Clinical trial NCT00006400: Hydroxyurea to Prevent Organ Damage in Children With Sickle Cell Anemia
Official title: Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hematologic Diseases
Anemia, Sickle Cell
Keywords: Blood Diseases
Sickle Cell Anemia
Lead sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Sponsor class: NIH
First posted: 2000-10-13
Enrollment: 193
Sex: ALL
Minimum age (years): 9
Maximum age (years): 18
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine if hydroxyurea therapy is effective in the prevention of chronic end organ damage in pediatric patients with sickle cell anemia.

Detailed description: BACKGROUND:

In 1995, the Multicenter Study of Hydroxyurea (MSH) demonstrated that hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The recently completed phase II study of hydroxyurea in children (PED HUG) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A recently completed pilot study of hydroxyurea given to children between the ages of 6 months and 24 months demonstrated that the drug is tolerated well by small infant, and that the fetal hemoglobin switch can be forced to remain in the "on position" by hydroxyurea administration.

A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH trial and the progress to date of the PED HUG study. The SEP recommended that NHLBI undertake the BABY HUG trial.

DESIGN NARRATIVE:

BABY HUG is a randomized, double-blind, placebo-controlled study to determine if hydroxyurea can prevent the onset of chronic end organ damage in young children with sickle cell anemia. Approximately 200 children with sickle cell disease will be recruited to receive either hydroxyurea or placebo. The children will be screened at study entry for signs of abnormal brain, kidney, pulmonary, and splenic function, and developmental milestones. They will then be randomly assigned to receive either hydroxyurea or placebo and followed yearly to assess chronic end organ damage of the major organ systems. The primary endpoint will be a 50% reduction in rates of damage to the major organs with surrogate markers of organ function during follow-up in Phase II of the trial.

Eligibility criteria: Inclusion Criteria:

* Majority fetal and sickle (FS or SF) hemoglobin pattern confirmed centrally by electrophoresis (screening may begin at 7 months of age)

Exclusion Criteria:

* Chronic transfusion therapy
* Cancer
* Less than 5th percentile (10th percentile for the pilot study) height, weight, or head circumference for age
* Severe developmental delay (e.g., cerebral palsy or other mental retardation, Grade III/IV intraventricular hemorrhage)
* Stroke with neurological deficit
* Surgical splenectomy
* Participating in other clinical intervention trials
* Probable or known diagnosis of Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin
* Known hemoglobin S-beta plus thalassemia (hemoglobin A present)
* Any condition or chronic illness, which in the opinion of the principal investigator, makes participation unadvised or unsafe
* Inability or unwillingness to complete baseline (pre-enrollment) studies, including blood or urine specimen collection, liver-spleen scan, abdominal sonogram, neurological examination, neuropsychological testing, or transcranial Doppler ultrasound (interpretable study not required, but confirmed velocity greater than 200 cm/sec results in ineligibility)
* Previous or current treatment with hydroxyurea (HU) or another anti-sickling drug
* The following exclusion criteria are transient; patients can be re-evaluated for eligibility:

  1. Hemoglobin less than 6.0 gm/dL
  2. Reticulocyte count less than 80,000/cu mm if hemoglobin is less than 9 gm/dL
  3. Neutrophil count less than 2,000/cu mm
  4. Platelet count less than 130,000/cu mm
  5. Blood transfusion in the 2 months prior to study entry unless HbA is less than 10%
  6. ALT greater than twice the upper limit of normal
  7. Ferritin less than 10 ng/ml
  8. Serum creatinine greater than twice the upper limit of normal for age
  9. Bayley standardized mental score below 70

Primary outcomes:
measure: Treatment Differences of the Change in Qualitative Splenic Function From Baseline
timeFrame: Before initiation of treatment and at 2 years
Secondary outcomes:
measure: Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR)
timeFrame: Before initiation of treatment and at 2 years
measure: Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula)
timeFrame: Before initiation of treatment and at 2 years
measure: Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula)
timeFrame: Before initiation of treatment and at 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Washington
country: United States
facility: Howard University
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Detroit
country: United States
facility: Children's Hospital of Michigan/Wayne State Univ.
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Brooklyn
country: United States
facility: SUNY Health Science Center, Brooklyn
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Philadelphia
country: United States
facility: Drexel University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas SW Medical Center
state: Texas
Study officials:
affiliation: Medical University of South Carolina
name: Sherron Jackson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: James F. Casella, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's National Research Institute
name: Lori Luchtman-Jones, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Mississippi Medical Center
name: Rathi V. Iyer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: SUNY Health Science Center, Brooklyn
name: Scott T. Miller, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Howard University
name: Sohail R. Rana, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas SW Medical Center
name: Zora R. Rogers, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Trials and Surveys Corp
name: Bruce W Thompson, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami Medical Center
name: Julio Barredo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Jude Children's Research Hospital
name: Winfred C. Wang, MD
role: STUDY_CHAIR
affiliation: Duke University
name: Courtney Thornburg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Thomas Howard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Drexel University
name: Lori Luck, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: R. Clark Brown, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Sharada Sarnaik, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Heeney MM, Whorton MR, Howard TA, Johnson CA, Ware RE. Chemical and functional analysis of hydroxyurea oral solutions. J Pediatr Hematol Oncol. 2004 Mar;26(3):179-84. doi: 10.1097/00043426-200403000-00007.
citation: Thompson BW, Miller ST, Rogers ZR, Rees RC, Ware RE, Waclawiw MA, Iyer RV, Casella JF, Luchtman-Jones L, Rana S, Thornburg CD, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik S, Howard TH, Luck L, Wang WC. The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatr Blood Cancer. 2010 Feb;54(2):250-5. doi: 10.1002/pbc.22269.
citation: Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, Rana S, Thornburg CD, Rogers ZR, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik SA, Howard TH, Wynn LW, Kutlar A, Armstrong FD, Files BA, Goldsmith JC, Waclawiw MA, Huang X, Thompson BW; BABY HUG investigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011 May 14;377(9778):1663-72. doi: 10.1016/S0140-6736(11)60355-3.
citation: Wang WC, Pavlakis SG, Helton KJ, McKinstry RC, Casella JF, Adams RJ, Rees RC; BABY HUG Investigators. MRI abnormalities of the brain in one-year-old children with sickle cell anemia. Pediatr Blood Cancer. 2008 Nov;51(5):643-6. doi: 10.1002/pbc.21612.
citation: Miller ST, Wang WC, Iyer R, Rana S, Lane P, Ware RE, Li D, Rees RC; BABY-HUG Investigators. Urine concentrating ability in infants with sickle cell disease: baseline data from the phase III trial of hydroxyurea (BABY HUG). Pediatr Blood Cancer. 2010 Feb;54(2):265-8. doi: 10.1002/pbc.22189.
citation: Pavlakis SG, Rees RC, Huang X, Brown RC, Casella JF, Iyer RV, Kalpatthi R, Luden J, Miller ST, Rogers ZR, Thornburg CD, Wang WC, Adams RJ; BABY HUG Investigators. Transcranial doppler ultrasonography (TCD) in infants with sickle cell anemia: baseline data from the BABY HUG trial. Pediatr Blood Cancer. 2010 Feb;54(2):256-9. doi: 10.1002/pbc.22282.
citation: Thornburg CD, Rogers ZR, Jeng MR, Rana SR, Iyer RV, Faughnan L, Hassen L, Marshall J, McDonald RP, Wang WC, Huang X, Rees RC; BABY HUG Investigators. Adherence to study medication and visits: data from the BABY HUG trial. Pediatr Blood Cancer. 2010 Feb;54(2):260-4. doi: 10.1002/pbc.22324.
citation: Ware RE, Rees RC, Sarnaik SA, Iyer RV, Alvarez OA, Casella JF, Shulkin BL, Shalaby-Rana E, Strife CF, Miller JH, Lane PA, Wang WC, Miller ST; BABY HUG Investigators. Renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial. J Pediatr. 2010 Jan;156(1):66-70.e1. doi: 10.1016/j.jpeds.2009.06.060.
citation: Wynn L, Miller S, Faughnan L, Luo Z, Debenham E, Adix L, Fish B, Hustace T, Kelly T, Macdermott M, Marasciulo J, Martin B, McDuffie J, Murphy M, Rackoff B, Reed C, Seaman P, Thomas G, Wang W. Recruitment of infants with sickle cell anemia to a Phase III trial: data from the BABY HUG study. Contemp Clin Trials. 2010 Nov;31(6):558-63. doi: 10.1016/j.cct.2010.08.007. Epub 2010 Aug 24.
citation: Rogers ZR, Wang WC, Luo Z, Iyer RV, Shalaby-Rana E, Dertinger SD, Shulkin BL, Miller JH, Files B, Lane PA, Thompson BW, Miller ST, Ware RE; BABY HUG. Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial. Blood. 2011 Mar 3;117(9):2614-7. doi: 10.1182/blood-2010-04-278747. Epub 2011 Jan 7.
citation: Wang WC, Oyeku SO, Luo Z, Boulet SL, Miller ST, Casella JF, Fish B, Thompson BW, Grosse SD; BABY HUG Investigators. Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia. Pediatrics. 2013 Oct;132(4):677-83. doi: 10.1542/peds.2013-0333. Epub 2013 Sep 2.
citation: Thornburg CD, Files BA, Luo Z, Miller ST, Kalpatthi R, Iyer R, Seaman P, Lebensburger J, Alvarez O, Thompson B, Ware RE, Wang WC; BABY HUG Investigators. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood. 2012 Nov 22;120(22):4304-10; quiz 4448. doi: 10.1182/blood-2012-03-419879. Epub 2012 Aug 22.
citation: Alvarez O, Miller ST, Wang WC, Luo Z, McCarville MB, Schwartz GJ, Thompson B, Howard T, Iyer RV, Rana SR, Rogers ZR, Sarnaik SA, Thornburg CD, Ware RE; BABY HUG Investigators. Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer. 2012 Oct;59(4):668-74. doi: 10.1002/pbc.24100. Epub 2012 Jan 31.
citation: Lebensburger JD, Miller ST, Howard TH, Casella JF, Brown RC, Lu M, Iyer RV, Sarnaik S, Rogers ZR, Wang WC; BABY HUG Investigators. Influence of severity of anemia on clinical findings in infants with sickle cell anemia: analyses from the BABY HUG study. Pediatr Blood Cancer. 2012 Oct;59(4):675-8. doi: 10.1002/pbc.24037. Epub 2011 Dec 20.
citation: Miller ST, Rey K, He J, Flanagan J, Fish BJ, Rogers ZR, Wang WC, Ware RE; BABY HUG Investigators. Massive accidental overdose of hydroxyurea in a young child with sickle cell anemia. Pediatr Blood Cancer. 2012 Jul 15;59(1):170-2. doi: 10.1002/pbc.23244. Epub 2011 Jul 8.
citation: McCarville MB, Luo Z, Huang X, Rees RC, Rogers ZR, Miller ST, Thompson B, Kalpatthi R, Wang WC; BABY HUG Investigators. Abdominal ultrasound with scintigraphic and clinical correlates in infants with sickle cell anemia: baseline data from the BABY HUG trial. AJR Am J Roentgenol. 2011 Jun;196(6):1399-404. doi: 10.2214/AJR.10.4664.