Stroke Prevention in Nigeria 2 Trial

NCT ID: NCT06526117

Last Updated: 2025-02-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 220 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-08-05
• Study Completion Date: 2030-06-30

Brief Summary

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.

Detailed Description

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.

Conditions

Sickle Cell Disease; Stroke

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Low or Moderate Dose Hydroxyurea

Initial treatment with Hydroxyurea at 10 mg/kg/day (range 7 to 15 mg/kg/day) for primary stroke prevention. Subsequent treatment with moderate-dose hydroxyurea (20 mg/kg/day (range 17.5 - 26 mg/kg/day)) based after at least two severe pain events requiring physician contact during the trial.

Group Type: EXPERIMENTAL

Hydroxyurea

Intervention Type: DRUG

The study intervention will include initial treatment with low-dose hydroxyurea therapy at 10 mg/kg/day (range 7 - 15 mg/kg/day), with subsequent increase to moderate dose hydroxyurea therapy at 20 mg/kg/day (range 17.5 - 26 mg/kg/day) after at least two severe events requiring physician contact.

Interventions

Hydroxyurea

The study intervention will include initial treatment with low-dose hydroxyurea therapy at 10 mg/kg/day (range 7 - 15 mg/kg/day), with subsequent increase to moderate dose hydroxyurea therapy at 20 mg/kg/day (range 17.5 - 26 mg/kg/day) after at least two severe events requiring physician contact.

Intervention Type: DRUG

Other Intervention Names

Hydrea

Eligibility Criteria

Inclusion Criteria

• 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

• 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.

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aminu Kano Teaching Hospital

OTHER

Sponsor Role: collaborator

Murtala Muhammed Specialist Hospital

OTHER

Sponsor Role: collaborator

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Michael DeBaun

Professor, Vice Chair, Chair, Clinical Research, Director, Vanderbilt/Meharry Center of SCD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael R DeBaun, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Aminu Kano Teaching Hospital

Kano, , Nigeria

Site Status: RECRUITING

Murtala Muhammad Specialist Hospital

Kano, , Nigeria

Site Status: RECRUITING

Countries

Nigeria

Central Contacts

Michael R DeBaun, MD, MPH

Role: CONTACT

m.debaun@vumc.org

615-875-3040 ext. 5-3040

Leshana Saint Jean, PHD

Role: CONTACT

leshana.saint.jean@vumc.org

615-875-1992

Facility Contacts

Shehu U Abdullahi, MD, FWACPaed

Role: primary

dr_suak@yahoo.com

234-802-850-3832

Abdulkadir H Yusuf, MSc

Role: backup

ahyusuf57@gmail.com

234-8039398712

Salma A Suwaid, MBBS FWACP

Role: primary

salmasuwaid@yahoo.com

234 803 659 6328

Awwal I Gambo, CCRP, PGDM, MDS, Stat Epid

Role: backup

awwalgambo@gmail.com

234-08065498171

References

Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998 Jul 2;339(1):5-11. doi: 10.1056/NEJM199807023390102.

Reference Type: BACKGROUND

PMID: 9647873 (View on PubMed)

Abdullahi SU, Jibir BW, Bello-Manga H, Gambo S, Inuwa H, Tijjani AG, Idris N, Galadanci A, Hikima MS, Galadanci N, Borodo A, Tabari AM, Haliru L, Suleiman A, Ibrahim J, Greene BC, Ghafuri DL, Rodeghier M, Slaughter JC, Kirkham FJ, Neville K, Kassim A, Trevathan E, Jordan LC, Aliyu MH, DeBaun MR. Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial. Lancet Haematol. 2022 Jan;9(1):e26-e37. doi: 10.1016/S2352-3026(21)00368-9.

Reference Type: BACKGROUND

PMID: 34971579 (View on PubMed)

Other Identifiers

U01NS129143

Identifier Type: NIH

Identifier Source: secondary_id

View Link

231110

Identifier Type: -

Identifier Source: org_study_id