
digit, case sensitive PIN
distributed by the sponsor
 Complete the Text Verification
field by copying the number
shown into the box provided
 Confirm all details are correct
and click “Save”
 This creates the user account
in My Study Portal
My Study Portal
Logging in

An email will be sent to each
account created in My Study
Portal containing the username
and a temporary password

Access My Study Portal, enter the
provided login credentials and click
“Sign In”

You will be asked to change your
password and provide the answer
to a favorite question.

This question will be asked if you
forget your password

Complete these fields then click
“Save”

If you already have an account in
My Study Portal please log in
using your current password
My Study Portal
Site Qualification


Click Site Qualification tab
Enter the protocol Qualification PIN and the Site Country and click “New Form”

The Site Qualification form will be displayed. The SQF entry contact must
enter the site number, along with the full site address and dialing details.
All fields marked with a red asterisk * must be completed
The SQF also contains fields for other site users’ contact details, each
contact listed with an email address can have an account created
(except shipping contact and local monitor) and an access email
containing the username and temporary password will be sent.
Use the radio button to collapse fields if contact details are the same
Specify if the user needs a My Study Portal account creating



My Study Portal
Site Qualification


Complete all required fields and click “Continue”.
Confirm all details are correct and click “Submit” to send the form to ERT.

A confirmation message will be displayed and emailed to the user.



Please allow 5-10 business days for shipping of equipment.
A tracking number will be provided under the Equipment & Supply tracking module
The Site Qualification Form only needs to be completed once per site
ECG Results Reporting
My Study Portal ECG reports and waveforms


The ECG Analysis Report will be provided to
the investigator site via My Study Portal within
72 business hours
This excludes weekends and holidays
ECG Analysis Report
Avoiding Queries

Please take care when entering data

Be sure to check the demography and
visit code information to avoid
unnecessary queries

ECG results will not be available until all
queries are resolved
Customer Care
Your Primary Contact Point for ERT Questions






Machine Technical Support
Result Inquiries
Site Information Updates
Transmission Problems
Web Based Training Inquiries
Dial the toll free number for your country and press option 1 for
cardiac safety assistance
Dedicated Toll-Free Phone and Fax Numbers World-wide
Available 24 hours a day, 7 days a week, 365 days a year
Multilingual Support
E-mail address: [email protected]
Enrollment Visit
23
Enrollment



Must be within 60 days of screening
Start ETR + OBR together
OBR must be approved by the team first
24
Intensive PK Visit
25
Intensive PK
 To be done on study day 14 (+/- 4 days)
 Subjects to have taken ETR doses for 7 days prior to
intensive PK, with no missed doses
 Sites encouraged to contact subjects family day before
intensive PK visit, to confirm full compliance
 If missed dose, reschedule intensive PK to occur 7-14 days
after last missed dose
 If missed dose reoccurs before rescheduled intensive PK
appointment, visit is to be cancelled, and subject
withdrawn from the study
 If PK levels require dose adjustment, repeat PK must be
scheduled for 7-14 days from adjustment
During the Intensive PK visit
 Scheduled so that a witnessed dose of ETR occurs within 11-13
hours after previous dose
 An appropriate meal should be offered after arrival at clinic
 PK dose of medication to be administered within 30 minutes of start of
meal
 Heparin lock to be used for intensive PK if possible
 If subject vomits within 15 minutes of taking medication, re-
administer the medication
 If vomiting occurs greater than 15 minutes but < 4 hours after taking
medication, must reschedule intensive PK assessment
 If vomiting >4 hours post dose, PK visit should be continued as usual
 Food allowed 2 hours after ETR dose during intensive PK visit
 If the protocol team believes the intensive PK was conducted
incorrectly or the results inaccurate, subjects may be asked to
repeat an intensive PK visit on the same dose
Sample Collection
 One (1) mL of blood will be collected at the following time
points for intensive PK: pre-dose, 1, 2, 4, 6, 9 and 12 hours
post dosing
 For flexibility, the 9-hour sample can be collected with a
window of 8 to 10 hours post-dose and the 12 hour sample
with a window of 11 to 13 hours.
 If necessary, the 1-hour post-dose sample and/or the 9-hours
post-dose sample can be deleted to reduce the amount of
total blood drawn from 7 samples over 12 hours to 5 or 6
samples, over 12 hours.
Dose adjustments
 If the subject's current dose is well tolerated (no toxicity ≥Grade 3) but
AUC12h is < 2350 ng•h/mL, then a new dose will be determined by
prorating the current dose to attain an AUC12h of approximately 2864
ng•h/mL (the 20th percentile of exposure in adults).
 The maximum dose increase for the initial PK-guided dose adjustment
would be capped at the adult dose of 200 mg twice daily. If a second PK
evaluation again reveals an AUC12h<2350ng•.h/mL, then the dose may be
increased above the 200mg twice daily initial BID cap, again, targeting an
AUC12h of approximately 2864 ng•h/mL.
 < 2350 ng•h/mL, not well tolerated (> grade 3) discontinue
29
Individual dose management
 If the subject's AUC12h is >4380 ng•h/mL(the median AUC12h value
in adults receiving ETR 200mg twice daily) but current dose is not
well tolerated (no toxicity ≥ Grade 3) then the dose will be prorated,
if possible given available dosage forms to achieve an AUC12h of
4380 ng•h/mLIf no dose reduction is possible, then the subject will
be discontinued from study treatment
 Subjects who require a dose adjustment but decline to undergo
repeat intensive PK (see Section 9.34 for management of individual
dose adjustments) will have ETR therapy discontinued and best
available therapy by their clinician will be initiated.
30
Population PK Visit
31
Population PK
 Blood samples collected at weeks 4, 8, 12, 24, 48, and determination of
virologic failure
 Re-schedule if missed any of last 3 doses
 Depending on week, samples to be collected at varying times post ETR
dose
Sample
obtained
Week
4
1-4 H post
ETR
X
4-8 H
post ETR
8-12 H
post ETR
Week
8
Week
12
Week
24
Week
48
X
X
X
X
Virologic Failure
33
Virologic Failure
• Visit to confirm failure within 1-4 weeks of suspected failure or
rebound
• Collect one PK sample in addition to SOE requirements any time
after dosing
– Always write down the correct time of dosing and blood draw!
• Virologic Failure or lack of response in the study OR Virologic
REBOUND is defined in Section 6.3 of the protocol
Adverse Event Reporting
& SAEs
35
AE Reporting
 IMPAACT study P1090 will use the SAE Reporting Category for expedited




reporting to DAIDS, as per Version 2.0 of the DAIDS EAE reporting manual
(January 2010), available on RSC website.
Other AE under expedited reporting for P1090:
 Erythema multiforme
 Suspected transmission of an infectious agent by study product, per
European Medicines Agency (EMA) requirement.
Sites with web-based DAERS should report via this route; if not on DAERS use
paper EAE reporting form.
EAE reporting period is as per DAIDS EAE Manual Version 2.0.
The protocol team should be notified of a Grade 3 event at
[email protected]
36
AE Reporting
 The DAIDS “tox table” to be used for grading AE severity (current: Version 1.0,
dated December 2004, August 2009 clarification).
http://rsc.tech-res.com/safetyandpharmacovigilance/
 Study-specific supplemental tox tables for grading certain AE (for use in
conjunction with standard DAIDS tox table Version 1.0)
 EKG PR Intervals (age-specific 98%iles): Protocol Appendix V.
 Neurological AE: Protocol Appendix VI.
 Cutaneous AE: Protocol Appendix VII-A
 Acute systemic allergic AE: Protocol Appendix VII-B
 All events submitted must have a updated final/stable outcome status, unless
final/stable at initial report .
37
Serious Adverse Event (SAE)
A serious adverse event (experience) or reaction is any untoward medical
occurrence that at any dose:





Results in death,
Is life-threatening,
Requires inpatient hospitalization or prolongation of existing hospitalization,
Results in persistent or significant disability/incapacity, or
Is a congenital anomaly/birth defect.
In addition, “…important medical events that may not be immediately lifethreatening 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…should also usually be considered serious.”
(ICH E2A)
38
Frontier Science Technology and Research Foundation (FSTRF)
Data Management Center (DMC)
Protocol Data Manager: Bobbie Graham
Why is P1090 different from other studies?
•
•
•
•
Studies submitted for drug licensing are more intensely
reviewed by many levels of reviewers.
Pharmaceutical companies and FDA prefer consistent
reporting styles so they can put data into industry standard
formats.
Protocol team monitors data more “real-time” and
therefore sites must enter data right after visit—especially
administrative, safety data, treatment record and PK forms.
DO NOT JUST SATISFY DELINQUENCY, SATISFY TEAM’s
NEED FOR INFORMATION!
Enrollment Procedures
(Per protocol section 4.4)
All potential participants must be added to a waiting list prior
to obtaining IC, screening or enrollment.
• The DMC protocol DM maintains waiting list.
• To add potential participants to the waiting list, email
protocol team. Please include:
•
Patid (or age if a patid has not been assigned)
• Prior ART experience (with current regimen listed)
• Cohort
• Site number
NOTE: Wait for DM to tell you when to begin the screening process.
Enrollment Procedures (con’t)
(Per protocol section 4.4)
• Sites will receive an email when a slot has been granted by
DMC DM. Please answer the email to accept slot and
include planned screening date.
• Sites should then screen to confirm eligibility as per
section 4.0 of the protocol document by performing
required evaluations.
• If participant is eligible, then complete the Eligibility
Checklist and enroll using the DMC Subject Enrollment
System (SES).
• Confirm that dose dispensed by pharmacist matches DMC
prescription file.
PHASE/ACCRUAL REPORT on DMC PORTAL
To monitor accrual and to
help determine whether
there are available slots,
refer to the PHASE/
ACCRUAL REPORTS located
on the DMC Portal. It is
found on the IMPAACT tab,
under REPORTS. Click on
desired study number and
‘Get Report’.
www.fstrf.org
PHASE/ACCRUAL REPORT on DMC WEBPAGE
Example of Phase/Accrual Report
Currently only
Cohort I for
≥2 to <6 years of
age is open
SCR0022 - P1090 SCREENING FAILURE/NONENROLLMENT TRACKING
Pharmaceutical sponsor needs reasons participants did not enroll. Only those with a
signed informed consent need to provide an actual reason.
REPORTING ANTIRETROVIRALS
• There are 3 distinct time periods for reporting medications (Before,
During, After).
• All ANTIRETROVIRAL medications reported within these time periods
must have distinct start and stop dates.
1
2
3
BEFORE
starting study
treatment
DURING
while on
study treatment
AFTER
stopping study
treatment
Start
date
Stop
date
PE0420
Start
date
Stop
date
TXW0262
Start
date
Stop
date
PE0420
REPORTING Tx INITIATION DELAY
CASE: Patient started study treatment 3 days after
enrolling (registering) to study.
Document on CRFs:
• Enter two ADM0021 forms.
• Enter two TXW0262 forms.
One of each form shows that Tx was not started, then the
other reports when Tx was started.
REPORTING Tx INITIATION DELAY (CONT’D)
TXW0262: Form #1 shows that study Tx was not started.
Leading question indicates “2-No modifications including Tx initiation” were made.
REPORTING Tx INITIATION DELAY (CONT’D)
TXW0262: Form #2 reports when study Tx was started.
NOTE: Quest #1 collects ETR, OBR and all ARTs taken while on study Tx.
REPORTING OPTIMIZED BACKGROUND
REGIMEN (OBR)
TXW0262: Question #2 collects the initial OBR.
NOTE: Codeset is:
1-Yes, 2-No, 3-Previously established and reported
The protocol team needs to approve the OBR.
REPORTING OPTIMIZED BACKGROUND
REGIMEN (OBR) (CONT’D)
TXW0262: Question #3 collects any subsequent changes
to the Background Regimen.
NOTE: Email team prior to switching OBR.
PILL COUNTS - Adherence Assessment
QLW0211 - P1090 ETRAVIRINE (ETR) ADHERENCE
Only general adherence information is required. The
statisticians will calculate the actual percent adherence
for protocol team use.
ETR TASTE and TEXTURE
EVW0274 collects taste and texture feedback from
either the patient and/or caregiver. It also collects whether
there were problems taking Etravirine
(e.g., Refusing, gagging) and frequency of problems.
INTENSIVE PHARMACOKINETICS (PKW0318)
NOTE INSTRUCTIONS ON MISSING DOSES:
Please note that no doses within the past 7 days should be
missed. If patient is in clinic and you find that patient has
missed any doses, contact the team.
INTENSIVE PHARMACOKINETICS (PKW0318)
NOTE ETR DOSING INSTRUCTIONS
INTENSIVE PHARMACOKINETICS (PKW0318)
NOTE BLOOD DRAW COLLECTION
 Refer to
protocol and LPC
for specifics.
 Note blood
draw time
windows.
 Note
instructions on
reducing blood
draws.
P1090 POPULATION PHARMACOKINETICS
Instructions list when sample should be collected by visit week.
Food intake and any missed doses guidelines.
SPECIAL EVALUATION FORMS
RASH and DERMATOLOGIC Evaluations: Reported on SSW0031 Cutaneous Toxicity Evaluation-III. [NOTE: Urticaria and
angioedema are reported on Anaphylaxis Evaluation (SSW0032)
form.
If overall grade 2: Dermatologic evaluation is required within 2448 hours. Biopsy and/or photograph is at
the discretion of the dermatologist.
If overall grade ≥ 3: Dermatologic evaluation, biopsy and
photograph are required within 24-48 hours.]
SPECIAL EVALUATION FORMS
ANAPHYLAXIS Evaluations:
Reported on SSW0032 - Anaphylaxis Evaluation
ECG Evaluations:
Reported on DGW0086 - P1090 Electrocardiogram (ECG)
Results.
Record site ECG interpretation on this form.
****NOTE: Tracings need to be transmitted to eResearch
Technology (eRT) via study provided modem for central
reading****
RELATIONSHIP TO TREATMENT
Form instructions for safety reporting.
RELATIONSHIP CODE OPTIONS:
11-Definitely related
12-Probably related
13-Possibly related
14-Probably not related
15-Not related
-1 - Not applicable (Not a Tx Study or History/Entry)
EVALUATION FORM (PE6863):
Please establish relationship to study treatment when completing the Evaluation form and provide supporting information for this conclusion
within the form.
QA TOOLS ON DMC PORTAL
These reports are great for reviewing your own data,
or to help in answering queries.
REMEMBER
GOOD DATA IN…
GOOD RESEARCH OUT
Katherine Shin, Pharm.D.
Pharmacist
Pharmaceutical Affairs Branch
DAIDS/ NIH
Dosing Schema
 Subjects enrolled into the study will be stratified by
age and ARV exposure into one of five cohorts.
 In all cohorts, etravirine study drug will be started
concurrently with an optimized ARV background
regimen (OBR).
Cohorts
Cohort
Description of Subject
I
≥2 year to <6 years who are
treatment experienced
II
≥1 year to <2 years who are
treatment experienced
≥2 months to <1 year who are
treatment experienced
III
Drug Regimen
ETR + OBR
(1 active boosted
PI+ at least 1 other active drug)
ETR + OBR
(1 active boosted
PI+ at least 1 other active drug)
ETR + OBR
(1 active boosted
PI+ at least 1 other active drug)
Drug Regimen
 Cohort 1 will open initially. Subjects in Cohort 1 will
take an initial starting dose of etravirine tablet(s)
orally twice daily within 30 minutes following a meal
per specific Dosing Table in Appendix 3 as notified by
the Protocol Team.
Duration of Study Drug Therapy
 Minimum of 48 weeks
 Long Term Safety Follow-up: see Section 5.5.
Study Products
 Etravirine 25 mg tablet (scored)
 Etravirine 100 mg tablet (not scored)
 Tablet cutter
(for cutting etravirine 25 mg scored tablet if needed)
Etravirine Study Drugs
 Etravirine study drugs must be stored at 25°C (77°F);
with excursions permitted to 15–30°C (59-86°F) [see
USP controlled room temperature] in the pharmacy.
 Store the tablets in the original bottle.
 Keep the bottle tightly closed to protect from moisture.
 Do not remove the desiccant pouch from the bottle.
 The ETR study drug tablets are to be dispensed by the
site pharmacist in the original manufacturer’s bottle,
which contains a desiccant.
Administration of Study Drugs
 Etravirine study drugs must be administered orally
according to the dosing table* in Appendix 3.
 The study drug tablets must be swallowed whole
with a sufficient amount of water or other liquid
within 30 minutes following a meal.
*Please note that the previous age-based dosing tables have been replaced with
a single weight-based dosing table.
Administration of Study Drugs (Cont’d)
 Subjects unable to swallow the tablets whole may
disperse the tablets in a container with a minimum of
5 mL (1 teaspoon) of water or other liquids as
described in Section 5.2.
 Any missed etravirine study drug dose should be
taken by the subject if it is within 6 hours of the
scheduled missed dosing time.
 If the subject vomits the etravrine study drug dose
within 15 minutes of taking the dose, then another
full dose should be taken by the subject.
71
Communication Among Site Study Staff
 A completed prescription signed by an authorized
prescriber should include pertinent information
including the subject’s weight (kg)/Cohort, to use for
initial dosing (See Appendix 3).
 A new prescription must be provided to the site
pharmacist for adjusted dosing.
Schedule of Evaluations
73
Preparing for the study
 Submit to IRB and RSC for approval
 Alert the pharmacy to order medication
 Create Source documentation forms or use CRFs as
source documentation when appropriate (use QA/QC
committee source doc forms)
 Meet with CAB
 Identify potential subjects
Schedule of Evaluations
 Informed Consent prior to screening
 Screening
 Entry evaluations within 60 days of screening
 Day 14 (+/-4) Intensive PK visit
 Must have taken medication the last 7 days with NO missed
doses
 Adherence phone call the day prior
Study Weeks
 Weeks 4, 8, 12- have +/- 1 week window
 Week 16, 24, 32, 40 and 48 have a +/- 2 week window
Study Evaluations
• History and Physical Exam
– Make sure that documentation of side effects/AE’s and
their resolution are done within the DAIDS guidelines
• Adherence/Pill Count and phone call
• Lab work-Non-fasting
– CBC with diff /plts
– Electrolytes (Na, K, HCO3), glucose, creatinine, lipase,
phosphorus, and LFTs (total bili; indirect bili; direct bili; alk
phos; AST, ALT and albumin). Indirect bili may be calculated
by the site.
Study Evaluations (cont’d)
• Cholesterol and triglycerides
– If elevated, are elevated, subjects should return for fasting labs.
– 1 year to 2 year old fast for 4 hours
– >2 years, Fast overnight
• Coagulation assays (in Version 2.0 will be done only at selected
sites)
– PT/PTT/INR
• Urinalysis
– Point of care dipstick; send to lab if dipstick abnormal (some sites
do not allow POC testing in which case it would be sent to lab).
Study Evaluations (cont’d)
Virology Evaluations
• HIV-1 RNA PCR-IMPAACT lab and Abbott platform only
• CYP genotyping (off same tube as RNA PCR)
• HIV genotype and phenotype
Immunology Evaluations
• Lymphocyte subsets (CD4 and CD8)
• Pellets/plasma for storage
ECG
 Are read locally by the investigator
 Also read centrally by an ECG reading service
 Turnaround time is 72 hours
 If significant abnormality, investigator can request
turnaround time to be 24 hours
 May use a local cardiologist in addition
Communication and Documentation
 Patient safety is always your priority
 When questions arise, contact the local PI AND/OR the
study team
 Document!
Lab Processing Chart
P1090
Bill Kabat
Section 1: Schedule of Laboratory Evaluations
From Appendices 1A through 1D for Cohorts I, II, and III
Study Visits
Screen1
Entry
(Day 0)
Day
14
Intens
PK
Visit
Visit Windows
Wk
4
Wk 8
Wk
12
Wk
16
Wk
24
Wk 32
Wk
40
Wk
48
±1
wk
±1
wk
±1
wk
±2
wk
±2 wk
±2wk
±2 wk
±2wk
Early
Study
D/C
Virologic
failure15
LABORATORY EVALUATIONS
Hematology
1mL
1mL
1mL
1mL
1mL
1mL
1mL
1mL
1mL
1mL
1mL
1mL
1mL
Chemistries
2mL
2mL
2mL
2mL
2mL
2mL
2mL
2mL
2mL
2mL
2mL
2mL
2mL
X
X
X
3mL
3mL
3mL
4mL
4mL
2mL
2mL
2mL
Cholesterol/triglycerides
Coagulation assay
Urinalysis
2mL
X
X
3mL
3mL
2mL
2mL
2mL
2mL
2mL
2mL
X
Virology Evaluations
HIV-1 RNA PCR7
3mL
3mL
3mL
3mL
3mL
3mL
3mL
X
CYP genotyping
HIV genotype &
phenotype
3mL
4mL
Immunology Evaluations
Lymphocyte subset
2mL
2mL
2mL
2mL
2mL
2mL
storage
2mL
2mL
2mL
2mL
2mL
2mL
1mL
1mL
Pharmacology Evaluations
7mL
Intensive
Pharmacokinetics
Population PKs10
TOTAL BLOOD VOLUME
14mL
10mL
13mL
1mL
1mL
1mL
9mL
9mL
13m
L
8mL
15mL
8mL
10mL
13mL
1mL16
12mL
13mL
Notes to Section 1
 The SOE in Section 1 is identical to the protocol SOE but
only contains laboratory requirements.
 Footnotes are in section 1 but not shown here. Please
make sure to read the footnotes for various collection
and procedural details.
Blood Collection Priorities

NOTE: For insufficient blood draws, priorities are as follows:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Hematology (1mL);
Chemistry (2mL);
Pharmacology (intensive [7mL] or population [1mL]);
Virology (HIV-1 RNA PCR – 3mL);
Resistance testing (HIV genotype and phenotype – 4mL);
Lymphocyte subsets (2mL);
CYP genotyping (2mL);
Cholesterol / triglycerides (2mL); WHEN REQUIRED
Coagulation assays (2mL);
Plasma/cell pellet for storage (2mL)
Section 2: Safety/Clinical Laboratory Evaluations
Defer to local clinical specimen collection guidelines for tube types and collection volumes as needed.
Evaluation
DMC Test Code
Tests
CRF #
Hematology
N/A
CBC, differential and platelets
PE6812
Chemistry with Liver Function
Testing
N/A
Collect non-fasting. Electrolytes (sodium, potassium, and HCO3), glucose,
creatinine, lipase, phosphorus, and LFTs. LFTs should include total bilirubin,
indirect bilirubin, direct bilirubin, alkaline phosphatase, AST, ALT, and albumin.
If indirect bilirubin is not reported by the site laboratory, it should be calculated
at the site and documented.
PE6817
Cholesterol and Triglycerides
Lipid
Collect non-fasting. If a subjects laboratory results show elevated
cholesterol/triglycerides AND if the subject is ≥1 year old, the subject should be
asked to return to clinic for fasting cholesterol/triglycerides.
PE6817
Coagulation Assays
N/A
Coagulation assays should include PT, PTT and INR.
PE6812
Urinalysis
N/A
•A urine dipstick should be performed. A complete microscopic urine
assessment is required only if a urine dipstick is abnormal.
PE0811
Urine Pregnancy Test
N/A
This test will only be required during long term
follow-up testing.
Pregnancy Test must have
a <25mIU sensitivity
CD4+/CD8+
CD4/CD8
CD4/CD8 cell counts and percentages
Dual platform labs only
must also have a WBC and
diff.
LBW0054
Notes for Section 2
 This section describes clinical tests that are to be done
locally at site laboratories
 Volumes listed are recommended volumes. Sites that can
perform testing with smaller volumes are encouraged to
do so. However do not exceed the total blood draw
volumes recommended.
 Remember priority list for short draws
Section 3: Specimen Processing – Refer to Section 4 for tube types and collection volumes
Evaluation
Tube
Type
Special Collection
Notes
CRF #
DMC Test Code
Processing
Shipping
Plasma HIV-1
RNA
Abbott
Realtime HIV1
EDTA
Invert tube 8-10 times
to mix.
F3006
RNAHIV
Spin blood at 800xg for 10 min. Remove
plasma; respin plasma at 800xg for 10 min.
Prepare 2x0.8mL plasma aliquot and store
at -70Co or colder.
Perform at any local VQA certified laboratory using
the Abbott platform. If Abbott platform is not
available locally at US sites, ship 2x0.8mL plasma
aliquot to UNC real time. Complete UNC P1090
Specimen Test Requisition (Appendix V of P1090
MOP) for UNC submissions. Non-U.S. sites should
ship RNA sample real-time to the nearest local VQA
certified laboratory with the Abbott platform.
CYP
Genotyping
EDTA
Packed blood cells
from a RNA PCR
collection is to be
prepared for this
assay.
F3006
PKGENO
Save packed cells from RNA PCR plasma
collection. Vortex packed blood cells and
transfer to a cryovial. Store at -70Co or
colder
CYP specimens should be batch shipped upon
request to BRI.
Plasma for
HIV genotype
and
phenotype
EDTA
Recommended
genotyping labs are
listed in Section 5 of
the LPC. HIV
phenotyping is to be
sent to Monogram
Biosciences.
F3006
GENOHIV
&
PHENOHIV
Spin blood at 800xg for 10 min. Remove
plasma; respin plasma at 800xg for 10 min.
Prepare 2x1.0mL plasma aliquots and store
at -70Co or colder until shipped to
appropriate laboratory
Shipping is collection and cohort specific as follows:
SCREENING (genotyping): Ship real time to closest
genotyping lab. Phenotyping: U.S. and Brazil – ship
real time to Monogram, All other sites – ship to BRI
as a pass through to Monogram.
Virologic Failure/Early Study D/C: (genotyping) All
sites - ship samples quarterly to closest VQA
certified genotyping lab. Phenotyping samples: U.S.
and Brazil – ship quarterly to Monogram. All other
sites – ship quarterly to BRI as a pass through to
Monogram.
Stored
Plasma
EDTA
NA
SPW0457
STORIMM
Spin blood at 400xg for 10 min. remove
plasma, respin plasma at 800xg for 10mins.
Prepare 2 x 0.5mL plasma aliquots and
store at -70Co or colder.
Ship to appropriate repository quarterly.
Stored PBMC
pellets
EDTA
NA
SPW0457
STORIMM
See Cross-Network PBMC Processing SOP
for PBMC isolation Prepare 2 (2x106
pellets). Store pellets at -70Co or colder
Ship to appropriate repository quarterly.
Intensive
PK’s
EDTA
Spray
Dried
Only
PK draw times are predose, 1, 2, 4, 6, 9, & 12
hours post dose.
Process within 1 hour
of collection.
PKW0318
PK-INT
Spin blood at 800g for 10min. remove
plasma and prepare a single aliquot for each
time point and store at -70Co or colder.
U.S. sites ship PKs real time to U. Colorado PK
Lab. All other sites - ship real time to BRI as pass
through to U. Colorado. See MOP 7.5.1 for pass
through instructions.
Remember to ship CRFs with PK samples.
Population
PK
EDTA
Spray
Dried
Only
Process within 1 hour
of collection.
PKW0319
PK-POP
Spin blood at 800xg for 10min. remove
plasma. Prepare a single aliquot for each
time point and store at -70Co or colder.
All sites should batch ship PKs at the end of the
study per team call-in instructions. U.S. sites will
batch ship PKs directly to U. Colorado PK Lab.
All other sites ship PK samples to U. Colorado
as BRI pass-through samples upon call-in.
Remember to ship CRFs with PK samples.
Notes for Section 3
 Abbott RealTimeTM is required for viral load testing
 CYP Genotyping is to be collected is prepared from the viral load collection. If
missed at screen, prepare at another viral load point.
 HIV Geno and phenotyping at screening is to be done real time. Early D/C and
virologic failure typing is to be batch shipped quarterly. Note that US site shipments
of these samples sent directly to testing labs. All non-US sites are to ship samples as
pass-through to BRI.
 Intensive PKs are to be sent real-time to U.Colorado US sites will ship directly and
non-US labs will ship to BRI as pass-through to U. Colorado.
 Population PK samples will be held locally until the P1090 team calls in the
samples. The mechanisms for shipping are the same as described above for
Intensive PKs. Note: Timing of popPK collection varies by study week. Examples:
Week4 - collect 1-4 hours post etravirine dose. Week 8 – collect 4-8 hours post
dose.
 For all PK shipments: Remember to submit PK CRFs when shipping PK samples to
U. Colorado.
Section 4 Sample
Entry evaluations by visit
Evaluation
Specimen
CRF
Aliquots
LDMS Code
Special Notes
Hematology
1mL EDTA blood
PE6812
N/A
N/A
Send to local lab
Chemistries
2mL NON or SST blood
PE6817
N/A
N/A
Send to local lab
Cholesterol/Triglyceri
des
2mL NON or SST blood
PE6817
N/A
N/A
Non-fasting.
Urinalysis
5-10mL clean catch
urine if possible.
PE0811
N/A
N/A
Send to testing lab as
soon as possible.
Refrigerate if there is
a delay in testing.
Abbott RealTime
HIV-1 RNA PCR
3mL EDTA blood
F3006 and
F3109 if
results are
not reported
in the LDMS
Freeze 2 x 0.8mL plasma
aliquots at
-70Co or lower.
BLD/EDT/PL2
Can be performed at
any VQA certified
local laboratory.
CYP Genotyping
Packed cells from RNA
sample above
F3006
Mix and transfer packed cell to
a single 2mL cryovial
BLD/EDT/WBP
Batch Ship to BRI
Lymphocyte Subsets
2mL EDTA (Spray Dried
Only) blood
LBW0054
None
BLD/EDT/BLD (if
entered into the
LDMS)
Send to local IQA
certified lab at
ambient temps.
Section 4 Notes
 Section 4 information is largely for laboratorians and
phlebotomists.
 Population PK collection timing information is noted in
section 4 as it is in Section 1.
 Appendix 1E information is incorporated after Early D/C
Visit Section evaluations.
Other LPC Sections
 Long Term Safety Follow-up Section contains
Appendix F table (lab piece) and Section 4 type
information.
 Section 5. Contains Shipping information details, a
link to additional lab manual information and revision
history of The LPC. NOTE: Contact Tim Persyn when
shipping to Monogram.
 Note that Repository storage is dependent on site
funding source. NICHD sites are to ship samples for
storage to the Fisher Repository. NIAID sites are to
ship samples for storage to BRI.
Questions?
[email protected]
93