Hydroxyurea Dosing in Very Young Children (HUGKISS): Challenges of Study Design

Introduction: The acute and chronic complications of sickle cell anemia (SCA) are well-known, with many of them arising in the first few years of life. The BABY HUG trial showed that 20 mg/kg/day of hydroxyurea therapy is safe, blunts the decline of fetal hemoglobin (HbF), and is clinically beneficial for very young infants and children with SCA. Nevertheless, children treated with hydroxyurea continued to develop acute complications and acquire end organ damage. Although the BABY HUG trial established the safety and efficacy of fixed dose hydroxyurea in very young children with SCA, further study was needed to define the optimal dosing regimen to maximize benefit in this group. We describe our approach to designing and implementing the Hydroxyurea Management in Kids: Intensive versus Stable Dosage Strategies (HUGKISS) study, which assessed the feasibility of enrolling and randomizing very young children with SCA to intensified versus fixed doses of hydroxyurea. The hematologic and clinical effects of both doses were also monitored.

Methods: The HUGKISS trial was designed as a single-blind, multicenter, randomized controlled pilot study. It was felt that the objectives of HUGKISS could be safely and more efficiently obtained with a single-blind design (with investigators blinded), because a double-blind design would be logistically challenging and would place significant burden on families and pharmacies. For example, in one double-blind design, caregivers would have to administer two aliquots of study drug (hydroxyurea + hydroxyurea or hydroxyurea + placebo), thereby providing a potential source for medication error. However, because the HUGKISS study required dosage adjustment of hydroxyurea based on complete blood count results, a HUGKISS Enabled Local Provider for Evaluating Response (HELPER) was utilized. Each HELPER was an unblinded local medical provider, unaffiliated with the steering committee or data analysis, who was knowledgeable about SCA. This individual monitored hydroxyurea concordance and toxicities in real time.

All patients received hydroxyurea at 20 mg/kg/day for 8 weeks. If they were stable and adherent, they were randomized to either continued fixed dosing or intensified dosing, which involved escalation of hydroxyurea dosing every 8 weeks to a maximum of 35 mg/kg/day. While the primary endpoint was assessing feasibility of enrollment and randomization, the main secondary endpoint assessed was changes in HbF levels. This choice reflected the age of the patient population, which would be undergoing a physiologic decline in HbF during the study period.

We monitored adherence via the Medication Adherence Measure (MAM) and measurement of remaining hydroxyurea suspension in the prescribed bottle. Both were performed every four weeks. A medication possession ratio was calculated using the results from both methods, and used to quantitate adherence.

Enrollment screening logs were also maintained at all sites. The most common reason for declining participation in HUGKISS was that families desired more time to "think about" hydroxyurea and participation in a trial, followed by disinterest in using hydroxyurea, and a fear of participating in clinical trials.

Conclusion: Important considerations when designing trials involving young children with SCA include choice of endpoints, obtaining adequate enrollment, maintaining blinding of a liquid formulation with dose adjustments, and assessment of medication adherence. The HUGKISS study employed a novel single-blind design to facilitate safe and efficient administration of hydroxyurea for families, while also ensuring close monitoring of toxicities through a HELPER.

Brown:Pfizer: Research Funding; Imara: Consultancy, Research Funding; Nova Nordisk: Consultancy; Novartis: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Research Funding; Forma Therapeutics: Research Funding. Rogers:Novartis: Consultancy; Magenta Therapeutics: Consultancy. Estepp:Agios: Current Employment, Current equity holder in private company; Daiichi Sankyo: Consultancy; Emmaus Life Sciences: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Eli Lilly and Co: Research Funding; Forma Therapeutics: Research Funding.

Hydroxyurea for the management of sickle cell disease in very young children