Nandrolone Decanoate in the Treatment of Telomeropathies

NCT ID: NCT02055456

Last Updated: 2023-08-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-01
• Study Completion Date: 2017-02-01

Brief Summary

Decrease in blood cell counts due to deficient bone marrow function, called bone marrow failure, as well as some lung diseases, called idiopathic pulmonary fibrosis, can be caused by genetic defects in telomere biology genes, eventually causing telomere erosion. These disorders are collectively termed "telomeropathies".

There is evidence that male hormones may improve blood cell counts in marrow failure, and these hormones are able to stimulate telomerase function in hematopoietic cells in vitro. We propose this study to the use of male hormone in patients with aplastic anemia and pulmonary fibrosis associated with defects in telomeres.

Detailed Description

Telomeres are repeated nucleotide sequences of non-coding DNA at the ends of chromosomes that have protective functions and avoid chromosomes recombinations and fusions.

Loss-of-function mutations in genes of the telomerase complex, a enzyme responsible for maintaining telomere length, has been associated with bone marrow failures, notedly mutations in DKC1 gene, detected in a rare inherited form of marrow aplasia, called dyskeratosis congenita. These findings implicated telomerase dysfunction and shortening telomere length in failed hematopoiesis.

In family members of probands with aplastic anemia, marrow aplasia and telomerase mutations also have been observed and associated to varying degrees of cytopenias, IPF and/or cirrhosis. Moreover, patients with varying degrees of cytopenias, with significant family history for cytopenias, IPF and/or cirrhosis, have been identified with very short telomeres and some mutations in telomerase complex genes. Additionally, telomere length has been associated with human cancer.

In vitro studies suggest that telomere length could be modulated with sex hormones. Normal lymphocytes and human bone marrow progenitor cells exposed to androgens increased telomerase activity in vitro, and in individuals with telomerase mutations (TERT) androgens increased telomerase activity.This could be the explanation for the hematologic improvement observed in some aplastic anemia patients treated over 40 years ago with male hormones.

Therefore, we hypothesize that androgens therapy might modulate telomere attrition in vivo and ameliorate progression or reverse the clinical consequences of shortening telomere length, and we propose androgens therapy in patients with cytopenias and/or IPF with a short age adjusted telomere length, with or without telomerase gene mutations.

The primary biologic endpoint will be the reduction 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. Secondary endpoints will be tolerability of nandrolone decanoate over two years, improvement in blood counts and/or pulmonary function.

Conditions

Aplastic Anemia; Bone Marrow Failure Syndromes; Idiopathic Pulmonary Fibrosis; Telomere Shortening

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Nandrolone Decanoate

Nandrolone Decanoate intramuscularly administered, every two weeks, 5 mg/kg/dose

Group Type: EXPERIMENTAL

Nandrolone Decanoate

Intervention Type: DRUG

Interventions

Nandrolone Decanoate

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Peripheral blood leukocytes telomeres short for age, below the first percentile of a curve based on 500 healthy individuals between 0 and 100 years, with or without a telomerase gene mutation.

AND

• One or more of the following cytopenias:

Anemia (symptoms of anemia with hemoglobin <9.5 g/dL, or need for transfusion > 2 units of packed red blood cells/month for at least two months, or absolute reticulocytes count <60.000/μL).

Thrombocytopenia (platelets counts <30.000/μL or <50.000/μL associated with bleeding, or megakaryocytes reduction in the bone marrow).

Neutropenia (absolute neutrophil counts <1.000/μL).

OR

• Idiopathic pulmonary fibrosis diagnosed according to the American Thoracic Society (ATS) criteria.

Exclusion Criteria

• Terminal disease or liver disease, renal, cardiac, neurological, infectious or concomitant metabolic state whose gravity prevents the ability of the patient to tolerate the treatment protocol, or probable death within 30 days.
• People with cancer who are undergoing chemotherapy.
• Pregnancy, or desire to not prevent pregnancy in childbearing age.
• Aplastic Anemia patients with indication for bone marrow transplantation and matched donor.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Conselho Nacional de Desenvolvimento Científico e Tecnológico

OTHER_GOV

Sponsor Role: collaborator

University of Sao Paulo

OTHER

Sponsor Role: lead

Responsible Party

Diego Villa Clé

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Rodrigo T Calado, MD, PhD

Role: STUDY_CHAIR

Ribeirao Preto School of Medicine at University of Sao Paulo

Diego V Clé, MD

Role: PRINCIPAL_INVESTIGATOR

Ribeirao Preto School of Medicine at University of Sao Paulo

Ana Beatriz Hortense, MD

Role: PRINCIPAL_INVESTIGATOR

Ribeirao Preto School of Medicine at University of Sao Paulo

José Antonio Baddini Martinez, MD, PhD

Role: STUDY_CHAIR

Ribeirao Preto School of Medicine at University of Sao Paulo

Locations

Ribeirao Preto School of Medicine, University of Sao Paulo

Ribeirão Preto, São Paulo, Brazil

Countries

Brazil

References

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.

Reference Type: BACKGROUND

PMID: 16778145 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18239083 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15814878 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19561322 (View on PubMed)

Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009 Dec 10;361(24):2353-65. doi: 10.1056/NEJMra0903373. No abstract available.

Reference Type: BACKGROUND

PMID: 20007561 (View on PubMed)

Ziegler P, Schrezenmeier H, Akkad J, Brassat U, Vankann L, Panse J, Wilop S, Balabanov S, Schwarz K, Martens UM, Brummendorf TH. Telomere elongation and clinical response to androgen treatment in a patient with aplastic anemia and a heterozygous hTERT gene mutation. Ann Hematol. 2012 Jul;91(7):1115-20. doi: 10.1007/s00277-012-1454-x. Epub 2012 Apr 4.

Reference Type: BACKGROUND

PMID: 22476886 (View on PubMed)

Cle DV, Catto LFB, Gutierrez-Rodrigues F, Donaires FS, Pinto AL, Santana BA, Darrigo LG, Valera ET, Koenigkam-Santos M, Baddini-Martinez J, Young NS, Martinez EZ, Calado RT. Effects of nandrolone decanoate on telomere length and clinical outcome in patients with telomeropathies: a prospective trial. Haematologica. 2023 May 1;108(5):1300-1312. doi: 10.3324/haematol.2022.281808.

Reference Type: DERIVED

PMID: 36579443 (View on PubMed)

Other Identifiers

11-H-RTC-0002

Identifier Type: -

Identifier Source: org_study_id