IMPAACT 2010 Protocol Specifications for Recruitment, Screening, and Enrollment No updates

Protocol References Section Title 4.1 Inclusion Criteria 4.2 Exclusion Criteria 4.3 Co-Enrollment Considerations 4.4 Recruitment, Screening and Enrollment Process 6.1 Screening Visits 6.2 Entry Visit 9.4.2 Accrual 9.5.1 CMC Review for Decision to Lift Cap on Accrual

Recruitment Context Recruitment methods for this study may vary across sites but are expected to rely on active identification and referral of 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. We will hear more about site-specific approaches to this following this presentation.

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.

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

Screening evaluations must be performed within 14 days prior to enrollment and enrollment must occur within 14 days of (non-study) ART initiation during the current pregnancy. SUN MON TUE WED THU FRI SAT 1 Starts ART 2 3 Screening Visit 4 5 6 7 8 9 10 11 12 13 14 Last day to enroll 15 16 17 18 19 20 21 22 23 24 25 26 In this example, the mother presents for antenatal care and is found to be HIV-positive on the 1st of the month. She is given the local standard ART regimen and takes her first dose of ART that same day. Two days later, on the 3rd of the month, she reports to the study clinic, provides informed consent, and undergoes screening evaluations. The protocol requires that all screening evaluations be performed within 14 days of enrollment, and inclusion criterion 4.1.3 requires that enrollment occur within 14 days of (non-study) ART initiation during the current pregnancy. In this case, ART was started before screening evaluations were performed, so the date of ART initiation determines the last possible day to enroll, which (as we see on the next slide) is the 14th of the month.

Screening evaluations must be performed within 14 days prior to enrollment and enrollment must occur within 14 days of (non-study) ART initiation during the current pregnancy. SUN MON TUE WED THU FRI SAT 1 Antenatal Care Visit 2 3 Screening Visit 4 Starts ART 5 6 7 8 9 10 11 12 13 14 15 16 Last day to enroll 17 18 19 20 21 22 23 24 25 26 On this slide we have a different example. In this example, the mother presents for antenatal care and is found to be HIV-positive on the 1st of the month. She is given the local standard ART regimen that day but does not start taking the medication that day. Two days later, on the 3rd of the month, she reports to the study clinic, provides informed consent, and undergoes screening evaluations. Following counseling received from study staff, she takes her first dose of non-study ART on the 4th of the month. Once again, all screening evaluations must be performed within 14 days of enrollment, and enrollment must occur within 14 days of (non-study) ART initiation during the current pregnancy. In this case, screening evaluations were performed before ART was initiated, so the screening visit date determines the last possible day to enroll, which (as shown on the next slide) is the 16th of the month. FROM EMAILS: Slide 17: I definitely do NOT think we should/would say that sites MUST start SOC ART first. I tried to say this explicitly during our first general webinar after realizing that sites could interpret the protocol as saying this. My perspective is that sites should facilitate access to the best possible SOC for participants locally, whatever/wherever that may be. We are just stating that up to 14 days of ART is allowable.

Initiate study drug and 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 We will discuss protocol-specific screening and enrollment procedures in a later session. Before doing that, this slides gives an overview of the flow from informed consent to screening and enrollment, as well as ome key details for how the process will be documented and tracked. When informed consent is obtained, participant identification numbers (PIDs) will be assigned to the mother and (unborn) infant, and a study-specific screening number will be obtained for the pair through the SES. For pairs found to be eligible, enrollment will occur upon successful entry of required eligibility data into the SES. Successful entry into the SES will generate study identification numbers (SIDs) for the mother and infant, the random assignment for the pair, and prescribing information for the maternal study drug regimen that corresponds to the random assignment For all mother-infant pairs, the relevant study drug regimen will be prescribed and dispensed on the day of enrollment, with the first dose expected to be taken on the day of enrollment or the following day. (CAN ASK QUESTION AT THS POINT, EXACTLY WHEN IS THE MOTHER-INFANT PAIR CONSIDERED ENROLLED IN THE STUDY? For pairs who are screened and found to be ineligible, or who do not otherwise enroll in the study for any reason, an electronic case report form (eCRF) will be entered to record the screening outcome. STOP HERE FOR QUESTIONS … STOP

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Study Accrual Period in Months VESTED Accrual Plan Cap is lifted upon favorable safety review outcome 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 First enrollments are currently planned in July July 2017. 60th enrollment should occur within 4-5 months of starting the study. Four months assumed for the 60 women to experience their pregnancy outcome followed by one month to enter, compile, report, and review the relevant data. [The protocol assumes 7 months to get to 60 enrolled, but the updated accrual plan indicates we could shave a month or two off this. Nonetheless, to be conservative, we have left the total time under the cap as 12 months (7+4+1=12 months under the cap).] Accrual continues under cap of 30 per month in Months 7-11, i.e., until safety/pregnancy outcomes for first 60 participants are reviewed by CMC. If the pre-specified criteria for lifting the cap are met, the cap will be lifted, as shown in the bars for months 12, 13, and 14; with the cap lifted, site projections indicate that up to 90-100 pairs could be enrolled per month. If the pre-specified criteria are not met, a by-arm data report will be prepared for DSMB review and the cap will remain in place pending the DSMB review. Study Accrual Period in Months

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.

Study Accrual Plan For Botswana

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

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

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

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

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

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 This timing will ensure that the screens are available to permit enrollment on the first day of the month at study sites in Asia and Africa.

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

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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