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Sickle Cell DiseasePhase 3SPRINGNCT02560935

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

A Phase 3 study testing Hydroxyurea (Moderate Dose) and Hydroxyurea (Low Dose) in people with Sickle Cell Disease and Stroke, run by Vanderbilt University Medical Center at 3 sites in Nigeria.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 5 to 12 years
Conditions the study is for
Sickle Cell Disease, Stroke
What is being tested?
Hydroxyurea (Moderate Dose) and Hydroxyurea (Low Dose)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
440 participants
Where
3 sitesNigeria
Study dates
19 Jul 2016to 3 Mar 2020
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 5 to 12 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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).
  • 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.

Who cannot join

  • 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;
  • 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);
  • 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;
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  • 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.
  • 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:
  • 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.
  • Inclusion Criteria for participants that will be randomized to hydroxyurea therapy for 36 months:
  • 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;
  • 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 (7/31/2021). If the study is terminated early, families will be informed of optimal dose and given the option to continue hydroxyurea therapy until 7/31/2021. 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.

Trial locations and contacts

3 sites in 1 country.

Nigeria3 sites

  • Barau Dikko Teaching Hospital/Kaduna State University

    Kaduna

  • Aminu Kano Teaching Hospital

    Kano

  • Murtala Muhammad Specialist Hospital

    Kano

Other trials in Nigeria

About this study

Official title: Primary Prevention of Stroke in Children With Sickle Cell Disease in Sub-Saharan Africa II

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.

Read the 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.

Being tested
Hydroxyurea (Moderate Dose), Hydroxyurea (Low Dose)
Keywords
primary stroke prevention, hydroxyurea, low income country, sub-Saharan Africa
Medical subject headings
Anemia, Sickle Cell, Stroke

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Hydroxyurea (Moderate Dose)Drug

    Also called Hydrea

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

  • Hydroxyurea (Low Dose)Drug

    Also called Hydrea

    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.

Study groups in NCT02560935
Study groupRoleWhat they receive
Moderate Dose HydroxyureaActive comparatorHydroxyurea at 20 mg/kg/day (range 17.5 to 26 mg/kg/day) for primary stroke prevention.
Receives: Drug: Hydroxyurea (Moderate Dose)
Low Dose HydroxyureaActive comparatorHydroxyurea at 10 mg/kg/day (range 7 to 15 mg/kg/day) for primary stroke prevention.
Receives: Drug: Hydroxyurea (Low Dose)

What is being measured

The primary outcome is the main question the study is designed to answer.

  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%.

    Measured: 3 Years

Secondary outcomes (1)

  1. Incidence of all cause hospitalizations

    To determine the efficacy of moderate dose hydroxyurea therapy for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, or other) when compared to low dose hydroxyurea therapy.

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Sep 2015 (estimated)
  2. Study start19 Jul 2016
  3. Primary completion3 Mar 2020
  4. Study completion3 Mar 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Single group
Masking
Double blind
Who is masked
Investigator, Outcomes assessor
Enrolment
440 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02560935
Sponsor's protocol ID
121383
Other IDs
1R01NS094041-01
Acronym
SPRING
Status last verified
Jul 2020
First submitted
2 Sep 2015
Last updated
3 Aug 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 14739570

  • 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.

    PubMed 17439437

  • 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.

    PubMed 36383708

  • 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.

    PubMed 34971579

  • 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.

    PubMed 30952488

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Hydroxyurea (Moderate Dose) and Hydroxyurea (Low Dose) in people with Sickle Cell Disease and Stroke, run by Vanderbilt University Medical Center at 3 sites in Nigeria.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Nigeria. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence rate of clinical stroke or TIA (time frame: 3 Years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02560935, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Aug 2020.

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