Additional Study Information

The BABY HUG program consisted of three related studies, each of which has associated datasets and bio-specimens.

• A randomized controlled trial comparing hydroxyurea to placebo in very young children with sickle cell anemia (BABY HUG Randomized Controlled Trial)
• The first observational follow-up study of children from the randomized controlled trial (BABY HUG Follow-Up Study I). All children in Follow-Up Study I were offered the option of taking open-label hydroxyurea, with treatment decisions made by the family and the clinical team caring for the child.
• The second observational follow-up study of children from BABY HUG Follow-Up Study I. All children in Follow-Up Study II were offered the option of taking open-label hydroxyurea, with treatment decisions made by the family and the clinical team caring for the child.

Objectives

The purpose of the Randomized Controlled Trial was to determine if hydroxyurea can safely prevent early end organ damage in very young children with sickle cell anemia.

The purpose of the BABY HUG Follow-up Study I was to provide structured follow-up of the children enrolled in the BABY HUG Randomized Controlled Trial, in order to characterize the long-term toxicities and unexpected risks (if any) associated with treatment with hydroxyurea at an early age.

The objective of Follow-Up Study II was to obtain additional data about the long-term safety and efficacy of hydroxyurea use in children with Sickle Cell Anemia through at least the first decade of life.

Background

Sickle cell anemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. In 1995, the Multicenter Study of Hydroxyurea (MSH) demonstrated that, in adults, hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The phase I/II study of hydroxyurea in children (HUG KIDS) 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 pilot study of hydroxyurea (HUSOFT) given to children between the ages of 6 months and 24 months demonstrated that the drug was well tolerated and that the fetal hemoglobin levels rose and remained elevated compared to baseline with continued 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 HUG KIDS study. The SEP recommended that NHLBI undertake the BABY HUG trial.

The BABY HUG Randomized Controlled Trial concluded that hydroxyurea treatment in very young children seemed to have an acceptable safety profile and to reduce complications of sickle cell anemia. However, more data were needed on the long-term safety of hydroxyurea use in very young children. As a result, follow-up studies were initiated. The Follow-Up Study II provided longer follow-up than Follow-Up Study I, and included more assessment types than Follow-Up Study I.

Participants

193 participants aged 9–18 months were randomized at 13 trial centers in the United States. (A fourteenth center was opened for enrollment but did not randomize any participants.) Eligible participants had HbSS or HbSβ⁰ thalassaemia, and were enrolled irrespective of clinical severity. All participants received standard age-appropriate care for sickle cell anemia, including penicillin prophylaxis, pneumococcal immunization, and parental education. Participants were excluded for transfusion within 2 months; malignancy; height, weight, or head circumference less than the fifth percentile; severe developmental delay; stroke with neurological deficit; surgical splenectomy; probable or known diagnosis of Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin; known hemoglobin S-beta plus thalassemia (hemoglobin A present); previous or current treatment with HU or another anti-sickling drug; or abnormal transcranial Doppler ultrasound (TCD) velocity.

Participants who completed at least 18 months of follow-up in the BABY HUG Randomized Controlled Trial were eligible to participate in Follow-Up Study I. There were 179 such participants. Of these, 163 consented to Follow-Up Study I; 127 agreed to active follow-up, and 36 agreed to passive follow-up. (See design section for descriptions of active and passive follow-up.)

Participants who completed at least 24 months of follow-up in Follow-Up Study I, and had not received stem cell transplant therapy, were eligible to participate in Follow-Up Study II. There were 156 such subjects. Of these, 150 consented to participate in Follow-Up Study II; 130 agreed to active follow-up (one of whom later switched to passive follow-up), and 20 agreed to passive follow-up (one of whom later switched to active follow-up). (See design section below for descriptions of active and passive follow-up.)

Design

The trial was undertaken in 13 centers in the United States between October, 2003 and September, 2009. Ninety-six participants were randomized to receive liquid hydroxyurea at 20 mg/kg per day (95 of whom actually started study treatment), and 97 were randomized to receive matching placebo and did not receive hydroxyurea. Study treatment continued for 2 years. Randomization assignments were generated by the medical coordinating center by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxyurea and placebo. Patients, caregivers, and coordinating center staff were masked to treatment allocation. Primary study endpoints were surrogate markers of splenic function (qualitative uptake on ⁹⁹Tc spleen scan) and renal function (glomerular filtration rate by ⁹⁹mTc-DTPA clearance). Additional assessments included blood counts, fetal hemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, abdominal sonograms, immunology markers, growth, and mutagenicity (In vivo measurements of acquired genotoxicity including chromosomal karyotype, illegitimate VDJ recombination events, and micronucleated reticulocyte formation). Data on adverse events and other clinical events were also collected. Study visits occurred every 2–4 weeks.

In the Follow-Up Study I, families were offered open-label hydroxyurea at the conclusion of the Randomized Controlled Trial. The decision about whether to use hydroxyurea, and the dosing schedule, were made by the family in conjunction with the child’s clinical care team. Children could participate in Follow-Up Study I when they finished the Randomized Controlled Trial whether or not they planned to use open-label hydroxyurea.

There were two ways of participating in Follow-Up Study I: passive follow-up, and active follow-up. In passive follow-up, the study collected data from routine clinical care visits, including such information as complete blood counts, growth parameters, transcranial Doppler imaging results, illnesses, treatments, and other clinical events. Data abstraction took place twice a year. Blood and urine samples were collected at the beginning of Follow-Up Study I and four years later or at the end of Follow-Up Study I, whichever occurred first, to test spleen and kidney function and DNA. Active follow-up included all the same data collection as passive follow-up, but also included transcranial Doppler readings one and two years into the Follow-Up Study, and visits two years into the study for an additional blood sample, liver-spleen scan, abdominal ultrasound, and neurodevelopmental testing.

Children could participate in Follow-Up Study II whether or not they planned to use open-label hydroxyurea. The decision about whether to use hydroxyurea, and the dosing schedule, were made by the family in conjunction with the child’s clinical care team.

There were two ways of participating in Follow-Up Study II: passive follow-up, and active follow-up. For passive follow-up, all participants were to have cystatin C, BUN, Creatinine, HbF, pit counts, HJB, VDJ, urine microalbumin:creatinine ratio and a stored blood sample collected at entry and exit to Follow-Up Study II, for central laboratory testing. CBCs, reticulocytes, differential, LDH, bilirubin and ALTs were to be collected at entry and exit and tested at the Clinical Center local laboratory. All other laboratory testing was limited to those tests performed in accordance with routine local clinical care, including HU monitoring for those subjects being treated with HU. Study data was abstracted from the medical record using structured forms and collected semi-annually. Parents/guardians were presented with a questionnaire regarding the subject’s health status related to enuresis, snoring/obstructive sleep apnea and priapism once every year. Subjects in the passive group might also have additional testing performed for clinical reasons, including liver/spleen scan, abdominal sonogram, pulmonary function testing, MRI/MRA, cardiac echocardiogram, or neuropsychology testing. Should this testing occur, the locally generated report and images closest to 10 years of age were centrally reviewed. Active follow-up included all the same assessments as passive follow-up, but in addition HbF, pit counts, HJB, VDJ, cystatin C, Creatinine and BUN, CBC, reticulocytes, differential, LDH, bilirubin and ALTs were to be performed every year; and data on liver-spleen scan information (quantitative and qualitative), neuropsychological testing, cardiac echocardiography with BNP, pulmonary function testing and MRI/MRA were also collected.

Conclusions

On the basis of the safety and efficacy data from this trial, hydroxyurea can be considered for all very young children with sickle cell anemia (Lancet. 2011; 377(9778):1663-72).

As of the time of posting this study, the study investigators have not yet published conclusions from the Follow-Up Study I and II data.

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