Low-Dose Danazol for Telomere Disease

Overseen By Tania R Machado

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must not be taking: Androgens, Anti-fibrotics, Chemotherapy, others

Disqualifiers: Thrombosis, Hepatitis B/C, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 12 months

40 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on androgen hormones or certain anti-fibrotic drugs unless stable for 6 months. It's best to discuss your specific medications with the trial team.

What evidence supports the effectiveness of the drug Danazol for telomere disease?

Research shows that Danazol, an androgen derivative, can enhance telomerase activity, which helps maintain telomere length in patients with telomere-related diseases like dyskeratosis congenita. This suggests it may be beneficial for telomere disease by improving cell proliferation and telomere elongation. ^{1 2 3 4 5}

What safety data exists for danazol treatment in humans?

Danazol has been associated with side effects such as weight gain, changes in lipid levels, elevated liver enzymes, and androgenic effects (related to male hormones). In some studies, side effects were few and transient, and often resolved when the dose was reduced. ^{1 2 6 7 8}

How does the drug Danazol differ from other treatments for telomere disease?

Danazol is unique for telomere disease as it is a low-dose treatment option, which may offer a different safety and side effect profile compared to other treatments. There are no standard treatments specifically for telomere disease, making Danazol a novel option in this context. ^{9 10 11 12 13}

Research Team

Emma M Groarke, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for people aged 3 and older with telomere diseases, specifically those with very short telomeres or certain gene changes. They must show signs of aplastic anemia, lung disease (pulmonary fibrosis), or liver disease (hepatic fibrosis). Participants need to have a weight over 12 Kg and not be pregnant, breastfeeding, unable to consent, or have other specific health conditions.

Inclusion Criteria

My telomeres are shorter than expected for my age, confirmed by a test.

My test shows a mutation in genes related to telomere maintenance.

I am at least 3 years old.

Exclusion Criteria

I am not pregnant and willing to use birth control or abstain from sex during the study.

I am currently on chemotherapy or drugs affecting my blood.

I do not have active blood clots, unexplained bleeding, porphyria, tumors that grow with male hormones, or enlarged prostate.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

6 months

Multiple visits for screening assessments

Treatment

Participants take danazol by mouth twice a day for 1 year

12 months

Clinic visits at 6 months and 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

1 visit (in-person) 6 months after stopping treatment

Treatment Details

Interventions

• Danazol

Trial Overview The trial is testing the safety and effectiveness of low-dose Danazol in treating diseases related to telomeres. Over one year, participants will take Danazol orally twice daily. They'll undergo various tests including blood tests, lung exams, walking tests, ultrasounds for the liver before starting treatment and at intervals during and after treatment.

Participant Groups

Group I: 200 mg Arm Active Control 1 Intervention

100 mg twice a day

Group II: 400 mg Arm Active Control 1 Intervention

200 mg twice a day

Danazol is already approved in United States, European Union for the following indications:

Approved in United States as Danocrine for:

• Endometriosis
• Hereditary Angioedema
• Fibrocystic Breast Disease

Approved in European Union as Danol for:

• Endometriosis
• Hereditary Angioedema
• Fibrocystic Breast Disease

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study of 58 patients with benign breast disorders, danazol was effective, providing complete relief of symptoms in 75.8% of participants over a treatment period of 74 to 310 days.

After stopping danazol, 65.3% of the 26 patients followed for 11 to 32 months remained symptom-free, indicating a lasting benefit, while side effects were minimal and temporary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of an impeded androgen--danazol--in the management of benign breast disorders. Asch, RH., Greenblatt, RB.[2019]

In a preliminary study of 41 patients with advanced breast cancer, danazol showed a response rate of 17%, indicating potential efficacy as a hormone treatment.

Side effects occurred in 22% of patients, but most were manageable and resolved with dose adjustments, suggesting that danazol can be safely administered with careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Danazol treatment of advanced breast cancer. Coombes, RC., Dearnaley, D., Humphreys, J., et al.[2013]

In a study of 69 advanced breast cancer patients treated with danazol, 14.9% experienced a positive response lasting between 3 to 19 months, indicating moderate efficacy.

Danazol was found to be moderately well tolerated, with side effects occurring in 25% of patients, but its response rate was lower compared to other treatments like tamoxifen or aminoglutethimide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Danazol treatment for advanced breast cancer. Coombes, RC., Perez, D., Gazet, JC., et al.[2019]

In a study involving rats treated with danazol for 169 days after exposure to a carcinogen, the treatment significantly delayed the appearance of tumors and reduced their size compared to control animals.

Danazol also decreased the overall incidence of mammary cancer and the average number of tumors per animal, suggesting that earlier and longer treatment enhances its inhibitory effects on tumor development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of an androgenic derivative on the development of chemically-induced mammary carcinogenesis in the rat. Escrich, E., Solanas, M., Bailly, C., et al.[2013]

In a study involving mononuclear cells from four patients with dyskeratosis congenita, three androgen derivatives (danazol, oxymetholone, and nandrolone) showed similar efficacy in enhancing telomerase activity and promoting cell proliferation, indicating they can be viable treatment options.

The study revealed that the beneficial effects of these androgen derivatives on bone marrow progenitor cells are linked to increased TERT expression, and these effects can be reversed by tamoxifen, highlighting the importance of TERT in their mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita. Vieri, M., Kirschner, M., Tometten, M., et al.[2021]

Nafarelin, administered intranasally at doses of 400 and 800 micrograms, was found to be as effective as oral danazol (600 and 800 mg) in treating endometriosis, based on symptom severity and laparoscopic scores from two large-scale trials.

While nafarelin caused some adverse effects like hot flashes and decreased bone density, these effects were reversible after treatment, and it had a more favorable safety profile compared to danazol, which led to weight gain and negative metabolic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nafarelin in the treatment of endometriosis. Henzl, MR., Kwei, L.[2019]

In a study involving 12 postmenopausal women, danazol treatment led to significant decreases in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels after 4 weeks, indicating its antigonadotropic effects.

Despite the reductions in hormone levels, there was no significant dose-response relationship observed across the different doses of danazol (400, 600, and 800 mg), suggesting that the efficacy may not depend on the dosage used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of danazol on serum concentrations of pituitary gonadotropins in postmenopausal women. Döberl, A., Jeppsson, S., Rannevik, G.[2019]

Danazol treatment in 16 women with endometriosis significantly increased levels of free testosterone compared to pretreatment levels, suggesting that its effects may be linked to this rise in free testosterone.

The study indicates that danazol's mechanism of action may involve its ability to displace testosterone from sex-hormone-binding globulin (SHBG), although its side effects are primarily androgenic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Free testosterone levels during danazol therapy. Nilsson, B., Södergård, R., Damber, MG., et al.[2019]

In the CENTAUR trial, coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) significantly reduced the risk of key events such as death, tracheostomy, or permanent assisted ventilation by 47% compared to placebo, indicating its efficacy in prolonging survival in ALS patients.

PB/TURSO also delayed the first hospitalization in ALS patients, with a 44% lower risk compared to those on placebo, suggesting it may improve overall patient management and quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial. Paganoni, S., Hendrix, S., Dickson, SP., et al.[2023]

Arimoclomol has shown promise as a potential treatment for amyotrophic lateral sclerosis (ALS), improving survival and muscle function in mouse models, and demonstrating safety in a 3-month Phase IIa study with doses up to 300 mg/day in ALS patients.

The drug works by amplifying heat shock protein expression, which is important for the cellular stress response, making it a compelling candidate for both sporadic and familial forms of ALS, especially in patients with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arimoclomol: a potential therapy under development for ALS. Lanka, V., Wieland, S., Barber, J., et al.[2012]

Arimoclomol (BRX-220) is an oral therapeutic candidate for amyotrophic lateral sclerosis (ALS) that works by enhancing the heat shock response to protect motor neurons from death, showing promise in preventing neuronal loss and promoting survival even after symptoms appear.

Clinical trials have indicated that arimoclomol is well-tolerated and safe, supporting its potential as a treatment for ALS, a currently incurable and fatal neurodegenerative disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arimoclomol, a coinducer of heat shock proteins for the potential treatment of amyotrophic lateral sclerosis. Phukan, J.[2012]

In a study using three different mouse models of spinal and bulbar muscular atrophy (SBMA), the nonsteroidal androgen receptor antagonist flutamide was found to protect against androgen-dependent toxicity, reversing or preventing motor dysfunction and significantly extending lifespan in the models.

These results suggest that AR antagonists like flutamide could have therapeutic potential for treating SBMA in humans, indicating that the toxic effects of the polyglutamine-expanded androgen receptor may share mechanisms with normal androgen receptor function before leading to disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy. Renier, KJ., Troxell-Smith, SM., Johansen, JA., et al.[2021]

Arimoclomol, an investigational drug for ALS, was found to be safe and well-tolerated at doses up to 300 mg per day in a study involving 84 participants.

The drug effectively crosses the blood-brain barrier and shows dose-linear pharmacokinetics, which supports its potential for further efficacy studies in ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. Cudkowicz, ME., Shefner, JM., Simpson, E., et al.[2012]

References

1. United States pubmed.ncbi.nlm.nih.gov

The use of an impeded androgen--danazol--in the management of benign breast disorders. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Danazol treatment of advanced breast cancer. [2013]

3. Germany pubmed.ncbi.nlm.nih.gov

Danazol treatment for advanced breast cancer. [2019]

4. Greece pubmed.ncbi.nlm.nih.gov

Effects of an androgenic derivative on the development of chemically-induced mammary carcinogenesis in the rat. [2013]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nafarelin in the treatment of endometriosis. [2019]

7. Denmark pubmed.ncbi.nlm.nih.gov

Effect of danazol on serum concentrations of pituitary gonadotropins in postmenopausal women. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Free testosterone levels during danazol therapy. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Arimoclomol: a potential therapy under development for ALS. [2012]

11. England pubmed.ncbi.nlm.nih.gov

Arimoclomol, a coinducer of heat shock proteins for the potential treatment of amyotrophic lateral sclerosis. [2012]

12. United States pubmed.ncbi.nlm.nih.gov

Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy. [2021]

13. United States pubmed.ncbi.nlm.nih.gov

Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. [2012]