Novel Dose Escalation to Predict Treatment With Hydroxyurea

NCT02042222 | Completed Early Phase 1 DMC FDA Drug

• 1 other identifier: H-32003 NDEPTH
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Sickle cell disease is a disorder in which red blood cells (RBCs) are abnormally shaped. This can result in painful episodes, serious infections, chronic anemia (a decrease in the number of red blood cells), and damage to body organs. Hydroxyurea therapy offers significant benefits for infants, children, and adolescents with sickle cell anemia. These include a reduction in the frequency of pain crises and acute chest syndrome (inflammation of the lungs) and an increase in hemoglobin (the oxygen-carrying protein) in the blood. Patients on hydroxyurea who receive a maximum tolerated dose (MTD) that is specific for them have greater clinical benefit than those who receive a standard lower dose. There is, however, no way currently to predict the MTD for individual patients. As such, MTD for each patient is currently determined by gradual increases in the dose over several months. This process is time-consuming, requires monthly clinic visits, and delays the benefits of hydroxyurea therapy. Our research group has come up with an equation that could be used to predict each patient's MTD using baseline clinical and laboratory measures before starting hydroxyurea treatment. The purpose of this research study is to compare the use of our equation for predicting MTD to the current standard practice of gradually increasing the hydroxyurea dose until MTD is reached. We want to see if the use of our predictive equation will allow us to achieve MTD faster and with no more side effects than with the standard practice.

Conditions

Sickle Cell Disease

Keywords

Sickle cell; Hydroxyurea; Dose prediction; Maximum tolerated dose

Outcome Measures

Primary Outcomes (1)

• Time to patients reaching the maximum tolerated dose (MTD) of the medication

  Compare the time required to achieve maximum tolerated dose (MTD) of the medication in a patient group treated using a MTD dose-prediction equation to that in a group on the standard dose escalation equation as measured in weeks for each study arm.

  6 months

Secondary Outcomes (1)

• Safety Analysis

  6 months

Study Arms (2)

Standard Arm

ACTIVE COMPARATOR

Half of the subjects initiating hydroxyurea will be randomly assigned to the standard treatment arm, consisting of escalation to the maximum tolerated dose (MTD) of hydroxyurea utilizing a previously published algorithm. Hydroxyurea dosing will commence at 20+/-2.5 mg/kg/day, given as a single daily oral dose. All patients will be offered the choice of a liquid formulation of hydroxyurea or hydroxyurea tablets, with the exact dose rounded up or down to the closest practical dose based on the chosen formulation but not differing from the intended dose by more than 2.5 mg/kg. It should take approximately 6 to 12 months for subjects to reach the MTD on this arm.

Drug: Hydroxyurea

Alternative Treatment Arm

ACTIVE COMPARATOR

Half of the subjects initiating hydroxyurea therapy will be assigned to the alternative treatment arm of the study. In this arm, the predicted hydroxyurea MTD will be calculated for each subject. As in the dose-escalation arm, the exact dose will be rounded up or down to the closest practical dose based on the chosen formulation of hydroxyurea. Since the most common toxicity associated with hydroxyurea use is excessive myelosuppression, the maximum dose at which a subject in the dose-prediction arm will be started will be 30 mg/kg/day or 2000 mg/day. Patients with a higher predicted MTD will subsequently be escalated to this higher dose after four weeks on therapy if there is no evidence of toxicity.

Drug: Hydroxyurea

Interventions

Hydroxyurea DRUG

Also known as: Siklos

Alternative Treatment Arm; Standard Arm

Eligibility Criteria

• Age: 1 Year - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• A severe form of sickle cell disease (HbSS or HbS beta-zero thalassemia)
• Age range of 1.0-15.99 years, inclusive, at the time of enrollment
• A decision by the subject's family and primary clinician to initiate hydroxyurea therapy, made independently of recruitment for the study (not applicable for the biological arm patients)
• Informed consent and assent (as applicable) obtained from parent/guardian and child.
• Ability to comply with all study related treatments, evaluations, and follow-up/study exit

You may not qualify if:

• Documented clinical stroke or transient ischemic attack (TIA).
• Known severe vasculopathy or moya-moya disease on brain imaging studies
• Asparagine aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times upper limit of normal or serum creatinine greater than 0.8 mg/dl
• Current participation in other interventional trials. Subjects must have been off any alternative therapy for at least three months prior to enrollment in this study
• Erythrocyte transfusion within the prior 2 months
• Any condition or chronic illness that in the opinion of the primary clinician makes participation in the trial ill advised
• Inability or unwillingness to complete required studies
• Pregnancy or unwillingness to use a medically acceptable form of contraception if sexually active (male OR female)
• Patients excluded from participation due to laboratory abnormalities, participation in other interventional trials, or recent transfusions may be re-screened at a later date

Sponsors & Collaborators

• Baylor College of Medicine: lead
• Children's Hospital Medical Center, Cincinnati: collaborator

Study Sites (1)

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, Smeltzer MP, Kimble AC, Aygun B, Wu S, Howard T, Sparreboom A. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood. 2011 Nov 3;118(18):4985-91. doi: 10.1182/blood-2011-07-364190. Epub 2011 Aug 29.

  PMID: 21876119 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Hydroxyurea

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals

Study Officials

• Alex George, MD, PhD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor Pediatrics

Study Record Dates

• First Submitted: January 20, 2014
• First Posted: January 22, 2014
• Study Start: October 1, 2013
• Primary Completion: July 31, 2020
• Study Completion: July 31, 2020
• Last Updated: November 18, 2020

Record last verified: 2020-11

Locations

US (1)