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Hydroxyurea Therapy: Optimizing Access in Pediatric Populations Everywhere

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03825341
Recruitment Status : Recruiting
First Posted : January 31, 2019
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Brief Summary:

Primary Objective

  1. Define the pharmacokinetics of liquid-formulated HU in infants (9 months to <2 years)
  2. 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.


Condition or disease Intervention/treatment Phase
Sickle Cell Disease Thalassemia Drug: Hydroxyurea Drug: Hydroxyurea Oral Capsule Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hydroxyurea Therapy: Optimizing Access in Pediatric Populations Everywhere
Actual Study Start Date : June 10, 2019
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Hydroxyurea

Arm Intervention/treatment
Active Comparator: Arm 1 Liquid Hydroxyurea
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
Drug: Hydroxyurea oral liquid dose administered will be 20mg/kg/day or infants's usual daily dose.
Other Names:
  • HU
  • Liquid Hydroxyurea

Active Comparator: Arm 2 Hydroxyurea Oral Capsule
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
Drug: Hydroxyurea both a sprinkle formulation and capsules (Droxia 200mg) administered on 2 separate occasions.
Other Names:
  • HU Sprinkle
  • Doxroxia




Primary Outcome Measures :
  1. The maximum concentration observed after dosing (Cmax) for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    Summary statistics including mean, standard deviation (SD) will be reported.

  2. The time of maximum observed concentration (Cmax) relative to time of dosing for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    Summary statistics including mean, standard deviation (SD) will be reported.

  3. AUClast for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    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.

  4. AUCinfinity for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    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.

  5. Mean Residence Time as generated by WinNonlin (AUMC/AUC) for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    Summary statistics including mean, standard deviation (SD) will be reported.

  6. Apparent clearance calculated from Dose/ AUCINF for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    Summary statistics including mean, standard deviation (SD) will be reported.

  7. Apparent clearance normalized for Body Weight (BW) for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    Summary statistics including mean, standard deviation (SD) will be reported.

  8. Elimination slope for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    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.

  9. Terminal elimination half-life obtained from: t½ = ln(2)/ λz for HU liquid formulation in infants (9 months to <2 years) [ Time Frame: 1 day ]
    Summary statistics including mean, standard deviation (SD) will be reported.


Secondary Outcome Measures :
  1. The maximum concentration observed after dosing (Cmax) for HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years) [ Time Frame: 2 days ]
    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. 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) [ Time Frame: 2 days ]
    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.

  3. AUClast for HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years) [ Time Frame: 2 days ]
    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.

  4. AUCinfinity for HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years) [ Time Frame: 2 days ]
    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.

  5. Mean Residence Time as generated by WinNonlin (AUMC/AUC) for HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years) [ Time Frame: 2 days ]
    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.

  6. Apparent clearance calculated from Dose/ AUCINF for HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years) [ Time Frame: 2 days ]
    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.

  7. Apparent clearance normalized for Body Weight (BW) for HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years) [ Time Frame: 2 days ]
    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.

  8. Elimination slope for HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years) [ Time Frame: 2 days ]
    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.

  9. Terminal elimination half-life obtained from: t½ = ln(2)/ λz for HU "sprinkles" compared to capsules in children and adolescents (≥2 to 18 years) [ Time Frame: 2 days ]
    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.

  10. The maximum concentration observed after dosing (Cmax) for infants versus older children [ Time Frame: 2 days ]
    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.

  11. The time of maximum observed concentration (Cmax) relative to time of dosing for infants versus older children [ Time Frame: 2 days ]
    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.

  12. AUClast for infants versus older children [ Time Frame: 2 days ]
    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.

  13. AUCinfinity for infants versus older children [ Time Frame: 2 days ]
    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.

  14. Mean Residence Time as generated by WinNonlin (AUMC/AUC) for infants versus older children [ Time Frame: 2 days ]
    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.

  15. Apparent clearance calculated from Dose/ AUCINF for In infants versus older children [ Time Frame: 2 days ]
    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.

  16. Apparent clearance normalized for Body Weight (BW) for infants versus older children [ Time Frame: 2 days ]
    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.

  17. Elimination slope for In infants versus older children [ Time Frame: 2 days ]
    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.

  18. Terminal elimination half-life obtained from: t½ = ln(2)/ λz for infants versus older children [ Time Frame: 2 days ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   9 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. See Appendix II for reference ranges. Known malignancy.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03825341


Contacts
Layout table for location contacts
Contact: Jeremie Estepp, MD 866-278-5833 referralinfor@stjude.org
Contact: Jeremie Estepp, MD

Locations
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United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Jeremie Estepp, MD    866-278-5833    referralinfo@stjude.org   
Principal Investigator: Jeremie Estepp, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
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Principal Investigator: Jeremie Estepp, MD St. Jude Children's Research Hospital

Additional Information:
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT03825341    
Other Study ID Numbers: HOPE18
First Posted: January 31, 2019    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data will be made available at the time of article publication.
Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors