Stroke Prevention in Nigeria 2 Trial

The primary goal of this study is to complete a multicenter single-arm, type I hybrid trial to assess the effectiveness of hydroxyurea therapy for primary stroke prevention in high-risk children with sickle cell anemia (SCA) living in Nigeria in routine care settings.

Strokes in sickle cell anemia (SCA), particularly in children living in Africa, are associated with significant morbidity and an increased risk of premature death. In the US, primary stroke prevention in children with SCA involves screening for elevated Transcranial Doppler ultrasound (TCD) velocity coupled with regular blood transfusion therapy for persons with elevated velocities. However, regular blood transfusion therapy is not a viable option for children with SCA in Nigeria for several reasons, including 1) inadequate supply of blood (still donor exchange system; 2) availability and cost of monthly blood transfusions for preventive therapy as opposed to emergency therapy; 3) unsafe blood supplies with a high probability of blood-borne infections and alloimmunization; and 4) children that receive regular blood transfusion will ultimately require daily iron chelation an unaffordable undertaking in low-income countries.

This multicenter open-label, single-arm type I hybrid trial will assess the effectiveness of Hydroxyurea therapy for primary stroke prevention in children with sickle cell anemia (SCA) living in Nigeria. A recently completed double-blind, parallel-group phase III randomized controlled trial (SPRING), involved comparing low-dose to moderate-dose hydroxyurea for primary stroke prevention in children with SCA and abnormal transcranial Doppler (TCD) velocities (\>200 cm/sec). Children with abnormal TCD velocities have a high stroke risk of approximately 10.7 events per 100 person-years (observation arm in the STOP trial). In the low- (n=109) and moderate-dose (n=111) hydroxyurea groups, the stroke incidence rates were 1.2 and 1.9 per 100 person-years, respectively, p=0.77 (combined incidence rate 1.5 per 100 person-years). Despite equal efficacy for stroke prevention in both treatment groups, moderate- when compared to low-dose hydroxyurea, was more effective in preventing severe acute pain and all-cause hospitalizations. Our findings supported the American Society of Hematology's evidence-based guidelines for hydroxyurea therapy for primary stroke prevention in low-income settings. The hypothesis to be tested in the SPRING-2 study is in a multicenter single-arm type I hybrid trial, for children with abnormal TCD velocities treated with hydroxyurea, the stroke incidence rate will be non-inferior to the SPRING trial results, with an upper non-inferiority margin of 4 strokes per 100-person-years. The point estimate method was used to determine the non-inferiority margin based on the Nigerian pediatrician's judgment of what maximum stroke rate would be clinically meaningful to demonstrate the effectiveness and justify treatment for the high-risk stroke group. A non-inferiority test with an overall sample size of 220 will achieve 91% power at a 0.050 significance level to detect non-inferiority when the expected proportion of strokes is 0.035, a minimum follow-up period of 2.5 years and a loss to follow-up of 10% per year. The study will follow standard of care procedures, including clinic visits every 3 months and complete blood cell counts every 6 months. The following aims will be conducted as part of the trial: 1) Determine the incidence of the first stroke in children with abnormal TCD velocities treated with hydroxyurea for 2.5 years in the type 1 hybrid trial; 2) Evaluate the implementation and sustainability of the intervention within the extended RE-AIM framework; 3) Evaluate the cost-effectiveness of low- compared to a higher dose of hydroxyurea for primary stroke prevention in children with abnormal TCD velocities. Capacity building for three Nigerian Multiple Principal Investigators, statisticians, and nurses will be focused on three areas-: 1) developing a Nigerian data coordinating center and the required skills to support a clinical trial; 2) developing a regional TCD course for nurses, enhancing task shifting and reach, and 3) performing cost-effective analysis for the type I hybrid trial comparing low-and moderate dose hydroxyurea.

Eligibility Criteria:
Inclusion Criteria:

The inclusion criteria for the SPRING-2 Trial will consist of:

* Diagnosis of HbSS or HbSB0 confirmed by high-performance liquid chromatography (HPLC);
* Informed consent from the parent/legal guardian and assent from the patient at least 7 years of age;
* Two TCD flow velocity readings of \>or equal to180 cm/sec and \< 220 cm/sec or one TCD velocity reading \> or equal to 220 cm/sec; typically the repeat TCD is performed on the same day so treatment can start immediately;
* Age between 5 and 12 years (assessment can take place up until the 13th birthday), which includes the peak age of onset of strokes in SCA, \~ 6 yo; and
* Ability to swallow the hydroxyurea capsule.

Exclusion Criteria:

The exclusion criteria will be the following:

* Prior stroke or TIA by history, or concern for moderate or severe neurological deficit based on a positive validated "10 questions" screening;
* Other significant organ system dysfunction or other contraindication to hydroxyurea;
* Children who are already on therapy with either blood transfusion or hydroxyurea therapy;
* Significant cytopenias (absolute neutrophil count (ANC) \<1500, platelets \<150,000/ul, reticulocytes \<80,000/ul, unless Hb is \> 9 g/dl\], renal insufficiency (creatinine \> 0.8 mg/dl); and
* History of seizures or diagnosis of epilepsy, and 6) metal in the body that would make MRI unsafe. The rationale for excluding children under 5 years old: Despite being a vulnerable age group for strokes, children younger than 5 years were excluded because a significant proportion of this population is unable to swallow a capsule, the only stable form of hydroxyurea available in Nigeria.