Study of Decitabine and Tetrahydrouridine (THU) in Patients With Sickle Cell Disease

This study is currently recruiting participants.
Verified February 2014 by The Cleveland Clinic
Sponsor:
Collaborator:
University of Illinois at Chicago
Information provided by (Responsible Party):
The Cleveland Clinic
ClinicalTrials.gov Identifier:
NCT01685515
First received: September 6, 2012
Last updated: February 19, 2014
Last verified: February 2014
  Purpose

The purposes of this study are to observe if oral tetrahydrouridine and decitabine can increase fetal hemoglobin levels and improve the symptoms of sickle cell disease, and to monitor how patient's bodies react to oral tetrahydrouridine and decitabine. The overall purpose is to develop disease modifying treatment for sickle cell disease that is less cytotoxic than the current standard of care, and which can directly and more efficiently reactivate fetal hemoglobin levels. The hypothesis is that patients treated with oral tetrahydrouridine and decitabine will have the same chance of severe non-hematologic toxicities as the placebo group. The primary end-point is ≥ grade 3 non-hematologic toxicity. The investigators' hypothesis is that patients in the treatment groups receiving oral THU-decitabine 2X/week over 8 weeks (n=15) will be equivalent to placebo group (n=10) with regards to the chance of ≥ grade 3 non-hematologic toxicity.


Condition Intervention Phase
Sickle Cell Disease
Drug: Oral Decitabine and Tetrahydrouridine
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Phase 1 Study of Oral Decitabine and Tetrahydrouridine (THU) in Patients With High Risk Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by The Cleveland Clinic:

Primary Outcome Measures:
  • Non-hematologic toxicity [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    Toxicities will be evaluated on a weekly basis and will be classified according to their grade and relationship to study treatment. Chi-square testing will be employed to examine the difference in number of patients with grade 3 or greater non-hematologic toxicity between treatment and placebo groups.


Estimated Enrollment: 25
Study Start Date: August 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Oral Decitabine and Tetrahydrouridine
Oral Decitabine and Tetrahydrouridine
Drug: Oral Decitabine and Tetrahydrouridine
Oral Decitabine and Oral Tetrahydrouridine (THU) given 1-2 hours apart on 2 consecutive days over 8 weeks
Other Name: Dacogen, 5-aza-2'-deoxycytydine, THU
Placebo Comparator: Placebo
Placebo
Drug: Placebo

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18 years or older.
  • Written, informed consent provided by the subject before study entry.
  • Confirmed SCD (SS, S-b0-thalassemia, S-b+-thalassemia or SC on hemoglobin electrophoresis).
  • Symptomatic SCD while on 6 months of HU OR symptomatic SCD and intolerant of HU (unable or unwilling to tolerate HU due to hematological or other toxicities). Symptomatic SCD is defined as having one of following:

    • HbF <5%, OR
    • 3 or more pain episodes per year requiring parenteral narcotics, OR
    • 1 or more acute chest syndrome episodes, OR
    • Hemoglobin <9 g/dL and absolute reticulocyte count <250,000/mm3.
  • Subject is in his/her steady state and not amidst any acute complication due to SCD (i.e., hospitalization, acute pain, or acute chest syndrome in the past 14 days).
  • Regular compliance with comprehensive care and previous therapy.

Exclusion Criteria:

  • Inability to give informed consent.
  • Experienced severe sepsis or septic shock within the previous 12 weeks.
  • Last HU dose was ingested within the previous 4 weeks.
  • Currently pregnant or breast-feeding.
  • ALT greater than or equal to 2X the upper limit of normal or albumin <2.0 mg/dL or direct (conjugated) bilirubin greater than or equal to 1.5 mg/dl.
  • Serum creatinine >2.9 mg/dL and calculated creatinine clearance <30 mL/min.
  • Platelet count >800 x 109/L.
  • Absolute neutrophil count <1.5 x 109/L.
  • Female of active childbearing potential who is unwilling to use at least one of the two following forms of birth control:

    (i) not having heterosexual sexual contact beginning at the screening visit and continuing until 4 weeks after the last dose of THU-decitabine OR (ii) intrauterine device (IUD).

  • Sexually active male who is unwilling to use a condom when engaging in any sexual contact with a female with child-bearing potential, beginning at the screening visit and continuing until 4 weeks after taking the last dose of THU-decitabine. This requirement applies also to males who have had a successful vasectomy.
  • Altered mental status or recurrent seizures requiring anti-seizure medications.
  • Moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such severity that death within 24 weeks is likely.
  • Concurrent diagnosis of malignancy including MDS, leukemia, or an abnormal karyotype.
  • Vitamin-B12, folate, or iron deficient (until corrected).
  • New York Heart Association (NYHA) class III/IV status.
  • Eastern Co-operative Oncology Group (ECOG) performance status greater than or equal to 3.
  • Participant is on chronic transfusion therapy (e.g., for history of TIA or stroke) and medically contraindicated to discontinue transfusions (unless multiple allo-antibodies prevent the patient from getting transfusions as scheduled).
  • Known history of illicit drug or alcohol abuse within the past 12 months.
  • Other experimental or investigational drug therapy in the past 28 days.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01685515

Locations
United States, Illinois
University of Illinois at Chicago Recruiting
Chicago, Illinois, United States, 60612
Contact: Lani Krauz, RN    312-413-0242      
Principal Investigator: Robert E Molokie, MD         
Sponsors and Collaborators
The Cleveland Clinic
University of Illinois at Chicago
Investigators
Principal Investigator: Yogen Saunthararajah, MD The Cleveland Clinic
  More Information

No publications provided

Responsible Party: The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT01685515     History of Changes
Other Study ID Numbers: CASE 10Z11
Study First Received: September 6, 2012
Last Updated: February 19, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Tetrahydrouridine
Decitabine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 22, 2014