TOTEM RRMS : TestOsterone TreatmEnt on Neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis

NCT03910738 | Recruiting Phase 2

• 1 other identifier: 7109
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 5

Brief Summary

Centra nervous system (CNF) damage in multiple sclerosis (MS), are mainly attributed to myelin destruction, axonal abnormalities and subsequent degeneration, and are responsible for serious deficiencies. Current therapies are focused on the treatment of inflammation with several types of anti-inflammatory agents. However, there is an urgent need for innovative therapies promoting neuroregeneration and particularly myelin repair. It has been demonstrated that testosterone can act through neural androgen receptors to promote proliferation and differentiation of oligodendrocyte precursors into mature oligodendrocytes in a cuprizone-induced animal model of demyelination. The rare clinical trials on testosterone are mainly exploratory. Here, we sought to demonstrate an effect of testosterone supplementation in testosterone-deficient patients in a multicenter, randomized, parallel-group, double-blind, placebo-controlled phase 2 trial. The main objective will be to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging techniques and thalamic atrophy analyzes. As secondary objectives, we would like to study the impact of testosterone supplementation on other conventional and unconventional MRI parameters and on clinical outcomes (cognition, fatigue, quality of life, impact on work / activity and anxiety / depression).

Conditions

Multiple Sclerosis, Relapsing-Remitting

Keywords

Neuroprotection; Remyelination; Relapsing Remitting Multiple sclerosis; Testosterone undecanoate; Diffusion tensor Imaging

Outcome Measures

Primary Outcomes (1)

• Change on MRI binary criterion combining thalamic atrophy and modification in transverse diffusivity of lesions

  The primary endpoint is a binary criterion comparing the success rate in each treatment group, defined by thalamic atrophy lower than 0.5% and modification in transverse diffusivity of lesions lower than 0.5% per year compared between baseline and week 66 in each group.

  At baseline, week 30 and week 66 (end of study)

Secondary Outcomes (15)

• Evolution of the number of T1 hypointense lesions as detected by conventional MRI

  At baseline, week 30 and week 66 (end of study)

• Evolution of the volume of T1 hypointense lesions as detected by conventional MRIconventional MRI

  At baseline, week 30 and week 66 (end of study)

• Evolution of the number of new or enlarged T2 lesions as detected by conventional MRI

  At baseline, week 30 and week 66 (end of study)

• Evolution of the volume of new or enlarged T2 lesions as detected by conventional MRI

  At baseline, week 30 and week 66 (end of study)

• Evolution of the total volume of hyper-intensity FLAIR lesion as detected by conventional MRI

  At baseline, week 30 and week 66 (end of study)

Study Arms (2)

Testosterone treatment (Nebido®)

EXPERIMENTAL

"Treatment/Nebido®" arm: in this experimental arm, each patient will be injected intramuscularly with 1000 mg / 4 ml of testosterone undecanoate (Nebido®). Treatment will be injected at baseline, week 6, 18, 30, 42 and 54

Drug: Nebido® Testosterone Undecanoate 1000 Mg/4 mL Solution for Injection; Procedure: MRI; Behavioral: Assessment of impact of MS on cognition; quality of life; fatigue; anxiety/depression and work and activities; Behavioral: Assessment of disability

Placebo

PLACEBO COMPARATOR

"Placebo" arm: In this arm, each patient will be injected intramuscularly with 4 ml of placebo solution. Placebo will be injected at baseline, week 6, 18, 30, 42 and 54

Drug: Placebo 4 mL Solution for Injection; Procedure: MRI; Behavioral: Assessment of impact of MS on cognition; quality of life; fatigue; anxiety/depression and work and activities; Behavioral: Assessment of disability

Interventions

Nebido® Testosterone Undecanoate 1000 Mg/4 mL Solution for Injection DRUG

Active treatment (Nebido® Testosterone Undecanoate ) will be injected at Baseline, at week 6 and then every 12 weeks (Week 18, 30, 42 and 54)

Testosterone treatment (Nebido®)

Placebo 4 mL Solution for Injection DRUG

Placebo will be injected at Baseline, at week 6 and then every 12 weeks (Week 18, 30, 42 and 54)

Placebo

MRI PROCEDURE

Conventional MS sequences (OFSEP recommendations) and unconventional MRI sequences (Baseline, week 30 and 66)

Placebo; Testosterone treatment (Nebido®)

Assessment of impact of MS on cognition; quality of life; fatigue; anxiety/depression and work and activities BEHAVIORAL

BICAMS; SF-36 and EQ-5D-3L; MFIS; HADS; WPAI:MS (at baseline, week 30 and 66)

Placebo; Testosterone treatment (Nebido®)

Assessment of disability BEHAVIORAL

EDSS (Baseline, week 30 and 66)

Placebo; Testosterone treatment (Nebido®)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Gender Eligibility Details: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Man between 18 and 55 years
• Patient affiliated to a social health insurance plan
• Patient able to understand the objectives and risks related to the research and able to comply with the requirements of the protocol throughout the duration of the study
• Patient having been informed of the results of the prior medical examination
• Patient having signed an informed consent
• Confirmed and documented diagnosis of MS, as defined by the revised McDonald criteria,
• Patient who have been receiving one of the following disease modifying therapies for at least one year prior to randomization: natalizumab , fingolimod, ponesimod, ocrelizumab, or ofatumumab, in accordance with their prescribing information. Switching from one molecule to another during the previous year is also permitted, provided that the switch was motivated by a non-neurological reason (relapse, MRI activity). Patients receiving ocrelizumab within 6 to 9 months are eligible, provided they have received full-dose ocrelizumab for at least 2 years.
• Biological hypogonadism defined by serum total testosterone levels below 20 nmol / L (checked by blood sampling during the screening visit)
• Stable neurological state in the month preceding randomization

You may not qualify if:

• Patients with progressive MS (primary or secondary)
• Patients with hypogonadism with clinical symptoms and treated with androgens
• Patients refusing or unable to undergo an MRI
• Patients with any other disease other than MS that may contribute to neurological symptoms and signs or affect their evaluation
• Patients with neurological signs compatible with progressive multifocal leukoencephalopathy (PML) or confirmed leukoencephalopathy
• Patients diagnosed with untreated sleep apnea
• Patients with or having had cancer or tumors of the liver, heart, kidney, prostate or mammary gland
• Patients with cardiovascular, renal, hepatic, hematological, gastrointestinal, pulmonary, uncontrolled diseases
• Patients wishing to procreate during the study period
• Patients with chronic infectious disease
• Patients with organic or psychiatric disease compromise their ability to understand the information given and to follow the protocol
• Patients with a history of hypersensitivity to treatment or any of the excipients, or drugs of similar chemical classes
• Patients who used experimental drugs and / or who participated in clinical drug trials in the 6 months prior to selection
• Impossibility of giving information to the patient (subject in emergency situation, difficulties in understanding the subject or other)
• Incapacitated subject (subject to a legal protection measure: safeguard of justice, curatorship, guardianship, future protection mandate, family habilitation)

Sponsors & Collaborators

• University Hospital, Strasbourg, France: lead
• Bayer: collaborator
• Fédération Hospitalo-Universitaire NEUROGENYCS: collaborator
• Grünenthal GmbH: collaborator

Study Sites (5)

CHU de Besançon

Besançon, 25000, France

RECRUITING

CHU Nancy

Nancy, 54000, France

RECRUITING

Hôpital Pitié-Salpêtrière

Paris, 75013, France

RECRUITING

CHU de Rennes/Pontchaillou

Rennes, 35000, France

RECRUITING

CHRU de Strasbourg

Strasbourg, 67000, France

RECRUITING

Related Publications (1)

• Metzger-Peter K, Kremer LD, Edan G, Loureiro De Sousa P, Lamy J, Bagnard D, Mensah-Nyagan AG, Tricard T, Mathey G, Debouverie M, Berger E, Kerbrat A, Meyer N, De Seze J, Collongues N. 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. Trials. 2020 Jun 29;21(1):591. doi: 10.1186/s13063-020-04517-6.

  PMID: 32600454 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

Solutions; Injections; Quality of Life; Exercise

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations; Drug Administration Routes; Drug Therapy; Therapeutics; Health Status; Demography; Epidemiologic Measurements; Public Health; Environment and Public Health; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Laurent D KREMER, MD

  CHU Strasbourg

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Laurent D KREMER, MD

CONTACT

+333 88 12 87 33; laurentdaniel.kremer@chru-strasbourg.fr

Nicolas COLLONGUES, MD

CONTACT

+333 88 12 87 33; nicolas.collongues@chru-strasbourg.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: multicenter, randomized, parallel-group, double-blind, placebo-controlled phase 2 trial

Study Record Dates

• First Submitted: April 1, 2019
• First Posted: April 10, 2019
• Study Start: October 29, 2019
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: June 29, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

FR (5)