Danazol for Genetic Bone Marrow and Lung Disorders

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01441037
• Collaborator: (none)
• Enrollment: 27
• Location: 1
• Arm: 1
• Duration (Months): 63.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Background:

• Some people have bone marrow and lung disorders that are caused by genetic problems. These problems often involve damage to the ends of the chromosomes that pass down genes. One of these disorders is aplastic anemia. This is a disorder in which the bone marrow does not make enough blood cells. Currently, doctors use a male hormone-based drug called Danazol to improve bone marrow function and treat aplastic anemia. More information is needed on whether Danazol can help repair the damaged chromosomes that cause aplastic anemia and similar disorders that cause low blood cell counts or lung problems.

Objectives:

• To study the safety and effectiveness of Danazol for bone marrow and lung disorders caused by damaged genes.

Eligibility:

• Individuals at least 2 years of age who have low blood cell counts or lung fibrosis caused by damaged genes.

Design:

• Participants will be screened with a physical exam and medical history. Then they will have blood and urine tests, imaging studies, and a lung function test. They will also take a 6-minute walking test and have a bone marrow biopsy.

• Participants will receive Danazol to take twice a day for the duration of the study.

• Participants will have regular study visits at 6, 12, and 24 months, with blood tests, imaging studies, a lung function test, and a 6-minute walking test. A bone marrow sample will be collected at the 12-month visit.

• Participants will remain on the study for up to 2 years. Researchers will follow up with them for 2 years after the end of the study.

Condition or Disease	Intervention/Treatment	Phase
Aplastic Anemia	Drug: Danazol	Phase 1/Phase 2

Detailed Description

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Telomeres were reported to be short in up to one-third of patients with SAA.Initially this occurrence was presumed to be secondary to hematopoietic stress. However, the discovery of loss-of-function mutations in genes of the telomerase complex (TERC, TERT) established a genetic etiology for telomere attrition in some patients with marrow failure who did not have the stigmata associated to an inherited bone marrow failure syndrome. These findings implicated telomerase dysfunction in failed hematopoiesis. In family members of probands with SAA, telomerase mutations have been observed which were associated to varying degrees of cytopenias, idiopathic pulmonary fibrosis (IPF) and/or cirrhosis.

Telomere length has been associated with human cancer. Telomere attrition has been implicated in a variety of solid organ malignancies including esophageal and colon adenocarcinoma. In a longitudinal population based study, shorter telomere length associated to a higher cancer mortality risk overtime. It is plausible that a shorter telomere length is not just a biomarker associated to development of cancer, but involved in its pathogenesis. Ample experimental data supports an important role of critically short telomere length in genomic instability. Furthermore, our laboratory data (unpublished) shows that similar chromosome instability occurs in bone marrow cells of mutant patients, confirming the experimental data. Thus, a common molecular mechanism appears to underlie risk for cancer and a range of clinical entities.

In vitro studies suggest that telomere length could, in theory, be modulated with sex hormones.15 Exposure of normal peripheral blood lymphocytes and human bone marrow derived CD34+ cells to androgens increased telomerase activity in vitro and androgens increased low baseline telomerase activity in individuals carrying a loss-of-function TERT mutation to normal levels. In retrospect, the beneficial effects of sex hormones on telomerase activity may be the mechanism by which SAA patients treated over 40 years ago with male hormones showed hematologic improvement in some cases.

In recent years we have seen patients referred to our clinic with varying degree of cytopenia(s) who had significant family history for cytopenia(s), IPF and/or cirrhosis. We have identified very short telomeres in these patients and in some mutations in TERC and TERT. We hypothesize that male hormone therapy might modulate telomere attrition in vivo and ameliorate progression or reverse the clinical consequences of accelerated telomere attrition. Therefore, we propose male hormone therapy in patients with cytopenia(s) and/or IPF who show evidence of telomere dysfunction by a short age adjusted telomere length associated to telomerase gene mutations. The primary biologic endpoint will be delay of telomere attrition over time compared to known rates of telomere erosion in normal individuals and in those who carry mutation in the telomerase genes. The main clinical endpoint will be tolerability of oral danazol over two years. Secondary endpoints will be improvement in blood counts and/or pulmonary function. The small sample size, lack of control groups, and variable clinical course among those with marrow failure and IPF, will not allow for definitive assessment of clinical benefit. Nevertheless, we believe this protocol will provide insight into the possible effects of androgen therapy on telomere attrition in humans and of possible clinical benefit in telomere related disorders, and serve as hypothesis generating for further larger controlled studies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Male Hormones for Telomere Related Diseases
• Study Start Date: Jul 19, 2011
• Actual Primary Completion Date: Nov 14, 2016
• Actual Study Completion Date: Nov 14, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Danazol Single arm in which danazol is administered orally at 800 mg daily for 2 years.	Drug: Danazol; Danazol, 800 mg daily by mouth for 2 years

Outcome Measures

Primary Outcome Measures

1. Number of Patients Having Attenuation of Accelerated Telomere Attrition [24 months]

   The primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The biologic response at 24 months, was defined as a reduction in the telomere length attrition rate to 96 bp per year or less. The normal rate of telomere loss of approximately 60 bp per year. Telomere length was determined with a semiautomated, Clinical Laboratory Improvement Amendments (CLIA)-approved real-time quantitative PCR (qPCR) assay performed in triplicate and validated for human cells

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. Short age-adjusted telomere length in the first percentile and/or a mutation in telomerase genes

2. One or more of the following cytopenia(s).

• Anemia

1. Symptomatic anemia with a hemoglobin < 9.5 g/dL or red cell transfusion requirements > 2 units/month for at least 2 months

2. Reticulocyte count < 60,000 /microL

• Thrombocytopenia

1. Platelet count < 30,000 /microL or < 50,000 /microL associated with bleeding

2. Decreased megakaryocytic precursors in the bone marrow

• Neutropenia

1. Absolute neutrophil count < 1,000 /microL

OR

1. Idiopathic pulmonary fibrosis diagnosed by either a lung biopsy of high resolution computed tomography scan of the chest according to guidelines from the American Thoracic Society and European Respiratory Society

2. Age greater than or equal to 2 years

3. Weight > 12 kg

EXCLUSION CRITERIA:

1. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy, or that death within 30 days is likely

2. Potential subjects with cancer who are on active chemotherapeutic treatment

3. Current pregnancy, or unwillingness to avoid pregnancy if of childbearing potential

4. Not able to understand the investigational nature of the study or give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

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

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood. 2008 May 1;111(9):4446-55. doi: 10.1182/blood-2007-08-019729. Epub 2008 Jan 31. Review.
• Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005 Apr 7;352(14):1413-24.
• Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006 Oct 15;108(8):2509-19. Epub 2006 Jun 15. Review.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT01441037
• Other Study ID Numbers: 110209; 11-H-0209
• First Posted: Sep 27, 2011
• Last Update Posted: Aug 15, 2018
• Last Verified: Dec 18, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Heart, Lung, and Blood Institute (NHLBI): Aplastic Anemia; Androgen; Telomeres; Sex hormone; Pulmonary fibrosis; Liver cirrhosis
• Additional relevant MeSH terms: Anemia, Aplastic; Danazol

Study Results

Participant Flow

Arm/Group Title	Danazol
Arm/Group Description	Oral administration of Danazol (800 mg daily divided into two doses per day) to be given for 2 years
Period Title: Overall Study
STARTED	27
COMPLETED	27
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Danazol
Arm/Group Description	Oral administration of Danazol (800 mg daily divided into two doses per day) to be given for 2 years
Overall Participants	27
Age (Count of Participants)
<=18 years	3 11.1%
Between 18 and 65 years	22 81.5%
>=65 years	2 7.4%
Sex: Female, Male (Count of Participants)
Female	15 55.6%
Male	12 44.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 11.1%
Not Hispanic or Latino	22 81.5%
Unknown or Not Reported	2 7.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 7.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.7%
White	18 66.7%
More than one race	3 11.1%
Unknown or Not Reported	3 11.1%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Having Attenuation of Accelerated Telomere Attrition
Description	The primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The biologic response at 24 months, was defined as a reduction in the telomere length attrition rate to 96 bp per year or less. The normal rate of telomere loss of approximately 60 bp per year. Telomere length was determined with a semiautomated, Clinical Laboratory Improvement Amendments (CLIA)-approved real-time quantitative PCR (qPCR) assay performed in triplicate and validated for human cells
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

The analyses included only those subjects who took Danazol

Arm/Group Title	Danazol
Arm/Group Description	Oral administration of Danazol (800 mg daily divided into two doses per day) to be given for 2 years
Measure Participants	27
Count of Participants [Participants]	12 44.4%

Adverse Events

Arm/Group Title	Danazol
Arm/Group Description	Oral administration of Danazol (800 mg daily divided into two doses per day) to be given for 2 years
All Cause Mortality
	Danazol
	Affected / at Risk (%)	# Events
Total	0/27 (0%)
Serious Adverse Events
	Danazol
	Affected / at Risk (%)	# Events
Total	3/27 (11.1%)
Gastrointestinal disorders
Diarrhoea	1/27 (3.7%)
General disorders
Joint swelling	1/27 (3.7%)
Oedema peripheral	1/27 (3.7%)
Injury, poisoning and procedural complications
Femur fracture	1/27 (3.7%)
Respiratory, thoracic and mediastinal disorders
Pneumocystis jirovecii pneumonia	1/27 (3.7%)
Other (Not Including Serious) Adverse Events
	Danazol
	Affected / at Risk (%)	# Events
Total	24/27 (88.9%)
Blood and lymphatic system disorders
Anaemia	2/27 (7.4%)
Pallor	1/27 (3.7%)
Cardiac disorders
Palpitations	1/27 (3.7%)
Tachycardia	1/27 (3.7%)
Ear and labyrinth disorders
Otitis externa	1/27 (3.7%)
Eye disorders
Scleritis	1/27 (3.7%)
Vitreous floaters	1/27 (3.7%)
Gastrointestinal disorders
Abdominal distension	2/27 (7.4%)
Abdominal pain upper	1/27 (3.7%)
Constipation	3/27 (11.1%)
Decreased appetite	1/27 (3.7%)
Dental caries	1/27 (3.7%)
Diarrhoea	1/27 (3.7%)
Gastrointestinal pain	1/27 (3.7%)
Infection	1/27 (3.7%)
Nausea	2/27 (7.4%)
Proctalgia	1/27 (3.7%)
Rectal haemorrhage	3/27 (11.1%)
Stomatitis	1/27 (3.7%)
Vomiting	2/27 (7.4%)
General disorders
Asthenia	2/27 (7.4%)
Back pain	1/27 (3.7%)
Cough	1/27 (3.7%)
Face oedema	1/27 (3.7%)
Fatigue	12/27 (44.4%)
Feeling hot	2/27 (7.4%)
Influenza like illness	1/27 (3.7%)
Irritability	1/27 (3.7%)
Oedema	2/27 (7.4%)
Oedema peripheral	1/27 (3.7%)
Pain	1/27 (3.7%)
Peripheral swelling	1/27 (3.7%)
Pyrexia	1/27 (3.7%)
Toothache	1/27 (3.7%)
Upper respiratory tract infection	1/27 (3.7%)
Immune system disorders
Sinus congestion	1/27 (3.7%)
Infections and infestations
Bronchitis	1/27 (3.7%)
Cellulitis	1/27 (3.7%)
Cystitis	1/27 (3.7%)
Sinusitis	2/27 (7.4%)
Tooth disorder	1/27 (3.7%)
Upper respiratory tract infection	6/27 (22.2%)
Urinary tract infection	2/27 (7.4%)
Viral infection	1/27 (3.7%)
Injury, poisoning and procedural complications
Clavicle fracture	1/27 (3.7%)
Contusion	2/27 (7.4%)
Increased tendency to bruise	1/27 (3.7%)
Lower limb fracture	1/27 (3.7%)
Spinal fracture	1/27 (3.7%)
Umbilical hernia	1/27 (3.7%)
Investigations
Alanine aminotransferase increased	1/27 (3.7%)
Blood creatine phosphokinase increased	1/27 (3.7%)
Blood creatinine increased	1/27 (3.7%)
Neutrophil count decreased	2/27 (7.4%)
Platelet count decreased	2/27 (7.4%)
Transaminases increased	1/27 (3.7%)
Weight increased	4/27 (14.8%)
Metabolism and nutrition disorders
Iron overload	1/27 (3.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/27 (3.7%)
Back pain	2/27 (7.4%)
Chest discomfort	1/27 (3.7%)
Joint effusion	1/27 (3.7%)
Joint range of motion decreased	1/27 (3.7%)
Joint swelling	1/27 (3.7%)
Muscle hypertrophy	1/27 (3.7%)
Muscle spasms	9/27 (33.3%)
Myalgia	1/27 (3.7%)
Pain	1/27 (3.7%)
Pain in extremity	1/27 (3.7%)
Nervous system disorders
Disturbance in attention	1/27 (3.7%)
Dizziness	5/27 (18.5%)
Headache	4/27 (14.8%)
Migraine	1/27 (3.7%)
Seizure	1/27 (3.7%)
Psychiatric disorders
Depression	3/27 (11.1%)
Hypersomnia	1/27 (3.7%)
Renal and urinary disorders
Nephrolithiasis	1/27 (3.7%)
Pollakiuria	1/27 (3.7%)
Reproductive system and breast disorders
Libido increased	1/27 (3.7%)
Vaginal discharge	1/27 (3.7%)
Respiratory, thoracic and mediastinal disorders
Cough	6/27 (22.2%)
Dysphonia	1/27 (3.7%)
Dyspnoea	3/27 (11.1%)
Dyspnoea exertional	4/27 (14.8%)
Epistaxis	2/27 (7.4%)
Nasal congestion	2/27 (7.4%)
Oropharyngeal pain	2/27 (7.4%)
Pneumonia	1/27 (3.7%)
Respiratory tract congestion	2/27 (7.4%)
Rhinitis allergic	2/27 (7.4%)
Sinusitis	2/27 (7.4%)
Tachypnoea	1/27 (3.7%)
Upper respiratory tract infection	1/27 (3.7%)
Skin and subcutaneous tissue disorders
Acne	1/27 (3.7%)
Alopecia	4/27 (14.8%)
Folliculitis	1/27 (3.7%)
Hirsutism	1/27 (3.7%)
Hot flush	1/27 (3.7%)
Hypertrichosis	1/27 (3.7%)
Night sweats	1/27 (3.7%)
Petechiae	2/27 (7.4%)
Rash	2/27 (7.4%)
Rash maculo-papular	1/27 (3.7%)
Rash pruritic	1/27 (3.7%)
Skin hyperpigmentation	2/27 (7.4%)
Skin hypopigmentation	1/27 (3.7%)
Skin lesion	1/27 (3.7%)
Subcutaneous abscess	1/27 (3.7%)
Vascular disorders
Haemangioma	1/27 (3.7%)
Haematoma	1/27 (3.7%)

Limitations/Caveats

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 end point.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.