Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 58
- 试验地点
- 4
- 主要终点
- Number of Patients Enrolled.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Investigator)
入排标准
- 年龄范围
- 9 Months 至 36 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Hydroxyurea (Drug)
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.
干预措施: Hydroxyurea (Drug)
结局指标
主要结局
Number of Patients Enrolled.
时间窗: at baseline
A count of the number of patients enrolled will be provided.
Number of Patients Randomized
时间窗: Eight weeks (± 2 weeks) after study enrollment
A count of the number of patients randomized will be provided.
Number of Randomized Patients With ≥80% Chronic Medication Compliance
时间窗: 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
时间窗: 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.
次要结局
- Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Frequency by Reason Given for Refusal for Study Participation(Once, at enrollment)
- Number of Patients With Hospitalizations by Arm(From baseline through completion of therapy, up to 56 weeks)
- Cumulative Number of Hospitalizations by Arms(From baseline through completion of therapy, up to 56 weeks)
- Mean Change in Hemoglobin (g/dL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Median Change in Hemoglobin (g/dL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Mean Change in Fetal Hemoglobin (%)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Median Change in Fetal Hemoglobin (%)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Mean Change in Mean Corpuscular Volume (fL)(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)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Change in Worry I Score(From baseline at study entry to completion of therapy, up to 56 weeks)
- Change in Worry II Score(From baseline at study entry to completion of therapy, up to 56 weeks)
- Change in Emotions Score(From baseline at study entry to completion of therapy, up to 56 weeks)
- Change in Treatment Score(From baseline at study entry to completion of therapy, up to 56 weeks)
- Median Change in Mean Corpuscular Volume (fL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Mean Change in Platelet Count (*10^3 Platelets/µL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Median Change in Platelet Count (*10^3 Platelets/µL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Mean Change in Bilirubin (mg/dL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Median Change in Bilirubin (mg/dL)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Mean Change in Lactate Dehydrogenase (Units/L)(From baseline at study entry to completion of therapy, up to 56 weeks)
- Median Change in Lactate Dehydrogenase (Units/L)(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(From baseline at study entry to completion of therapy, up to 56 weeks)
- Number of Participants Who Undergo Surgery(From start of therapy through completion of therapy, up to 56 weeks)
- Number of Participants Who Undergo Transfusion(From start of therapy through completion of therapy, up to 56 weeks)
- Number of Patients With Toxicities Related to Hydroxyurea Dosing(From start of therapy through completion of therapy, up to 56 weeks)
- Number of Toxicities Related to Hydroxyurea Dosing(From start of therapy through completion of therapy, up to 56 weeks)
- Change in Pain and Hurt Score(From baseline at study entry to completion of therapy, up to 56 weeks)
- Change in Pain Impact Score(From baseline at study entry to completion of therapy, up to 56 weeks)
- Change in Pain Management Score(From baseline at study entry to completion of therapy, up to 56 weeks)
- Change in Communication I Score(From baseline at study entry to completion of therapy, up to 56 weeks)
- Change in Communication II Score(From baseline at study entry to completion of therapy, up to 56 weeks)