← Back
NeuroTrials.ai
Neurology Clinical Trial Database

BABY HUG

The Pediatric Hydroxyurea Phase III Clinical Trial - Impact of Hydroxyurea on Clinical Events

Share Share Copied! Compare

Year of Publication: 2012

Authors: Courtney D. Thornburg, Beatrice A. Files, Zhaoyu Luo, ..., for the BABY HUG Investigators

Journal: Blood

Citation: Blood. 2012;120(22):4304-4310

Clinical Question

Does hydroxyurea reduce sickle cell disease-related clinical events (pain, dactylitis, acute chest syndrome, hospitalizations, transfusions) and infections in infants with sickle cell anemia?

Bottom Line

Hydroxyurea significantly reduced rates of pain, dactylitis, acute chest syndrome, hospitalizations, and transfusions in infants with sickle cell anemia without increasing risk of bacteremia or serious infection. Benefits were seen even in infants who were asymptomatic at enrollment.

Major Points

  • Hydroxyurea reduced pain events by 2.2-fold (94 vs 203 per 100 patient-years, HR 0.59, P=.002)
  • Dactylitis reduced by 5.2-fold (12.7 vs 66.5 per 100 patient-years, HR 0.27, P<.001)
  • Acute chest syndrome reduced by 3.5-fold (4.2 vs 14.6 per 100 patient-years, HR 0.36, P=.02)
  • Hospitalizations reduced (123 vs 175 per 100 patient-years, HR 0.73, P=.05)
  • Transfusions reduced (21% vs 34% of patients, P=.04)
  • No increased risk of bacteremia or serious infection despite mild myelosuppression
  • Gastroenteritis unexpectedly reduced (HR 0.35, P<.001)
  • Asymptomatic children at enrollment also benefited from hydroxyurea
  • All 3 S. pneumoniae infections occurred in children not taking hydroxyurea
  • No deaths during the treatment period

Design

Study Type: Phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial (secondary analysis of clinical events)

Randomization: 1

Blinding: Double-blind. Subjects, families, clinical center staff, and outcome assessors blinded to treatment assignment. Only NHLBI project officer and MCC medical consultants aware of treatment assignment for safety monitoring.

Enrollment Period: October 2003 - September 2009

Follow-up Duration: 2 years (374 patient-years total observation)

Centers: 14

Countries: United States

Sample Size: 193

Analysis: Chi-square and Fisher exact tests for frequency comparisons. Cox models for event rate comparisons. Log-rank test for time to first event. Wilcoxon rank-sum test for continuous variables. GEE Poisson regression for multivariate analyses of multiple events. SAS Version 9.2.

Inclusion Criteria

  • Age 9-18 months at enrollment
  • Diagnosis of HbSS or HbS-β0 thalassemia
  • Enrolled regardless of clinical severity

Exclusion Criteria

  • Not specified in this publication (see primary protocol paper)

Arms

FieldControlHydroxyurea
InterventionPlacebo administered orally daily for 2 years. All children received prophylactic penicillin and age-appropriate immunizations.Hydroxyurea 20 mg/kg/day administered orally daily for 2 years. No dose escalation to maximum tolerated dose. 9% had dose reductions due to myelosuppression. All children received prophylactic penicillin and age-appropriate immunizations.
Duration2 years2 years

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Rate of painful events (pain lasting ≥2 hours without obvious cause requiring pain medication, later expanded to include any mention of pain)Primary203 events per 100 patient-years; 375 total events; 77% with ≥1 event; 42% with ≥4 events94 events per 100 patient-years; 177 total events; 65% with ≥1 event; 14% with ≥4 events0.59.002
Dactylitis (pain and tenderness with or without swelling of hands/feet)Secondary66.5 per 100 patient-years; 123 total events; 43% with ≥1 event; 14% with ≥4 events12.7 per 100 patient-years; 24 total events; 14% with ≥1 event; 0% with ≥4 events0.27<.001
Acute chest syndromeSecondary14.6 per 100 patient-years; 27 total events; 18% with ≥1 event; 8% with ≥2 events4.2 per 100 patient-years; 8 total events; 8% with ≥1 event; 1% with ≥2 events0.36.02
Hospitalizations (all-cause)Secondary175 per 100 patient-years; 324 total events; 87% with ≥1 event; 41% with ≥4 events123 per 100 patient-years; 232 total events; 72% with ≥1 event; 22% with ≥4 events0.73.05
Hospitalizations for feverSecondary240 events181 events.01
Hospitalizations for painSecondary128 events73 events<.001
Hospitalizations for ACSSecondary27 events8 events.02
Prolonged hospitalization (≥7 days)Secondary4.3 per 100 patient-years2.7 per 100 patient-years.40
Patients receiving transfusionSecondary34% (33/97); 63 total transfusions21% (20/96); 35 total transfusions.04
Patients with ≥2 transfusionsSecondary52% (17/33 transfused)35% (7/20 transfused).06
Splenic sequestration eventsSecondary12 events in 9 patients (median age 22 months)12 events in 8 patients (median age 28 months)NS
Fever episodesSecondary217.4 per 100 patient-years; 402 events186.2 per 100 patient-years; 352 events0.89.5
GastroenteritisSecondary37.9 per 100 patient-years; 70 events; 42% of patients13.8 per 100 patient-years; 26 events; 19% of patients0.35<.001
Bacteremia/sepsis/meningitisSecondary3.2 per 100 patient-years; 6 events; 5% of patients1.6 per 100 patient-years; 3 events; 2% of patients0.4.3
StrokeSecondary1 event (1 patient)0 events
Abnormal TCD at study exitSecondary3 patients1 patient
Total AEsAdversePart of 2560 total AEsPart of 2560 total AEs
Total SAEsAdversePart of 107 total SAEsPart of 107 total SAEs
DeathAdverse00
Mild-moderate neutropenia (ANC 0.5-1.249 × 10^9/L)AdverseLess frequent (exact numbers in primary paper)More frequent (expected treatment effect)
Severe neutropenia (ANC <0.5 × 10^9/L)Adverse2 events5 events
Neutropenia associated with viral illnessAdverse1/2 events3/5 events1.0
Thrombocytopenia (<80 × 10^9/L)Adverse7 patients11 patients
Severe anemia (Hb <7 g/dL and ARC <80 × 10^9/L)Adverse2 patients (aplastic crisis)1 patient (aplastic crisis)
S. pneumoniae infectionsAdverse2 (plus 1 assigned to but not yet exposed to HU)0
EczemaAdverse11% (11/97)13% (12/96).80
Asthma diagnosis by study endAdverse6% (6/97)9% (9/96).44
MalignancyAdverse00
Cholelithiasis at exitAdverse5 patients5 patients
Gallbladder sludge at exitAdverse6 patients8 patients

Subgroup Analysis

Asymptomatic children at baseline (52/96 HU, 49/97 placebo): Hydroxyurea associated with significantly fewer dactylitis events (HR 4.2, P=.006), hospitalizations (HR 1.9, P=.006), and transfusions (HR 2.7, P=.04). Trends toward less ACS (HR 2.5, P=.17) and splenic sequestration (HR 3.8, P=.07). No difference in pain events (HR 1.3, P=.35). In multivariate analysis of gastroenteritis: ANC positively correlated (P=.006), WBC negatively correlated (P=.006), and placebo group positively correlated (P=.002).

Criticisms

  • Many clinical events identified by self-report, which may introduce recall bias
  • This paper is a secondary analysis; not powered for all clinical event comparisons
  • No dose escalation to maximum tolerated dose was used in this trial
  • Primary endpoint of the trial (spleen and kidney damage reduction by ≥50%) was not achieved
  • Relatively short follow-up period (2 years)
  • Definition of pain was expanded mid-study at NICHD request, potentially affecting consistency
  • Single country (United States) study population
  • 86% completion rate means 14% had incomplete data

Funding

NHLBI/National Institutes of Health Contracts N01-HB-07150 through N01-HB-07160, with additional support from the Best Pharmaceuticals for Children Act and NICHD.

Based on: BABY HUG (Blood, 2012)

Authors: Courtney D. Thornburg, Beatrice A. Files, Zhaoyu Luo, ..., for the BABY HUG Investigators

Citation: Blood. 2012;120(22):4304-4310

Content summarized and formatted by NeuroTrials.ai.