Low-Dose Danazol for the Treatment of Telomere Related Diseases

Sponsor

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT03312400

Collaborator

(none)

Enrollment

Location

Arms

116.6

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Feb 8, 2018

Anticipated Primary Completion Date :

Apr 29, 2026

Anticipated Study Completion Date :

Oct 29, 2027

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Reduction of telomere attrition rate [Over 6 months]
Reduction of telomere attrition rate (decreased rate of telomere attrition by 50%, as compared to the baseline rate)

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA:

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 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.

EXCLUSION CRITERIA:

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