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Randomized controlled trial of fixed low-vs moderate-dose hydroxyurea for primary stroke prevention in Sub-Saharan Africa: Final results of the Spring Trial

Randomized controlled trial of fixed low-vs moderate-dose hydroxyurea for primary stroke prevention in Sub-Saharan Africa: Final results of the Spring Trial
Randomized controlled trial of fixed low-vs moderate-dose hydroxyurea for primary stroke prevention in Sub-Saharan Africa: Final results of the Spring Trial
Introduction: In children with sickle cell anemia (SCA) without transcranial Doppler (TCD) screening, the incidence rates of ischemic strokes is approximately the same among children living in low- and high- low-resource settings (Pediatr Neurol. 2019;95:73-78.) with a prevalence of ~ 11%. However, in high-income settings, the standard use of TCD ultrasonography, coupled initially with monthly blood transfusion therapy has dropped the stroke prevalence to < 1%. In a low-income setting, such as Nigeria, where 50% of children in the world with SCA are born (150,000 per year), initial monthly blood transfusion therapy is not practical for most children.In the Stroke Prevention in Nigeria (SPIN) Feasibility Trial (NCT01801423), fixed moderate-dose hydroxyurea was associated with a decreased rate of strokes in children with SCA and abnormal time-averaged mean of the maximum velocity (TAMMV) TCD measurements (≥200cm/sec) when compared to no treatment in the STOP Trial, 0.76 and 10.7 strokes per 100 person-years, repsectively (Am J Hematol. 2020). Based on the success of the SPIN trial, plus the challenges of real-world implementation of a government-supported primary stroke prevention programs for estimated 40,0000 children with SCA in three states in Nigeria, we tested the hypothesis that fixed-moderate dose (~20 mg/kg/day) hydroxyurea therapy for primary stroke prevention results in a 66% relative risk reduction (9 to 3 events per 100 person-years) when compared to fixed low-dose hydroxyurea (~10 mg/kg/day) therapy in a randomized controlled trial (The SPRING Trial; NCT02560935).
Methods: In this partial-blind controlled phase III trial, we randomly assigned children between 5 and 12 years of age with SCA and a TCD time-averaged mean of the maximum velocity (TAMMV) ≥ 200 cm/sec measured independently twice or TAMMV ≥220 cm/sec once at study screening to receive fixed low-dose or fixed moderate-dose hydroxyurea. The primary endpoint was a clinical stroke or a transient ischemic attack (TIA). Myelosuppression was assessed with monthly complete blood counts (CBCs). Adherence to hydroxyurea was primarily based on an increase in MCV from baseline and monthly pill count return as a percent of dispensed pills. Hemoglobin F levels were measured at baseline, annually and upon trial exit. To evaluate the safety of hydroxyurea in the trial, children attending the same SCA clinics with TCD (TAMMV) <200 cm/sec at study screening were prospectively followed with biweekly phone calls and annual research visits.
Results: A total of 220 children (mean age: 7.5 years, 51.8% female) were randomly assigned to fixed low- (10 mg/kg/day) or moderate- (20 mg/kg/day) dose hydroxyurea, and were followed for a median of 2.4 years (IQR 2.0-2.8). NINDS Clinical Trials leaders stopped the trial early because of futility for the primary outcome. In the fixed low- and moderate-dose hydroxyurea groups, the incidence rates of strokes per 100 person-years were 1.19 and 1.92 respectively, with an incidence rate ratio of 1.60 (95% CI: 0.31-10.34), p = 0.768. The incidence rate ratio of mortality when comparing the children treated with low- and moderate- fixed-dose hydroxyurea to the non-elevated TCD group (no hydroxyurea therapy, n= 211) was 1.97 (95% CI: 0.64-6.02) and 0.47 (95% CI: 0.05-2.38), p = 0.265 and 0.545, respectively. Returned pills during the trial was 5.4% and 4.8% in the fixed low- and moderate-dose groups, respectively, p= 0.144. MCV from baseline to endpoint increased 1.5fl and 7.2 fl in the fixed low- and moderate-dose groups, respectively, p<0.001. Upon exit from the trial 29.4% and 66.7% of the fixed- low and moderate -dose groups, respectively, had either hemoglobin level ≥ 9.0 g/dl, or a fetal hemoglobin level ≥ 20%.
Conclusions: For primary stroke prevention in children with SCA, fixed low-dose, when compared to fixed moderate-dose hydroxyurea therapy, demonstrated no difference in the incidence rate of strokes. Both fixed low- and moderate -dose hydroxyurea doses are superior to no treatment for primary stroke prevention with abnormal TCD values. In partnership with Katsina, Kano, and Kaduna health department's leaders in Nigeria, 9 distinct SCA and primary stroke prevention clinics have been established, with the provision of free fixed low-dose hydroxyurea therapy (Bond Chemical, Nigeria; $0.15 per 500 mg) for abnormal TCD values, and biannual CBCs as standard care ,for over 40,000 children with SCA.
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Abdullahi, Shehu Umar
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Jibir, Binta W.
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Idris, Nura
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Abdullahi, Shehu Umar, Jibir, Binta W., Bello-Manga, Halima, Gambo, Safiya, Inuwa, Hauwa, Tijjani, Aliyu Gaya, Galadanci, Aisha Amal, Borodo, Awwal Musa, Galadanci, Najibah Aliyu, Idris, Nura, Tabari, Abulkadir M, Haliru, Lawal, Bulama, Khadija, Bahago, Gloria, Sani, Mohammed A., Suleiman, Aisha, Umar, Murtala, Dooshima, Charity, Kazaure, Aisha, Musa, Bilya Sani, Usman, Fahad M, Sani, Abdulrasheed, Gambo, Awwal, Ibrahim, Jamila S., Hikima, Mustapha, Musa, Aisha B., Dambatta, Abdu H., Galadanci, Jamil Aliyu, Greene, Brittany Covert, Ghafuri, Djamila Labib, Rodeghier, Mark, Slaughter, James, Kirkham, Fenella Jane, Neville, Kathleen, Kassim, Adetola A., Aliyu, Muktar, Jordan, Lori C., Trevathan, Edwin and DeBaun, Michael R. (2020) Randomized controlled trial of fixed low-vs moderate-dose hydroxyurea for primary stroke prevention in Sub-Saharan Africa: Final results of the Spring Trial. Blood, 136 (Supplement 1), 4-5. (doi:10.1182/blood-2020-141436).

Record type: Meeting abstract

Abstract

Introduction: In children with sickle cell anemia (SCA) without transcranial Doppler (TCD) screening, the incidence rates of ischemic strokes is approximately the same among children living in low- and high- low-resource settings (Pediatr Neurol. 2019;95:73-78.) with a prevalence of ~ 11%. However, in high-income settings, the standard use of TCD ultrasonography, coupled initially with monthly blood transfusion therapy has dropped the stroke prevalence to < 1%. In a low-income setting, such as Nigeria, where 50% of children in the world with SCA are born (150,000 per year), initial monthly blood transfusion therapy is not practical for most children.In the Stroke Prevention in Nigeria (SPIN) Feasibility Trial (NCT01801423), fixed moderate-dose hydroxyurea was associated with a decreased rate of strokes in children with SCA and abnormal time-averaged mean of the maximum velocity (TAMMV) TCD measurements (≥200cm/sec) when compared to no treatment in the STOP Trial, 0.76 and 10.7 strokes per 100 person-years, repsectively (Am J Hematol. 2020). Based on the success of the SPIN trial, plus the challenges of real-world implementation of a government-supported primary stroke prevention programs for estimated 40,0000 children with SCA in three states in Nigeria, we tested the hypothesis that fixed-moderate dose (~20 mg/kg/day) hydroxyurea therapy for primary stroke prevention results in a 66% relative risk reduction (9 to 3 events per 100 person-years) when compared to fixed low-dose hydroxyurea (~10 mg/kg/day) therapy in a randomized controlled trial (The SPRING Trial; NCT02560935).
Methods: In this partial-blind controlled phase III trial, we randomly assigned children between 5 and 12 years of age with SCA and a TCD time-averaged mean of the maximum velocity (TAMMV) ≥ 200 cm/sec measured independently twice or TAMMV ≥220 cm/sec once at study screening to receive fixed low-dose or fixed moderate-dose hydroxyurea. The primary endpoint was a clinical stroke or a transient ischemic attack (TIA). Myelosuppression was assessed with monthly complete blood counts (CBCs). Adherence to hydroxyurea was primarily based on an increase in MCV from baseline and monthly pill count return as a percent of dispensed pills. Hemoglobin F levels were measured at baseline, annually and upon trial exit. To evaluate the safety of hydroxyurea in the trial, children attending the same SCA clinics with TCD (TAMMV) <200 cm/sec at study screening were prospectively followed with biweekly phone calls and annual research visits.
Results: A total of 220 children (mean age: 7.5 years, 51.8% female) were randomly assigned to fixed low- (10 mg/kg/day) or moderate- (20 mg/kg/day) dose hydroxyurea, and were followed for a median of 2.4 years (IQR 2.0-2.8). NINDS Clinical Trials leaders stopped the trial early because of futility for the primary outcome. In the fixed low- and moderate-dose hydroxyurea groups, the incidence rates of strokes per 100 person-years were 1.19 and 1.92 respectively, with an incidence rate ratio of 1.60 (95% CI: 0.31-10.34), p = 0.768. The incidence rate ratio of mortality when comparing the children treated with low- and moderate- fixed-dose hydroxyurea to the non-elevated TCD group (no hydroxyurea therapy, n= 211) was 1.97 (95% CI: 0.64-6.02) and 0.47 (95% CI: 0.05-2.38), p = 0.265 and 0.545, respectively. Returned pills during the trial was 5.4% and 4.8% in the fixed low- and moderate-dose groups, respectively, p= 0.144. MCV from baseline to endpoint increased 1.5fl and 7.2 fl in the fixed low- and moderate-dose groups, respectively, p<0.001. Upon exit from the trial 29.4% and 66.7% of the fixed- low and moderate -dose groups, respectively, had either hemoglobin level ≥ 9.0 g/dl, or a fetal hemoglobin level ≥ 20%.
Conclusions: For primary stroke prevention in children with SCA, fixed low-dose, when compared to fixed moderate-dose hydroxyurea therapy, demonstrated no difference in the incidence rate of strokes. Both fixed low- and moderate -dose hydroxyurea doses are superior to no treatment for primary stroke prevention with abnormal TCD values. In partnership with Katsina, Kano, and Kaduna health department's leaders in Nigeria, 9 distinct SCA and primary stroke prevention clinics have been established, with the provision of free fixed low-dose hydroxyurea therapy (Bond Chemical, Nigeria; $0.15 per 500 mg) for abnormal TCD values, and biannual CBCs as standard care ,for over 40,000 children with SCA.

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Published date: 5 November 2020

Identifiers

Local EPrints ID: 446246
URI: http://eprints.soton.ac.uk/id/eprint/446246
ISSN: 0006-4971
PURE UUID: 8f6e5f54-a89a-4b4f-a629-a8f33527ea4d
ORCID for Fenella Jane Kirkham: ORCID iD orcid.org/0000-0002-2443-7958

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Date deposited: 01 Feb 2021 17:30
Last modified: 17 Mar 2024 02:53

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Contributors

Author: Shehu Umar Abdullahi
Author: Binta W. Jibir
Author: Halima Bello-Manga
Author: Safiya Gambo
Author: Hauwa Inuwa
Author: Aliyu Gaya Tijjani
Author: Aisha Amal Galadanci
Author: Awwal Musa Borodo
Author: Najibah Aliyu Galadanci
Author: Nura Idris
Author: Abulkadir M Tabari
Author: Lawal Haliru
Author: Khadija Bulama
Author: Gloria Bahago
Author: Mohammed A. Sani
Author: Aisha Suleiman
Author: Murtala Umar
Author: Charity Dooshima
Author: Aisha Kazaure
Author: Bilya Sani Musa
Author: Fahad M Usman
Author: Abdulrasheed Sani
Author: Awwal Gambo
Author: Jamila S. Ibrahim
Author: Mustapha Hikima
Author: Aisha B. Musa
Author: Abdu H. Dambatta
Author: Jamil Aliyu Galadanci
Author: Brittany Covert Greene
Author: Djamila Labib Ghafuri
Author: Mark Rodeghier
Author: James Slaughter
Author: Kathleen Neville
Author: Adetola A. Kassim
Author: Muktar Aliyu
Author: Lori C. Jordan
Author: Edwin Trevathan
Author: Michael R. DeBaun

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