Optimizing Clinical Trial Design to Maximize Evidence Generation in Pediatric HIV

Abstract

Abstract:For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in “basket” trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing

“…Children (< 18 years) were recruited at sites located in Uganda, South Africa, Zimbabwe, Thailand, Portugal, Germany, Spain and the United Kingdom. A basket design allows for enrolment to occur to two (or more) cohorts simultaneously at the same clinical sites, thereby improving efficiency and minimizing time and costs [22]. At trial design we planned to randomise 700 children (310 in ODYSSEY A and 390 in ODYSSEY B) 1:1 to receive 2 NRTIs with DTG (DTG arm) or SOC (bPI-, NNRTI-or non-DTG INSTI-based ART; SOC arm) (Fig.…”

Coronavirus Disease 2019 (COVID-19) Pharmacologic Treatments for Children: Research Priorities and Approach to Pediatric Studies

“…Although not primarily efficacy trials, these studies should carefully document outcomes and treatment response, including with any biomarkers, in relation to drug exposures. Pediatric trials should follow emerging best practices, including enrolling children of all ages in parallel rather than utilizing an age de-escalation design as has been frequently used historically, and dosing medications in weight bands [30]. Child-friendly formulations of orally administered medications that are acceptable, palatable, and able to be taken by young children are important pediatric considerations and will ultimately be needed.…”

Combining factorial and multi-arm multi-stage platform designs to evaluate multiple interventions efficiently

“…This has not been explored in detail in the literature. Generally, they have been regarded as alternative designs 3 or as competitors MRC Clinical Trials Unit at UCL, London, UK rather than as elements to combine. 4 One MAMS trial explicitly rejected a factorial design because the assumptions of a factorial design were not met.…”

“…9 However, this article is of broader relevance. Our aims are to (1) introduce the factorial-MAMS trial design and suggest some visual representations, (2) identify some difficulties in design, conduct and analysis that arise when factorial and MAMS elements are combined, (3) suggest how these difficulties should be addressed and (4) offer guidance on when such a trial may be useful. We focus on the underlying principles and ideas rather than the statistical details of the design.…”