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Realizing Effectiveness Across Continents with Hydroxyurea(REACH): A Phase I/II Pilot Study of Hyroxyurea for Children with Sickle Cell Anemia

Award Number: U01HL133883
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Realizing Effectiveness Across Continents with Hydroxyurea(REACH): A Phase I/II Pilot Study of Hyroxyurea for Children with Sickle Cell Anemia - ABSTRACT Sickle cell anemia (SCA) is among the world’s most common inherited blood disorders, and causes severe morbidity and early mortality. SCA is highly prevalent in sub-Saharan Africa, affecting over 300,000 births annually, with an estimated 30% increase in the next generation. To address the burden of SCA within Africa, neonatal screening is needed to establish the proper diagnosis, and hydroxyurea treatment is needed to ameliorate morbidity and decrease mortality. Hydroxyurea is listed by the World Health Organization as an Essential Medicine for children with SCA, representing the only realistic and affordable disease-modifying therapy in this setting. Until recently, hydroxyurea had been studied primarily in high-income countries, with virtually no data available regarding its safe and effective use in Africa. To address this critical unmet need, we designed and launched REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731), a prospective open-label study of hydroxyurea for young children with SCA in sub-Saharan Africa. In the current funding period, 606 children in four African countries received hydroxyurea escalated to maximum tolerated dose (MTD). Despite COVID, our research teams in Angola, Democratic Republic of Congo, Kenya, and Uganda collected unprecedented data on the safety, feasibility, and benefits of hydroxyurea for SCA in Africa, with >3000 patient-years of treatment. We documented reductions in sickle- related clinical events and found unexpected reductions in malaria, transfusions, and death. We performed whole exome sequencing to investigate inter-patient variability including hydroxyurea pharmacokinetics, pharmacodynamics, and pharmacogenomics. In the renewal, we will make additional contributions by extending hydroxyurea treatment to this unique cohort, whose average age is now 11 years and soon entering puberty, using a continued supply of hydroxyurea donated by Bristol Myers Squibb. Though our initial results are encouraging, REACH does not have a placebo-controlled cohort for comparison. Accordingly, we will enroll a new cohort of age-matched children with SCA at all four sites, to provide pre-treatment data for comparison to our treated cohort. In the first specific aim, we will assess the long-term effects of hydroxyurea at MTD to ameliorate SCA-related clinical complications and preserve organ function (especially brain but also kidneys, spleen, and eyes). We will obtain longitudinal data on the effects of hydroxyurea at MTD on physical growth, sexual development, and overall reproductive health, and collect serial DNA to test for the emergence of clonal hematopoiesis. In the second aim, we will investigate mechanisms by which hydroxyurea reduces malaria infections, combining epidemiological data with in vitro parasite invasion assays and an agnostic search for protective genetic polymorphisms. In the third aim, we will simplify and optimize hydroxyurea treatment using novel and innovative approaches, by testing the feasibility and safety of a pharmacokinetics-based dosing algorithm in the new patient cohort to minimize dose adjustments and lab monitoring, and then by validating our newly identified genetic polymorphisms that predict HbF treatment responses. REACH will expand hydroxyurea treatment in Africa, build local capacity, and establish a robust research infrastructure for future collaborations, including planned NIH curative therapies. REACH is uniquely poised to elucidate benefits and risks of extended hydroxyurea, allowing safe and evidence-based dosing in Africa.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,422,454 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	002	9	9/14/2025	SUPPLEMENT FOR EXPANSION	$196,803
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	004	9	9/15/2025	SUPPLEMENT FOR EXPANSION	$244,008
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	9	9/11/2025	NON-COMPETING CONTINUATION	$500,339
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	003	9	9/15/2025	SUPPLEMENT FOR EXPANSION	$19,975
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	005	9	9/15/2025	SUPPLEMENT FOR EXPANSION	$178,823
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	001	9	9/13/2025	SUPPLEMENT FOR EXPANSION	$282,506
														Subtotal = $1,422,454

Issue Date FY: 2024 ( Subtotal = $1,423,588 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	002	8	8/10/2024	NON-COMPETING CONTINUATION	$1,423,588
2024	2022	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	001	6	3/26/2024	COMPETING CONTINUATION	$1,150
2024	2021	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	5	3/26/2024	NON-COMPETING CONTINUATION	-$1,150
														Subtotal = $1,423,588

Issue Date FY: 2023 ( Subtotal = $1,431,382 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	7	8/16/2023	NON-COMPETING CONTINUATION	$1,431,382
														Subtotal = $1,431,382

Issue Date FY: 2022 ( Subtotal = $1,545,130 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	001	6	9/24/2022	COMPETING CONTINUATION	$0
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	6	8/8/2022	COMPETING CONTINUATION	$1,545,130
														Subtotal = $1,545,130

Issue Date FY: 2021 ( Subtotal = $675,820 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	5	8/12/2021	NON-COMPETING CONTINUATION	$675,820
														Subtotal = $675,820

Issue Date FY: 2020 ( Subtotal = $676,152 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	4	7/24/2020	NON-COMPETING CONTINUATION	$676,152
														Subtotal = $676,152

Issue Date FY: 2019 ( Subtotal = $676,152 )
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	001	3	8/23/2019	NON-COMPETING CONTINUATION	$676,152
2019	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	2	10/26/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $676,152

Issue Date FY: 2018 ( Subtotal = $685,789 )
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	2	8/15/2018	NON-COMPETING CONTINUATION	$685,789
														Subtotal = $685,789

Issue Date FY: 2017 ( Subtotal = $769,765 )
2017	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	000	1	7/17/2017	NEW	$757,780
2017	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Blood Diseases and Resources Research	001	1	7/21/2017	NEW	$11,985
														Subtotal = $769,765

Grand Total All Awards = $9,306,232

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Realizing Effectiveness Across Continents with Hydroxyurea(REACH): A Phase I/II Pilot Study of Hyroxyurea for Children with Sickle Cell Anemia

Award Number: U01HL133883

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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