Primary Prevention of Stroke in Children With SCD in Sub-Saharan Africa II

NCT02560935 | Completed Phase 3 DMC

• 2 other identifiers: 1213831R01NS094041-01
• Study Type: interventional
• Target: 440
• Locations: 1 country
• Sites: 3

Brief Summary

The overall goal of this proposal is to conduct a partial double-blind randomized Phase III clinical trial for primary stroke prevention in children with sickle cell anemia (SCA) in sub-Saharan Africa.

Conditions

Sickle Cell Disease; Stroke

Keywords

primary stroke prevention; hydroxyurea; low income country; sub-Saharan Africa

Outcome Measures

Primary Outcomes (1)

• Incidence rate of clinical stroke or TIA

  To determine the efficacy of moderate vs. low dose hydroxyurea therapy for primary stroke prevention. Among over 10,000 children actively followed with SCA, ages 5 to 12 years. There will be a total of 110 participants in each treatment group followed for 3 years. We will have at least 90% power to detect a 66% relative risk reduction (based on our feasibility trial demonstrating that after 3 months, 2/3rds of participants had normal TCD measurements), with an alpha level of 0.05 and a dropout rate of 10%.

  3 Years

Secondary Outcomes (1)

• Incidence of all cause hospitalizations

  3 years

Study Arms (2)

Moderate Dose Hydroxyurea

ACTIVE COMPARATOR

Hydroxyurea at 20 mg/kg/day (range 17.5 to 26 mg/kg/day) for primary stroke prevention.

Drug: Hydroxyurea (Moderate Dose)

Low Dose Hydroxyurea

ACTIVE COMPARATOR

Hydroxyurea at 10 mg/kg/day (range 7 to 15 mg/kg/day) for primary stroke prevention.

Drug: Hydroxyurea (Low Dose)

Interventions

Hydroxyurea (Moderate Dose) DRUG

The study intervention will include moderate dose hydroxyurea therapy at 20 mg/kg/day (range 17.5 - 26 mg/kg/day) for 36 months.

Also known as: Hydrea

Moderate Dose Hydroxyurea

Hydroxyurea (Low Dose) DRUG

The study intervention will include random allocation to low dose hydroxyurea therapy at 10 mg/kg/day (range 7 - 15 mg/kg/day) for 36 months.

Also known as: Hydrea

Low Dose Hydroxyurea

Eligibility Criteria

• Age: 5 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients with hemoglobin SS or SB0 thalassemia, S variant with baseline hemoglobin less than 10 g/dL or other sickle cell syndromes apart from SC confirmed by hemoglobin electrophoresis, HPLC, or IEF;
• Informed consent from a parent or legal guardian and assent of participant ages 5 through 12 (in best estimate pre-puberty, if no date of birth is documented, a frequent event in this region of Nigeria, then we will use the pediatricians best estimate and the patient must be pre-pubertal);
• Patient must be 5 through 12 years of age (i.e., must have attained their 5th but not their 13th birthday when the consent and assent is signed, or best estimate based on absence of documentation. For such patients we will use July 1st of the postulated birth year as their birth date).
• \. Hemoglobin greater than 6.0 g/dL based on initial CBC completed after study consent was obtained for screening, before neurological evaluation and TCD measurement are done. Participants will continue study screening with neurological evaluation and if no evidence of stroke, a TCD will be completed.

You may not qualify if:

• Prior overt stroke (a focal neurological deficit of acute onset) by history, focal neurological deficit on standardized neurological examination, or concern for moderate or severe neurological deficit (which could be due to stroke) based on a positive "10 questions" screening (an established tool in resource poor countries). A "positive" screening is defined as answering yes to any one of the 10 questions. The negative predictive value (child does not have moderate or several neurological impairment) of the "10 questions" is greater than 94% in children;
• Patients for whom are currently receiving hydroxyurea therapy or under consideration prior to study consent/education;
• Patients who have previously been treated with hydroxyurea and are being considered to restart hydroxyurea therapy;
• Other chronic comorbid disease other than asthma;
• History of seizures or diagnosis of epilepsy;
• Any other condition illness, which in the opinion of the site's Principal Investigator (PI) makes participation ill-advised or unsafe;
• Participants of childbearing age who are pregnant or may become pregnant should not take hydroxyurea. If a participant becomes pregnant during the study, their hydroxyurea therapy will be stopped immediately. The onsite will notify the Coordinating Center and the principal investigators of the case. The site principal investigator and study principal investigators will determine what therapy the participant should receive during pregnancy that is of standard care;
• Hemoglobin less than 6.0 g/dL based on initial CBC completed after study consent was obtained for screening, before TCD measurement is done. These patients will be excluded because of evidence that TCD is correlated with anemia. Children with very low hemoglobin levels less than 6.0 g/dL are likely to have nutritional deficiency most likely iron that can be corrected with supplementation.
• Successful completion of screening procedures inclusive of cerebral blood flow velocity less than or equal to 199 cm/sec in the terminal portion of internal carotid, middle cerebral artery, or both vessels;
• Informed consent from a parent or legal guardian and assent from the participant;
• Acceptance to be followed for a minimum of three years in the study. Hydroxyurea may be given for other reasons as part of the participant's ongoing care, but it will not be given as part of the study (SPRING Trial), unless annual TCD reading meets criteria of an elevated TCD measurement based on eligibility criteria for study therapy.
• Successful completion of screening procedures inclusive of cerebral blood flow velocity greater than or equal to 200 cm/sec measured twice or at least one measurement greater than or equal to 220 cm/sec in the middle cerebral artery, internal carotid, or both vessels with non-imaging or imaging technique and greater than or equal to 180 cm/sec in the middle cerebral artery with non-imaging or imaging technique performed by two study personnel;
• If the participant has elevated TCD levels (greater than or equal to 200 cm/sec on two consecutive measurements or a single measurement greater than or equal to 220 cm/sec), they will be offered blood transfusion first, as standard care at the clinical site. If the participant and family elect not to receive blood transfusions, they will be invited to participate in the study.
• Informed consent from a parent or legal guardian for study therapy and assent of the participant completed;
• Participant is able to swallow a capsule, as observed by study personnel;

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead
• Aminu Kano Teaching Hospital: collaborator
• Murtala Muhammed Specialist Hospital: collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Barau Dikko Teaching Hospital/Kaduna State University: collaborator

Study Sites (3)

Barau Dikko Teaching Hospital/Kaduna State University

Kaduna, Nigeria

Location

Aminu Kano Teaching Hospital

Kano, Nigeria

Location

Murtala Muhammad Specialist Hospital

Kano, Nigeria

Location

Related Publications (5)

• Mung'ala-Odera V, Meehan R, Njuguna P, Mturi N, Alcock K, Carter JA, Newton CR. Validity and reliability of the 'Ten Questions' questionnaire for detecting moderate to severe neurological impairment in children aged 6-9 years in rural Kenya. Neuroepidemiology. 2004 Jan-Apr;23(1-2):67-72. doi: 10.1159/000073977.

  PMID: 14739570 BACKGROUND

• Mung'ala-Odera V, Newton CR. Identifying children with neurological impairment and disability in resource-poor countries. Child Care Health Dev. 2007 May;33(3):249-56. doi: 10.1111/j.1365-2214.2006.00714.x.

  PMID: 17439437 BACKGROUND

• Klein LJ, Abdullahi SU, Gambo S, Stallings VA, Acra S, Rodeghier M, DeBaun MR. Underweight children older than 5 years with sickle cell anemia are at risk for early mortality in a low-resource setting. Blood Adv. 2023 Jun 13;7(11):2339-2346. doi: 10.1182/bloodadvances.2022008623.

  PMID: 36383708 DERIVED

• 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.

  PMID: 34971579 DERIVED

• Abdullahi SU, DeBaun MR, Jordan LC, Rodeghier M, Galadanci NA. Stroke Recurrence in Nigerian Children With Sickle Cell Disease: Evidence for a Secondary Stroke Prevention Trial. Pediatr Neurol. 2019 Jun;95:73-78. doi: 10.1016/j.pediatrneurol.2019.01.008. Epub 2019 Jan 17.

  PMID: 30952488 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell; Stroke

Interventions

Hydroxyurea

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals

Study Officials

• Michael R. DeBaun, MD, MPH

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Vice Chair, Clinical Research, Director, Vanderbilt/Meharry Center of SCD

Study Record Dates

• First Submitted: September 2, 2015
• First Posted: September 25, 2015
• Study Start: July 19, 2016
• Primary Completion: March 3, 2020
• Study Completion: March 3, 2020
• Last Updated: August 3, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

NG (3)