Low-Dose Danazol for the Treatment of Telomere Related Diseases

NCT03312400 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: 18000418-H-0004
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Telomere Disease

Keywords

Telomeres; Aplastic Anemia; Pulmonary Fibrosis; Androgens; Hepatic Fibrosis

Outcome Measures

Primary Outcomes (1)

• Reduction of telomere attrition rate

  Reduction of telomere attrition rate (decreased rate of telomere attrition by 50%, as compared to the baseline rate)

  Over 6 months

Secondary Outcomes (4)

• Toxicities associated with low dose danazol use

  During 12 months of treatment

• Progression of pulmonary function testing

  After 6 and 12 months of treatment

• Progression of fibroscan and transient elastography by ARFI

  After 6 and 12 months of treatment

• Hematologic response

  After 6 and 12 months of treatment

Study Arms (2)

200 mg Arm

ACTIVE COMPARATOR

100 mg twice a day

Drug: Danazol

400 mg Arm

ACTIVE COMPARATOR

200 mg twice a day

Drug: Danazol

Interventions

Danazol DRUG

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.

200 mg Arm; 400 mg Arm

Eligibility Criteria

• Age: 3 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• A mutation in telomere maintenance genes (TERT, TERC, DKC1, TINF2, NHP2, NOP10, WRAP53, TERF2, PARN, RTEL1, ACD, CTC1, USB1) as tested in a CLIA (or international equivalent) certified laboratory
• Age greater than or equal to 3 years
• Weight greater than or equal to 12 Kg
• AND
• At least one of the following criteria:
• Anemia with a hemoglobin less than or equal to 10 g/dL without red blood cell transfusion
• Thrombocytopenia with a platelet count less than or equal to 50,000/microliter without transfusion
• 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.
• 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.

You may not qualify if:

• Patients on androgen hormones to include testosterone or high dose estrogen (estradiol 0.5 mg/day or greater) for the12 months prior to enrollment
• Patients with active thrombosis or thromboembolic disease and history of such events, undiagnosed abnormal genital bleeding, porphyria, androgendependent tumor, or prostatic hypertrophy
• 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.
• Patients with active hepatitis B or C
• Patients who have received a bone marrow transplant
• Patient with other hereditary bone marrow failure syndromes such as Fanconi anemia or Diamond Blackfan anemia
• Patients with infections not adequately responding to appropriate therapy
• 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
• Lactating women, due to the potentially harmful effects on the nursing child
• Patients with cancer who are actively receiving systemic chemotherapeutic treatment or who take drugs with hematological effects
• Patients with decompensated liver disease to include persistent ascites, encephalopathy, variceal hemorrhage, or MELD score of 10 or greater
• 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
• Inability to swallow a capsule

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (3)

• Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, Young NS. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009 Sep 10;114(11):2236-43. doi: 10.1182/blood-2008-09-178871. Epub 2009 Jun 26.

  PMID: 19561322 BACKGROUND

• Townsley DM, Dumitriu B, Liu D, Biancotto A, Weinstein B, Chen C, Hardy N, Mihalek AD, Lingala S, Kim YJ, Yao J, Jones E, Gochuico BR, Heller T, Wu CO, Calado RT, Scheinberg P, Young NS. Danazol Treatment for Telomere Diseases. N Engl J Med. 2016 May 19;374(20):1922-31. doi: 10.1056/NEJMoa1515319.

  PMID: 27192671 BACKGROUND

• Khincha PP, Wentzensen IM, Giri N, Alter BP, Savage SA. Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol. 2014 May;165(3):349-57. doi: 10.1111/bjh.12748. Epub 2014 Feb 12.

  PMID: 24666134 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Aplastic; Pulmonary Fibrosis; Liver Cirrhosis

Interventions

Danazol

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Emma M Groarke, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tania R Machado

CONTACT

(301) 661-1505; tania.machado@nih.gov

Emma M Groarke, M.D.

CONTACT

(301) 496-5093; emma.groarke@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2017
• First Posted: October 17, 2017
• Study Start: February 8, 2018
• Primary Completion: April 29, 2026
• Study Completion (Estimated): October 29, 2027
• Last Updated: April 24, 2026

Record last verified: 2026-04-14

Locations

US (1)