IMPAACT 2010 Protocol Specifications for Recruitment, Screening, and Enrollment

1. IMPAACT 2010Protocol Specifications forRecruitment, Screening, and Enrollment

2. Protocol References

3. Recruitment Context Recruitment methods for this study may vary across sites but are expected to rely on active identification and referralof HIV-1-infected pregnant women who are not taking ART at the time of presenting for antenatal care. Based on current standards of care, it is expected that many such women will be started on a non-study ART regimen at the time of presenting for antenatal care. This is permitted by the study eligibility criteria. However, recruitment and eligibility screening procedures will need to be performed in a timely manner to ensure that eligible women are enrolled within 14 days of starting non-study ART. Upon enrollment, women will discontinue their non-study ART regimen (if they had started a non-study regimen) and initiate a study drug regimen.

4. Informed Consent Upon identification of a potentially eligible pregnant woman, study staff will provide information about the study to her. Women 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 informed consent process may be initiated at any time during pregnancy but — based on the required timing of study entry — is generally not expected before approximately 12 weeks gestation or after approximately 26 weeks gestation. Written informed consent must be obtained before any study-specific screening procedures are performed.

5. 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

6. Screening evaluations must be performed within 14 days prior to enrollment and enrollment must occur within 14 daysof (non-study) ART initiation during the current pregnancy.

7. Screening evaluations must be performed within 14 days prior to enrollment and enrollment must occur within 14 daysof (non-study) ART initiation during the current pregnancy.

8. 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

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10. Study Accrual Period in Months Cap is lifted upon favorable safety review outcome VESTED Accrual Plan 549 Cap remains in place pending pregnancy outcomes, data analysis, and safety review (~290 cumulatively enrolled through Month 12) Accrual of 60 mother-infant pairs for safety review under cap of 30 per month

11. Study Accrual Plan Plan is based on site-specific enrollment projections established during the site selection process and updated in Q1-Q2 2017. At each site, accrual will begin after all required approvals are obtained and a site-specific study activation notice is issued by the IMPAACT Operations Center. As a condition for study activation, each site must establish SOPs for participant accrual. All sites are responsible for following these SOPs, and for updating them if needed to meet their accrual projections, throughout the study accrual period.

12. Study Accrual Plan

13. Initial Monthly Cap on Accrual • Accrual across sites will initially be capped at 30 mother-infant pairs per month • Cap will remain in place until CMC reviews pooled maternal safety and pregnancy outcomes for the first 60 mothers with a recorded pregnancy outcome who have reached their expected full-term dates based on estimated gestational age at study entry • If pre-specified criteria are met, cap will be lifted • If pre-specified criteria are not met, cap will remain in effect pending DSMB review

14. Managing the Accrual Cap • Data from the Subject Enrollment System (SES) will be used to track the number of participants screened and enrolled at each site and across all sites • A study-specific screening number will be obtained from the SES for each mother-infant pair for whom informed consent is obtained • Each screening number will be linked to either enrollment of the pair (through the SES) or to reasons for screen failure entered into the SCR10001, Screening Failure and Non-Enrollment Results eCRF

15. Managing the Accrual Cap The DMC will generate: • Screening Reports • Number of mother-infant pairs currently in screening • Number of mother-infant pairs enrolled in the current calendar month • Current statistics (mean and median) for the number of days spent in screening • Accrual Reports • Number of mother-infant pairs enrolled in the study overall

16. Managing the Accrual Cap • Initially in each month, reports will be generated weekly • Once 20 mother-infant pairs have been enrolled • Reports will be generated daily • Members of the protocol team will communicate with sites as needed to determine the number of mother-infant pairs currently in screening and the scheduled enrollment dates for these pairs

17. Managing the Accrual Cap • The Protocol Team may advise sites to slow or stop screening efforts for enrollments in the current month • The team will also assist with managing the cap across sites • For example, if multiple sites may be enrolling participants around the time when the cap is reached, the team will determine whether a small number of over-enrollments may be permitted in a given month

18. Managing the Accrual Cap • In general, up to 3 over-enrollments may be permitted in a given month, but the cap is otherwise expected to be adhered to on a monthly basis • SES will be pre-programmed to permit enrollment of 30 mother-infant pairs per month, with options available to allow more than 30 at the discretion of the team • The Protocol Chairs, Medical Officers, and Statisticians will be involved in all decisions to permit over-enrollments • At the close of each month (5:00 pm US ET on the last day of each month), the DMC will re-open the enrollment screens for the following month

19. On-Site Considerations • Sites are responsible for reviewing the DMC reports and coordinating their participant accrual activity accordingly • Collectively across sites, every effort should be made to reach the accrual cap each month • At each site, avoid screening additional participants who will not likely complete the eligibility determination and enrollment process before the monthly cap is reached • Participants screened toward the end of a month may be enrolled in the following month, provided the 14-day screening period is not exceeded

20. On-Site Considerations • Sites are responsible for reviewing the DMC reports and coordinating their participant accrual activity accordingly • Collectively across sites, every effort should be made to reach the accrual cap each month • At each site, avoid screening additional participants who will not likely complete the eligibility determination and enrollment process before the monthly cap is reached • Participants screened toward the end of a month may be enrolled in the following month, provided the 14-day screening period is not exceeded For this process to work well, screening failure eCRFs must be entered as soon as possible after determining that a mother-infant pair will not be enrolled.

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