Multiple Sclerosis, Relapsing-Remitting
Conditions
Brief summary
The goal of this randomized, double-blind, placebo-controlled multicenter study is to investigate whether the combination of food supplementation with Tonalin® and specific probiotics is a safe and effective add-on to first-line disease modifying treatment (DMT, interferon-beta derivatives as well as glatirameracetate and other glatirameroids) in relapsing remitting MS (RRMS). 100 patients will be randomly assigned in a 1:1 ratio to receive either both food supplements for 48 weeks or to receive placebo in addition to their established first-line disease modifying treatment (DMT). The two randomized groups will be compared concerning the change in volume of T2-weighted hyperintense lesions from baseline to 48 weeks.
Interventions
DIETARY_SUPPLEMENTVivomixx®
Daily application of four sachets, i.e. 1.800 bio bacteria/day for 48 weeks
DIETARY_SUPPLEMENTConjugated linoleic acid (CLA/Tonalin® FFA 80)
Daily application of two capsules p.o., i.e. 2g/day for 48 weeks
OTHERMaltose placebo
Daily application of four sachets for 48 weeks
OTHERSunflower oil placebo
Daily application of two capsules p.o for 48 weeks
Sponsors
Universität Münster
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Patients will be randomized after successful screening and inclusion. They will be randomized with a 1:1 ratio to receive either conjugated linoleic acid (CLA/Tonalin®) and probiotics (Vivomixx®) or the corresponding placebos as add-on therapy. Randomization will be stratified according to first-line therapy with Interferon-beta, Glatirameracetat / other glatirameroids, or Teriflunomid.
Intervention model description
two-arm, randomized, double-blind, placebo-controlled, multicenter
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Relapsing-remitting multiple sclerosis according to current McDonald Criteria, EDSS maximal 5.5, 18-60 years * stable treatment with first-line DMT (IFNbeta, teriflunomide or glatiramer acetate/ other glatirameroids) for at least 6 months * absence of a clinical relapse for at least 3 months before inclusion * Written informed consent
Exclusion criteria
* diagnosis of primary or secondary progressive MS or other active autoimmune disease * intake/administration of the following disease modifying therapies: 1. at any time point: alemtuzumab, cladribine 2. during the last 6 months before inclusion: natalizumab, fingolimod, dimethyl fumarate, siponimod 3. during the last 12 months before inclusion: mitoxantron, ocrelizumab, ofatumumab, rituximab * ingestion of other dietary supplementation (e.g. vitamins, probiotics, iron, calcium, prebiotics, such as omega-3-fatty acids) * significant gastroenterological abnormality (e.g. inflammatory bowel disease, short bowel disease, preexisting digestive lesions) * accompanying systemic immunosuppressive treatment * relevant dietary restriction (e.g. strictly vegan nutrition) * women during pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of volume of 'hyperintense lesions in the T2-weighted MRI images' between baseline and after 48 weeks of therapy | 48 weeks | The two randomised study groups (intervention and placebo groups) are compared with regard to the change of volume of new or enlarged 'hyperintense lesions in the T2-weighted MRI images' (hereafter T2 lesions) between the start of the study and after 48 weeks. T2 lesions were chosen as primary endpoint as this has been used as a surrogate marker of efficacy in several recent MS studies |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of new or enlarging T2-weighted hyperintense lesions | 48 weeks | Number of new or enlarging T2-weighted hyperintense lesions based on the comparison of brain MRI-scans after 48 weeks of intervention as compared to baseline |
| Change in T2 lesions at 48 weeks compared to baseline | 48 weeks | Change in T2 lesions at 48 weeks compared to baseline (yes/no) |
| Volume of new or enlarged 'hyperintense lesions in the T2-weighted MRI images' as well as double inversion recovery (DIR) images | 48 weeks | Volume of new or enlarged 'hyperintense lesions in the T2-weighted MRI images' as well as double inversion recovery (DIR) images will be compared between the intervention arm and the placebo arm. This approach has been recently published and rises the probability to detect new brain lesions in MS without application of gadolinium with a sensitivity of 98.1% |
| Annualized relapse rate | 48 weeks | All relapses confirmed by a physician will be documented and analysed. Clinical relapses are defined as onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by objective abnormalities on a neurological examination, which are not explained solely by non-MS processes such as fever, infection, severe stress or drug toxicity. Annualized relapse rates are compared between the two study groups. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assessment of patient-reported outcomes (PRO) and quality of life via BDI-II (Beck's Depression Inventory) | 48 weeks | Assessment of patient-reported outcomes (PRO) and quality of life by use of the following validated and commonly used questionnaires: BDI-II (Beck's Depression Inventory) to assess concomitant psychiatric symptoms Patients will be asked to fill in this questionnaires at baseline, after 24 weeks of therapy and after 48 weeks of therapy. These additional outcomes are clinically relevant as the EDSS preferentially focuses on motor function with predominance of the lower limb. |
| Assessment of patient-reported outcomes (PRO) and quality of life via TSQM-9 (Treatment Satisfaction Questionnaire for Medication) | 48 weeks | Assessment of patient-reported outcomes (PRO) and quality of life by use of the following validated and commonly used questionnaires: TSQM-9 (Treatment Satisfaction Questionnaire for Medication) to assess treatment satisfaction Patients will be asked to fill in this questionnaires at baseline, after 24 weeks of therapy and after 48 weeks of therapy. These additional outcomes are clinically relevant as the EDSS preferentially focuses on motor function with predominance of the lower limb. |
| Changes in key peripheral blood immune signatures | 48 weeks | Highly standardized flow-cytometry of PBMC will be performed in order to determine treatment-related changes in peripheral immune signatures. |
| Focus on signs of gastrointestinal and systemic side effects | 48 weeks | The rate and nature of adverse events, changes in vital signs and physical examinations, and abnormal laboratory results will be documented and analysed. |
| Disease progression throughout the study | 48 weeks | Disease progression throughout the study will be documented by assessment of the Expanded Disability Status Scale (EDSS) at baseline and at 48 weeks of the study as well as in case of unscheduled visits such as in case of a relapse. EDSS is a standardized measure of MS-related disability and a key endpoint in many clinical trials in MS. |
| Correlation of identified immunological effects with main endpoints of MRI and clinical efficacy | 48 weeks | The correlation of identified immunological effects with main endpoints of MRI (including rate of global brain and grey matter atrophy derived from structural MRI) and clinical efficacy will be analysed using multivariable regression methods or machine learning approaches. |
| Changes in diffuse white matter damage (measured by fractional anisotropy FA) | 48 weeks | Changes in diffuse white matter damage (measured by fractional anisotropy FA) |
| Global brain atrophy, grey matter atrophy and white matter atrophy | 48 weeks | Rate of global brain and grey matter atrophy derived from structural MRI. |
| Functional characterization of human myeloid cells | 48 weeks | A comprehensive and detailed characterization of all major immune cell populations of the peripheral blood will be done. In addition a characterization of their maturity status, their activation state, as well as certain functional properties including cytokine production as well as production of cytolytic molecules will be assessed. The aim of the immunological analysis of peripheral blood immune signatures is to investigate whether a change in the composition and activation state of the immune cells in the peripheral blood can be observed as a consequence of the combined intervention with Tonalin® and Vivomixx® as compared to the placebo group. A particular focus will be on the reduction in proinflammatory properties of different myeloid cell populations, based on our preliminary work. The different immune cell populations will be analyzed both as percentages and as absolute cell numbers. |
| Assessment of patient-reported outcomes (PRO) and quality of life via MSIS-29 (Multiple Sclerosis Impact Scale) | 48 weeks | Assessment of patient-reported outcomes (PRO) and quality of life by use of the following validated and commonly used questionnaires: MSIS-29 (Multiple Sclerosis Impact Scale) to assess quality of life Patients will be asked to fill in this questionnaires at baseline, after 24 weeks of therapy and after 48 weeks of therapy. These additional outcomes are clinically relevant as the EDSS preferentially focuses on motor function with predominance of the lower limb. |
| Assessment of patient-reported outcomes (PRO) and quality of life via FSMC (Fatigue Scale for Motion and Cognition) | 48 weeks | Assessment of patient-reported outcomes (PRO) and quality of life by use of the following validated and commonly used questionnaires: FSMC (Fatigue Scale for Motion and Cognition) to assess MS-related fatigue Patients will be asked to fill in this questionnaires at baseline, after 24 weeks of therapy and after 48 weeks of therapy. These additional outcomes are clinically relevant as the EDSS preferentially focuses on motor function with predominance of the lower limb. |
| Assessment of patient-reported outcomes (PRO) and quality of life via SDMT (Symbol-Digit Modalities Test) | 48 weeks | Assessment of patient-reported outcomes (PRO) and quality of life by use of the following validated and commonly used questionnaires: SDMT (Symbol-Digit Modalities Test) to assess MS-related cognition Patients will be asked to fill in this questionnaires at baseline, after 24 weeks of therapy and after 48 weeks of therapy. These additional outcomes are clinically relevant as the EDSS preferentially focuses on motor function with predominance of the lower limb. |
| Assessment of patient-reported outcomes (PRO) and quality of life via HADS (Hospital Anxiety and Depression Scale) | 48 weeks | Assessment of patient-reported outcomes (PRO) and quality of life by use of the following validated and commonly used questionnaires: HADS (Hospital Anxiety and Depression Scale) to assess concomitant psychiatric symptoms Patients will be asked to fill in this questionnaires at baseline, after 24 weeks of therapy and after 48 weeks of therapy. These additional outcomes are clinically relevant as the EDSS preferentially focuses on motor function with predominance of the lower limb. |
Countries
Germany
Contacts
Primary ContactLuisa Klotz, Prof.
Backup ContactJan Lünemann, Prof.
Outcome results
None listed