Clinical trial NCT03020615: Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
Official title: Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sickle Cell Anemia
Keywords: Sickle cell
Hydroxyurea
Infants
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2017-01-13
Enrollment: 58
Sex: ALL
Minimum age (years): 9
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Patients Enrolled.
timeFrame: at baseline
measure: Number of Patients Randomized
timeFrame: Eight weeks (± 2 weeks) after study enrollment
measure: Number of Randomized Patients With ≥80% Chronic Medication Compliance
timeFrame: At completion of therapy, up to 56 weeks after study enrollment
measure: Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit
timeFrame: At baseline and at completion of the protocol, up to 56 weeks after study enrollment
Secondary outcomes:
measure: Frequency by Reason Given for Refusal for Study Participation
timeFrame: Once, at enrollment
measure: Number of Patients With Hospitalizations by Arm
timeFrame: From baseline through completion of therapy, up to 56 weeks
measure: Cumulative Number of Hospitalizations by Arms
timeFrame: From baseline through completion of therapy, up to 56 weeks
measure: Mean Change in Hemoglobin (g/dL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in Hemoglobin (g/dL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Mean Change in Fetal Hemoglobin (%)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in Fetal Hemoglobin (%)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Mean Change in Mean Corpuscular Volume (fL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in Mean Corpuscular Volume (fL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Mean Change in Platelet Count (*10^3 Platelets/µL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in Platelet Count (*10^3 Platelets/µL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Mean Change in Bilirubin (mg/dL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in Bilirubin (mg/dL)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Mean Change in Lactate Dehydrogenase (Units/L)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Median Change in Lactate Dehydrogenase (Units/L)
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Number of Participants Who Undergo Surgery
timeFrame: From start of therapy through completion of therapy, up to 56 weeks
measure: Number of Participants Who Undergo Transfusion
timeFrame: From start of therapy through completion of therapy, up to 56 weeks
measure: Number of Patients With Toxicities Related to Hydroxyurea Dosing
timeFrame: From start of therapy through completion of therapy, up to 56 weeks
measure: Number of Toxicities Related to Hydroxyurea Dosing
timeFrame: From start of therapy through completion of therapy, up to 56 weeks
measure: Change in Pain and Hurt Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Change in Pain Impact Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Change in Pain Management Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Change in Worry I Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Change in Worry II Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Change in Emotions Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Change in Treatment Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Change in Communication I Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
measure: Change in Communication II Score
timeFrame: From baseline at study entry to completion of therapy, up to 56 weeks
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University/Children's Health Care of Atlanta
state: Georgia
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Jeremie Estepp, MD
role: PRINCIPAL_INVESTIGATOR
References: