TOTEM RRMS : TestOsterone TreatmEnt on Neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 40
- 试验地点
- 5
- 主要终点
- Change on MRI binary criterion combining thalamic atrophy and modification in transverse diffusivity of lesions
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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, 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).
- •Biological hypogonadism defined by serum total testosterone levels below 20 nmol / L (checked by blood sampling during the screening visit)
- •For patients under natalizumab : Negative status for JC virus or JC virus synthesis index ≤ 1.5 (checked by blood sampling at the inclusion visit)
- •No relapses in the year prior to inclusion
- •Disability status during the selection visit with an EDSS score of 0 to 7 (verified by questionnaire during the inclusion visit)
- •Stable neurological state in the month preceding randomization
排除标准
- •Patients with progressive MS (primary or secondary)
- •Patients with hypogonadism with clinical symptoms and treated with androgens
- •Patients with PSA (prostate specific antigen)> 2.5 ng / ml (for an age less than 49 years old) or> 3.5 ng / ml (for age ≥ 50 years) (checked by a blood test at the inclusion visit)
- •Patients with a hemoglobin concentration> 16 g / dL (checked by blood sampling during the inclusion visit)
- •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
- •Patient in exclusion period (determined by previous study or in progress)
- •Impossibility of giving information to the patient (subject in emergency situation, difficulties in understanding the subject or other)
- •Patients under tutors or curators
- •Patients under the protection of justice
研究组 & 干预措施
Testosterone treatment (Nebido®)
"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
干预措施: Nebido® Testosterone Undecanoate 1000 Mg/4 mL Solution for Injection (Drug)
Testosterone treatment (Nebido®)
"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
干预措施: MRI (Procedure)
Testosterone treatment (Nebido®)
"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
干预措施: Assessment of impact of MS on cognition; quality of life; fatigue; anxiety/depression and work and activities (Behavioral)
Testosterone treatment (Nebido®)
"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
干预措施: Assessment of disability (Behavioral)
Placebo
"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
干预措施: Placebo 4 mL Solution for Injection (Drug)
Placebo
"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
干预措施: MRI (Procedure)
Placebo
"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
干预措施: Assessment of impact of MS on cognition; quality of life; fatigue; anxiety/depression and work and activities (Behavioral)
Placebo
"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
干预措施: Assessment of disability (Behavioral)
结局指标
主要结局
Change on MRI binary criterion combining thalamic atrophy and modification in transverse diffusivity of lesions
时间窗: At baseline, week 30 and week 66 (end of study)
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.
次要结局
- 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 cognitive performance as measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)(At baseline, week 30 and week 66 (end of study))
- Changes in quality of life as measured by the SF-36 questionnaire(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.(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 total volume of hyper-intensity FLAIR lesion as detected by conventional MRI(At baseline, week 30 and week 66 (end of study))
- 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 diffusion tensor imaging (NODDI) as detected by unconventional MRI(At baseline, week 30 and week 66 (end of study))
- Evolution of quantitative magnetization transfer imaging (MPF) as detected by unconventional MRI(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).(At baseline, week 30 and week 66 (end of study))
- Changes in fatigue, measured by the Multidimensional Fatigue Impact Scale (MFIS)(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(At baseline, week 30 and week 66 (end of study))
- Evolution of disability measured MS specific Expanded Disability Status scale (EDSS)(At baseline, week 30 and week 66 (end of study))
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability](From Visit 0/baseline to end of study visit (66 weeks))