Danazol for Genetic Bone Marrow and Lung Disorders

NCT01441037 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 11020911-H-0209
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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.

Conditions

Aplastic Anemia

Keywords

Aplastic Anemia; Androgen; Telomeres; Sex hormone; Pulmonary fibrosis; Liver cirrhosis

Outcome Measures

Primary Outcomes (1)

• Number of Patients Having Attenuation of Accelerated Telomere Attrition

  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

  24 months

Study Arms (1)

Danazol

EXPERIMENTAL

Single arm in which danazol is administered orally at 800 mg daily for 2 years.

Drug: Danazol

Interventions

Danazol DRUG

Danazol, 800 mg daily by mouth for 2 years

Danazol

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Short age-adjusted telomere length in the first percentile and/or a mutation in telomerase genes
• One or more of the following cytopenia(s).
• Anemia
• Symptomatic anemia with a hemoglobin \< 9.5 g/dL or red cell transfusion requirements \> 2 units/month for at least 2 months
• Reticulocyte count \< 60,000 /microL
• Thrombocytopenia
• Platelet count \< 30,000 /microL or \< 50,000 /microL associated with bleeding
• Decreased megakaryocytic precursors in the bone marrow
• Neutropenia
• Absolute neutrophil count \< 1,000 /microL
• \. 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
• \. Age greater than or equal to 2 years
• \. Weight \> 12 kg

You may not qualify if:

• 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
• Potential subjects with cancer who are on active chemotherapeutic treatment
• Current pregnancy, or unwillingness to avoid pregnancy if of childbearing potential
• 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.

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006 Oct 15;108(8):2509-19. doi: 10.1182/blood-2006-03-010777. Epub 2006 Jun 15.

  PMID: 16778145 BACKGROUND

• 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.

  PMID: 18239083 BACKGROUND

• 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. doi: 10.1056/NEJMoa042980.

  PMID: 15814878 BACKGROUND

• 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.

  PMID: 27192671 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Aplastic; Pulmonary Fibrosis; Liver Cirrhosis

Interventions

Danazol

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Limitations and 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.

Results Point of Contact

• Title: Young, Neal
• Organization: National Heart Lung and Blood Institute

youngns@mail.nih.gov

+1 301 496 5093

Study Officials

• Neal S Young, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2011
• First Posted: September 27, 2011
• Study Start: July 19, 2011
• Primary Completion: November 14, 2016
• Study Completion: November 14, 2016
• Last Updated: August 15, 2018
• Results First Posted: July 11, 2018

Record last verified: 2017-12-18

Locations

US (1)