The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design.
Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9-17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400).
Thompson
Bruce W
BW
Clinical Trials & Surveys Corp., Baltimore, Maryland 21117, USA. bthompson@c-tasc.com
Miller
Scott T
ST
Rogers
Zora R
ZR
Rees
Renee C
RC
Ware
Russell E
RE
Waclawiw
Myron A
MA
Iyer
Rathi V
RV
Casella
James F
JF
Luchtman-Jones
Lori
L
Rana
Sohail
S
Thornburg
Courtney D
CD
Kalpatthi
Ram V
RV
Barredo
Julio C
JC
Brown
R Clark
RC
Sarnaik
Sharada
S
Howard
Thomas H
TH
Luck
Lori
L
Wang
Winfred C
WC
D000367:Age Factors; D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D000986:Antisickling Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D016903:Drug Monitoring; D023381:Endpoint Determination; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D010865:Pilot Projects; D016032:Randomized Controlled Trials as Topic; D012107:Research Design
D000986:Antisickling Agents; D006918:Hydroxyurea