|First Submitted Date ICMJE||June 16, 2011|
|First Posted Date ICMJE||June 17, 2011|
|Results First Submitted Date||January 10, 2017|
|Results First Posted Date|
|Last Update Posted Date||March 1, 2017|
|Start Date ICMJE||June 2011|
|Primary Completion Date||December 2015 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||The Percentage Change in HbF Level From Baseline to the Average Over the Final 1 Month of Study. [ Time Frame: Final 1 month of study ]|
|Original Primary Outcome Measures ICMJE
||Absolute percent change in HbF level from baseline [ Time Frame: 3 months ]|
|Change History||Complete list of historical versions of study NCT01375608 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Decitabine for High-Risk Sickle Cell Disease|
|Official Title ICMJE||An Extended Phase 2 Study of Decitabine in Subjects With High Risk Sickle Cell Disease|
- To test the safety and effectiveness of decitabine in increasing fetal hemoglobin levels and improving the symptoms of sickle cell disease.
- People at least 18 years of age who have sickle cell disease that has not improved after at least 6 months of hydroxyurea therapy. Those who cannot take hydroxyurea because of side effects may also participate.
Overview: Elevated fetal hemoglobin (HbF), whether pharmacologically induced or congenital, has a favorable impact on the morbidity and mortality of SCD. The agent currently used to elevate HbF, hydroxyurea (HU), has limited efficacy. There are mechanistic reasons to believe that the DNA methyltransferase inhibitor 5-aza-2 -deoxycytidine (decitabine) can more potently increase HbF. This has been demonstrated in vivo in animals and small phase 1/2 studies of decitabine in SCD subjects. Decitabine at low, non-cytotoxic doses was very well tolerated and very efficacious at increasing HbF and total hemoglobin (Hb) in subjects who did not respond to, or were intolerant of, HU. In addition to HbF levels, major improvements were noted in a range of surrogate clinical endpoints measuring red blood cell (RBC) adhesion, endothelial damage, and coagulation pathway activity. Also, substantial clinical improvement was seen in severely ill patients treated off-label. The primary objective herein is to provide evidence and guidance for a phase III study by demonstrating the dose and schedule of decitabine that when given over a 12 month period, produces sustained elevations in HbF without significant toxicity. Secondary objectives examine patient reported outcome measurements (PROMIS), crisis frequency, and laboratory indices that measure different domains of sickle cell pathophysiology and DNA methylation. These secondary and scientific measurements will be correlated with each other and examined over time to understand mechanisms of disease and the mechanism of action of the study drug.
Intervention: Decitabine starting dose of 0.2 mg/kg (range, 0.05-0.3 mg/kg) 1-2x/wk x 48 weeks
In SCD subjects at risk of early death, non-cytotoxic DNMT1 depletion using a metronomic (frequent but intermittent) regimen of the nucleoside analogue decitabine directly antagonizes a mechanism of gamma-globin repression, and produces sustained, clinically significant HbF elevations.
Primary Objective: To measure, in high-risk SCD subjects, the effect of chronic metronomic subcutaneous (SQ) decitabine administration on HbF levels. These aims are achieved through the conduct of an extended, open-label, phase 2 study in subjects who remain at high risk of early mortality and morbidity despite HU therapy.
Secondary Objectives: To measure, in high-risk SCD subjects, the effect of chronic metronomic SQ decitabine administration on clinical and laboratory indices of safety, patient reported outcome measures (PROMIS), frequency of crises, SCD pathophysiologic activity (hemolysis, coagulation, platelet activation and inflammation), and molecular effects of study drug.
Criteria for Evaluation:
Primary Endpoint: the percentage change in HbF level from baseline to the average percent over the final 3 months of the study period (48 weeks).
Secondary Endpoints: clinical and laboratory assessment of safety, patient reported outcomes (PROMIS), frequency of crises, quantity of F cells and F cell subsets, measurements of hemolysis, coagulation, platelet activation, inflammation, endothelial damage, pulmonary arterial pressure, DNMT levels, global and beta-globin locus specific DNA methylation.
Study Design: This is an extended, single arm, open-label, phase II clinical trial.
Study Population: Adults with symptomatic SCD who are at high risk of early mortality despite greater than or equal to 6 months of HU therapy. Specifically, they still have: HbF <5 percent, 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 (ARC) less than or equal to 250,000/mm(3). Subjects who meet the above criteria for high risk but are unwilling or unable to tolerate HU are also eligible.
Clinical and Laboratory Evaluations:
Pre-treatment and every 2 weeks: CBC, chem 20 including LDH, and retic count
Pre-treatment and every 4 weeks: interim medical history & physical exam, HbF%, and pregnancy test
Pre-treatment and every 12 weeks: urinanalysis, percent F-cells & percent F-reticulocytes, biomarkers, scientific correlative studies of DNA methylation
Pre-treatment, 24 and 48 weeks: PROMIS, PFT, 6 minute walk, endo-PAT
Pre-treatment and 48 weeks: erythropoietin level
Follow-ups every 3-4 months between 52-54 weeks and 93-96 weeks: interim medical history & physical exam, CBC, reticulocyte count, HbF percent, chem 20 (including LDH), and pregnancy test
Sample Size: 40 subjects
Data Analyses: The effect of decitabine on HbF levels over time will be explored using a general linear mixed model from which the average percent change from baseline to the average HbF level on the final 3 months of treatment will be estimated along with a 95 percent confidence interval. AE and other safety measurements will be summarized by age group, dose, and dose frequency at the time of AE onset. No interim analyses will be performed in this study.
Human Subjects: There is a risk of neutropenia, thrombocytosis, and teratogenicity. Patients must take precautions to use contraception and avoid pregnancy during treatment.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Drug: Decitabine
0.2mg/kg (range, 0.05-0.3 mg/kg) 1-2X/wk for a period of 48 weeks. Dose and frequency will be determined by hematologic toxicity and the achievement of an HbF level of greater the or equal to 20 percent.
Intervention: Drug: Decitabine
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||February 2016|
|Primary Completion Date||December 2015 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Subjects who meet all of the following criteria are eligible for enrollment into the study:
Since the protocol targets an at risk population, and the tolerability and potential benefits of this approach have been suggested in off-label treatment of seriously ill SCD patients, the exclusion criteria are not overly stringent and are primarily directed at avoiding teratogenic risks.
Subjects who meet any of the following criteria are disqualified from enrollment in the study:
For female participants: Not having heterosexual sexual contact starting 4 weeks before beginning to take decitabine and continuing until 4 weeks after the last dose of decitabine OR using TWO methods of birth control. One birth control method must be highly effective, such as an Intrauterine Device (IUD), birth control pills, Depo-Provera (medroxyprogesterone acetate) injections, or tying of the fallopian tubes. The other additional effective method of birth control can be use of a diaphragm or a condom by the male partner. Birth control should begin at the screening visit and continue until 4 weeks after the last dose of decitabine. These steps must be taken even if the patient has a history of infertility, unless the patient has had a hysterectomy or has not had periods for at least 24 months.
For male participants: during decitabine treatment and 8 weeks after last dose of drug, a condom must be used when engaging in any sexual contact with a woman of child-bearing age, even in patients who have had a successful vasectomy.
|Ages||18 Years and older (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01375608|
|Other Study ID Numbers ICMJE||110184
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )|
|Study Sponsor ICMJE||National Heart, Lung, and Blood Institute (NHLBI)|
|Collaborators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||January 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP