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Protocol Details

Low Dose Danazol for the Treatment of Telomere Related Diseases

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

18-H-0004

Sponsoring Institute

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 3
Max Age: 999

Referral Letter Required

No

Population Exclusion(s)

None

Special Instructions

Currently Not Provided

Keywords

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

Recruitment Keyword(s)

None

Condition(s)

Telomere Disease

Investigational Drug(s)

None

Investigational Device(s)

None

Intervention(s)

Drug: Danazol

Supporting Site

National Heart, Lung, and Blood Institute

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.

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Eligibility

INCLUSION CRITERIA:

1. Age-adjusted telomere length less than or equal to the first percentile

2. A mutation in telomere maintenance genes (TERT, TERC, DKC1, TINF2, NHP2, NOP10, WRAP53, TERF2, PARN, RTEL1, ACD, CTC1, USB1)

3. Age greater than or equal to 3 years

4. Weight greater than or equal to 12 Kg

AND

5. At least one of the following criteria:

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

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

c. Neutropenia with an absolute neutrophil count less than or equal to 1,000/ microliter

OR

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.

OR

6. 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:

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 such events, 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 and who have not undergone a 1 month washout period

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 anemia or 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 barrier methods of birth control or practice abstinence to refrain from pregnancy if of childbearing 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 treatment or 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 informed consent or without a legally authorized representative or surrogate that can provide informed consent

13. Inability to swallow a capsule


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Citations:

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.

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.

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.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Neal S. Young, M.D.
National Heart, Lung and Blood Institute (NHLBI)



Carrie E. Diamond, M.D.
National Heart, Lung and Blood Institute (NHLBI)
BG 10-CRC RM 3-5140
10 CENTER DR
BETHESDA MD 20814
(630) 730-5918
carrie.diamond@nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: 1-866-411-1010
PRPL@cc.nih.gov

Clinical Trials Number:

NCT03312400

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