Hydroxyurea Therapy for Neurological and Cognitive Protection in Pediatric Sickle Cell Anemia in Uganda ( BRAINSAFE-II )

NCT04750707 | Completed Phase 3 DMC

• 2 other identifiers: REC REF 2019-147R01HD096559
• Study Type: interventional
• Target: 270
• Locations: 1 country
• Sites: 1

Brief Summary

Worldwide, an estimated 200,000 babies are born with Sickle Cell Anemia (SCA) annually. Affected children suffer chronic ill health with some having frequent hospitalization. The patients are also at a high risk of brain injury arising from small and large cerebral blood vessel damage in SCA, also called sickle cell vasculopathy (SCV). SCV is associated with the high risk of stroke. Such injury may manifest with neurological and cognitive impairment. An abnormal blood flow to the brain, as measured by a Doppler Ultrasound scan is a known risk factor for stroke. The hypothesis is that hydroxyurea therapy will prevent, stabilize or improve SCV and its effects. The study is an open label, single arm clinical trial to test the impact of hydroxyurea treatment in 270 children with SCA starting at ages 3-9 years. Following baseline assessments, all participants will begin hydroxyurea therapy starting at about 20mg/kg/day. Changes in the frequency and severity of each test (neurological and cognitive tests and cerebral blood flow velocity) will be compared with their baseline tests (prior to hydroxyurea) by repeating these tests at 18 and 36 months. In a randomly selected subset of 90 participants, an evaluation of the impact of hydroxyurea on structural brain vascular injury using magnetic resonance brain imaging (MRI) and magnetic vessel imaging ,also called angiography (MRA) at baseline and at 36 months. Lastly, an assessment of changes to biomarkers of anemia, inflammation and malnutrition from before and during hydroxyurea therapy and determine their relationship to the outcomes. The proposed intervention with hydroxyurea is the first Africa-based trial to broadly prevent or ameliorate manifestations of SCV.

Conditions

Sickle Cell Anemia in Children

Outcome Measures

Primary Outcomes (3)

• The frequency, age specific prevalence and severity of Sickle Cell Vasculopathy manifested by New stroke as assessed by the Pediatric NIH Stroke Scale (PedNIHSS) over the 3-year study while on hydroxyurea treatment, compared to baseline assessments.

  Baseline assessment will be completed for all study participants and over the 3-year study, scheduled outcome assessments will be performed at study months 18 and 36. These assessments will aim to document New (incident) stroke as assessed by the PedNIHSS

  3 years

• The frequency, age specific prevalence and severity of Sickle Cell Vasculopathy manifested by a change in transcranial doppler (TCD) velocity by 15cm/sec or more over the 3-year study while on hydroxyurea treatment, compared to baseline assessment.

  Baseline assessment will be completed for all study participants and over the 3-year study, scheduled outcome assessments will be performed at study months 18 and 36.These assessments will aim to document a change in TCD velocity by 15cm/sec or more.

  3 years

• The frequency, age specific prevalence and severity of SCV manifested by New or worsening cognitive impairment, both quantitative and categorical over the 3-year study while on hydroxyurea treatment, compared to baseline assessments.

  Baseline assessment will be completed for all study participants and over the 3-year study, scheduled outcome assessments will be performed at study months 18 and 36.These assessments will aim to document new or worsening cognitive impairment - both quantitative and categorical (by standardized criteria ≤-2 z-score) compared to established criteria

  3 years

Secondary Outcomes (2)

• Stabilized or worsened structural changes on brain Magnetic Resonance Imaging(MRI) over the 3 years compared to baseline

  3 years

• Stabilized or worsened structural changes on brain Magnetic Resonance Angiography(MRA) over the 3 years compared to baseline

  3 years

Study Arms (1)

single arm

OTHER

Single arm, open label of hydroxyurea starting at 20mg/kg and increased to 30mg/kg depending on clinical need and according to standard guidelines

Drug: Hydroxyurea

Interventions

Hydroxyurea DRUG

The study intervention will be daily oral Hydroxyurea given in single doses starting at approximately 20mg/kg/day and escalated to a maximum 30mg/kg/day depending on clinical need and according to standard guidelines.

Also known as: Siklos

single arm

Eligibility Criteria

• Age: 3 Years - 9 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Documented laboratory diagnosis of HbSS or HbS-B 0 thalassemia (both types are treated equally in SCA studies)
• Ages 3 through 9 years (inclusive) at enrolment
• To ensure clinic follow-up, child has attended Mulago Hospital Sickle Cell Anaemia (SCA)clinic 2 times in the prior 4 years, or at least once in the past 2 years if younger than \< 4 years
• No history of hydroxyurea use for longer than 6 months
• Parent/legal guardian has provided a written consent (and if child is ≥8 years of age, has provided assent)

You may not qualify if:

• History of neurological abnormality known before age 4 months (to avoid those with non SCA brain injury)
• Child is currently enrolled in another clinical intervention trial
• Prior stroke as detected by standard Pediatric NIH Stroke Scale (PedNIHSS) examination
• Pre-existing hematological toxicity
• Hemoglobin \<4.0 gm/dL
• Hemoglobin \<6.0 gm/dL with Absolute Reticulocyte Count \<100 x 10 9/L
• Absolute Reticulocyte Count \<80 x 109/L with Hemoglobin \<7.0 gm/dL
• Platelets \<80 x 109/L
• Absolute Neutrophil Count \<1.0 x 109/L
• Found to be with acute illness at enrolment with fever in last 1 week, respiratory infection, etc.

Sponsors & Collaborators

• Global Health Uganda LTD: lead
• Columbia University: collaborator
• University of Pittsburgh: collaborator
• Emory University: collaborator
• Mulago Hospital, Uganda: collaborator
• Makerere University: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Global Health Uganda

Kampala, +256, Uganda

Location

Related Publications (3)

• Galadanci NA, Umar Abdullahi S, Vance LD, Musa Tabari A, Ali S, Belonwu R, Salihu A, Amal Galadanci A, Wudil Jibir B, Bello-Manga H, Neville K, Kirkham FJ, Shyr Y, Phillips S, Covert BV, Kassim AA, Jordan LC, Aliyu MH, DeBaun MR. Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial). Am J Hematol. 2017 Aug;92(8):780-788. doi: 10.1002/ajh.24770. Epub 2017 Jun 15.

  PMID: 28439953 BACKGROUND

• Naggayi SK, Kalibbala D, Mboizi V, Ssenkusu J, Jin Z, Rosano C, Munube D, Wambaka B, Namazzi R, Kasirye P, Kabatabaazi M, Nambatya G, Murungi S, Nabaggala C, Nakafeero M, Troidl IR, Opoka R, Idro R, Bangirana P, Green NS. Neurocognitive gains among Ugandan children with sickle cell anemia on hydroxyurea: 18-month interim trial results. Blood Adv. 2025 Jun 24;9(12):3116-3127. doi: 10.1182/bloodadvances.2024015073.

  PMID: 40085947 DERIVED

• Mboizi V, Nabaggala C, Munube D, Ssenkusu JM, Kasirye P, Kamya S, Kawooya MG, Boehme A, Minja F, Mupere E, Opoka R, Rosano C, Idro R, Green NS. Hydroxyurea therapy for neurological and cognitive protection in pediatric sickle cell anemia in Uganda (BRAIN SAFE II): Protocol for a single-arm open label trial. Contemp Clin Trials Commun. 2024 Nov 28;42:101404. doi: 10.1016/j.conctc.2024.101404. eCollection 2024 Dec.

  PMID: 39717517 DERIVED

MeSH Terms

Interventions

Hydroxyurea

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals

Study Officials

• Richard Idro, PhD

  Makerere University

  PRINCIPAL INVESTIGATOR

• Nancy Green, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2021
• First Posted: February 11, 2021
• Study Start: March 9, 2021
• Primary Completion: March 10, 2025
• Study Completion: March 10, 2025
• Last Updated: April 17, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: 3 years

Locations

UG (1)