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NCT Number: NCT03020615

Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

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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Key information

Conditions

Sickle Cell Anemia Anemia Anemia, Hemolytic Anemia, Hemolytic, Congenital Anemia, Sickle Cell Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemoglobinopathies

Age range

9 month–36 month

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Emory University/Children's Health Care of Atlanta, Atlanta, Georgia, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Hydroxyurea

Drug

Given orally once daily.

Other names: HU

Primary outcomes

  1. Number of Patients Enrolled.

    Time frame: at baseline

    A count of the number of patients enrolled will be provided.

  2. Number of Patients Randomized

    Time frame: Eight weeks (± 2 weeks) after study enrollment

    A count of the number of patients randomized will be provided.

  3. Number of Randomized Patients With ≥80% Chronic Medication Compliance

    Time frame: 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].

  4. Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit

    Time frame: 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.

Secondary outcomes

  1. Frequency by Reason Given for Refusal for Study Participation

    Time frame: Once, at enrollment

    Descriptive statistics of count and frequency will be provided for participants who were approached but refused to be enrolled on the study.

  2. Number of Patients With Hospitalizations by Arm

    Time frame: From baseline through completion of therapy, up to 56 weeks

    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.

  3. Cumulative Number of Hospitalizations by Arms

    Time frame: From baseline through completion of therapy, up to 56 weeks

    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.

  4. Mean Change in Hemoglobin (g/dL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  5. Median Change in Hemoglobin (g/dL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  6. Mean Change in Fetal Hemoglobin (%)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  7. Median Change in Fetal Hemoglobin (%)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  8. Mean Change in Mean Corpuscular Volume (fL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  9. Median Change in Mean Corpuscular Volume (fL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  10. Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  11. Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  12. Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  13. Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  14. Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  15. Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  16. Mean Change in Platelet Count (*10^3 Platelets/µL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  17. Median Change in Platelet Count (*10^3 Platelets/µL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  18. Mean Change in Bilirubin (mg/dL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  19. Median Change in Bilirubin (mg/dL)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  20. Mean Change in Lactate Dehydrogenase (Units/L)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  21. Median Change in Lactate Dehydrogenase (Units/L)

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Descriptive statistics of the change between baseline and completion of the study will be provided.

  22. Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    Normal TCD velocities will be defined as TCD velocities <170 cm/s.

  23. Number of Participants Who Undergo Surgery

    Time frame: From start of therapy through completion of therapy, up to 56 weeks

    Any operative procedure will be included.

  24. Number of Participants Who Undergo Transfusion

    Time frame: From start of therapy through completion of therapy, up to 56 weeks

    Transfusion will be defined as the provision of red blood cells to correct anemia.

  25. Number of Patients With Toxicities Related to Hydroxyurea Dosing

    Time frame: From start of therapy through completion of therapy, up to 56 weeks

    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).

  26. Number of Toxicities Related to Hydroxyurea Dosing

    Time frame: From start of therapy through completion of therapy, up to 56 weeks

    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).

  27. Change in Pain and Hurt Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  28. Change in Pain Impact Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  29. Change in Pain Management Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  30. Change in Worry I Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  31. Change in Worry II Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  32. Change in Emotions Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  33. Change in Treatment Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  34. Change in Communication I Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

  35. Change in Communication II Score

    Time frame: From baseline at study entry to completion of therapy, up to 56 weeks

    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.

Sponsors and collaborators

Lead sponsor

St. Jude Children's Research Hospital

Other

Collaborators

  • National Heart, Lung, and Blood Institute (NHLBI)

Registry information

Important dates

Study start
2017
Primary completion
2020
Study completion
2020
First posted
Jan 13, 2017
Registry last updated
Jun 25, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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