Low-Dose Danazol for the Treatment of Telomere Related Diseases

Last updated: April 3, 2025
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Overall Status: Active - Recruiting

Phase

2

Condition

N/A

Treatment

Danazol

Clinical Study ID

NCT03312400
180004
18-H-0004
  • Ages 3-99
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

  • INCLUSION CRITERIA:

  1. Age-adjusted telomere length less than or equal to the first percentile byflow-FISH method. In patients with a known pathogenic or likely pathogenicmutation in a telomere maintenance gene, age adjusted telomere length less thanor 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 (orinternational equivalent) certified laboratory

  3. Age greater than or equal to 3 years

  4. Weight greater than or equal to 12 KgAND

  5. At least one of the following criteria:

  6. Anemia with a hemoglobin less than or equal to 10 g/dL without red bloodcell transfusion

  7. Thrombocytopenia with a platelet count less than or equal to 50,000/microliter without transfusion

  8. Neutropenia with an absolute neutrophil count less than or equal to 1,000/microliterORPulmonary fibrosis diagnosed by either a lung biopsy or computed tomographyscan of the chest according to guidelines from the American Thoracic Societyand European Respiratory Society.OR

  9. Hepatic fibrosis diagnosed by Transient Elastography by Fibroscan value greaterthan 10 kpa or US evidence of cirrhotic liver or splenomegaly, or transjugularliver biopsy demonstrating fibrosis.

Exclusion

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 suchevents, 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 6months 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 anemiaor 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 barriermethods of birth control or practice abstinence to refrain from pregnancy if ofchildbearing 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 treatmentor 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 informedconsent or without a legally authorized representative or surrogate that can provideinformed consent

  13. Inability to swallow a capsule

Study Design

Total Participants: 40
Treatment Group(s): 1
Primary Treatment: Danazol
Phase: 2
Study Start date:
February 08, 2018
Estimated Completion Date:
October 29, 2027

Study 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.

Connect with a study center

  • National Institutes of Health Clinical Center

    Bethesda, Maryland 20892
    United States

    Active - Recruiting

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