Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

Study Overview
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Brief Summary
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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
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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.

Official Title
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Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

Conditions
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Sickle Cell Anemia

Intervention / Treatment
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* Drug: Hydroxyurea


Participation Criteria
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Eligibility Criteria
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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 mg/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

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 36 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stable Dosing<br>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<br>* Given orally once daily.<br>* Other names: HU;|
| Experimental: Intensive Dosing<br>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<br>* Given orally once daily.<br>* Other names: HU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Enrolled. | A count of the number of patients enrolled will be provided. | at baseline | 
| Number of Patients Randomized | A count of the number of patients randomized will be provided. | Eight weeks (± 2 weeks) after study enrollment | 
| Number of Randomized Patients With ≥80% Chronic Medication Compliance | 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]. | At completion of therapy, up to 56 weeks after study enrollment | 
| Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit | The number of patients who have successfully provided %HbF at baseline and study exit will be provided. | At baseline and at completion of the protocol, up to 56 weeks after study enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency by Reason Given for Refusal for Study Participation | Descriptive statistics of count and frequency will be provided for participants who were approached but refused to be enrolled on the study. | Once, at enrollment | 
| Number of Patients With Hospitalizations by Arm | The number of patients with hospitalizations will be provided by arm. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events. | From baseline through completion of therapy, up to 56 weeks | 
| Cumulative Number of Hospitalizations by Arms | The total number of hospitalization events will be provided by arms. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events. | From baseline through completion of therapy, up to 56 weeks | 
| Mean Change in Hemoglobin (g/dL) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in Hemoglobin (g/dL) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Mean Change in Fetal Hemoglobin (%) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in Fetal Hemoglobin (%) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Mean Change in Mean Corpuscular Volume (fL) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in Mean Corpuscular Volume (fL) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Mean Change in Platelet Count (*10^3 Platelets/µL) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in Platelet Count (*10^3 Platelets/µL) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Mean Change in Bilirubin (mg/dL) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in Bilirubin (mg/dL) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Mean Change in Lactate Dehydrogenase (Units/L) | Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Median Change in Lactate Dehydrogenase (Units/L) | Descriptive statistics of the change between baseline and completion of the study will be provided. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities | Normal TCD velocities will be defined as TCD velocities <170 cm/s. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Number of Participants Who Undergo Surgery | Any operative procedure will be included. | From start of therapy through completion of therapy, up to 56 weeks | 
| Number of Participants Who Undergo Transfusion | Transfusion will be defined as the provision of red blood cells to correct anemia. | From start of therapy through completion of therapy, up to 56 weeks | 
| Number of Patients With Toxicities Related to Hydroxyurea Dosing | Number of patients with toxicities 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). | From start of therapy through completion of therapy, up to 56 weeks | 
| Number of Toxicities Related to Hydroxyurea Dosing | 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). | From start of therapy through completion of therapy, up to 56 weeks | 
| Change in Pain and Hurt Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Change in Pain Impact Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Change in Pain Management Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Change in Worry I Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Change in Worry II Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Change in Emotions Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Change in Treatment Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Change in Communication I Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 
| Change in Communication II Score | Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score. | From baseline at study entry to completion of therapy, up to 56 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle cell, Hydroxyurea, Infants