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

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ClinicalTrials.gov Identifier: NCT04750707
Recruitment Status : Recruiting
First Posted : February 11, 2021
Last Update Posted : March 29, 2021
Sponsor:
Collaborators:
Columbia University
University of Pittsburgh
Emory University
Mulago Hospital, Uganda
Makerere University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Global Health Uganda LTD

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.


Condition or disease Intervention/treatment Phase
Sickle Cell Anemia in Children Drug: Hydroxyurea Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 270 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Hydroxyurea Therapy for Neurological and Cognitive Protection in Pediatric Sickle Cell Anemia in Uganda: A Single Arm Open Label Trial, "BRAIN SAFE II"
Actual Study Start Date : March 9, 2021
Estimated Primary Completion Date : August 2024
Estimated Study Completion Date : August 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anemia
Drug Information available for: Hydroxyurea

Arm Intervention/treatment
single arm
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
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.
Other Name: Siklos




Primary Outcome Measures :
  1. 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. [ Time Frame: 3 years ]

    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


  2. 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. [ Time Frame: 3 years ]
    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. 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. [ Time Frame: 3 years ]
    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


Secondary Outcome Measures :
  1. Stabilized or worsened structural changes on brain Magnetic Resonance Imaging(MRI) over the 3 years compared to baseline [ Time Frame: 3 years ]
    Brain magnetic resonance will be performed on a subset of subjects at baseline and study month 36 only. Stabilized or worsened structural changes on brain Magnetic Resonance Imaging(MRI) over the 3 years compared to baseline will be assessed.

  2. Stabilized or worsened structural changes on brain Magnetic Resonance Angiography(MRA) over the 3 years compared to baseline [ Time Frame: 3 years ]
    Brain magnetic resonance angiography will be performed on a subset of subjects, at baseline and study month 36 only. Stabilized or worsened structural changes on brain Magnetic Resonance Angiography over the 3 years compared to baseline will be assessed.



Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 9 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Documented laboratory diagnosis of HbSS or HbS-B 0 thalassemia (both types are treated equally in SCA studies)
  2. Ages 3 through 9 years (inclusive) at enrolment
  3. 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
  4. No history of hydroxyurea use for longer than 6 months
  5. Parent/legal guardian has provided a written consent (and if child is ≥8 years of age, has provided assent)

Exclusion Criteria:

  1. History of neurological abnormality known before age 4 months (to avoid those with non SCA brain injury)
  2. Child is currently enrolled in another clinical intervention trial
  3. Prior stroke as detected by standard Pediatric NIH Stroke Scale (PedNIHSS) examination

    Temporary exclusion criteria

  4. Pre-existing hematological toxicity

    1. Hemoglobin <4.0 gm/dL
    2. Hemoglobin <6.0 gm/dL with Absolute Reticulocyte Count <100 x 10 9/L
    3. Absolute Reticulocyte Count <80 x 109/L with Hemoglobin <7.0 gm/dL
    4. Platelets <80 x 109/L
    5. Absolute Neutrophil Count <1.0 x 109/L
  5. Found to be with acute illness at enrolment with fever in last 1 week, respiratory infection, etc.
  6. History of a sickle crisis within the prior 2 weeks, or blood transfusion within the past 90 days Participants with temporary exclusion can be enrolled later when stable or the excluding criteria has resolved

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04750707


Contacts
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Contact: Richard Idro, PhD +256 774 274173 ridro1@gmail.com
Contact: Nancy Green, MD 202-305-0494 nsg11@cumc.columbia.edu

Locations
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Uganda
Global Health Uganda Recruiting
Kampala, Uganda, +256
Contact: Richard Idro, PhD    +256 774 274173    ridro1@gmail.com   
Contact: Robert Opoka, PhD    +256 772 996164    opokabob@yahoo.com   
Principal Investigator: Richard Idro, PhD         
Sponsors and Collaborators
Global Health Uganda LTD
Columbia University
University of Pittsburgh
Emory University
Mulago Hospital, Uganda
Makerere University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Richard Idro, PhD Makerere University
Principal Investigator: Nancy Green, MD Columbia University
Publications:
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Responsible Party: Global Health Uganda LTD
ClinicalTrials.gov Identifier: NCT04750707    
Other Study ID Numbers: REC REF 2019-147
R01HD096559 ( U.S. NIH Grant/Contract )
First Posted: February 11, 2021    Key Record Dates
Last Update Posted: March 29, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Provider Investigator- Dr Richard Idro Recipient Investigator- Dr Nancy Green Permitted Uses of Data Set Scientific publication Inform policies Systematic reviews Safety investigations Other legitimate academic and policy issues.

Data Set Content

  1. Demographic data
  2. Interventional drug data
  3. Cognitive data including all neurocognitive tests administered at 0, 18 and 36 months follow-ups.
  4. Laboratory data including hemograms, haemoglobin electrophoresis, serum chemistry results, inflammatory markers, SCA variants at all scheduled time points.
  5. Neuroimaging data including all MRI data
  6. TCD data
  7. Scheduled visit clinical data including history, physical examination, PedNIHSS at baseline,18 and 36 months.
  8. Unscheduled visits data including all adverse events
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: 3 years

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anemia
Anemia, Sickle Cell
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors