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

Primary Purpose

Sickle Cell Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Oral Decitabine and Tetrahydrouridine
Placebo
Sponsored by
Yogen Saunthararajah
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age 18 years or older.
  • Written, informed consent provided by the subject before study entry.
  • Confirmed Sickle Cell Disease (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 take HU due to hematological or other toxicities). Symptomatic SCD is defined as having one of following:

    • Fetal Hemoglobin (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.
  • Alanine aminotransferase (ALT) greater than or equal to two times (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 myelodysplastic syndromes (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 Transient Ischemic Attack (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.

Sites / Locations

  • University of Illinois at Chicago

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Oral Decitabine and Tetrahydrouridine

Placebo

Arm Description

Oral Decitabine and Tetrahydrouridine

Placebo

Outcomes

Primary Outcome Measures

Non-hematologic toxicity
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.

Secondary Outcome Measures

Full Information

First Posted
September 6, 2012
Last Updated
September 7, 2018
Sponsor
Yogen Saunthararajah
Collaborators
University of Illinois at Chicago
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1. Study Identification

Unique Protocol Identification Number
NCT01685515
Brief Title
Study of Decitabine and Tetrahydrouridine (THU) in Patients With Sickle Cell Disease
Official Title
Phase 1 Study of Oral Decitabine and Tetrahydrouridine (THU) in Patients With High Risk Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
August 2012 (undefined)
Primary Completion Date
June 2018 (Actual)
Study Completion Date
June 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Yogen Saunthararajah
Collaborators
University of Illinois at Chicago

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Oral Decitabine and Tetrahydrouridine
Arm Type
Experimental
Arm Description
Oral Decitabine and Tetrahydrouridine
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Oral Decitabine and Tetrahydrouridine
Other Intervention Name(s)
Dacogen, 5-aza-2'-deoxycytydine, THU
Intervention Description
Oral Decitabine and Oral Tetrahydrouridine (THU) given 1-2 hours apart on 2 consecutive days over 8 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Water
Intervention Description
Plain water will be dispensed at a similar volume and in the same containers as study drug. The water placebo has a similar appearance and taste to the study drug, since the study drug is highly diluted in water.
Primary Outcome Measure Information:
Title
Non-hematologic toxicity
Description
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.
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 years or older. Written, informed consent provided by the subject before study entry. Confirmed Sickle Cell Disease (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 take HU due to hematological or other toxicities). Symptomatic SCD is defined as having one of following: Fetal Hemoglobin (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. Alanine aminotransferase (ALT) greater than or equal to two times (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 myelodysplastic syndromes (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 Transient Ischemic Attack (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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yogen Saunthararajah, MD
Organizational Affiliation
The Cleveland Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
28880867
Citation
Molokie R, Lavelle D, Gowhari M, Pacini M, Krauz L, Hassan J, Ibanez V, Ruiz MA, Ng KP, Woost P, Radivoyevitch T, Pacelli D, Fada S, Rump M, Hsieh M, Tisdale JF, Jacobberger J, Phelps M, Engel JD, Saraf S, Hsu LL, Gordeuk V, DeSimone J, Saunthararajah Y. Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study. PLoS Med. 2017 Sep 7;14(9):e1002382. doi: 10.1371/journal.pmed.1002382. eCollection 2017 Sep.
Results Reference
derived

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

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