HOPS: Hydroxyurea Optimization Through Precision Study

Sponsor

Children's Hospital Medical Center, Cincinnati (Other)

Overall Status

Recruiting

CT.gov ID

NCT03789591

Collaborator

Doris Duke Charitable Foundation (Other)

116

Enrollment

Locations

Arms

59.4

Anticipated Duration (Months)

8.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Hydroxyurea Optimization through Precision Study (HOPS) is a prospective, multi-center, randomized trial that will directly compare a novel, individualized dosing strategy of hydroxyurea to standard weight-based dosing for children with SCA. The primary objective of the study is to evaluate whether a pharmacokinetics-based starting hydroxyurea dose thieves superior fetal hemoglobin response to to standard weight-based initial dosing. Patients will be recruited from the pediatric sickle cell clinic at Cincinnati Children's Hospital Medical Center and from additional pediatric sickle cell centers within the United States.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Disease Sickle Cell Anemia	Drug: Hydroxyurea	Phase 3

Detailed Description

The trial will recruit patients who have decided to initiate hydroxyurea therapy. All participants will have pharmacokinetics studies performed at baseline, following a 20 mg/kg oral dose of hydroxyurea. Pharmacokinetic sampling will use a sparse sampling approach, requiring collection of blood at 3 time points (15 minutes, 60 minutes, 180 minutes) following the hydroxyurea dose. Enrolled participants will be randomized to receive either hydroxyurea using a starting dose of 20 mg/kg/day (Standard Arm) or a personalized PK-guided dose (Alternative Arm) to target an area under the curve (AUC) of 115 mg*h/L based to approximate hydroxyurea exposure seen when patients are escalated to maximum tolerated dose (MTD).

Following randomization and selection of the initial dose, participants in both arms will follow the same procedures of laboratory medication holds for hematological toxicity. The primary endpoint is fetal hemoglobin (HbF) six months following the initiation of hydroxyurea therapy with the hypothesis that participants starting with a PK-guided dose will achieve HbF at least 5% greater than those starting with a 20 mg/kg dose. Based upon the estimated number of new hydroxyurea starts at each site, it is anticipated that it will take 24 months to enroll the 116 participants required to achieve sufficient power to assess the primary endpoint. The study will conclude for each participant 12 months following hydroxyurea initiation.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

116 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

The study is designed with a double-blind design. The clinical provider and participant/family will be aware of the absolute (mg) starting dose and could theoretically calculate the mg/kg starting dose, but the treatment assignment will not explicitly be provided to the provider or the family, and the same procedures will be used for dose escalation or reduction. Although most doses in the Alternative Arm will be different than 20 mg/kg, there are some patients on the standard arm who may have a PK-guided dose that is close to or at 20 mg/kg. Thus, although it may be possible to deduce the study arm, the study is designed technically in a double-blind fashion.

Primary Purpose:

Prevention

Official Title:

Hydroxyurea Optimization Through Precision Study (HOPS): A Prospective, Multi-center, Randomized Trial of Personalized, Pharmacokinetics-guided Dosing of Hydroxyurea Versus Standard Weight-based Dosing for Children With Sickle Cell Anemia.

Actual Study Start Date :

Jan 17, 2019

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard Arm Participants randomized to the standard arm will receive a starting dose of hydroxyurea of 20 mg/kg/day.	Drug: Hydroxyurea The alternative arm will use PK data to choose a starting hydroxyurea dose to achieve an AUC of 115 mg*h/L to approximate maximum tolerated dose. On the standard arm, participants will start at the traditional, weight-based dose of 20 mg/kg/day. Following selection of the starting dose, all participants will follow the same dose escalation and laboratory monitoring procedures.
Experimental: Alternative Arm Participants randomized to the alternative arm will receive a pharmacokinetic guided starting dose of hydroxyurea based on PK labs drawn at a baseline visit to target an area under the curve (AUC) of 115 mg*h/L in an attempt to approximate maximum tolerated dose (MTD). This dose will not exceed the maximum tolerated dose of 35 mg/kg/day.	Drug: Hydroxyurea The alternative arm will use PK data to choose a starting hydroxyurea dose to achieve an AUC of 115 mg*h/L to approximate maximum tolerated dose. On the standard arm, participants will start at the traditional, weight-based dose of 20 mg/kg/day. Following selection of the starting dose, all participants will follow the same dose escalation and laboratory monitoring procedures.

Arm

Intervention/Treatment

Active Comparator: Standard Arm

Participants randomized to the standard arm will receive a starting dose of hydroxyurea of 20 mg/kg/day.

Drug: Hydroxyurea

The alternative arm will use PK data to choose a starting hydroxyurea dose to achieve an AUC of 115 mg*h/L to approximate maximum tolerated dose. On the standard arm, participants will start at the traditional, weight-based dose of 20 mg/kg/day. Following selection of the starting dose, all participants will follow the same dose escalation and laboratory monitoring procedures.

Experimental: Alternative Arm

Participants randomized to the alternative arm will receive a pharmacokinetic guided starting dose of hydroxyurea based on PK labs drawn at a baseline visit to target an area under the curve (AUC) of 115 mg*h/L in an attempt to approximate maximum tolerated dose (MTD). This dose will not exceed the maximum tolerated dose of 35 mg/kg/day.

Drug: Hydroxyurea

Outcome Measures

Primary Outcome Measures

Fetal Hemoglobin (HbF) Response Following Six Months of Hydroxyurea Therapy [6 months after starting daily hydroxyurea therapy]
The primary outcome will be HbF response six months after starting hydroxyurea therapy with the hypothesis that participants in the Alternative Arm (PK-guided starting dose) will have at least 5% higher HbF than the Standard Arm (20 mg/kg starting dose)

Secondary Outcome Measures

F Cells [Baseline, 6 and 12 months after initiating daily hydroxyurea therapy]
In addition to traditional %HbF measurement, F cells will be measured at baseline, 6 months, and 12 months
Gene Expression Patterns of Study Participants [6 Months after initial Hydroxyurea therapy]
The epigenomic signature and gene expression patterns of study participants receiving hydroxyurea therapy at MTD. MTD is defined as a stable dose without any dose increases (except to account for weight gain), holds, or decreases within 8 weeks with laboratory criteria within the target range. This outcome will explain the mechanisms that yield high HbF responses.

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Months to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of sickle cell anemia (HbSS, HbSD, HbS/β0-thalassemia, or similarly severe SCA genotype)
Age 6 months to 21 years at the time of enrollment
Clinical decision by patient, family, and healthcare providers to initiate hydroxyurea therapy

Exclusion Criteria:

Current treatment with chronic, monthly blood transfusions or erythrocytapheresis
Treatment with hydroxyurea within the past 3 months
Hemoglobin SC disease, HbS/β+-thalassemia
Current treatment with other investigational sickle cell medications
Current known pregnancy or lactation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
2	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30342
3	Children's Hospital of Illinois	Peoria	Illinois	United States	61637
4	Carle Foundation Hospital	Urbana	Illinois	United States	61801
5	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana	United States	46202
6	Indiana Hemophilia & Thrombosis Center, Inc. (IHTC)	Indianapolis	Indiana	United States	46260
7	Boston Children's Hospital	Boston	Massachusetts	United States	02215
8	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota	United States	55404
9	Cohen Children's Medical Center/Northwell Health	New Hyde Park	New York	United States	11040
10	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
11	Rainbow Babies / University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
12	Cleveland Clinic Children's	Cleveland	Ohio	United States	44195
13	Nationwide Children's Hospital.	Columbus	Ohio	United States	43205
14	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226