Protocol References

1. 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

2. Protocol References

3. Protocol References (cont.)

4. Recruitment, Screening, and Enrollment in Cohort 1

5. Recruitment Context Recruitment of participants for Cohort 1 is expected to rely on current patients being seen at a study clinic or from active identification and referral of HIV-1-infected children and adolescents who are ART-experienced and virologically suppressed

6. Informed Consent Upon identification of a potentially eligible adolescent, study staff will provide information about the study to the parent or guardian and/or the potential participant (as applicable). Those who express interest in learning more about the study will be provided additional information, education, and counseling as part of the study informed consent process. The process will include detailed review of the study informed consent and assent forms (as applicable), time to address any questions or concerns the potential participant, parent, or guardian may have, and an assessment of understanding, before proceeding to informed consent and assent decisions. Written informed consent must be obtained before any study-specific screening procedures are performed.

7. Additional Considerations for Informed Consent Site SOPs for obtaining informed consent and assent should detail the operational approach that each site will take to fulfill the requirements of the study Site IRB/EC risk determinations will guide whether the consent of one or both parents may be required for this study. All IRB/EC requirements must be followed Based on the age range of participants in this study, it is generally anticipated that potential participants will be asked to provide informed assent Consent status for study participation is captured in the study database on LGW10010, Informed Consent Status Log

8. Additional Considerations for Informed Consent Should the consenting parent (or guardian) of a participant die or no longer be available for any reason, sites should follow the guidelines and procedures as described by their IRBs/ECs. Given the duration of study participation in Cohort 1, this scenario is very unlikely See protocol Sections 4.6 and 13.3

9. Consent for Storage and Future Research Testing Consenters will be asked whether they agree to storage and future research testing of biological specimens remaining after all protocol-specified testing has been performed This storage and future use is optional and may be declined with no impact on other aspects of study participation Genetic testing of residual specimens is optional and may be declined Consent status for storage and future use is captured in the study database on TRK1000, Specimen Consent for Non-Protocol Defined Testing

10. Eligibility Screening Each site must establish SOPs for eligibility determination that describe: • Where and when screening procedures will be performed • Roles and responsibilities for performing the required procedures • Roles and responsibilities for assessing and confirming eligibility • Procedures and materials for documenting the process Taking into consideration the required timing of enrolment

11. Process Flow START Informed Consent Obtained ? Initiate study drug and follow per SoE • Assign PIDs • Obtain screening number from SES yes yes Enrolled in SES ? yes Eligible? no no no STOP Enter eCRF to record screen failure STOP

12. Two Schedules of Evaluations Cohort 1

13. Two Schedules of Evaluations Cohort 2

14. Cohort 1Evaluations

15. Appendix I-A:Schedule of Evaluations for Cohort 1

16. Appendix I-A:Schedule of Evaluations for Cohort 1 Details previously included in SoE footnotes are now in Section 6. Footnotes continue to be important reminders of key procedures but most of the detail for each visit is included in subsections of Section 6. Note that there are only TWO footnotes in the Cohort 1 SoE.

17. Section 6: Example of Procedure Table

18. Section 6: Example of Procedural Text

19. Cohort 1 Screening Reminders

20. Cohort 1 Screening Reminders Potential participants may be screened up to 30 days prior to Entry

21. Cohort 1 Screening Reminders Potential participants may be screened up to 30 days prior to Entry Multiple visits may be conducted within the 30 days

22. Cohort 1 Screening Reminders Potential participants may be screened up to 30 days prior to Entry Multiple visits may be conducted within the 30 days Screening is discontinued when ineligibility is determined

23. Cohort 1 Screening Reminders Potential participants may be screened up to 30 days prior to Entry Multiple visits may be conducted within the 30 days Screening is discontinued when ineligibility is determined Screening procedures may be repeated, with the latest outcome used for eligibility determination

24. Cohort 1 Screening Reminders Potential participants may be screened up to 30 days prior to Entry Multiple visits may be conducted within the 30 days Screening is discontinued when ineligibility is determined Screening procedures may be repeated, with the latest outcome used for eligibility determination Participants may be re-screened once in a six-month period

25. Repeat Screening Attempts Participants may be re-screened once in a six-month period if determined to be ineligible on the initial screening process. In this case, all procedures listed in protocol Section 6.1, must be repeated except: • New PIDs should not be assigned • Confirmatory HIV testing and genotype need not be repeated • Previously documented medical and medications history information should be reviewed and updated through the date of re-screening (it is not necessary to re-record history information that was previously documented) • Informed consent need not be repeated, if re-screening occurs less than 60 days after the initial consent

26. Cohort 1 Screening Visit Operational guidance for the Screen Visit are included in protocol Section 6.1

27. Cohort 1 Screening Visit

28. Medical History protocol Section 6.7 describes the process of obtaining a complete medical and medications history, required at screening and each scheduled visit. • Protocol Table 17 lists documentation requirements for medical and medication history • History maybe obtained from individual or parent/guardian’s report • Available medical records should be obtained when possible

29. Medical History • Documented medical conditions will be assessed for severity as described in Section 7.3.3 • New conditions occurring during follow-up will also be assessed for relationship to study drug asdescribed in Section 8.1. • Relevant dates will be recorded for all conditions and medications. • Baseline history is established at Screening and Entry • Interval histories are obtained at follow up visits

30. Physical exam • A physical examination is required at each scheduled visit. For Cohort 1, complete exams are required at the Screening and Entry Visits; a symptom-directed exam is required at Week 2. • The complete exam includes height/weight and vital signs, and all body systems, include Neuro and Sexual Maturity rating (at Entry)

31. Confirmatory HIV Testing Testing for HIV infection may be done at the Screen Visit if needed per protocol Section 4.1.2

32. Other Laboratory Evaluations • Chemistries at screening: • Creatinine • Lipase • LFTs (AST, ALT, and alkphos)

33. Estimating Glomerular Filtration Rate Inclusion criteria 4.1.8 requires eGFR ≥60 mL/min/1.73 m2, on specimens obtained at screening, As soon as the creatinine result is obtained, the estimated GFR should be calculated using the Schwartz formula, graded for severity, and assessed for clinical significance concurrent with all other laboratory test results. GFR (mL/min/1.73 m2) = K x Ht x cm/Pcreat

34. Other Laboratory Evaluations Grade 1 Grade 2 Grade 3 Grade 4 As soon as the creatinine result is obtained, the estimated GFR should be calculated using the Schwartz formula, graded for severity, and assessed for clinical significance concurrent with all other laboratory test results.

35. Other Laboratory Evaluations • HIV-1 RNA assays must be performed in real time in a CLIA-certified (US sites) or VQA-approved (non-US sites) laboratory using the testing platform specified in the LPC. • This will be the Abbott RealTime Viral Load Assay

36. What are your questions about the Cohort 1 Screen Visit?

37. Cohort 1 Entry Visit

38. Cohort 1 Entry Visit Day of Entry = Day 0

39. Cohort 1 Entry Visit Procedures that may provide information relevant to eligibility should be performed first, prior to final eligibility determination and proceeding to enrollment.

40. Cohort 1 Entry Visits Key operational reminders Final eligibility determination and confirmation (medical history, complete physical exam, and, if needed, pregnancy testing) must precede enrollment Enrollment must precede prescribing of study drug Prescribing must precede dispensing of study drug Pre-dose PK blood sample must precede ingestion of the single does of study drug Ingestion of study drug must precede palatability and acceptability assessment

41. Pregnancy Testing

42. Pregnancy Testing • Appendix I-A, footnote 1: At entry, all females who have reached menarche or who are engaging in sexual activity that could lead to pregnancy must have a pregnancy test, with results available prior to enrollment. Urine (5 mL) or blood (1 mL) tests are acceptable. The total blood volume shown above accommodates collection of 1 mL of blood, if needed. • Inclusion Criterion, 4.1.9: For females who have reached menarche or who are engaging in sexual activity (self-reported), negative pregnancy test at entry

43. Other Laboratory Evaluations: Entry

44. Other Laboratory Evaluations: Entry • Complete blood count with differentials and platelet count • Chemistries: • Electrolytes (sodium, potassium, and HCO3) • Glucose • Creatinine • Lipase • Phosphorous • LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, AST, ALT, and albumin) • CD4 cell counts • HIV-1 RNA • Intensive PK evaluations, per protocol Table 14

45. Pre-dose PK blood sample must precede ingestion of the single dose of study drug. When would you collect this sample? With the blood for pregnancy testing With the blood for CBC, chemistries, CD4 cell counts, and HIV-1 RNA We would not collect the PK sample with other samples Something else

46. Pre-dose PK blood sample must precede ingestion of the single dose of study drug. When would you collect this sample? With the blood for pregnancy testing With the blood for CBC, chemistries, CD4 cell counts, and HIV-1 RNA We would not collect the PK sample with other samples Something else

47. Drug Administration A single dose of 100 mg doravirine will be observed in the clinic on the same day as the intensive PK evaluation and ideally on the day of entry, per protocol Section 6.2.1

48. Palatability and Acceptability Assessment A palatability and acceptability questionnaire (EVW10019) is completed after the dosing is completed, per protocol Section 6.2.1

49. 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

50. 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