The overall goal of the proposed study is to determine the effectiveness of hydroxyurea therapy for secondary stroke prevention and prevention of other neurological events in children with SCA with an acute overt stroke.
Sub-Saharan Africans are disproportionately affected with sickle cell disease (SCD). In the most populous country in sub-Saharan Africa, Nigeria, over 150,000 children with the most severe form of SCD, sickle cell anemia (SCA), are born per year as compared to about 1,100 births in the United States. In Nigeria, for every birth year cohort of children with SCA followed to their 18th birthday with no premature deaths, there are at least 15,000 overt strokes. The prevalence of stroke among children with SCA, particularly in low-income countries, is associated with an increased rate of morbidity and premature death. If untreated, 50% of children who have had their first overt stroke will have a recurrent stroke within two years of the event. Regular blood transfusion is standard therapy for secondary stroke prevention in this high stroke risk population. However, monthly blood transfusion therapy is not a feasible option for children with SCA in sub-Saharan Africa for several reasons, including the high cost of monthly transfusion and limited supply of blood. Preliminary data from observational studies suggest that hydroxyurea (HU) therapy may be an effective alternative strategy for secondary stroke prevention in children with SCA. In sub-Saharan Africa, the critical unanswered question is what appropriate HU dose for secondary stroke prevention maximizes therapeutic benefit while minimizing toxicity to children. In the first National Institutes of Health (NIH)-sponsored primary stroke prevention trial1 in SCA in sub-Saharan Africa (SPIN Trial: NCT01801423), where children with SCD and elevated transcranial Doppler (TCD) measurements, a risk factor for overt stroke, received HU therapy at 20 mg/kg/day, we achieved the following milestones: 1) demonstrated the feasibility of HU therapy for primary stroke prevention in Africa, with 92% of the eligible participants enrolled; 2) showed favorable data that moderate dose HU therapy (20 mg/kg/day) is safe; 3) demonstrated that HU therapy may be effective for primary stroke prevention (3 months after starting HU therapy, two-thirds of the children in the SPIN Trial (n=25) with baseline elevated TCD measurements decreased their TCD values to normal levels); 4) demonstrated short-term safety of HU therapy, with no deaths or increase in hospitalizations when compared to a prospectively followed comparison group (n=210) that has had 4 deaths and a higher rate of all-cause hospitalizations; 5) revealed very good adherence to HU therapy based on the biological correlate, mean corpuscular volume (MCV), and the validated Morisky Medication Adherence Scale; and 6) conducted a one-month intensive clinical research training at Vanderbilt University paired with ongoing mentoring for more than one year with multi-disciplinary teams from Aminu Kano Teaching Hospital (AKTH) and an affiliated satellite clinic, Murtala Muhammad Specialist Hospital (MMSH) both located in Kano, Nigeria. Our results to date indicate that no children have developed a stroke while on HU therapy, and the rate of adverse events has been lower than in the comparison group with a normal TCD measurement who were followed for the same period of time (median of 15 months) with no deaths in the treatment group and three deaths in the comparison group. Both the treatment group and the control group are being followed for 3 years. Based on our encouraging early results for primary stroke prevention in children with SCA (SPIN Trial) in Kano, Nigeria, we propose a definitive phase III trial with the same study team, wherein we will test the hypothesis that moderate dose HU therapy (20 mg/kg/day) results in 80% relative risk reduction when compared to low dose HU therapy (10 mg/kg/day) for secondary stroke prevention among children 1 - 18 years of age with SCA and acute overt stroke.
- Moderate Dose Hydroxyurea Drug
Other Names: Hydrea Intervention Desc: Hydroxyurea therapy at 20 mg/kg/day for primary stroke prevention. ARM 1: Kind: Experimental Label: Hydroxyurea (Moderate Dose) Description: The study intervention will include moderate dose hydroxyurea therapy at 20 mg/kg/day (range 17.5 - 26 mg/kg/day) for 24 months.
- Low Dose Hydroxyurea Drug
Other Names: Hydrea Intervention Desc: Hydroxyurea therapy at 10 mg/kg/day (range 7 - 15 mg/kg/day) for primary stroke prevention. ARM 1: Kind: Experimental Label: Hydroxyurea (Low Dose) Description: The study intervention will include random allocation to low dose hydroxyurea therapy at 10 mg/kg/day (range 7 - 15 mg/kg/day) for 24 months.
- Allocation: Randomized
- Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
- Purpose: Prevention
- Endpoint: Safety/Efficacy Study
- Intervention: Single Group Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||Rate of clinical stroke recurrence||24 months||Yes|
|Secondary||Incidence of All Cause Hospitalizations||24 months||No|