Trial no.:	PACTR202312522038774	Date of Approval:	22/12/2023
Trial Status:	Registered in accordance with WHO and ICMJE standards

TRIAL DESCRIPTION

Public title

Primary Prevention of Stroke in Children with SCD in Sub-Saharan Africa II: A Multicenter, Open-label, Single-arm Type I Hybrid Clinical Trial

Official scientific title

Primary Prevention of Stroke in Children with SCD in Sub-Saharan Africa II: A Multicenter, Open-label, Single-arm Type I Hybrid Clinical Trial

Brief summary describing the background and objectives of the trial

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 persons with elevated velocities. However, regular blood transfusion therapy is not feasible in Africa due to the inadequate supply of safe blood and the reluctance of parents to accept regular blood transfusion therapy for their children. We propose a multicenter open-label, single-arm type I hybrid trial to assess the effectiveness of hydroxyurea therapy for primary stroke prevention in children with sickle cell anemia (SCA) living in Nigeria. Our team just completed a double-blind, parallel-group phase III randomized controlled trial (SPRING), where we compared low-dose to moderate-dose hydroxyurea for primary stroke prevention in children with SCA and abnormal transcranial Doppler (TCD) velocities (>200 cm/sec). Children with abnormal TCD velocities have a high stroke risk of approximately 10.7 events per 100 person-years (observation arm in the STOP trial). In the low- (n=109) and moderate-dose (n=111) hydroxyurea groups, the stroke incidence rates were 1.2 and 1.9 per 100 person-years, respectively, p=0.77 (combined incidence rate 1.5 per 100 person-year). Despite equal efficacy for stroke prevention in both treatment groups, moderate- when compared to low-dose hydroxyurea, was more effective in preventing severe acute pain and all-cause hospitalizations. Our findings supported the American Society of Hematology's evidence-based guidelines for hydroxyurea therapy for primary stroke prevention in low-income settings. The hypothesis to be tested in the SPRING-2 study is: in a multicenter single-arm type I hybrid trial, for children with abnormal TCD velocities treated with hydroxyurea.

Type of trial

Non-Randomised

Acronym (If the trial has an acronym then please provide)

SPRING 2

Disease(s) or condition(s) being studied

Haematological Disorders,Paediatrics

Sub-Disease(s) or condition(s) being studied

Purpose of the trial

Prevention

Anticipated trial start date

01/01/2024

Actual trial start date

01/01/2024

Anticipated date of last follow up

31/12/2028

Actual Last follow-up date

Anticipated target sample size (number of participants)

220

Actual target sample size (number of participants)

Recruitment status

Not yet recruiting

Publication URL

Secondary Ids	Issuing authority/Trial register

STUDY DESIGN
Intervention assignment	Allocation to intervention	If randomised, describe how the allocation sequence was generated	Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms	Masking	If masking / blinding was used
Single Group	Non-randomised		Allocation was determined by the holder of the sequence who is situated off site	Open-label(Masking Not Used)

INTERVENTIONS
Intervention type	Intervention name	Dose	Duration	Intervention description	Group size	Nature of control
Experimental Group	Hydroxyurea	Daily dose of 10mg/kg and escalated dose of 20mg/kg	30 months	Hydroxyurea	220

ELIGIBILITY CRITERIA
List inclusion criteria	List exclusion criteria	Age Category	Minimum age	Maximum age	Gender
1) diagnosis of HbSS or HbSB0 confirmed by electrophoresis 2) informed consent from the parent/legal guardian and assent from patient 3) two TCD flow velocity readings of >200 cm/sec and < 220 cm/sec or one TCD velocity reading > 220 cm/sec; typically the repeat TCD is performed on the same day so treatment can start immediately 4) age between 5 and 12 years (assessment can take place up until the 13th birthday), which includes the peak age of onset of strokes in SCA, ~ 6 yo 5) ability to swallow the hydroxyurea capsule.	1) prior stroke or TIA by history, or concern for moderate or severe neurological deficit based on a positive validated "10 questions" screening 2) other significant organ system dysfunction or other contraindication to hydroxyurea 3) Children who are already on therapy with either blood transfusion or hydroxyurea therapy 4) significant cytopenias (absolute neutrophil count (ANC) <1500, platelets <150,000/ul, reticulocytes <80,000/ul, unless Hb is > 9 g/dl], renal insufficiency (creatinine > 0.8 mg/dl) 5) other significant organ system dysfunction, or other contraindication to hydroxyurea therapy 6) history of seizures or diagnosis of epilepsy, and 7) metal in the body that would make MRI unsafe.	Child: 6 Year-12 Year	6 Year(s)	12 Year(s)	Both

ETHICS APPROVAL

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

02/08/2023

Aminu Kano Teaching Hospital Kano

Ethics Committee Address
Street address	City	Postal code	Country
No 2 Zaria Road	Kano	700233	Nigeria

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

17/07/2023

Vanderbilt University Medical Centre Ethics Committee

Ethics Committee Address
Street address	City	Postal code	Country
2525 West End Street	Nasville	37203	United States of America

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

30/06/2023

KANO STATE MINISTRY OF HEALTH ETHICS COMMITTEE

Ethics Committee Address
Street address	City	Postal code	Country
POST OFFICE ROAD KANO	Kano	700211	Nigeria

OUTCOMES
Type of outcome	Outcome	Timepoint(s) at which outcome measured
Primary Outcome	(the primary outcome measure): The Nigerian radiologist's review panel (n=3) and the Nigerian psychiatrist/neurologist (n=1) will be blinded to the clinical history. As in the SPRING Trial cases, all potential strokes will be adjudicated in a masked fashion. We will use the WHO definition of a stroke28. The core radiology team has already been formally certified to detect strokes based on the MRI in children with sickle cell anemia and will follow the methodology previously established in the SIT trial study group. The Nigerian team clinical staff were trained to identify stroke using the Pediatric NIH Stroke Scale (PedNIHSS), a validated, standardized neurological examination assessing and quantifying the severity of stroke in children. Outcomes. The primary outcome will be an incident stroke or TIA. In addition to careful instructions reporting stroke symptoms to the hospital, parents will be asked about stroke symptoms, and children will have a neurological exam every 6 months at clinic visits. The pediatric NIH stroke scale30 and a gait exam have been used to detect strokes. Capacity building for Aim 1: Creating a coordinating data center for the SPRING-2 in Kano, Nigeria. A major goal of our capacity-building effort is transferring the skills required to become a data coordinating center and perform a DSMB.	12 Months
Secondary Outcome	The secondary outcome measure will be hospitalization for any cause. As with SPRING, all hospital admissions will be centrally adjudicated without knowing the treatment assignment. Each hospitalization and unscheduled outpatient visit will be adjudicated for the primary reason for admission in the following hierarchal and mutually exclusive categories: stroke, acute chest syndrome, pain, or fever (temperature > 38°C), with each event assigned only one primary reason. The acute vaso-occlusive event will be defined as either pain or acute chest syndrome. Malaria will be diagnosed as per the World Health Organization and local study site clinical practice.	12 months

RECRUITMENT CENTRES
Name of recruitment centre	Street address	City	Postal code	Country
Aminu Kano Teaching Hospital	No 2 Zaria Road	Kano	700233	Nigeria
Murtala Muhammad Specialist Hospital	Kofar Mata Road	Kano	700244	Nigeria

FUNDING SOURCES
Name of source	Street address	City	Postal code	Country
Vanderbilt University Medical Centre	2525 West End Avenue, Nashville	Nashville	37203	United States of America

SPONSORS
Sponsor level	Name	Street address	City	Postal code	Country	Nature of sponsor
Primary Sponsor	Vanderbilt University Medical Centre	2525West End Avenue	Nashville	37203	United States of America	University

COLLABORATORS
Name	Street address	City	Postal code	Country
Vanderbilt University Medical Centre	2525 West End Avenue	Nashville	37203	United States of America

CONTACT PEOPLE
Role	Name	Email	Phone	Street address
Principal Investigator	Shehu Abdullahi	dr_suak@yahoo.com	08028503832	No 2 Zaria Road
City	Postal code	Country	Position/Affiliation
Kano	700233	Nigeria	Site Principal Investigator
Role	Name	Email	Phone	Street address
Public Enquiries	Bilya Musa	bilyasani@yahoo.com	08036005052	no 2 Zaria Road
City	Postal code	Country	Position/Affiliation
Kano	700233	Nigeria	Trials Manager
Role	Name	Email	Phone	Street address
Scientific Enquiries	Binta Jibir	hajiyakarama@yahoo.co.uk	08037002249	Zoo Road
City	Postal code	Country	Position/Affiliation
Kano		Nigeria	Co Principal Investigator

REPORTING
Share IPD	Description	Additional Document Types	Sharing Time Frame	Key Access Criteria
Yes	The outcome of the study will be publicized in Journals and relevant international conferences	Clinical Study Report,Informed Consent Form,Study Protocol	12 Months after completion of trial	Controlled
URL	Results Available	Results Summary	Result Posting Date	First Journal Publication Date
	No
Result Upload 1:	Result Upload 2:	Result Upload 3:	Result Upload 4:	Result Upload 5:

Result URL Hyperlinks	Link To Protocol
Result URL Hyperlinks

Changes to trial information
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Study Design	Allocation concealment	20/10/2023	update		Allocation was determined by the holder of the sequence who is situated off site
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Eligibility	Inclusion criteria	02/03/2025	New TCD value threshold	1) diagnosis of HbSS or HbSB0 confirmed by electrophoresis 2) informed consent from the parent/legal guardian and assent from patient 3) two TCD flow velocity readings of >200 cm/sec and < 220 cm/sec or one TCD velocity reading > 220 cm/sec; typically the repeat TCD is performed on the same day so treatment can start immediately 4) age between 5 and 12 years (assessment can take place up until the 13th birthday), which includes the peak age of onset of strokes in SCA, ~ 6 yo 5) ability to swallow the hydroxyurea capsule.	1) diagnosis of HbSS or HbSB0 confirmed by electrophoresis 2) informed consent from the parent/legal guardian and assent from patient 3) two TCD flow velocity readings of >180 cm/sec and < 200 cm/sec or one TCD velocity reading > 200 cm/sec; typically the repeat TCD is performed on the same day so treatment can start immediately 4) age between 5 and 12 years (assessment can take place up until the 13th birthday), which includes the peak age of onset of strokes in SCA, ~ 6 yo 5) ability to swallow the hydroxyurea capsule.
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Trial Information	Disease(s)	03/11/2023	correction	Haematological Disorders	Haematological Disorders, Paediatrics
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Outcome	OutCome List	18/12/2023	Reviewer's comment	Primary Outcome, (the primary outcome measure): The Nigerian radiologist's review panel (n=3) and the Nigerian psychiatrist/neurologist (n=1) will be blinded to the clinical history. As in the SPRING Trial cases, all potential strokes will be adjudicated in a masked fashion. We will use the WHO definition of a stroke28. The core radiology team has already been formally certified to detect strokes based on the MRI in children with sickle cell anemia and will follow the methodology previously established in the SIT trial study group. The Nigerian team clinical staff were trained to identify stroke using the Pediatric NIH Stroke Scale (PedNIHSS), a validated, standardized neurological examination assessing and quantifying the severity of stroke in children. Outcomes. The primary outcome will be an incident stroke or TIA. In addition to careful instructions reporting stroke symptoms to the hospital, parents will be asked about stroke symptoms, and children will have a neurological exam every 6 months at clinic visits. The pediatric NIH stroke scale30 and a gait exam have been used to detect strokes. Capacity building for Aim 1: Creating a coordinating data center for the SPRING-2 in Kano, Nigeria. A major goal of our capacity-building effort is transferring the skills required to become a data coordinating center and perform a DSMB., 5 years	Primary Outcome, (the primary outcome measure): The Nigerian radiologist's review panel (n=3) and the Nigerian psychiatrist/neurologist (n=1) will be blinded to the clinical history. As in the SPRING Trial cases, all potential strokes will be adjudicated in a masked fashion. We will use the WHO definition of a stroke28. The core radiology team has already been formally certified to detect strokes based on the MRI in children with sickle cell anemia and will follow the methodology previously established in the SIT trial study group. The Nigerian team clinical staff were trained to identify stroke using the Pediatric NIH Stroke Scale (PedNIHSS), a validated, standardized neurological examination assessing and quantifying the severity of stroke in children. Outcomes. The primary outcome will be an incident stroke or TIA. In addition to careful instructions reporting stroke symptoms to the hospital, parents will be asked about stroke symptoms, and children will have a neurological exam every 6 months at clinic visits. The pediatric NIH stroke scale30 and a gait exam have been used to detect strokes. Capacity building for Aim 1: Creating a coordinating data center for the SPRING-2 in Kano, Nigeria. A major goal of our capacity-building effort is transferring the skills required to become a data coordinating center and perform a DSMB., 12 Months
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Outcome	OutCome List	18/12/2023	Reviewer's comment	Secondary Outcome, The secondary outcome measure will be hospitalization for any cause. As with SPRING, all hospital admissions will be centrally adjudicated without knowing the treatment assignment. Each hospitalization and unscheduled outpatient visit will be adjudicated for the primary reason for admission in the following hierarchal and mutually exclusive categories: stroke, acute chest syndrome, pain, or fever (temperature > 38°C), with each event assigned only one primary reason. The acute vaso-occlusive event will be defined as either pain or acute chest syndrome. Malaria will be diagnosed as per the World Health Organization and local study site clinical practice., 5 Years	Secondary Outcome, The secondary outcome measure will be hospitalization for any cause. As with SPRING, all hospital admissions will be centrally adjudicated without knowing the treatment assignment. Each hospitalization and unscheduled outpatient visit will be adjudicated for the primary reason for admission in the following hierarchal and mutually exclusive categories: stroke, acute chest syndrome, pain, or fever (temperature > 38°C), with each event assigned only one primary reason. The acute vaso-occlusive event will be defined as either pain or acute chest syndrome. Malaria will be diagnosed as per the World Health Organization and local study site clinical practice., 12 months
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Ethics	Ethics List	20/10/2023	Additional approval		TRUE, Vanderbilt University Medical Centre Ethics Committee, 2525 West End Street, Nasville, 37203, United States of America, , 17 Jul 2023, +16152432979, chelsea.vanwyk@vumc.org, 25764_25923_4737.pdf
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Ethics	Ethics List	03/11/2023	correction		TRUE, KANO STATE MINISTRY OF HEALTH ETHICS COMMITTEE, POST OFFICE ROAD KANO, Kano, 700211, Nigeria, , 30 Jun 2023, 08023307354, moh.kano2019@gmail.com, 25764_25957_4737.pdf
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Reporting	IPD-Sharing time frame	09/11/2023	reviewers correction	5 years	12 Months after completion of trial
Section Name	Field Name	Date	Reason	Old Value	Updated Value
Eligibility	Minimum age	23/10/2023	correction	5 Year(s)	6 Year(s)

Pan African Clinical Trials Registry