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| Name | Class |
|---|---|
| Bayer | INDUSTRY |
| Fédération Hospitalo-Universitaire NEUROGENYCS | UNKNOWN |
| Grünenthal GmbH | INDUSTRY |
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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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
|
| 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Evolution of the number of T1 hypointense lesions as detected by conventional MRI | Efficacy will be assessed by comparing results between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Evolution of the volume of T1 hypointense lesions as detected by conventional MRIconventional MRI |
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Inclusion Criteria:
Exclusion Criteria:
male
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| 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 |
| Name | Affiliation | Role |
|---|---|---|
| Laurent D KREMER, MD | CHU Strasbourg | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU de Besançon | Recruiting | Besançon | 25000 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32600454 | Derived | 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. |
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multicenter, randomized, parallel-group, double-blind, placebo-controlled phase 2 trial
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| 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) |
|
| MRI | Procedure | Conventional MS sequences (OFSEP recommendations) and unconventional MRI sequences (Baseline, week 30 and 66) |
|
| 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) |
|
| Assessment of disability | Behavioral | EDSS (Baseline, week 30 and 66) |
|
Efficacy will be assessed by comparing results between the 2 groups and in each group between baseline, week 30 and week 66. |
| 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 | Efficacy will be assessed by comparing results between the 2 groups and in each group between baseline, week 30 and week 66. | 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 | Efficacy will be assessed by comparing results between the 2 groups and in each group between baseline, week 30 and week 66. | 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 | Efficacy will be assessed by comparing results between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Evolution of diffusion tensor imaging (NODDI) as detected by unconventional MRI | Efficacy will be assessed by comparing results between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Evolution of quantitative magnetization transfer imaging (MPF) as detected by unconventional MRI | Efficacy will be assessed by comparing results between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Evolution of cognitive performance as measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) | BICAMS is a composite cognitive assessment tool comprising of the three components: Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II) and Brief visuospatial memory test- Revised (BVMT-R). Efficacy will be assessed by comparing the composite score between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Changes in quality of life as measured by the SF-36 questionnaire | SF-36 questionnaire is a 36-item Short Form survey designed to examine the perceived health status measured in eight health concepts. Answers to each question are scored and summed to produce raw scale scores for each health concept. Efficacy will be assessed by comparing scores between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Changes in quality of life related to health as measured by the EQ-5D-3L (European Quality of Life in 3 Dimensions) questionnaire. | EQ-5D-3L is a standardized instrument used as a measure of health outcome. It is a health questionnaire that consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. Efficacy will be assessed by comparing the composite scores between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Changes in work productivity and daily activities due to MS, as assessed by the WPAI:MS questionnaire (Work Productivity and Activity Impairment in MS). | WPAI questionnaire measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (work time missed) 2. Presenteeism (impairment at work / reduced on-the-job effectiveness) 3. Work productivity loss (overall work impairment / absenteeism plus presenteeism) 4. Activity Impairment. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. Efficacy will be assessed by comparing score between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Changes in fatigue, measured by the Multidimensional Fatigue Impact Scale (MFIS) | MFIS is a 21-item questionnaire that assesses overall self-reported fatigue. Subjects rate agreement with a series of statements on a scale of 0 (rarely) to 4 (almost always), in context of their fatigue over the preceding four weeks. Total possible score of 84. Individuals with an MFIS score of > 38 are considered to experience moderate to severe "fatigue". Efficacy will be assessed by comparing score between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Changes in anxiety and depression as measured by the Hospital assessment for Anxiety and Depression Scale (HADS) questionnaire | HADS is a 14-item self-rating scale that assesses anxiety and depression. Each question is scored on a scale ranging from 0 to 3. Responses are summed to provide separate scores for anxiety and depression that range from 0 to 21. For each corresponding subscale, a total score of 0-7 equals normal, 8-10 equals borderline case, and 11-21 equals case. Efficacy will be assessed by comparing score between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Evolution of disability measured MS specific Expanded Disability Status scale (EDSS) | EDSS measures disability status on a scale ranging from 0 to 10, in eight functional system scale: motor, sensory, cerebellar, brain stem, visual, mental, sphincter and other systems. The EDSS is formed on the score in each functional system; higher scores indicating more disability (0 = normal examination and 10= death from MS). Efficacy will be assessed by comparing score between the 2 groups and in each group between baseline, week 30 and week 66. | At baseline, week 30 and week 66 (end of study) |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Safety of treatment will be followed by the number and type of adverse or severe adverse events (AE/SAE) throughout the protocol (from baseline to week 66) | From Visit 0/baseline to end of study visit (66 weeks) |
| CHU Nancy | Recruiting | Nancy | 54000 | France |
|
| Hôpital Pitié-Salpêtrière | Recruiting | Paris | 75013 | France |
|
| CHU de Rennes/Pontchaillou | Recruiting | Rennes | 35000 | France |
|
| CHRU de Strasbourg | Recruiting | Strasbourg | 67000 | France |
|
| ID | Term |
|---|---|
| D020529 | Multiple Sclerosis, Relapsing-Remitting |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D012996 | Solutions |
| D007267 | Injections |
| D011788 | Quality of Life |
| D015444 | Exercise |
| ID | Term |
|---|---|
| D004364 | Pharmaceutical Preparations |
| D004333 | Drug Administration Routes |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
| D006304 | Health Status |
| D003710 | Demography |
| D015991 | Epidemiologic Measurements |
| D011634 | Public Health |
| D004778 | Environment and Public Health |
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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