Hydroxyurea Therapy: Optimizing Access in Pediatric Populations Everywhere

Study Overview
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Brief Summary
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Primary Objective Define the pharmacokinetics of liquid-formulated HU in infants (9 months to <2 years) Assess the relative bioavailability of HU sprinkles compared to capsules in children and adolescents (≥2 to 18 years). Secondary Objective: Compare PK parameters in infants versus older children on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Exploratory Objectives: Capture information regarding the taste of HU sprinkles using palatability questionnaire. This trial is an open label, single center assessment of the pharmacokinetics of two formulations of hydroxyurea (HU) designed to (1) determine the pharmacokinetic profile of a liquid formulation in infants and to (2) determine the bioavailability of sprinkles, a novel method of administration for older children. The study aims to generate data to facilitate FDA approval for HU in children and potentially validate a new mode of administration (sprinkles) that will optimize access and adherence for children in the US and globally.

Detailed Description
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HOPE18 will be an open label, 2-arm study of HU disposition in 48 children with SCD. In Arm 1, n=18 infants ages 9 months to 2 years will be administered an extemporaneous oral liquid formulation of HU on a single occasion followed by PK sampling. The dose administered will be  20 mg/kg/day or the infant's usual daily dose. In Arm 2, n=30 children who range in age from 2 to 18 years will be administered HU, both a sprinkle formulation and capsules (Droxia® 200 mg), on two separate occasions separated by at least 1 day but no more than 30 days in a randomized, crossover fashion. The doses of HU on each occasion will be rounded to the nearest 200 mg and will not exceed 35 mg/kg or 2000 mg. We hypothesize that the PK profile of the sprinkle formulation will not differ significantly from the PK profile of Droxia® capsules in children and adolescents ages ≥2 - 18 years of age. Participants in both arms will be followed up to 30 days from receiving last HU dose.

Official Title
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Hydroxyurea Therapy: Optimizing Access in Pediatric Populations Everywhere

Conditions
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Sickle Cell Disease, Thalassemia

Intervention / Treatment
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* Drug: Hydroxyurea
* Drug: Hydroxyurea Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants will be eligible for this study if only if all of the following inclusion criteria apply: Laboratory (i.e. electrophoretic, chromatographic or DNA) confirmation of HbSS or HbSβ0thalassemia. Participants may or may not be currently receiving HU. If participants are taking HU, then their most recent dose must be ≥24 hours prior to the start of the study. Participant is in the well state (defined by ≥ 2 weeks since the last SCD-related complication). Clinical evidence of normal gastrointestinal function and structure. No clinical evidence of hepatic compromise, including transaminases < 3 times the upper limit of normal. Estimated glomerular filtration rate (Schwartz equation) > 70 ml/min/1.73m2. Body mass index (BMI) ≥5th and ≤95th percentile as per CDC growth charts. In addition: For the Pharmacokinetic Study (Arm 1): Age ≥ 9 months and < 2 years. Able to consume a minimum of 30 ml of water following ingestion of the study article. For the Bioavailability Study (Arm 2): Age ≥ 2 years and ≤ 18 years. Weight of ≥ 10 kg Females of child-bearing potential must have a negative pregnancy test prior to dosing and be willing to practice appropriate contraceptive measures, including abstinence, from the time of the initial pregnancy testing through the remainder of the study (30 days after last administration of investigational agents). Males of child-bearing potential must be willing to practice appropriate contraceptive measures, including abstinence, during study participation (30 days after last administration of investigational agents). Able to ingest both sprinkles and capsule study articles and consume a minimum of 30 ml of water following ingestion of each agent. Exclusion Criteria: Chronic transfusion therapy, or transfused within 3 months of study participation. Known renal impairment (creatinine >1.5x the upper limit of normal for age). Known hepatic impairment or Grade 2 or higher transaminases and bilirubin levels. Diagnoses other than sickle cell anemia or sickle beta-zero thalassemia (i.e., other sickle cell variants or sickle/ hereditary persistence of fetal hemoglobin). Blood count parameters as follows: hemoglobin <6.0 gm/dL, absolute reticulocyte count <80,000/mm3, absolute neutrophil count <1000/mm3, or platelet count <80,000/mm3. The participant has used opiates, H2 blockers, proton pump inhibitors, antacids, other GI motility agents or any other medication that, in the opinion of the investigator, will interfere with the study procedures or affect the interpretation of the results of the study for 3 days prior to the first dose of study. Participants taking antiretroviral drugs (including didanosine and stavudine) due to increased risk of toxicity with concomitant use. Participation in another clinical intervention trial utilizing an IND/IDE agent, but can participate in HUGKISS since same drug agent.

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 Liquid Hydroxyurea<br>In Arm 1 of this study, n=18 infants ages 9 months to 2 years will be administered an extemporaneous oral liquid formulation of HU on a single occasion followed by PK sampling. The dose administered will be  20 mg/kg/day or the infant's usual daily dose. | Drug: Hydroxyurea<br>* Drug: Hydroxyurea oral liquid dose administered will be 20mg/kg/day or infants's usual daily dose.<br>* Other names: Liquid Hydroxyurea;|
| Active Comparator: Arm 2 Hydroxyurea Oral Capsule<br>In Arm 2, n=30 children who range in age from 2 to 18 years will be administered oral capsule HU, both a sprinkle formulation and capsules (Droxia® 200 mg), on two separate occasions separated by at least 1 but no more than 30 days in a randomized, crossover fashion. The doses of HU on each occasion will be rounded to the nearest 200 mg and will not exceed 35 mg/kg or 2000 mg | Drug: Hydroxyurea Oral Capsule<br>* Drug: Hydroxyurea both a sprinkle formulation and capsules (Droxia 200mg) administered on 2 separate occasions.<br>* Other names: Doxroxia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Concentration Observed After Dosing (Cmax) for HU Liquid Formulation in Infants (9 Months to <2 Years) | Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 
| The Time of Maximum Observed Concentration (Cmax) Relative to Time of Dosing for HU Liquid Formulation in Infants (9 Months to <2 Years) | Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 
| AUClast for HU Liquid Formulation in Infants (9 Months to <2 Years) | The area under the concentration-time curve from time of dosing of the drug to the time of the last measurable concentration or when concentrations were Below the Limit of Quantitation (BLQ) were calculated using either the linear (concentration before Cmax) or log trapezoidal rule (concentrations after Cmax). Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 
| AUCinfinity for HU Liquid Formulation in Infants (9 Months to <2 Years) | The AUC extrapolated from the last measured concentration (Clast) to time infinity using the formula AUClast + Clast / λz. Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 
| Mean Residence Time as Generated by WinNonlin (AUMC/AUC) for HU Liquid Formulation in Infants (9 Months to <2 Years) | Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 
| Apparent Clearance Calculated From Dose/ AUCINF for HU Liquid Formulation in Infants (9 Months to <2 Years) | Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 
| Apparent Clearance Normalized for Body Weight (BW) for HU Liquid Formulation in Infants (9 Months to <2 Years) | Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 
| Elimination Slope for HU Liquid Formulation in Infants (9 Months to <2 Years) | The first-order linear slope associated with the terminal (log-linear) portion of the curve and estimated via linear regression of log concentrations vs. time. Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 
| Terminal Elimination Half-life Obtained From: t½ = ln(2)/ λz for HU Liquid Formulation in Infants (9 Months to <2 Years) | Summary statistics including mean, standard deviation (SD) will be reported. | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Concentration Observed After Dosing (Cmax) for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| The Time of Maximum Observed Concentration (Cmax) Relative to Time of Dosing for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| AUClast for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | The AUC extrapolated from the last measured concentration (Clast) to time infinity using the formula AUClast + Clast / λz. Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| AUCinfinity for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | The AUC extrapolated from the last measured concentration (Clast) to time infinity using the formula AUClast + Clast / λz. Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Mean Residence Time as Generated by WinNonlin (AUMC/AUC) for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Apparent Clearance Calculated From Dose/ AUCINF for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Apparent Clearance Normalized for Body Weight (BW) for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Elimination Slope for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | The first-order linear slope associated with the terminal (log-linear) portion of the curve and estimated via linear regression of log concentrations vs. time. Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Terminal Elimination Half-life Obtained From: t½ = ln(2)/ λz for HU Sprinkles Compared to Capsules in Children and Adolescents (≥2 to 18 Years) | Summary statistics including mean and SD will be reported for sprinkles and capsules and will be compared using two-sample t-test or Wilcoxon rank sum test depending on the normality of the data at a significance level of 0.05 per study design above. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| The Maximum Concentration Observed After Dosing (Cmax) for Infants Versus Older Children | The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| The Time of Maximum Observed Concentration (Cmax) Relative to Time of Dosing for Infants Versus Older Children | The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| AUClast for Infants Versus Older Children | The area under the concentration-time curve from time of dosing of the drug to the time of the last measurable concentration or when concentrations were Below the Limit of Quantitation (BLQ) were calculated using either the linear (concentration before Cmax) or log trapezoidal rule (concentrations after Cmax). The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| AUCinfinity for Infants Versus Older Children | The AUC extrapolated from the last measured concentration (Clast) to time infinity using the formula AUClast + Clast / λz. The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Mean Residence Time as Generated by WinNonlin (AUMC/AUC) for Infants Versus Older Children | The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Apparent Clearance Calculated From Dose/ AUCINF for In Infants Versus Older Children | The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Apparent Clearance Normalized for Body Weight (BW) for Infants Versus Older Children | The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Elimination Slope for In Infants Versus Older Children | The first-order linear slope associated with the terminal (log-linear) portion of the curve and estimated via linear regression of log concentrations vs. time. The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days | 
| Terminal Elimination Half-life Obtained From: t½ = ln(2)/ λz for Infants Versus Older Children | The older children will include children on arm 2 on this study and those from our previous Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia (NCT01506544) trial. Summary statistics will be reported for the infants and older children and will be compared using two sample t-test or Wilcoxon rank sum test depending on the normality of the data. Logarithmic transformation will be applied if data do not follow normal. | 2 days |