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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if low doses of the hormone drug danazol can safely assist individuals with telomere disease. Telomere disease affects the ends of DNA strands, causing problems with bone marrow, lung, or liver function. Participants must have very short telomeres and show signs of related conditions such as aplastic anemia, lung, or liver disease. The trial will compare two dosages of danazol to assess its effects. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that danazol has been safe in previous studies with patients who have telomere diseases. These studies found that danazol not only stops telomeres (the protective ends of DNA) from getting shorter but can also make them longer, suggesting the treatment is generally well-tolerated.

However, another study on danazol in patients with pulmonary fibrosis (a lung disease) found no significant difference in telomere loss compared to a placebo group. This indicates that while danazol has been safe for many, its effectiveness can vary depending on the condition.

Overall, danazol's history of use and positive findings on telomere preservation support its safety. As with any treatment, regular monitoring and follow-ups are important to ensure ongoing safety for participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for telomere diseases, which often involve more aggressive therapies like bone marrow transplants or androgen therapy at higher doses, Danazol offers a potentially safer, low-dose alternative. Researchers are excited about Danazol because it is an androgen that works by stabilizing and possibly lengthening telomeres, which are crucial for cell health and longevity. The low doses being tested, 100 mg and 200 mg twice a day, might minimize side effects while still offering therapeutic benefits, making it an appealing option for patients who cannot tolerate more intensive treatments.

What evidence suggests that low-dose danazol might be an effective treatment for telomere disease?

Research has shown that danazol may help treat telomere diseases. In earlier studies, patients taking danazol had noticeably longer telomeres after 6, 12, and 24 months of treatment. Telomeres, which act like protective caps on the ends of DNA, contribute to healthier cells when longer. However, a different study on lung disease found that danazol did not prevent telomeres from shortening compared to a placebo. Overall, danazol has shown potential benefits for conditions related to telomeres, but its effectiveness can vary depending on the specific disease.

This trial will compare two different dosages of danazol: a 200 mg arm and a 400 mg arm, to evaluate its impact on telomere length in patients with telomere disease. ^{1 5 6 7 8}

Who Is on the Research Team?

Emma M Groarke, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4968696/

Danazol Treatment for Telomere Diseases - PMC Significant telomere elongation was found at 6, 12, and 24 months after the initiation of treatment with danazol, as compared with baseline. When treatment with ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124031860

Danazol Treatment for Telomere Biology Disorders: Long ... Patients were treated with 800mg danazol, daily, for two years, with a primary biologic endpoint of telomere attrition (determined by qPCR).

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03312400

Study Details | NCT03312400 | Low-Dose Danazol for the ... 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 ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27192671/

Danazol Treatment for Telomere Diseases - PubMed - NIH Conclusions: In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National ...

5. atsjournals.org atsjournals.org/doi/abs/10.1164/ajrccm.2025.211.Abstracts.A1010

Efficacy and Safety of Danazol in Pulmonary Fibrosis ... CONCLUSIONS: In this randomized trial of danazol in PF-ST, danazol did not attenuate telomere attrition compared to placebo at 12 months. The absence of a ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03312400?term=DANAZOL&rank=7

Low-Dose Danazol for the Treatment of Telomere Related ... 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 ...

7. nejm.org nejm.org/doi/abs/10.1056/nejmoa1515319

Danazol Treatment for Telomere Diseases In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials ...

8. ashpublications.org ashpublications.org/ashclinicalnews/news/2565/Treatment-with-Danazol-Restores-Telomere-Length-in

Treatment with Danazol Restores Telomere Length in Patients ... Danazol, a synthetic sex hormone with androgenic properties, preserves telomere length in patients with diseases associated with telomere dysfunction.