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Low-Dose Danazol for the Treatment of Telomere Related Diseases

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03312400
Recruitment Status : Recruiting
First Posted : October 17, 2017
Last Update Posted : August 12, 2022
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:


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.


To study the safety and effect of low dose danazol.


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.


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.

Condition or disease Intervention/treatment Phase
Telomere Disease Drug: Danazol Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Low Dose Danazol for the Treatment of Telomere Related Diseases
Actual Study Start Date : February 8, 2018
Estimated Primary Completion Date : April 29, 2026
Estimated Study Completion Date : October 29, 2027

Resource links provided by the National Library of Medicine

Drug Information available for: Danazol

Arm Intervention/treatment
Active Comparator: 200 mg Arm
100 mg twice a day
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.

Active Comparator: 400 mg Arm
200 mg twice a day
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.

Primary Outcome Measures :
  1. 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)

Secondary Outcome Measures :
  1. Toxicities associated with low dose danazol use [ Time Frame: During 12 months of treatment ]
  2. Progression of pulmonary function testing [ Time Frame: After 6 and 12 months of treatment ]
  3. Progression of fibroscan and transient elastography by ARFI [ Time Frame: After 6 and 12 months of treatment ]
  4. Hematologic response [ Time Frame: After 6 and 12 months of treatment ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   3 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

    1. Age-adjusted telomere length less than or equal to the first percentile by flow-FISH method. In patients with a known pathogenic or likely pathogenic mutation in a telomere maintenance gene, age adjusted telomere length less than or equal to the 10th percentile is sufficient.
    2. A mutation in telomere maintenance genes (TERT, TERC, DKC1, TINF2, NHP2, NOP10, WRAP53, TERF2, PARN, RTEL1, ACD, CTC1, USB1) as tested in a CLIA certified laboratory
    3. Age greater than or equal to 3 years
    4. Weight greater than or equal to 12 Kg


    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


      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.


    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.


  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 unless stable on anti-fibrotic drug for at least 6 months prior to starting on danazol as demonstrated by PFTs.
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03312400

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Contact: Ivana Darden, R.N. (301) 827-2988
Contact: Emma M Groarke, M.D. (301) 496-5093

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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Emma M Groarke, M.D. National Heart, Lung, and Blood Institute (NHLBI)
Additional Information:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT03312400    
Other Study ID Numbers: 180004
First Posted: October 17, 2017    Key Record Dates
Last Update Posted: August 12, 2022
Last Verified: August 10, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: .It is not yet known

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Aplastic Anemia
Pulmonary Fibrosis
Hepatic Fibrosis
Additional relevant MeSH terms:
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Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs