impaact p1090 a phase i/ii, open-label trial to evaluate safety, tolerability, pharmacokinetics and...
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IMPAACT P1090IMPAACT 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: Richard RutsteinProtocol Vice Chairs: Rolando Viani, Andrew Wiznia, Rami YogevNIAID Medical Officer: Ellen Townley NICHD Medical Officer: George SiberryClinical Trials Specialist: Megan Valentine and Kathryn LypenStatisticians: Terry Fenton and Carmelita AlveroPharmacologists: Jennifer Kiser and Joseph RowerLaboratory Technologist: Bill KabatData Manager: Bobbie Graham
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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.
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Objectives 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.
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Schema/Study DesignSchema/Study DesignDESIGN: 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)
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Inclusion/Exclusion CriteriaInclusion/Exclusion CriteriaCohorts I, II, III:
Ages 2 months-6yrsFailing 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
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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 assessmentchanges 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.
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Description of Cohorts
Cohor
t
Description of
Subject
Drug
Regimen
Phenotyping /Genotyping Information
Comments
Anticipated Accrual
MiniCohort
To complete
a full cohort
Total coho
rt size
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
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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
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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.
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Algorithm for Cohort Management
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SafetyLess neuropsych symptoms than reported for EFVRash 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
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Endpoints/Data Analysis
PK parameters as notedSafetyVirologic 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 24o 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 responsesAlso will look at CYP genotype vs. PK of ETR
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Screening
Request screening slot- if approved, must screen within two weeks
Screening requires real time geno- and phenotype assaysECG also required (via eRT)OBR must be approved prior to enrollmentPossible 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)
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eResearchTechnology, Inc. (ERT)
Centralized Digital 12-Lead ECG Services
DAIDSP1090
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 PortalCreating an account
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 PortalLogging in
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.
Click Site Qualification tab Enter the protocol Qualification PIN and the Site Country and click “New Form”
My Study PortalSite Qualification
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
Use the radio button to collapse fields if contact details are the same Specify if the user needs a My Study Portal account creating
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.
My Study PortalSite Qualification
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
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 Results ReportingMy Study Portal ECG reports and waveforms
ECG Analysis Report
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
Avoiding Queries
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]
Customer Care
Enrollment Visit
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Enrollment
Must be within 60 days of screeningStart ETR + OBR togetherOBR must be approved by the team first
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Intensive PK Visit
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Intensive PKTo be done on study day 14 (+/- 4 days)Subjects to have taken ETR doses for 7 days prior to
intensive PK, with no missed dosesSites encouraged to contact subjects family day before
intensive PK visit, to confirm full complianceIf missed dose, reschedule intensive PK to occur 7-14 days
after last missed doseIf 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 clinicPK dose of medication to be administered within 30 minutes of start of meal
Heparin lock to be used for intensive PK if possibleIf 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 visitIf 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
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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.
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Population PK Visit
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Population PKBlood samples collected at weeks 4, 8, 12, 24, 48, and determination of
virologic failureRe-schedule if missed any of last 3 dosesDepending on week, samples to be collected at varying times post ETR
dose
Sample obtained
Week4
Week8
Week 12
Week24
Week 48
1-4 H post ETR
X X
4-8 H post ETR
X
8-12 H post ETR
X X
Virologic Failure
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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
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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 multiformeSuspected 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
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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-AAcute systemic allergic AE: Protocol Appendix VII-B
All events submitted must have a updated final/stable outcome status, unless final/stable at initial report .
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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 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…should also usually be considered serious.”
(ICH E2A)
IMPAACT P1090 Enrollment Procedures and
Case Report Forms (CRF) Tips
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
www.fstrf.orgTo 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’.
PHASE/ACCRUAL REPORT on DMC WEBPAGEExample of Phase/Accrual Report
Currently only Cohort I for ≥2 to <6 years of age is open
SCR0022 - P1090 SCREENING FAILURE/NON-ENROLLMENT 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
Start Stop date date
PE0420
DURING while on
study treatment
Start Stop date date
TXW0262
AFTER stopping study
treatment
Start Stop date date
PE0420
REPORTING Tx INITIATION DELAYCASE: 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)
Leading question indicates “2-No modifications including Tx initiation” were made.
TXW0262: Form #1 shows that study Tx was not started.
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)
The protocol team needs to approve the OBR.
TXW0262: Question #2 collects the initial OBR. NOTE: Codeset is:
1-Yes, 2-No, 3-Previously established and reported
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)
Refer to protocol and LPC for specifics.
Note blood draw time windows.
Note instructions on reducing blood draws.
NOTE BLOOD DRAW COLLECTION
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 24-48 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 FORMSANAPHYLAXIS 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 TREATMENTForm instructions for safety reporting.
EVALUATION FORM (PE6863): Please establish relationship to study treatment when completing the Evaluation form and provide supporting information for this conclusion within the form.
RELATIONSHIP CODE OPTIONS:
11-Definitely related 14-Probably not related 12-Probably related 15-Not related13-Possibly related -1 - Not applicable (Not a Tx Study or History/Entry)
QA TOOLS ON DMC PORTALThese reports are great for reviewing your own data, or to help in answering queries.
GOOD DATA IN…GOOD RESEARCH OUT
REMEMBER
Pharmacy Considerations IMPAACT P1090
Katherine Shin, Pharm.D.Pharmacist
Pharmaceutical Affairs BranchDAIDS/ 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
Drug Regimen
I
≥2 year to <6 years who are
treatment experienced
ETR + OBR (1 active boosted
PI+ at least 1 other active drug)
II
≥1 year to <2 years who are
treatment experienced
ETR + OBR (1 active boosted
PI+ at least 1 other active drug)
III
≥2 months to <1 year who are treatment experienced
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.
Etravirine 25 mg tablet (scored)
Etravirine 100 mg tablet (not scored)
Tablet cutter (for cutting etravirine 25 mg scored tablet if needed)
Study Products
Etravirine Study DrugsEtravirine 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 DrugsEtravirine 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.
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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 approvalAlert the pharmacy to order medicationCreate Source documentation forms or use CRFs as
source documentation when appropriate (use QA/QC committee source doc forms)
Meet with CABIdentify potential subjects
Schedule of Evaluations
Informed Consent prior to screeningScreeningEntry evaluations within 60 days of screeningDay 14 (+/-4) Intensive PK visit
Must have taken medication the last 7 days with NO missed doses
Adherence phone call the day prior
Study WeeksWeeks 4, 8, 12- have +/- 1 week windowWeek 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 phenotypeImmunology Evaluations• Lymphocyte subsets (CD4 and CD8)• Pellets/plasma for storage
ECGAre read locally by the investigatorAlso read centrally by an ECG reading service
Turnaround time is 72 hoursIf 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 priorityWhen questions arise, contact the local PI AND/OR the
study teamDocument!
Lab Processing ChartP1090
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
IntensPK
Visit
Wk 4
Wk 8 Wk 12
Wk 16
Wk 24
Wk 32 Wk 40
Wk 48
EarlyStudy D/C
Virologic failure15
Visit Windows ±1 wk
±1 wk
±1 wk
±2 wk
±2 wk ±2wk ±2 wk ±2wk
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
Cholesterol/triglycerides 2mL 2mL 2mL 2mL
Coagulation assay 2mL 2mL 2mL 2mL
Urinalysis X X X X X X
Virology Evaluations
HIV-1 RNA PCR7 3mL 3mL 3mL 3mL 3mL 3mL 3mL 3mL 3mL 3mL 3mL 3mL 3mL
CYP genotyping X
HIV genotype & phenotype
4mL 4mL 4mL
Immunology Evaluations
Lymphocyte subset 2mL 2mL 2mL 2mL 2mL 2mL 2mL 2mL 2mL 2mL 2mL 2mL
storage 2mL 2mL
Pharmacology Evaluations
Intensive Pharmacokinetics
7mL
Population PKs10 1mL 1mL 1mL 1mL 1mL 1mL16
TOTAL BLOOD VOLUME 14mL 10mL 13mL 9mL 9mL 13m
L8mL 15mL 8mL 10mL 13mL 12mL 13mL
Notes to Section 1The 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. Hematology (1mL); 2. Chemistry (2mL); 3. Pharmacology (intensive [7mL] or population [1mL]);4. Virology (HIV-1 RNA PCR – 3mL); 5. Resistance testing (HIV genotype and phenotype – 4mL); 6. Lymphocyte subsets (2mL); 7. CYP genotyping (2mL); 8. Cholesterol / triglycerides (2mL); WHEN REQUIRED9. Coagulation assays (2mL); 10. Plasma/cell pellet for storage (2mL)
Section 2: Safety/Clinical Laboratory EvaluationsDefer 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 LipidCollect 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/AThis 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 2This section describes clinical tests that are to be done
locally at site laboratoriesVolumes 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 HIV-
1
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.
F3006PKGENO
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.
F3006GENOHIV
&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 SPW0457STORIMM
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 SPW0457STORIMM
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
EDTASpray Dried Only
PK draw times are pre-dose, 1, 2, 4, 6, 9, & 12 hours post dose.
Process within 1 hour of collection.
PKW0318PK-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
EDTASpray Dried Only
Process within 1 hour of collection.
PKW0319PK-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 SampleEntry 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/Triglycerides
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 SectionsLong 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.
