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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
58
Given orally once daily.
Emory University/Children's Health Care of Atlanta
Atlanta, Georgia, United States
University of Mississippi Medical Center
Jackson, Mississippi, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States
Number of Patients Enrolled.
A count of the number of patients enrolled will be provided.
Time frame: at baseline
Number of Patients Randomized
A count of the number of patients randomized will be provided.
Time frame: 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 \[(days medication in family's possession/days prescribed medication) \* 100\].
Time frame: 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.
Time frame: At baseline and at completion of the protocol, up to 56 weeks after study enrollment
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: From baseline at study entry to completion of therapy, up to 56 weeks
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