Webinar Reminder and Study Details

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Reminder: Document this training! Study IoRs are responsible for ensuring that study staff members are adequately trained to serve their designated site- and study-specific functions. Per the DAIDS policy on Requirements for Manual of Operational Procedures, all sites must establish and follow a standard operation procedure (SOP) for personnel training and certification documentation. Each IoR (or designee) is responsible for documentation of eachstudy staff member completing study-specific training modules and webinars corresponding to their designated role. This documentation must be on file at the site and available for inspection/monitoring at any time, and per this SOP. 2 1

Reminder: Document this training! Study CTSs will provide an email documenting the training was conducted. Sites: you are responsible for documenting individual staff attendance of this webinar. A sample sign-in log is shown here, but a site institution s format (or the format specified in the training SOP) may be used. 2

IMPAACT 2014 Phase 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 na ve or virologically suppressed Sample Size: Cohort 1: Cohort 2: Up to 20 participants to achieve 12 evaluable Up to 45 participants to achieve 40 evaluable 5

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 6

Primary Objective: Cohort 2 Evaluate the 24-week safety and tolerability of DOR/3TC/TDF in HIV-1-infected children and adolescents 7

IMPAACT 2014 Eligibility 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? A. Yes B. No C. Maybe 9

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? A. Yes B. No C. Maybe 10

Lets 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? 11

Lets 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 12

Lets 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 13

Lets 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 14

Lets 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 15

Inclusion Criterion 4.1.5.1, Cohort 1: ART Exposure Requirements Which of the following must be met for inclusion into Cohort 1? A. At entry, receiving combination ART with RAL or DTG plus 2 NRTIs B. At entry, has not received NNRTIs, PIs, or cobicistat within the previous 30 days C. Neither are true D. Both are true 16

Inclusion Criterion 4.1.5.1, Cohort 1: ART Exposure Requirements Which of the following must be met for inclusion into Cohort 1? A. At entry, receiving combination ART with RAL or DTG plus 2 NRTIs B. At entry, has not received NNRTIs, PIs, or cobicistat within the previous 30 days C. Neither are true D. Both are true 17

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? 18

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! 19

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? 20

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? Answer: No! This participant has a viral load within 3 months of entry that is above the level of quantification 21

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? 22

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. 23

Inclusion Criterion 4.1.6 Which of the following values are acceptable for inclusion? A. Grade 1 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening B. Grade 2 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening C. Grade 3 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening 24

Inclusion Criterion 4.1.6 Which of the following values are acceptable for inclusion? A. Grade 1 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening B. Grade 2 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening C. Grade 3 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens obtained at screening 25

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? A. All females who have reached menarche must use effective contraception B. All females must have a negative pregnancy test at entry C. Females engaging in sexual activity that could lead to pregnancy must agree to use contraception D. Males who are engaging in sexual activity must use condoms E. Only C and D are true 26

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? A. All females who have reached menarche must use effective contraception B. All females must have a negative pregnancy test at entry C. Females engaging in sexual activity that could lead to pregnancy must agree to use contraception D. Males who are engaging in sexual activity must use condoms E. Only C and D are true 27

Study Entry Which of the following evaluations must be performed at the Entry Visit prior to enrollment? A. Update medical and medications history since last visit B. Collect blood for CBC, chemistries, CD4 cell counts, HIV-1 RNA, and intensive PK evaluation C. Collect blood or urine for a pregnancy test D. Prescribe study drug 28

Study Entry Which of the following evaluations must be performed at the Entry Visit prior to enrollment? A. Update medical and medications history since last visit B. Collect blood for CBC, chemistries, CD4 cell counts, HIV-1 RNA, and intensive PK evaluation C. Collect blood or urine for a pregnancy test D. Prescribe study drug 29

Sequence of Entry Visit Procedures Conduct final eligibility determination and confirmation (medical history, complete physical exam, and pregnancy testing) Enter checklist into SES to enroll participant and generate SID Collect blood for CBC, chemistries, and pre-dose PK sample Prescribe, dispense, and facilitate administration of the DOR dose 30

Physical exam Which of the following are required as part of the physical examination at the Entry visit? A. Pulse B. Weight C. Neurological exam D. Sexual Maturity Rating E. Height F. A, B, and E only G. B, D, and E only H. All of the above 31

Physical exam Which of the following are required as part of the physical examination at the Entry visit? A. Pulse B. Weight C. Neurological exam D. Sexual Maturity Rating E. Height F. A, B, and E only G. B, D, and E only H. All of the above 32

Physical exam 33

Sequence of Entry Visit Procedures Conduct final eligibility determination and confirmation (medical history, complete physical exam, and pregnancy testing) Enter checklist into SES to enroll participant and generate SID Collect blood for CBC, chemistries, and pre-dose PK sample Prescribe, dispense, and facilitate administration of the DOR dose 34

Sequence of Entry Visit Procedures Conduct final eligibility determination and confirmation (medical history, complete physical exam, and pregnancy testing) Enter checklist into SES to enroll participant and generate SID Collect blood for CBC, chemistries, and pre-dose PK sample Prescribe, dispense, and facilitate administration of the DOR dose 35

Cohort 1 Study Drug Administration Storage Dose Store between 2 C and 30 C (36 F-86 F) Protect from light & moisture, in original container, tightly closed 100 mg tablet Added to current regimen of DTG or RAL Dispensing & Administering Single dose, administered orally Directly observed in clinic on the day of intensive PK evaluations Must be swallowed whole do NOT crush or split Formulation Film-coated, compressed oral tablet 10 tablets per bottle 36

The palatability and acceptability assessment must be administered AFTER administration of the DOR dose. When would you administer the questionnaire? A. Immediately after the participant swallows the tablet B. At the next study visit C. Something else 37

The palatability and acceptability assessment must be administered AFTER administration of the DOR dose. When would you administer the questionnaire? A. Immediately after the participant swallows the tablet B. At the next study visit C. Something else 38

Cohort 1 Intensive PK Evaluation Sampling Time Points 39

Sequence of Entry Visit Procedures (continued) Collect blood for 1 hour post-dose PK sample ( 15 minutes) Administer palatability & acceptability assessment Plan for next PK collections Schedule Week 2 visit and provide site contact instructions Collect blood for 2 hours post-dose PK sample ( 15 minutes) Collect blood for 4 hours post-dose PK sample ( 1 hour) Collect blood for 8 hours post-dose PK sample ( 1 hour) Collect blood for 12 hours post-dose PK sample ( 1 hour) 40

What tube volume is required for the intensive PK evaluation blood collections? A. 1.0 mL K2 EDTA B. 3.5 mL K2 EDTA C. 2.0 mL K2 EDTA D. 1.0 mL externally threaded cryotube 41

What tube volume is required for the intensive PK evaluation blood collections? A. 1.0 mL K2 EDTA B. 3.5 mL K2 EDTA C. 2.0 mL K2 EDTA D. 1.0 mL externally threaded cryotube It is essential to use the correct tube volume and tube type so as not to compromise sample integrity and laboratory results. 42

For each PK blood sample obtained during the intensive PK evaluations, how long do you have to process the sample? A. Within 30 minutes of specimen collection B. Within 1 hour of specimen collection C. Within 2 hours of specimen collection 43

For each PK blood sample obtained during the intensive PK evaluations, how long do you have to process the sample? A. Within 30 minutes of specimen collection B. Within 1 hour of specimen collection C. Within 2 hours of specimen collection 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. 44

Sequence of Entry Visit Procedures (continued) Collect blood for 24 hours post-dose PK sample ( 2 hours) 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. Collect blood for 48 hours post-dose PK sample ( 2 hours) Collect blood for 72 hours post-dose PK sample ( 2 hours) Ship intensive PK samples immediately after completion of the visit 45

When should the intensive PK samples be shipped? A. Immediately after completion of the visit B. After the shipping box is full C. After all enrolled participants at you site have completed the visit 46

When should the intensive PK samples be shipped? A. Immediately after completion of the visit B. After the shipping box is full C. After all enrolled participants at you site have completed the visit 47

Which forms should you complete first when entering into Medidata Rave? A. Visit Tracking (ADM10027) B. IMPAACT 2014 Study Event (SVW10003) C. Adverse Event Log (ADE10000) D. A and B only E. A and C only F. B and C only G. All of the above 48

Which forms should you complete first when entering into Medidata Rave? A. Visit Tracking (ADM10027) B. IMPAACT 2014 Study Event (SVW10003) C. Adverse Event Log (ADE10000) D. A and B only E. A and C only F. B and C only G. All of the above 49

On which of the following can the Week 2 visit be scheduled? A. Day 11 after Entry B. Day 13 after Entry C. Day 17 after Entry 50