Nandrolone Decanoate in the Treatment of Telomeropathies

August 28, 2023 updated by: Diego Villa Clé, University of Sao Paulo

Male Hormones for Telomere Related Diseases

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Brazil
    • Sao Paulo
      • Ribeirao Preto, Sao Paulo, Brazil, 14048-900
        • Ribeirao Preto School of Medicine, University of Sao Paulo

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Nandrolone Decanoate
Nandrolone Decanoate intramuscularly administered, every two weeks, 5 mg/kg/dose
Drug: Nandrolone Decanoate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Reduction in telomere attrition
Time Frame: 2 years
The biologic endpoint is reduction in telomere attrition rate yearly compared to known rates of telomere erosion in normal individuals and in those who carry mutation in the telomerase genes
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival
Time Frame: 2 years
2 years
Hematologic response
Time Frame: 2 years

The hematologic response will be determined by one or more of the following:

  1. absolute neutrophil counts (increase of more than 500/μL above initial value)
  2. platelets (increase of more than 20.000/μL above initial value)

  3. Hemoglobin:

    • Increase in hemoglobin of more than 1.5 g/dL above initial value OR
    • Transfusion independence in transfusion-dependent patients (more than 2 months without transfusion) OR
    • Reduction of the transfusion needs in more than 50%
2 years
Clonal evolution
Time Frame: 2 years
Number of participants that evolute to myelodysplasia or acute leukemia.
2 years
Improvement in lung function
Time Frame: 2 years

The pulmonary response will be determined by the presence of one or more of the following:

  1. Improvement of dyspnea severity, objectively evaluated by "Baseline Dyspnea Index";
  2. forced vital capacity (10% absolute increase)
  3. Diffusion of carbon monoxide (DLCO) corrected for hemoglobin (15% increase)
  4. No worsening of pulmonary fibrosis and reduction of assessed ground-glass opacities in computed tomography of the chest
2 years
Safety
Time Frame: 2 years
Number of participants with adverse effects attributed to the use of nandrolone decanoate during the 24 months treatment period.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Sao Paulo

Collaborators

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Investigators

  • Study Chair: Rodrigo T Calado, MD, PhD, Ribeirao Preto School of Medicine at University of Sao Paulo
  • Principal Investigator: Diego V Clé, MD, Ribeirao Preto School of Medicine at University of Sao Paulo
  • Principal Investigator: Ana Beatriz Hortense, MD, Ribeirao Preto School of Medicine at University of Sao Paulo
  • Study Chair: José Antonio Baddini Martinez, MD, PhD, Ribeirao Preto School of Medicine at University of Sao Paulo

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2014

Primary Completion (Actual)

February 1, 2017

Study Completion (Actual)

February 1, 2017

Study Registration Dates

First Submitted

February 3, 2014

First Submitted That Met QC Criteria

February 4, 2014

First Posted (Estimated)

February 5, 2014

Study Record Updates

Last Update Posted (Estimated)

August 31, 2023

Last Update Submitted That Met QC Criteria

August 28, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11-H-RTC-0002

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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