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

This study is currently recruiting participants.
Verified March 2017 by Michael DeBaun, Vanderbilt University Medical Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT02560935
First Posted: September 25, 2015
Last Update Posted: March 22, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Aminu Kano Teaching Hospital
Murtala Muhammed Specialist Hospital
National Institute of Neurological Disorders and Stroke (NINDS)
Barau Dikko Teaching Hospital/Kaduna State University
Information provided by (Responsible Party):
Michael DeBaun, Vanderbilt University Medical Center
  Purpose
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.

Condition Intervention Phase
Sickle Cell Disease Stroke Drug: Hydroxyurea (Moderate Dose) Drug: Hydroxyurea (Low Dose) Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Primary Prevention of Stroke in Children With Sickle Cell Disease in Sub-Saharan Africa II

Resource links provided by NLM:


Further study details as provided by Michael DeBaun, Vanderbilt University Medical Center:

Primary Outcome Measures:
  • Incidence rate of clinical stroke or TIA [ Time Frame: 3 Years ]
    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%.


Secondary Outcome Measures:
  • Incidence of all cause hospitalizations [ Time Frame: 3 years ]
    To determine the efficacy of moderate dose hydroxyurea therapy for decreasing the incidence of all cause-hospitalization for any cause (pain, acute chest syndrome, infection, or other) when compared to low dose hydroxyurea therapy.

  • Long-term safety of hydroxyurea therapy [ Time Frame: 3 Years ]
    To assess the long-term safety of hydroxyurea therapy (6.5 years) in participants from the feasibility trial with an elevated TCD measurement (n=25) when compared to children with an initial normal TCD (n= 210 followed for at least 3 years).


Estimated Enrollment: 440
Study Start Date: July 2016
Estimated Study Completion Date: December 2021
Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Moderate Dose Hydroxyurea
Hydroxyurea therapy at 20 mg/kg/day for primary stroke prevention.
Drug: Hydroxyurea (Moderate Dose)
The study intervention will include moderate dose hydroxyurea therapy at 20 mg/kg/day (range 17.5 - 26 mg/kg/day) for 36 months.
Other Name: Hydrea
Active Comparator: Low Dose Hydroxyurea
Hydroxyurea therapy at 10 mg/kg/day (range 7 to 15 mg/kg/day) for primary stroke prevention.
Drug: Hydroxyurea (Low Dose)
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.
Other Name: Hydrea

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 those with elevated velocities. However, regular blood transfusion therapy is not feasible in Africa due to inadequate supply of safe blood and the reluctance of parents to accept regular blood transfusion therapy for their children. Promising preliminary data from our feasibility trial in Kano, Nigeria (1R21NS080639-NCE, NCT01801423; October 2012 - August 2014) support the potential use of moderate dose hydroxyurea (HU) therapy of 20 mg/kg/day for primary prevention of stroke in children with SCA. In the feasibility trial, we screened 331 participants; 92% (25 of 27) of participants with elevated TCD measurements elected to enroll and receive HU therapy. About 75% (210 of 280) of the screened participants with non-elevated TCD measurements agreed to be followed for a minimum of three years to assess the background rate of morbidity and mortality. Among those on HU therapy, 80% (20 of 25) of the participants who reached their third month on HU therapy dropped their elevated TCD value to below 200 cm/sec in both middle cerebral arteries. Based on the results from the recently completed Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea trial (NCT01425307), demonstrating that children with an elevated TCD measurement can be switched to HU therapy after one year of blood transfusion, coupled with our preliminary trial results indicating a decrease in TCD velocities in 2/3rds of the participants over 3 months, we propose a three center randomized partial double-blind Phase III clinical trial (1R01NS094041-01; September 2015 - July 2020) to test the following hypothesis: There will be a 66% relative risk reduction of primary strokes in children with SCA, and elevated TCD measurements (n=220), randomly allocated to moderate dose vs. low dose HU therapy (10 vs. 20 mg/kg/day) for 3 years. The aims of the randomized partial double-blind Phase III clinical trial are to: 1) determine the efficacy of moderate vs. low dose HU therapy for primary stroke prevention; 2) determine the efficacy of moderate dose HU therapy for decreasing the incidence of all cause-hospitalization for any cause (pain, acute chest syndrome, infection, or other) when compared to low dose HU therapy; and 3) assess long-term safety of HU therapy (mean 6.5 years) in participants from the feasibility trial with an elevated TCD measurement (n=25), when compared to children with an initial normal TCD (n= 210, followed for at least 3 years). In preparation for this application, the teams from Nigeria have received 1 month of patient-oriented research training at Vanderbilt University School of Medicine. This trial will help us to determine whether moderate dose HU therapy can prevent thousands of strokes in children at high risk in Africa, while simultaneously helping build research capacity among the next cadre of physician scientists in Nigeria.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   5 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria for initial screening inclusive of CBC:

  1. 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;
  2. 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);
  3. 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).

Inclusion criteria for continuance of study screening to determine eligibility for study therapy:

1. 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.

Exclusion Criteria for screening:

  1. 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).1,2 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;1
  2. Other exclusions: significant cytopenias [absolute neutrophil count (ANC) <1.5 X 109/L, /µl, platelets <150,000/µl, reticulocytes <80,000/µl, unless Hb is > 9 g/dl], renal insufficiency (creatinine > 0.8 mg/dl);
  3. Patients for whom are currently receiving hydroxyurea therapy or under consideration prior to study consent/education;
  4. Patients who have previously been treated with hydroxyurea and are being considered to restart hydroxyurea therapy;
  5. Other chronic comorbid disease other than asthma;
  6. History of seizures or diagnosis of epilepsy;
  7. Any other condition illness, which in the opinion of the site's Principal Investigator (PI) makes participation ill-advised or unsafe;
  8. Participants of child bearing 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;
  9. 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.

Inclusion Criteria for participants that are not eligible to receive hydroxyurea therapy, but willing to be followed for a minimum of three years in the non-elevated TCD group:

  1. 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;
  2. Informed consent from a parent or legal guardian and assent from the participant;
  3. 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.

Inclusion Criteria for participants that will be randomized to hydroxyurea therapy for 36 months:

  1. 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.

  2. Informed consent from a parent or legal guardian for study therapy and assent of the participant completed;
  3. Participant is able to swallow a capsule, as observed by study personnel;
  4. Acceptance of hydroxyurea therapy for at least three years. At 36 months, a decision between the family and provider can be made whether to continue with hydroxyurea therapy until the end of the study (7/31/2020). If the study is terminated early, families will be informed of optimal dose and given the option to continue hydroxyurea therapy until 7/31/2020. The provisions of hydroxyurea will be continued to assess the toxicity of the study medication among study groups.

Exclusion criteria for study therapy and non-elevated TCD group:

1. Unable to commit to follow up visits for the duration of the study.

  Contacts and Locations
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): NCT02560935


Contacts
Contact: Michael R. DeBaun, MD, MPH 615-875-3040 ext 5-3040 m.debaun@vanderbilt.edu
Contact: Muktar Aliyu, MBBS, MPH, DrPH 615-343-4174/615-3434-0626 muktar.aliyu@Vanderbilt.Edu

Locations
Nigeria
Barau Dikko Teaching Hospital/Kaduna State University Not yet recruiting
Kaduna, Nigeria
Contact: Halima Bello-Manga, MBBS, MPH, FMCPath    +2348033470592    mamanzara@yahoo.co.uk   
Contact: Lawal Haliru, MBBS, FWACP, PGDPA    +234 8036896210    drdaddy002@yahoo.com   
Aminu Kano Teaching Hospital Recruiting
Kano, Nigeria
Contact: Shehu U. Abdullahi, MD, FWACPaed    234-802-850-3832    dr_suak@yahoo.com   
Contact: Najibah Galadanci, MBBS, MPH    234-803-700-5452    jibaliyu@yahoo.com   
Principal Investigator: Najibah Galadanci, MBBS,FMCPath,MPH         
Murtala Muhammad Specialist Hospital Recruiting
Kano, Nigeria
Contact: Binta W. Jibir, MBBS, MTroped, FWACP    234-803-700-2249    bintajibir@gmail.com   
Contact: Awwal I Gambo    234-8052886441    awwalgambo@gmail.com   
Sponsors and Collaborators
Vanderbilt University Medical Center
Aminu Kano Teaching Hospital
Murtala Muhammed Specialist Hospital
National Institute of Neurological Disorders and Stroke (NINDS)
Barau Dikko Teaching Hospital/Kaduna State University
Investigators
Principal Investigator: Michael R. DeBaun, MD, MPH Vanderbilt University Medical Center
  More Information

Publications:
Responsible Party: Michael DeBaun, Professor, Vice Chair, Clinical Research, Director, Vanderbilt/Meharry Center of SCD, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT02560935     History of Changes
Other Study ID Numbers: 121383
1R01NS094041-01 ( U.S. NIH Grant/Contract )
First Submitted: September 2, 2015
First Posted: September 25, 2015
Last Update Posted: March 22, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Michael DeBaun, Vanderbilt University Medical Center:
primary stroke prevention
hydroxyurea
low income country
sub-Saharan Africa

Additional relevant MeSH terms:
Stroke
Anemia, Sickle Cell
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors