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Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

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ClinicalTrials.gov Identifier: NCT03020615
Recruitment Status : Recruiting
First Posted : January 13, 2017
Last Update Posted : July 9, 2018
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Brief Summary:
This is a pilot study, single-blind, randomized, multicenter, therapeutic clinical trial designed to evaluate the feasibility of enrolling infants and toddlers (9 months to 36 months) with sickle cell anemia (SCA; HbSS or HbSβ^0thalassemia), regardless of disease severity, to a therapeutic trial. A prior clinical trial at St. Jude Children's Research Hospital (SJCRH) (BABYHUG, NCT01783990) demonstrated that a fixed dose (20 mg/kg/day) of hydroxyurea was safe and effective in decreasing SCA-related complications in very young children (9-18 months), and largely due to these findings, hydroxyurea is recommended to be offered to all children (≥9 months old) with SCA, independent of disease severity. Nevertheless, children in the treatment arm of BABYHUG continued to experience vaso-occlusive symptoms and to incur organ damage. In clinical trials of older children with SCA, intensification of hydroxyurea to a maximum tolerated dosage (MTD), defined by mild to moderate myelosuppression, may be associated with improved laboratory parameters compared to fixed lower-dosing, but the clinical benefits gained from dose intensification have not been described. Therefore, in this trial, children in the standard treatment arm will receive a fixed dose of hydroxyurea (20 mg/kg/day), and participants in the experimental arm will receive hydroxyurea intensified to MTD, defined by a goal absolute neutrophil count (ANC) of 1500-3000 cells/µL. This trial aims to establish a multicenter infrastructure that will identify, enroll and randomize very young children (9-36 months) to receive fixed dose versus intensified-dose hydroxyurea in a single blinded manner, and to obtain prospective pilot data comparing the clinical and laboratory outcomes between the treatment arms to facilitate design of a definitive phase III trial.

Condition or disease Intervention/treatment Phase
Sickle Cell Anemia Drug: Hydroxyurea Phase 2

Detailed Description:

All participants will initially receive hydroxyurea at a dose of ~20 mg/kg/day in an open label fashion for eight weeks (+ 2 weeks) prior to randomization. Participants will receive monthly medical evaluations (every 4 ± 2 weeks) where they will have height and weight measurements, medical history, physical examination, and medication adherence assessments. During these monthly visits complete blood counts with absolute reticulocyte count will be monitored. Hemoglobin electrophoresis, complete serum chemistries, urinalysis, lactate dehydrogenase and quality of life measurements will be obtained every 20 (±2) weeks. Transcranial Doppler (TCD) ultrasound velocities will be obtained at study entry (in participants ≥2 years of age) and study exit. Participants randomized to receive hydroxyurea at MTD will have their dose increased by 5 mg/kg/day every 8 weeks, in the absence of toxicity, until a goal ANC of 1500-3000 cells/µL is achieved, up to a maximum of 35 mg/kg/day.

Both groups will receive their assigned treatment for 48 weeks (± 3 weeks). Participants will be in the study for a total of 56 weeks (± 3 weeks) and have 14 clinic visits to the St. Jude outpatient Hematology Clinic during that time. After the 56 weeks, participants will be followed for an additional 30 days for side effects and will then be taken off study.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
Actual Study Start Date : May 12, 2017
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anemia
Drug Information available for: Hydroxyurea

Arm Intervention/treatment
Active Comparator: Stable Dosing
In the first 8 weeks (+ 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (+ 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.
Drug: Hydroxyurea
Given orally once daily.
Other Name: HU

Experimental: Intensive Dosing
In the first 8 weeks (+ 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (+ 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Drug: Hydroxyurea
Given orally once daily.
Other Name: HU




Primary Outcome Measures :
  1. Number of patients enrolled and randomized [ Time Frame: At completion of therapy, up to 56 weeks after study enrollment ]
    A count of the number of patients enrolled and randomized will be provided.

  2. Number of randomized patients with ≥80% chronic medication compliance [ Time Frame: At completion of therapy, up to 56 weeks after study enrollment ]
    Chronic medication compliance is defined based on medication possession ratio (MPR), a measure of the percentage of time that a patient has access to medication. Each participant's MPR is calculated as [(days medication in family's possession/days prescribed medication) * 100].

  3. Number of patients who have the % fetal hemoglobin (%HbF) collected at baseline and at study exit [ Time Frame: At baseline and at completion of the protocol, up to 56 weeks after study enrollment ]
    The number of patients who have successfully provided %HbF at baseline and study exit will be provided.


Secondary Outcome Measures :
  1. Frequency by reason given for agreement or refusal for study participation [ Time Frame: Once, at enrollment ]
    Descriptive statistics will be provided

  2. Number of patients with hospitalizations and the cumulative hospitalizations by arm [ Time Frame: From baseline through completion of therapy, up to 56 weeks ]
    The number of patients will be provided by arm.

  3. Change in hemoglobin (g/dL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  4. Change in fetal hemoglobin (%) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  5. Change in mean corpuscular volume (fL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  6. Change in absolute reticulocyte count (*10^3/µL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  7. Change in white blood cells (*10^3/µL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  8. Change in absolute neutrophil count (*10^3/µL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  9. Change in platelet count (*10^3/µL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  10. Change in bilirubin (mg/dL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  11. Change in lactate dehydrogenase (units/L) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided

  12. Change in transcranial doppler (TCD) ultrasound velocities [ Time Frame: At baseline (study entry) and at completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided.

  13. Number of participants who undergo surgery [ Time Frame: From start of therapy through completion of therapy, up to 56 weeks ]
    Any operative procedure will be included.

  14. Number of participants who undergo transfusion [ Time Frame: From start of therapy through completion of therapy, up to 56 weeks ]
    Transfusion will be defined as the provision of red blood cells to correct anemia.

  15. Number of toxicities related to hydroxyurea dosing [ Time Frame: From start of therapy through completion of therapy, up to 56 weeks ]
    Number of patients with toxicities and the number of toxicities will be reported to include: neutropenia (ANC <1000*/µL), reticulocytopenia (ARC <80*10^3/µL and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^3/µL).

  16. Time to the event of first hospitalization [ Time Frame: From start of therapy through completion of therapy, up to 56 weeks ]
    Cumulative incidence of the event will be estimated using Kalbfleisch-Prentice method with death as competing risk event and will be reported. The event is defined as the first hospitalization event.

  17. Change in pain and hurt score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.

  18. Change in pain impact score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.

  19. Change in pain management score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.

  20. Change in Worry I score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.

  21. Change in Worry II score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.

  22. Change in emotions score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.

  23. Change in treatment score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.

  24. Change in Communication I score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.

  25. Change in Communication II score [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Change in PedsQL 4.0 score will be reported.



Information from the National Library of Medicine

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Ages Eligible for Study:   9 Months to 36 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Children with HbSS or sickle hemoglobin (HbS)/β^0thalassemia
  • ≥9 to ≤ 36 months of age at study initiation
  • Enrollment will occur irrespective of clinical severity

Exclusion Criteria:

Permanent:

  • Receiving chronic red blood cell transfusion therapy.
  • Condition or chronic illness, which in the opinion of the PI makes participation unsafe.

Transient (participants may be re-evaluated after ≥14 days):

  • Recent (<30 days) participation in another clinical intervention trial utilizing an investigational new drug/investigational device exemption (IND/IDE) agent.
  • Erythrocyte transfusion in the past 2 months.
  • Laboratory Assessments:

    • Hemoglobin <6.0 g/dL
    • Absolute reticulocyte count <80 * 10^3/µL if hemoglobin <9.0 g/dL
    • Absolute neutrophil count <1.5 * 10^3/µL
    • Platelet count <100 * 10^3/µL
    • Serum creatinine > twice the upper limit of normal for age
    • Alanine aminotransferase (ALT) > twice the upper limit of normal

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): NCT03020615


Contacts
Contact: Jeremie Estepp, MD 866-278-5833 referralinfo@stjude.org

Locations
United States, Georgia
Emory University/Children's Health Care of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Robert C. Brown, MD    404-785-3641    clark.brown@choa.org   
Principal Investigator: Robert C. Brown, MD         
United States, Mississippi
University of Mississippi Medical Center Recruiting
Jackson, Mississippi, United States, 39216
Contact: Melissa McNaull, MD    601-984-5220    mrhodes@umc.edu   
Principal Investigator: Melissa McNaull, MD         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Jeremie Estepp, MD    866-278-5833    referralinfo@stjude.org   
Principal Investigator: Jeremie Estepp, MD         
United States, Texas
University of Texas Southwestern Medical Center at Dallas Recruiting
Dallas, Texas, United States, 75390-9063
Contact: Zora Rogers, MD    214-648-4374    zora.rogers@UTSouthwestern.edu   
Principal Investigator: Zora Rogers, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Jeremie Estepp, MD St. Jude Children's Research Hospital

Additional Information:
Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT03020615     History of Changes
Other Study ID Numbers: HUGKISS
R34HL127162 ( U.S. NIH Grant/Contract )
First Posted: January 13, 2017    Key Record Dates
Last Update Posted: July 9, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Jude Children's Research Hospital:
Sickle cell
Hydroxyurea
Infants

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors