Enrollment and transition challenges in the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) network's PROMISE trial for resource-limited regions

Abstract

Background: We describe enrollment and accrual challenges in the "Promoting Maternal and Infant Survival Everywhere" (PROMISE) trial conducted in resource-limited countries, as well as the challenges in transitioning participants from the antepartum to the postpartum components of the study.

Methods: PROMISE was a large multi-national randomized controlled trial of the safety and efficacy of interventions to reduce perinatal transmission of HIV-1 (HIV) during pregnancy and breastfeeding and of interventions to preserve maternal health after cessation of perinatal transmission risk. The PROMISE study included two protocols for HIV-infected pregnant women in resource-limited countries who intended to either breastfeed or formula-feed their infants and did not meet country criteria for antiretroviral treatment. The PROMISE breastfeeding protocol (1077BF) used a sequential randomization design with up to three randomizations (Antepartum, Postpartum, and Maternal Health). The PROMISE formula-feeding protocol (1077FF) had two randomizations (Antepartum and Maternal Health). Women presenting to the clinic during early or active labor or in the immediate postpartum period were registered as Late Presenters and screened to determine whether eligible to participate in the Postpartum randomization.

Results: The study was conducted at 14 sites in seven countries and opened to enrollment in April 2011. A total of 3259 pregnant women intending to breastfeed and an additional 284 pregnant women intending to formula feed were randomized in the Antepartum component. A total of 204 Late Presenters were registered during labor or after delivery. Enrollment was high among breastfeeding women (representing 96% of the target of 3400 women) but was lower than expected among women intending to formula feed (28% of 1000 expected) and late-presenting women (8% of 2500 expected). The successful overall enrollment and final primary study analyses results were attributed to substantial preparation before the study opened, collaboration among all stakeholders, close study monitoring during implementation and the flexibility to change and streamline the protocol.

Conclusions: Experiences from the PROMISE study illustrate the challenges of enrolling in longer term studies in the setting of rapidly evolving prevention and treatment standards priorities. The lessons learned will help the community, site investigators, and study coordinators in the design and implementation of future clinical trials.

Keywords: AIDS; HIV-1; PROMISE study; antiretroviral therapy; enrollment; prevention of perinatal transmission; randomized clinical trial; resource-limited settings.

Figure 1.

PROMISE target and actual accrual and transition rates 1077BF: PROMISE Breastfeeding protocol; enrolled women who intended to breastfeed their infants 1077FF: PROMISE Formula-feeding protocol; enrolled women who intended to formula-feed their infants Component: one of the randomizations in the 1077BF or 1077FF protocols * Target initial enrollment in PROMISE (in italics). Originally, the 1077BF protocol also had a fourth randomization for HIV-uninfected infants who ceased breastfeeding prior to age 12 months, to assess the efficacy and safety of continued cotrimoxazole prophylaxis versus placebo for the prevention of infant mortality and morbidity following breastfeeding cessation. This Infant Health component however, did not open to enrollment due to a change in WHO guidelines to recommend breastfeeding of HIV-exposed infants beyond age 12 months. It is important to note that the overall number of unique mother-infant pairs in PROMISE is much less than the sum of the component sample sizes. This is because 1077BF had only two points of entry (Antepartum and Late Presenters) and 1077FF had only one point of entry (Antepartum); the remaining PROMISE components would only enroll women and/or infants who participated in one of these initial PROMISE components. Transition and non-enrollment rates were calculated among the eligible MI pairs per component and protocol.