Novel Dose Escalation to Predict Treatment With Hydroxyurea
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Early Phase 1

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.
    

Detailed description: 
      To be eligible to participate in this study, patients must have decided that they want to
      begin hydroxyurea therapy. Patients choosing to participate in this study will be assigned
      randomly (like flipping a coin) to one of two hydroxyurea treatment groups. Both groups of
      patients will receive hydroxyurea treatment, but the determination of the starting
      hydroxyurea dose will be different between the two groups:

        1. Group 1: The standard (dose increase) group: Patients assigned to this group will be
           treated following the method that is currently standard for all patients starting
           hydroxyurea at our institution. All patients will be started at a dose of 20 milligrams
           per kilogram of body weight. Dose changes will be made every eight weeks until the
           patient is judged to be at his or her MTD.

        2. Group 2: The alternative (dose-prediction) group: Patients assigned to this group will
           have their predicted MTD determined using our dose-prediction equation and will be
           started directly at this dose.

      Patients in both groups will be assessed monthly to see if they are having any side effects
      to hydroxyurea. We will also check to see if the MTD has been reached. Once it is decided
      that the patient has reached their maximum dose, they will continue to be monitored for two
      additional clinic visits (approximately eight additional weeks) to complete collection of
      end-of-study biological blood and urine samples and to ensure that there is no late harmful
      effects from hydroxyurea. The maximum time the patient will be on the study is 12 months
      after starting hydroxyurea therapy.

      Patients will also be asked to participate in optional associated studies.

      Biologic studies: The purpose of these studies is to determine the effect of hydroxyurea
      therapy on blood and urine markers that may be increased or decreased because of sickle cell
      disease. Patients participating in these studies will have one blood sample of 2 teaspoons
      (10 milliliters) and a urine sample collected before starting hydroxyurea therapy. Another
      blood and urine sample will be collected when they complete the study. These samples will be
      used to analyze markers associated with the following disease processes in sickle cell
      disease:

        1. inflammation, blood vessel damage and oxidative stress.

        2. blood viscosity.

        3. early kidney disease.

        4. early brain disease.

        5. altered function of white blood cells, red blood cells, and platelets.
    

Intervention name(s): Hydroxyurea
Intervention type(s): Drug
Other intervention name(s): Siklos
Intervention MeSH terms: Hydroxyurea
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Sickle cell; Hydroxyurea; Dose prediction; Maximum tolerated dose