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Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

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ClinicalTrials.gov Identifier: NCT03020615
Recruitment Status : Active, not recruiting
First Posted : January 13, 2017
Last Update Posted : June 21, 2019
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Tracking Information
First Submitted Date  ICMJE January 11, 2017
First Posted Date  ICMJE January 13, 2017
Last Update Posted Date June 21, 2019
Actual Study Start Date  ICMJE May 12, 2017
Estimated Primary Completion Date June 8, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 10, 2017)
  • 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.
  • 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].
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 11, 2017)
  • Number of patients enrolled and randomized [ Time Frame: At completion of therapy, up to 56 weeks after study enrollment ]
  • 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].
  • 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 ]
Change History Complete list of historical versions of study NCT03020615 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 1, 2017)
  • Frequency by reason given for agreement or refusal for study participation [ Time Frame: Once, at enrollment ]
    Descriptive statistics will be provided
  • 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.
  • 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
  • Change in fetal hemoglobin (%) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2017)
  • Frequency by reason given for agreement or refusal for study participation [ Time Frame: Once, at enrollment ]
    Descriptive statistics will be provided
  • Number of patients with hospitalizations and the cumulative hospitalizations by arm [ Time Frame: From baseline through completion of therapy, up to 56 weeks ]
  • 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
  • Change in fetal hemoglobin (%) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided
  • 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
  • Change in absolute reticulocyte count (*10^3) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided
  • 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
  • Change in absolute neutrophil count (*10^6/µL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
    Descriptive statistics will be provided
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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*10^6/L), reticulocytopenia (ARC (80*10^6/L and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^6/L).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
Official Title  ICMJE Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Anemia
Intervention  ICMJE Drug: Hydroxyurea
Given orally once daily.
Other Name: HU
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Hydroxyurea
  • 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.
    Intervention: Drug: Hydroxyurea
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 19, 2019)
59
Original Estimated Enrollment  ICMJE
 (submitted: January 11, 2017)
50
Estimated Study Completion Date  ICMJE June 8, 2020
Estimated Primary Completion Date June 8, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 9 Months to 36 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03020615
Other Study ID Numbers  ICMJE HUGKISS
R34HL127162 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party St. Jude Children's Research Hospital
Study Sponsor  ICMJE St. Jude Children's Research Hospital
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Jeremie Estepp, MD St. Jude Children's Research Hospital
PRS Account St. Jude Children's Research Hospital
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP