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Hydroxyurea Optimization Through Precision Study (HOPS)

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ClinicalTrials.gov Identifier: NCT03789591
Recruitment Status : Recruiting
First Posted : December 28, 2018
Last Update Posted : September 13, 2019
Sponsor:
Collaborator:
Doris Duke Charitable Foundation
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

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.


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Study Type : Interventional  (Clinical Trial)
Estimated 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 : January 17, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anemia
Drug Information available for: Hydroxyurea

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.




Primary Outcome Measures :
  1. Fetal Hemoglobin (HbF) Response Following Six Months of Hydroxyurea Therapy [ Time Frame: 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 :
  1. F Cells [ Time Frame: 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

  2. Gene Expression Patterns of Study Participants [ Time Frame: 12 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.



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Ages Eligible for Study:   6 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03789591


Contacts
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Contact: Patrick McGann, MD 513-803-4991 Patrick.McGann@cchmc.org
Contact: Amanda Pfeiffer 513-803-4977 Amanda.Pfeiffer@cchmc.org

Locations
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United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30342
Contact: Amanda Wyatt    404-785-3934    Amanda.Wyatt@choa.org   
Contact: Maa-Ohui Quarmyne       Maa-Ohui.Quarmyne@choa.org   
United States, Illinois
Children's Hospital of Illinois Recruiting
Peoria, Illinois, United States, 61637
Contact: Kay Savings, MD    309-624-4015    kls@uic.edu   
Contact: Nicole Bohnker, MPH    309-624-4015    nbohnker@uic.edu   
United States, Indiana
Indiana Hemophilia & Thrombosis Center, Inc. (IHTC) Recruiting
Indianapolis, Indiana, United States, 46260
Contact: Adrianna Williamson, BS, MA    317-871-0011 ext 283    awilliamson@ihtc.org   
Contact: Emmelise Cho, RN, BSN    317-871-0011 ext 110    echo@ihtc.org   
United States, Massachusetts
Boston Children's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Matthew Henney, MD    617-919-3242    Matthew.Heeney@childrens.harvard.edu   
Contact: Matthew Heeney, MPH    617-355-7407    Latoya.Lashley@childrens.harvard.edu   
United States, Minnesota
Children's Hospitals and Clinics of Minnesota Not yet recruiting
Minneapolis, Minnesota, United States, 55404
Contact: Stephen Nelson, MD    612-813-5940    Stephen.Nelson@childrensmn.org   
Contact: Ashley Kinsella    612-813-6969    Ashley.Kinsella@childrensmn.org   
United States, New York
Cohen Children's Medical Center Not yet recruiting
New Hyde Park, New York, United States, 11040
Contact: Abena Appiah-Kubi, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Patrick McGann, MD    513-803-4991    Patrick.McGann@cchmc.org   
Contact: Amy Pfeiffer    513-803-4977    Amanda.Pfeiffer@cchmc.org   
University Hospitals Cleveland Medical Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Amanda Rivera    216-844-4908    Amanda.Rivera@UHhospitals.org   
Contact: Connie Piccone, MD         
Cleveland Clinic Children's Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Luba Platt    216-445-4153    plattl@ccf.org   
Contact: Ravi Talati    216-444-3360      
Nationwide Children's Hospital. Recruiting
Columbus, Ohio, United States, 43205
Contact: Amy Yekisa    614-722-6570    Amy.Yekisa@nationwidechildrens.org   
Contact: Myra Christian-Rancy    614-722-3690    Myra.Christian-Rancy@nationwidechildrens.org   
United States, Wisconsin
Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: J. Paul Scott, MD    414-955-4170    jpscott@mcw.edu   
Contact: Dawn Retherford    414-955-5792    dretherf@mcw.edu   
Principal Investigator: J. Paul Scott, MD         
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Doris Duke Charitable Foundation
Investigators
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Principal Investigator: Patrick T McGann, MD Children's Hospital Medical Center, Cincinnati

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Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT03789591     History of Changes
Other Study ID Numbers: CCHMC_HOPS
First Posted: December 28, 2018    Key Record Dates
Last Update Posted: September 13, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Children's Hospital Medical Center, Cincinnati:
Hydroxyurea
HbSS
HbSD
TREAT
Additional relevant MeSH terms:
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Anemia
Anemia, Sickle Cell
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors