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Open Access 01-12-2020 | Magnetic Resonance Imaging | Study protocol

The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial

Authors: Katline Metzger-Peter, Laurent Daniel Kremer, Gilles Edan, Paulo Loureiro De Sousa, Julien Lamy, Dominique Bagnard, Ayikoe-Guy Mensah-Nyagan, Thibault Tricard, Guillaume Mathey, Marc Debouverie, Eric Berger, Anne Kerbrat, Nicolas Meyer, Jérôme De Seze, Nicolas Collongues

Published in: Trials | Issue 1/2020

Abstract

Background

Central nervous system damage in multiple sclerosis (MS) is responsible for serious deficiencies. Current therapies are focused on the treatment of inflammation; however, there is an urgent need for innovative therapies promoting neuroregeneration, particularly myelin repair.

It is demonstrated that testosterone can act through neural androgen receptors and several clinical observations stimulated an interest in the potential protective effects of testosterone treatment for MS. Here, we sought to demonstrate the effects of a testosterone supplementation in testosterone-deficient men with relapsing-remitting MS.

Methods/design

This report presents the rationale and methodology of TOTEM RRMS, a French, phase 2, multicenter, randomized, placebo-controlled, and double-blind trial, which aims to prevent the progression of MS in men with low testosterone levels by administration of testosterone undecanoate, who were kept under natalizumab (Tysabri®) to overcome the anti-inflammatory effect of testosterone. Forty patients will be randomized into two groups receiving either a testosterone treatment (Nebido®) or a matching placebo. The intervention period for each group will last 66 weeks (treatment will be injected at baseline, week 6, and then every 12 weeks). The main objective is to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging techniques and thalamic atrophy analyses. As secondary objectives, impacts of the testosterone supplementation will be studied using other conventional and unconventional MRI parameters and with clinical outcomes.

Discussion

The action of testosterone is observed in different experimental autoimmune encephalomyelitis models and epidemiological studies in humans. However, despite several preclinical data and some small clinical trials in MS, clear evidence for a therapeutic effect of hormone therapy is still missing. Therefore, our goal is to demonstrate the effects of testosterone therapies in MS. As there is no effective treatment currently available on fatigue in MS, careful attention should also be paid to secondary endpoints: fatigue, cognitive functions, and other symptoms that may improve life quality.

Assuming a positive outcome of the trial, this treatment could be considered as a new neuroprotective and remyelinating therapy in relapsing-remitting MS and could be applicable to other demyelinating diseases.

Trial registration

ClinicalTrials.gov NCT03910738. Registered on 10 April 2019.

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Title: The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial
Authors: Katline Metzger-Peter
Laurent Daniel Kremer
Gilles Edan
Paulo Loureiro De Sousa
Julien Lamy
Dominique Bagnard
Ayikoe-Guy Mensah-Nyagan
Thibault Tricard
Guillaume Mathey
Marc Debouverie
Eric Berger
Anne Kerbrat
Nicolas Meyer
Jérôme De Seze
Nicolas Collongues
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Magnetic Resonance Imaging
Magnetic Resonance Imaging
Multiple Sclerosis
Natalizumab
Testosterone
Published in: Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-020-04517-6

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