Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

• ClinicalTrials.gov Identifier: NCT03020615
• Recruitment Status: Completed
• First Posted: January 13, 2017
• Results First Posted: June 25, 2021
• Last Update Posted: June 25, 2021
• Sponsor: St. Jude Children's Research Hospital
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): St. Jude Children's Research Hospital

Tracking Information

• First Submitted Date: January 11, 2017
• First Posted Date: January 13, 2017
• Results First Submitted Date: May 6, 2021
• Results First Posted Date: June 25, 2021
• Last Update Posted Date: June 25, 2021
• Actual Study Start Date: May 12, 2017
• Actual Primary Completion Date: June 8, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 6, 2021)

• Number of Patients Enrolled. [ Time Frame: at baseline ]
  A count of the number of patients enrolled will be provided.
• Number of Patients Randomized [ Time Frame: 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 [ 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].
• 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.

Original Primary Outcome Measures (submitted: January 11, 2017)

• Number of patients enrolled and randomized [ Time Frame: At completion of therapy, up to 56 weeks after study enrollment ]
• 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].
• 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 ]

Current Secondary Outcome Measures (submitted: June 3, 2021)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: January 11, 2017)

• Frequency by reason given for agreement or refusal for study participation [ Time Frame: Once, at enrollment ]
  Descriptive statistics will be provided
• Number of patients with hospitalizations and the cumulative hospitalizations by arm [ Time Frame: From baseline through completion of therapy, up to 56 weeks ]
• Change in hemoglobin (g/dL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in fetal hemoglobin (%) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in mean corpuscular volume (fL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in absolute reticulocyte count (*10^3) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in white blood cells (*10^3/µL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in absolute neutrophil count (*10^6/µL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in platelet count (*10^3/µL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in bilirubin (mg/dL) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in lactate dehydrogenase (units/L) [ Time Frame: From baseline at study entry to completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided
• Change in transcranial doppler (TCD) ultrasound velocities [ Time Frame: At baseline (study entry) and at completion of therapy, up to 56 weeks ]
  Descriptive statistics will be provided.
• 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.
• 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.
• Number of toxicities related to hydroxyurea dosing [ Time Frame: From start of therapy through completion of therapy, up to 56 weeks ]
  Number of patients with toxicities and the number of toxicities will be reported to include: neutropenia (ANC <1000*10^6/L), reticulocytopenia (ARC (80*10^6/L and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^6/L).
• Time to the event of first hospitalization [ Time Frame: From start of therapy through completion of therapy, up to 56 weeks ]
  Cumulative incidence of the event will be estimated using Kalbfleisch-Prentice method with death as competing risk event and will be reported. The event is defined as the first hospitalization event.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
• Official Title: Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Investigator); Primary Purpose: Treatment
• Condition: Sickle Cell Anemia

Intervention

Drug: Hydroxyurea

Given orally once daily.

Other Name: HU

Study Arms

• Active Comparator: 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.
  Intervention: Drug: Hydroxyurea
• Experimental: 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.
  Intervention: Drug: Hydroxyurea

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 6, 2021): 58
• Original Estimated Enrollment (submitted: January 11, 2017): 50
• Actual Study Completion Date: June 8, 2020
• Actual Primary Completion Date: June 8, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 9 Months to 36 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03020615
• Other Study ID Numbers: HUGKISS; R34HL127162 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: St. Jude Children's Research Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: St. Jude Children's Research Hospital
• Original Study Sponsor: Same as current
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Jeremie Estepp, MD; St. Jude Children's Research Hospital

• PRS Account: St. Jude Children's Research Hospital
• Verification Date: May 2021