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Low-Dose Danazol for the Treatment of Telomere Related Diseases

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ClinicalTrials.gov Identifier: NCT03312400
Recruitment Status : Recruiting
First Posted : October 17, 2017
Last Update Posted : October 8, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information
First Submitted Date  ICMJE October 14, 2017
First Posted Date  ICMJE October 17, 2017
Last Update Posted Date October 8, 2020
Actual Study Start Date  ICMJE February 8, 2018
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 29, 2018)
Reduction of telomere attrition rate [ Time Frame: Over 6 months ]
Reduction of telomere attrition rate (decreased rate of telomere attrition by 50%, as compared to the baseline rate)
Original Primary Outcome Measures  ICMJE
 (submitted: October 14, 2017)
Reduction of telomere attrition rate [ Time Frame: Over 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 12, 2020)
  • Hematologic response [ Time Frame: After 6 and 12 months of treatment ]
    Hematologic response
  • Progression of pulmonary function testing [ Time Frame: After 6 and 12 months of treatment ]
    Progression of pulmonary function testing
  • Progression of fibroscan and transient elastography by ARFI [ Time Frame: After 6 and 12 months of treatment ]
    Progression of fibroscan and transient elastography by ARFI
  • Toxicities associated with low dose danazol use [ Time Frame: During 12 months of treatment ]
    Toxicities associated with low dose danazol use
Original Secondary Outcome Measures  ICMJE
 (submitted: October 14, 2017)
  • Hematologic response [ Time Frame: After 6 and 12 months of treatment ]
  • Progression of pulmonary function testing [ Time Frame: After 6 and 12 months of treatment ]
  • Progression of fibroscan and transient elastography by ARFI [ Time Frame: After 6 and 12 months of treatment ]
  • Toxicities associated with low dose danazol use [ Time Frame: During 12 months of treatment ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Low-Dose Danazol for the Treatment of Telomere Related Diseases
Official Title  ICMJE Low Dose Danazol for the Treatment of Telomere Related Diseases
Brief Summary

Background:

DNA is a structure in the body. It contains data about how the body develops and works. Telomeres are found on the end of chromosomes in DNA. Some people with short telomeres or other gene changes can develop diseases of the bone marrow, lung, and liver. Researchers want to see if low doses of the hormone drug danazol can help.

Objective:

To study the safety and effect of low dose danazol.

Eligibility:

People ages 3 and older with a telomere disease who have either very short telomeres and a specific gene change. They must also show signs of aplastic anemia, lung, or liver disease.

Design:

Participants will be screened in another protocol.

Participants will have:

  • Medical history
  • Physical exam
  • Blood tests
  • Lung exam. They will breathe into an instrument that records the amount and rate of air breathed in and out over a period of time.

    6-minute walking test.

  • Abdominal ultrasound and liver scan. These tests use sound waves to measure the fibrosis in the liver.

Some participants will have:

  • Pregnancy test
  • Small sample of the liver removed
  • Bone marrow biopsy. The bone will be numbed and a small needle will take a sample of the marrow.

All participants will have hormone levels checked.

All child participants will see a pediatric endocrinologist. Children may need to have a hand x-ray.

We will monitor patients for 6 months before starting danazol.

Participants will take danazol by mouth twice a day for 1 year.

Participants must return to the clinic at 6 months and 12 months while on danazol and 6 months after stopping it. They will have blood and urine tests, a lung exam, abdominal ultrasound, and liver scan.

Detailed Description

Telomere disease is caused by accelerated telomere attrition and results in multi-organ dysfunction. Telomeres are nucleotide repeats of non-coding DNA at the end of the chromosomes which function as protective caps to prevent erosion of genomic DNA during cell division and to protect chromosomes from recognition as single stranded DNA. Telomeric DNA is elongated by the telomerase complex, which is comprised of a reverse transcriptase catalytic subunit (encoded by TERT), an RNA template (encoded by TERC) and associated proteins. Telomerase activity is crucial in maintaining telomere length in cells with a high proliferative capacity, such as hematopoietic stem cells (HSCs) and lymphocytes. Presentation of telomeropathies can vary from severe aplastic anemia (SAA) and dyskeratosis congenital (DKC) early in childhood, to pulmonary or hepatic fibrosis later in life. There is no standard of care for the treatment of telomere disease.

Considerable evidence suggests that sex hormones regulate telomerase. Calado et al. demonstrated that human lymphocytes and CD34+ hematopoietic cells up regulate both TERT gene expression and telomerase enzymatic activity in response to androgens in vitro. A recent observational cohort study demonstrated hematologic response in 14 of 16 pediatric patients with DKC treated with androgens. In a prospective trial from our Branch, Townsley et al demonstrated that patients with telomere diseases who were treated with the synthetic sex hormone danazol showed telomere elongation, and hematologic response were seen in 79% of patients after only three months of treatment. This study used the highest dose of danazol, 800 mg daily, and known adverse effects, such as elevated liver enzyme levels and muscle cramps, occurred in 41% and 33% of patients, respectively. Overall the treatment was well tolerated, but some patients did require dose reduction. After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary endpoint. Because of the limited power, we were unable to draw definitive conclusions regarding further clinical effect of danazol but stabilization or improvement was observed in a few cases in other organ function, measured by DLCO for pulmonary fibrosis and Fibroscan for cirrhosis.

We now propose a phase II study designed to determine the efficacy of low dose danazol in decreasing the rate of telomere attrition in subjects with a short age-adjusted telomere length. The secondary aim is to determine the clinical effect of this therapy in conditions that are related to short telomeres, to include cytopenia(s), pulmonary fibrosis, and/or hepatic fibrosis.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Telomere Disease
Intervention  ICMJE Drug: Danazol

Adult: 200 mg daily versus 400 mg daily.

Pediatric: 4 mg/kg/day divided in twice daily dose (max 400 mg daily) for 6 months or 2 mg/kg/day divided in twice daily dose (max 200 mg daily) for 6 months.

Study Arms  ICMJE
  • Active Comparator: 200 mg Arm
    100 mg twice a day
    Intervention: Drug: Danazol
  • Active Comparator: 400 mg Arm
    200 mg twice a day
    Intervention: Drug: Danazol
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 14, 2017)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2021
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

    1. Age-adjusted telomere length less than or equal to the first percentile
    2. A mutation in telomere maintenance genes (TERT, TERC, DKC1, TINF2, NHP2, NOP10, WRAP53, TERF2, PARN, RTEL1, ACD, CTC1, USB1)
    3. Age greater than or equal to 3 years
    4. Weight greater than or equal to 12 Kg

      AND

    5. At least one of the following criteria:

      1. Anemia with a hemoglobin less than or equal to 10 g/dL without red blood cell transfusion
      2. Thrombocytopenia with a platelet count less than or equal to 50,000/microliter without transfusion
      3. Neutropenia with an absolute neutrophil count less than or equal to 1,000/ microliter

      OR

      Pulmonary fibrosis diagnosed by either a lung biopsy or computed tomography scan of the chest according to guidelines from the American Thoracic Society and European Respiratory Society.

      OR

    6. Hepatic fibrosis diagnosed by Transient Elastography by Fibroscan value greater than 10 kpa or US evidence of cirrhotic liver or splenomegaly, or transjugular liver biopsy demonstrating fibrosis.

EXCLUSION CRITERIA:

  1. Patients on androgen hormones to include testosterone or high dose estrogen (estradiol 0.5 mg/day or greater) for the12 months prior to enrollment
  2. Patients with active thrombosis or thromboembolic disease and history of such events, undiagnosed abnormal genital bleeding, porphyria, androgendependent tumor, or prostatic hypertrophy
  3. Patients with pulmonary fibrosis who are receiving anti-fibrotic drug treatment, such as pirfenidone or nintedanib and who have not undergone a 1 month washout period
  4. Patients with active hepatitis B or C
  5. Patients who have received a bone marrow transplant
  6. Patient with other hereditary bone marrow failure syndromes such as Fanconi anemia or Diamond Blackfan anemia
  7. Patients with infections not adequately responding to appropriate therapy
  8. Current pregnancy, or unwillingness to take oral contraceptives or use the barrier methods of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during the course of the study
  9. Lactating women, due to the potentially harmful effects on the nursing child
  10. Patients with cancer who are actively receiving systemic chemotherapeutic treatment or who take drugs with hematological effects
  11. Patients with decompensated liver disease to include persistent ascites, encephalopathy, variceal hemorrhage, or MELD score of 10 or greater
  12. Inability to understand the investigational nature of the study or to give informed consent or without a legally authorized representative or surrogate that can provide informed consent
  13. Inability to swallow a capsule
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ivana Darden, R.N. (301) 596-5093 ivana.darden@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03312400
Other Study ID Numbers  ICMJE 180004
18-H-0004
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE 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
Investigators  ICMJE
Principal Investigator: Neal S Young, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 30, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP