Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

58 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-05-12

Study Completion Date

2020-06-08

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.

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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.

Conditions

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Sickle Cell Anemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Investigators

Study Groups

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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.

Group Type ACTIVE_COMPARATOR

Hydroxyurea

Intervention Type DRUG

Given orally once daily.

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.

Group Type EXPERIMENTAL

Hydroxyurea

Intervention Type DRUG

Given orally once daily.

Interventions

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Hydroxyurea

Given orally once daily.

Intervention Type DRUG

Other Intervention Names

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HU

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

Minimum Eligible Age

9 Months

Maximum Eligible Age

36 Months

Eligible Sex

ALL

Accepts Healthy Volunteers

No