Alternative Dosing And Prevention of Transfusions (ADAPT)

Alternative Dosing And Prevention of Transfusions (ADAPT): A Prospective Study to Reduce Transfusion Requirements for Children With Sickle Cell Anemia Using Pharmacokinetics-based Hydroxyurea Dosing

ADAPT is a prospective cohort study at Jinja Regional Referral Hospital (JRRH) primarily to assess the effect of hydroxyurea on blood transfusion utilization and secondarily to determine the feasibility of PK-guided hydroxyurea dosing.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Hydroxyurea

Detailed Description

Hypothesis

• There will be a 50% reduction in the rate of blood transfusions received during the hydroxyurea treatment period compared with the pre-treatment period.
• A PK-guided starting dose will be generated for 80% of participants.
• Participants on PK-guided hydroxyurea treatment will require 25% fewer blood transfusions during their first year of hydroxyurea than those on dose escalation.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Russell Ware, MD, PhD; Phone Number: (513) 803-1108; Email: russell.ware@cchmc.org
• Study Contact Backup: Name: Teresa Latham, M.A., LPCC-S; Phone Number: (513) 803-7922; Email: teresa.latham@cchmc.org

Study Locations

• Uganda
  • Jinja, Uganda
    • Recruiting
    • Jinja Regional Referral Hospital (JRRH), Department of Paediatrics, Sickle Cell Clinic
    • Contact: Robert O. Opoka, MB ChB, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 8 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with documented HbSS disease
• Age: ≥ 12 months and ≤ 10 years of age, at the time of enrollment
• Parent or guardian willing and able to provide informed consent
• Able to comply with all study related treatments, evaluations, and follow-up

Exclusion Criteria:

• Current hydroxyurea treatment (or within the past 6 months)
• Regular blood transfusions (6 or more within the past 12 months)
• Transfusion within the last 30 days (temporary exclusion)
• Known malignancy or other known chronic illnesses including but not limited to active tuberculosis, renal disease
• Current participation in other therapeutic clinical trials, or within 6 months of prior disease-modifying treatments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; All participants will receive an individualized PK hydroxyurea assessment. Participants for whom the PK-process successfully generates a dose in the predicted treatment range of 15-35 mg/kg/day, will start on that personalized dose. Participants for whom the process does not generate a starting hydroxyurea dose in the predicted treatment range, due to potential pitfalls in lab draws, serum storage, sample processing, or hydroxyurea analysis, will start at a default dose of 20.0 ± 2.5 mg/kg/day. For all participants, the hydroxyurea dose will be adjusted as needed based on blood counts to establish the optimal dose. Where necessary, a weekly dosing average will be determined, so that treatment can occur solely with locally available and affordable 500mg hydroxyurea capsules.

Drug: Hydroxyurea; All participants will receive an individualized PK hydroxyurea assessment. Participants for whom the PK-process successfully generates a dose in the predicted treatment range of 15-35 mg/kg/day, will start on that personalized dose. Participants for whom the process does not generate a starting hydroxyurea dose in the predicted treatment range, due to potential pitfalls in lab draws, serum storage, sample processing, or hydroxyurea analysis, will start at a default dose of 20.0 ± 2.5 mg/kg/day. For all participants, the hydroxyurea dose will be adjusted as needed based on blood counts to establish the optimal dose. Where necessary, a weekly dosing average will be determined, so that treatment can occur solely with locally available and affordable 500mg hydroxyurea capsules.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the rates of blood transfusions overall and by specific indications in children with sickle cell anaemia (SCA), prior to and during hydroxyurea treatment	The incidence rate ratio of transfusions overall and by specific indication during the screening phase as compared to the treatment phase	One year (Enrollment - Month 15)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine clinical and laboratory factors associated with reduction in blood transfusions for children with SCA on hydroxyurea treatment	The relative risk of transfusion due to the most common clinical diagnoses and laboratory factors for children with SCA on hydroxyurea treatment.	One year (Enrollment - Month 15)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the feasibility and safety of a pharmacokinetic (PK)-based hydroxyurea dose within the predicted treatment range for Uganda	The percentage of successful PK-dosing assessments, defined as assessments completed in entirety resulting in the generation of a PK-guided starting dose. The incidence rate ratio of clinical and laboratory adverse events among those started on the PK-guided hydroxyurea dose during the screening phase compared with the treatment phase.	One year (Enrollment - Month 15)
To quantify rates of SCA-related complications (including stroke, sepsis, and pain) in participants receiving PK-guided hydroxyurea dosing and within the overall cohort on hydroxyurea treatment	The number of participants with sickle cell-related complications (including stroke, sepsis and pain) in participants receiving PK-guided hydroxyurea dosing compared to the rate of events in the default dosing group.	One year (Enrollment - Month 15)

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Jinja Regional Referral Hospital (JRRH), Sickle Cell Clinic, Jinja, Uganda
• Investigators: Study Director: Russell Ware, MD, PhD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: October 4, 2022
• First Submitted That Met QC Criteria: December 14, 2022
• First Posted (Actual): December 22, 2022

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Hydroxyurea; Transfusion
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antisickling Agents; Hydroxyurea
• Other Study ID Numbers: ADAPT

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No