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IMPAACT 2014Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A) in HIV-1-infected Children and Adolescents

IMPAACT 2014 Design: Phase I/II, multi-site, open-label, non-comparative PK and safety study Population: HIV-1-infected children and adolescents, from 12 years to less than 18 years of age who weigh at least 35 kg. Cohort 1 and 2 will enroll sequentially: Cohort 1: Virologically suppressed on a combination of DTG or RAL plus two NRTIs Cohort 2: Antiretroviral treatment naïve or virologically suppressed Sample Size:Cohort 1: Up to 20 participants to achieve 12 evaluableCohort 2: Up to 45 participants to achieve 40 evaluable

Primary Objectives: Cohort 1 • Evaluate the pharmacokinetics of a single-dose of DOR in HIV-1-infected children and adolescents, when added to a stable ART regimen of one InSTI plus two NRTIs, using intensive PK sampling at Entry for identification of minimum weight threshold for DOR 100 mg dose • Evaluate the 2-week safety and tolerability of a single-dose of DOR in HIV-1-infected children and adolescents, when added to a stable ART regimen of one InSTI plus two NRTIs

Primary Objective: Cohort 2 • Evaluate the 24-week safety and tolerability of DOR/3TC/TDF in HIV-1-infected children and adolescents

IMPAACT 2014Eligibility Criteria For Cohort 1 only

Inclusion Criterion 4.1.4 Question: A potential participant is a long-standing patient at your clinic, who was diagnosed with HIV infection as an infant. • Adequate documentation of an antibody test is available, including date of specimen collection, date of testing, test performed, and test result. • The child also has had viral load tests performed annually. Is any further testing required? • Yes • No • Maybe

Let’s break this down… Question: A potential participant is a long-standing patient at your clinic, who was diagnosed with HIV infection as an infant. • Adequate documentation of an antibody test is available, including date of specimen collection, date of testing, test performed, and test result. • The child also has had viral load tests performed annually. Is any further testing required?

Let’s break this down… Question: A potential participant is a long-standing patient at your clinic, who was diagnosed with HIV infection as an infant. • Adequate documentation of an antibody test is available, including date of specimen collection, date of testing, test performed, and test result. • The child also has had viral load tests performed annually. Is any further testing required? Sample #1

Let’s break this down… Question: A potential participant is a long-standing patient at your clinic, who was diagnosed with HIV infection as an infant. • Adequate documentation of an antibody test is available, including date of specimen collection, date of testing, test performed, and test result. • The child also has had viral load tests performed annually. Is any further testing required? What antibody test was performed? Was it a rapid test? Were 2 rapid tests performed? Was the testing done in a lab that operates according to GCLP guidelines and participates in an EQA program? Sample #1

Let’s break this down… Question: A potential participant is a long-standing patient at your clinic, who was diagnosed with HIV infection as an infant. • Adequate documentation of an antibody test is available, including date of specimen collection, date of testing, test performed, and test result. • The child also has had viral load tests performed annually. Is any further testing required? Sample #2

Let’s break this down… Question: A potential participant is a long-standing patient at your clinic, who was diagnosed with HIV infection as an infant. • Adequate documentation of an antibody test is available, including date of specimen collection, date of testing, test performed, and test result. • The child also has had viral load tests performed annually. Is any further testing required? Was the testing performed in a CLIA-certified lab? Is adequate source documentation available? Sample #2

Inclusion Criterion 4.1.5.1, Cohort 1: ART Exposure Requirements Which of the following must be met for inclusion into Cohort 1? At entry, receiving combination ART withRAL or DTG plus 2 NRTIs At entry, has not received NNRTIs, PIs, or cobicistat within the previous 30 days Neither are true Both are true

Confirmation of Virologic Suppression (1) A potential participant comes to your clinic for screening on 31 January 2018. Medical records show one viral load result from 6 January 2017 that was <40 copies/mL. His viral load from screening is <40 copies/mL. Is this adequate for inclusion?

Confirmation of Virologic Suppression (1) A potential participant comes to your clinic for screening on 31 January 2018. Medical records show one viral load result from 6 January 2017 that was <40 copies/mL. His viral load from screening is <40 copies/mL. Is this adequate for inclusion? • Answer: Yes!

Confirmation of Virologic Suppression (2)A potential participant comes to your clinic for screening on 31 January 2018. Medical records show viral load results from 6 January 2017 that was <40 copies/mL and from 27 December 2017 that was 45 copies/mL. His viral load from screening is <40 copies/mL. Is this adequate for inclusion?

Confirmation of Virologic Suppression (2)A potential participant comes to your clinic for screening on 31 January 2018. Medical records show viral load results from 6 January 2017 that was <40 copies/mL and from27 December 2017 that was 45 copies/mL. His viral load from screening is <40 copies/mL. Is this adequate for inclusion? • Answer: No! This participant has a viral load within 3 months of entry that is above the level of quantification

Confirmation of Virologic Suppression (3) A potential participant comes to your clinic for screening on 31 January 2018. Medical records show viral load results from 6 January 2017 that was <40 copies/mL and from 2 October 2017 that was 45 copies/mL. His viral load from screening is <40 copies/mL. Is this adequate for inclusion?

Confirmation of Virologic Suppression (3) A potential participant comes to your clinic for screening on 31 January 2018. Medical records show viral load results from 6 January 2017 that was <40 copies/mL and from 2 October 2017 that was 45 copies/mL. His viral load from screening is <40 copies/mL. Is this adequate for inclusion? • Answer: Yes! The VL greater than the level of detection was less than 500 copies/mL, was not confirmed, and between 3 and 15 months prior to Entry.

Inclusion Criterion 4.1.6 Which of the following values are acceptable for inclusion? Grade 1 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening Grade 2 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening Grade 3 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening

Inclusion Criteria 4.1.9, 4.1.10, 4.1.11 Which of the following are true regarding contraception and pregnancy testing requirements for IMPAACT 2014? • All females who have reached menarche must use effective contraception • All females must have a negative pregnancy test at entry • Females engaging in sexual activity that could lead to pregnancy must agree to use contraception • Males who are engaging in sexual activity must use condoms • Only C and D are true

Study Entry Which of the following evaluations must be performed at the Entry Visit prior to enrollment? Update medical and medications history since last visit Collect blood for CBC, chemistries, CD4 cell counts, HIV-1 RNA, and intensive PK evaluation Collect blood or urine for a pregnancy test Prescribe study drug

Sequence of Entry Visit Procedures

Physical exam • Pulse • Weight • Neurological exam • Sexual Maturity Rating • Height • A, B, and E only • B, D, and E only • All of the above Which of the following are required as part of the physical examination at the Entry visit?

Physical exam

Sequence of Entry Visit Procedures

Cohort 1 Study Drug Administration

The palatability and acceptability assessment must be administered AFTER administration of the DOR dose. When would you administer the questionnaire? Immediately after the participant swallows the tablet At the next study visit Something else

Cohort 1 Intensive PK Evaluation Sampling Time Points

Sequence of Entry Visit Procedures (continued) • Administer palatability & acceptability assessment • Plan for next PK collections • Schedule Week 2 visit and provide site contact instructions

What tube volume is required for the intensive PK evaluation blood collections? 1.0 mL K2 EDTA 3.5 mL K2 EDTA 2.0 mL K2 EDTA 1.0 mL externally threaded cryotube

What tube volume is required for the intensive PK evaluation blood collections? It is essential to use the correct tube volume and tube type so as not to compromise sample integrity and laboratory results. 1.0 mL K2 EDTA 3.5 mL K2 EDTA 2.0 mL K2 EDTA 1.0 mL externally threaded cryotube

For each PK blood sample obtained during the intensive PK evaluations, how long do you have to process the sample? Within 30 minutes of specimen collection Within 1 hour of specimen collection Within 2 hours of specimen collection

For each PK blood sample obtained during the intensive PK evaluations, how long do you have to process the sample? Specimens should be processed within 30 minutes of collection. If processing will be delayed (e.g., due to home collection, tubes must remain in an ice bath (NOT FROZEN) and processed within 2 hours of collection. Within 30 minutes of specimen collection Within 1 hour of specimen collection Within 2 hours of specimen collection

Sequence of Entry Visit Procedures (continued) • Depending on site capacity and participant preferences, participants and their parents or guardians may stay at the clinical research facility overnight for the PK sampling.

When should the intensive PK samples be shipped? Immediately after completion of the visit After the shipping box is full After all enrolled participants at you site have completed the visit

Which forms should you complete first when entering into Medidata Rave? Visit Tracking (ADM10027) IMPAACT 2014 Study Event (SVW10003) Adverse Event Log (ADE10000) A and B only A and C only B and C only All of the above

On which of the following can the Week 2 visit be scheduled? Day 11 after Entry Day 13 after Entry Day 17 after Entry

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