This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator. The Pediatric Hydroxyurea Phase III Clinical Trial (BABYHUG) is a randomized, double-blind, placebo-controlled trial to investigate the use of hydroxyurea (HU) in very young children with sickle cell anemia (Hgb SS). The primary objective is to determine whether or not treatment with hydroxyurea (HU) will reduce the rate of chronic end organ damage, by at least 50%, as determined by surrogate markers. Secondary objectives are two-fold: to determine the relationship between fetal hemoglobin levels (Hgb F) and chronic organ damage in this age group and to investigate the safety of hydroxyurea in young children with regards to growth and development, neuropsychological development, immunologic response, and mutagenic effects on DNA. The study anticipates enrollment of 200 children aged 9-17 months with Hgb SS (100 in each treatment arm) to receive either hydroxyurea or placebo for a period of two years. Twenty of these children will be recruited to enter through the Baltimore/Washington consortium sites (Johns Hopkins University, Sinai Hospital of Baltimore, and Georgetown University). The primary objective of the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) is to determine the safety and effectiveness of hydroxyurea (HU) in the prevention of chronic end organ injury occurring among sickle cell anemia patients who are 9 through 17 months of age at the time of study entry. A Feasibility and Safety Pilot Study initiated BABY HUG recruitment with 40 patients 12 through 17 months of age to (1) determine the feasibility of the protocol design, (2) provide additional safety and toxicity data and (3) validate the proposed methods of quantitating splenic and renal function. The initial group was studied intensively and monitored closely. The DSMB has recommended that 160 additional participants be enrolled in BABY HUG for a total of 200 patients in the full Phase III trial. The primary analyses on the full study will compare the frequency of worsening of spleen function (from normal to decreased or absent, or from decreased to absent) as measured by splenic uptake on a technetium -99m sulfur colloid liver-spleen scan and continuing renal damage, as measured by glomerular filtration rate (GFR), at two years of follow-up after study entry in patients randomly assigned to treatment with hydroxyurea versus those assigned to placebo. Data monitoring analyses are scheduled every six months from the start of enrollment in the study. Inclusion criteria for this study include: a hemoglobin pattern in a male or female child, that shows a majority of fetal and sickle hemoglobin (SF or FS), confirmed by central electrophoresis; age range of 9-17 months (12-17 months for the internal pilot); and completion of the informed consent by the child's parents/guardians. Patient screening may begin at 7 months of age. Exclusion criteria include: chronic transfusions, malignancy, less than 10th percentile height, weight, or head circumference for age, severe developmental delay, stroke with neurological deficit, surgical splenectomy, participation in another clinical intervention trial, probable or known Hereditary Persistence of Fetal Hemoglobin (HPFH), hemoglobin S-beta plus thalassemia, chronic illness, or inability to complete baseline testing, previous or current treatment with HU or another anti-sickling drug. Transient exclusion criteria include: hgb <6.0gm/dl, retic count < 80,000/cu mm if hemoglobin is less than 9 gm/dL, neutrophil count <2,000/cu mm, platelet count <130,000/cu mm, blood transfusion in the past 2 months, ALT or creatinine >2x normal, ferritin less than 10 ng/ml, and Bayley's score <70. Once the condition(s) associated with the transient criteria have been resolved, children may be re-evaluated for the trial. The rationale for these exclusion criteria is that children with underlying or secondary medical conditions, if enrolled, may add confounding variables and alter the results of the study. Also, preventing harm to infants with risk factors such as low baseline counts is of tantamount importance, as hydroxyurea can be myelotoxic. Older children were excluded because the incidence of asplenia rises with age. Primary endpoints of the study will be will be spleen function (Will loss of function, as assessed by 99Tc sulfur colloid uptake, be delayed by HU?) and GFR (Will HU attenuate the rapid rise in GFR normally seen in infants with sickle cell disease, and will this translate into less glomerular damage over the years?). Urinary concentrating ability will also be followed as a secondary endpoint. Other secondary endpoints include impact of HU on brain (neuropsychologic testing, pediatric neurologist examination), lungs (oxygen saturation), hepatobiliary (liver examination, liver toxicity, abdominal sonogram for gallstones), immune function, pitted red cells, penicillin compliance, and acute events. The children will be screened at entry and exit, and in some cases, sequentially throughout the trial (See Appendix A in Protocol Summary). After exit from the trial, a less intensive follow-up regimen will potentially be offered for an additional 5 years. Pharmacokinetic studies will be done on approximately the first 10 infants enrolled on the internal pilot, and ancillary studies looking at transcranial doppler, ultrasonography, MR spectroscopy of the brain, and biological markers (vascular and cellular adhesion molecules) may be added if the proposing investigators obtain funding. Infants will be treated at a dose of 20mg/kg/day of study drug; there will be no dose escalations. Blood counts will be monitored at 2-week intervals until stable and then every four weeks. The local laboratory will perform automated (manual if automated is invalidated) CBC counts and the Primary Endpoint Person (PEP) will enter them into the BABY HUG database via the internet Data Entry System within one day of collecting the blood or by 9:00 a.m. the following day. The PEP will review the local results to determine of a toxicity is present in the data. If there is a toxicity, the PEP will notify the Clinical Center staff of the need for a stop order.
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