Male Hormones for Telomere Related Diseases
Danazol for Genetic Bone Marrow and Lung Disorders
Sponsors
Source
National Institutes of Health Clinical Center (CC)
Oversight Info
Has Dmc
Yes
Is Fda Regulated Drug
Yes
Is Fda Regulated Device
No
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.
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.
Overall Status
Completed
Start Date
2011-07-19
Completion Date
2016-11-14
Primary Completion Date
2016-11-14
Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
|
Number of Patients Having Attenuation of Accelerated Telomere Attrition |
24 months |
Enrollment
27
Condition
Intervention
Intervention Type
Drug
Intervention Name
Description
Danazol, 800 mg daily by mouth for 2 years
Arm Group Label
Danazol
Eligibility
Criteria
- 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
3. 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
4. Age greater than or equal to 2 years
5. 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.
Gender
All
Minimum Age
2 Years
Maximum Age
N/A
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
|
Neal S Young, M.D. |
Principal Investigator |
National Heart, Lung, and Blood Institute (NHLBI) |
Location
Facility |
|
National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland 20892 United States |
Location Countries
Country
United States
Verification Date
2017-12-18
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Sponsor
Keywords
Has Expanded Access
No
Condition Browse
Secondary Id
11-H-0209
Number Of Arms
1
Intervention Browse
Mesh Term
Danazol
Arm Group
Arm Group Label
Danazol
Arm Group Type
Experimental
Description
Single arm in which danazol is administered orally at 800 mg daily for 2 years.
Firstreceived Results Date
N/A
Reference
Citation
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.
PMID
16778145
Citation
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.
PMID
18239083
Citation
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.
PMID
15814878
Firstreceived Results Disposition Date
N/A
Study Design Info
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Study First Submitted
September 24, 2011
Study First Submitted Qc
September 24, 2011
Study First Posted
September 27, 2011
Last Update Submitted
July 18, 2018
Last Update Submitted Qc
July 18, 2018
Last Update Posted
August 15, 2018
Results First Submitted
June 14, 2018
Results First Submitted Qc
June 14, 2018
Results First Posted
July 11, 2018
ClinicalTrials.gov processed this data on December 12, 2019
Conditions
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conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.