Clinical trial NCT02055456: Nandrolone Decanoate in the Treatment of Telomeropathies
Official title: Male Hormones for Telomere Related Diseases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Aplastic Anemia
Bone Marrow Failure Syndromes
Idiopathic Pulmonary Fibrosis
Telomere Shortening
Keywords: Hormones
Androgens
Aplastic Anemia
Bone Marrow Failure Syndromes
Idiopathic Pulmonary Fibrosis
Telomere
Telomere Shortening
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
Collaborators: name: Conselho Nacional de Desenvolvimento Científico e Tecnológico
First posted: 2014-02-05
Enrollment: 20
Sex: ALL
Minimum age (years): 2
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Reduction in telomere attrition
timeFrame: 2 years
Secondary outcomes:
measure: Hematologic response
timeFrame: 2 years
measure: Clonal evolution
timeFrame: 2 years
measure: Improvement in lung function
timeFrame: 2 years
measure: Survival
timeFrame: 2 years
measure: Safety
timeFrame: 2 years
Other outcomes:
Locations:
city: Ribeirao Preto
country: Brazil
facility: Ribeirao Preto School of Medicine, University of Sao Paulo
state: Sao Paulo
Study officials:
affiliation: Ribeirao Preto School of Medicine at University of Sao Paulo
name: Rodrigo T Calado, MD, PhD
role: STUDY_CHAIR
affiliation: Ribeirao Preto School of Medicine at University of Sao Paulo
name: Diego V Clé, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ribeirao Preto School of Medicine at University of Sao Paulo
name: Ana Beatriz Hortense, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ribeirao Preto School of Medicine at University of Sao Paulo
name: José Antonio Baddini Martinez, MD, PhD
role: STUDY_CHAIR
References:
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. doi: 10.1182/blood-2006-03-010777. Epub 2006 Jun 15.
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.
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. doi: 10.1056/NEJMoa042980.
citation: 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.
citation: Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009 Dec 10;361(24):2353-65. doi: 10.1056/NEJMra0903373. No abstract available.
citation: 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.