Ignite Creation Date:
2024-05-06 @ 10:38 AM
Last Modification Date:
2024-10-26 @ 12:33 PM
Study NCT ID:
NCT03312400
Status:
RECRUITING
Last Update Posted:
2024-07-03
First Post:
2017-10-14
Brief Title:
Low-Dose Danazol for the Treatment of Telomere Related Diseases
Sponsor:
National Heart Lung and Blood Institute NHLBI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Low Dose Danazol for the Treatment of Telomere Related Diseases
Status:
RECRUITING
Status Verified Date:
2024-07-25
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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
Detailed Description:
Telomere disease is caused by accelerated telomere attrition and results in multi-organ dysfunction Telomeres are nucleotide repeats of non-coding DNA at the end of the chromosomes which function as protective caps to prevent erosion of genomic DNA during cell division and to protect chromosomes from recognition as single stranded DNA Telomeric DNA is elongated by the telomerase complex which is comprised of a reverse transcriptase catalytic subunit encoded by TERT an RNA template encoded by TERC and associated proteins
Telomerase activity is crucial in maintaining telomere length in cells with a high proliferative capacity such as hematopoietic stem cells HSCs and lymphocytes Presentation of telomeropathies can vary from severe aplastic anemia SAA and dyskeratosis congenital DKC early in childhood to pulmonary or hepatic fibrosis later in life There is no standard of care for the treatment of telomere disease
Considerable evidence suggests that sex hormones regulate telomerase Calado et al demonstrated that human lymphocytes and CD34 hematopoietic cells up regulate both TERT gene expression and telomerase enzymatic activity in response to androgens in vitro A recent observational cohort study demonstrated hematologic response in 14 of 16 pediatric patients with DKC treated with androgens In a prospective trial from our Branch Townsley et al demonstrated that patients with telomere diseases who were treated with the synthetic sex hormone danazol showed telomere elongation and hematologic response were seen in 79 of patients after only three months of treatment This study used the highest dose of danazol 800 mg daily and known adverse effects such as elevated liver enzyme levels and muscle cramps occurred in 41 and 33 of patients respectively Overall the treatment was well tolerated but some patients did require dose reduction 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 endpoint Because of the limited power we were unable to draw definitive conclusions regarding further clinical effect of danazol but stabilization or improvement was observed in a few cases in other organ function measured by DLCO for pulmonary fibrosis and Fibroscan for cirrhosis
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-adjusted telomere length The secondary aim is to determine the clinical effect of this therapy in conditions that are related to short telomeres to include cytopenias pulmonary fibrosis andor hepatic fibrosis
Telomerase activity is crucial in maintaining telomere length in cells with a high proliferative capacity such as hematopoietic stem cells HSCs and lymphocytes Presentation of telomeropathies can vary from severe aplastic anemia SAA and dyskeratosis congenital DKC early in childhood to pulmonary or hepatic fibrosis later in life There is no standard of care for the treatment of telomere disease
Considerable evidence suggests that sex hormones regulate telomerase Calado et al demonstrated that human lymphocytes and CD34 hematopoietic cells up regulate both TERT gene expression and telomerase enzymatic activity in response to androgens in vitro A recent observational cohort study demonstrated hematologic response in 14 of 16 pediatric patients with DKC treated with androgens In a prospective trial from our Branch Townsley et al demonstrated that patients with telomere diseases who were treated with the synthetic sex hormone danazol showed telomere elongation and hematologic response were seen in 79 of patients after only three months of treatment This study used the highest dose of danazol 800 mg daily and known adverse effects such as elevated liver enzyme levels and muscle cramps occurred in 41 and 33 of patients respectively Overall the treatment was well tolerated but some patients did require dose reduction 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 endpoint Because of the limited power we were unable to draw definitive conclusions regarding further clinical effect of danazol but stabilization or improvement was observed in a few cases in other organ function measured by DLCO for pulmonary fibrosis and Fibroscan for cirrhosis
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-adjusted telomere length The secondary aim is to determine the clinical effect of this therapy in conditions that are related to short telomeres to include cytopenias pulmonary fibrosis andor hepatic fibrosis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 18-H-0004 | None | None | None |