Relapsing Remitting Multiple Sclerosis (RRMS)
Conditions
Keywords
indole-3-propionic acid, multiple sclerosis, gut bacterial metabolite, dietary supplement, gut-brain axis
Brief summary
This study, iPROACT-MS, is part of the iPROACT group of clinical trials aiming to investigate the effects of oral supplementation with indole-3-propionic acid (IPA) in humans. IPA is naturally produced as a gut bacterial metabolite with the amino acid tryptophan as substrate. The primary aim of iPROACT-MS is to investigate whether patients with relapsing-remitting multiple sclerosis (RRMS) can benefit from supplementation with IPA. The hypothesis is that supplementation with IPA will protect against MS-related disease activity, neurodegeneration and metabolic abnormalities. Secondary, iPROACT-MS aims at elucidating the complex relationships between lifestyle, gut microbial factors, inflammation, oxidative stress, metabolic health, MS disease severity and MS disease activity.
Interventions
DIETARY_SUPPLEMENTPlacebo
Two capsules are taken every morning and two capsules are taken every evening for 27 consecutive months. Placebo capsules are taken orally.
DIETARY_SUPPLEMENTIndole-3-propionic acid (IPA)
Two capsules are taken every morning and two capsules are taken every evening for 27 consecutive months. Active capsules are taken orally and contain 250 mg of IPA each resulting in a total daily dose of 1000 mg of IPA.
Sponsors
Glostrup University Hospital, Copenhagen
University of Copenhagen
University of Southampton
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Each set of capsule containers (the containers to be used by a study participant during the intervention) is labelled with a unique ID and no other identifier. A randomization key is prepared by an external party randomizing study participants to IPA or placebo using stratified block randomization with random block sizes of 4 or 6. Stratification accounts for recent evidence of disease activity (yes vs. no) defined as experience of clinical relapses within the past year or demonstration of new, contrast-enhanced or enlarged lesions on a clinical MRI scan performed within the last 12 months from randomization. A software system is used to reveal the unique container ID to be used by each randomized participant without revealing its corresponding arm. Only after all study participants have completed the trial and the collected data have been cleaned and quality checked, are the researchers performing the statistical analyses informed about which participants belong to each arm.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Women and men ≥18 and ≤65 years of age * Diagnosed with RRMS according to the 2017 McDonald criteria (or newer updates) * Routinely treated and monitored for MS * Speak and read Danish * Deemed physically and mentally able to participate in this study
Exclusion criteria
* Active malignancy * Diagnosis of Crohn's disease and ulcerative colitis * Other comorbidities deemed to be relevant * Haematopoietic stem cell transplantation * Current or past treatment with non-MS related treatments deemed to be relevant * Pregnancy or lactation * People with MR contraindications: * Severe claustrophobia * Incompatible implants/ foreign objects, including implanted pacemakers, heart valve prostheses, prostheses in the middle ear, implanted devices (e.g., insulin pump), metal debris, e.g., metal splinters in the eyes, miscellaneous shunts and catheters, metal clips from operations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| No evidence of disease activity (NEDA) | The time between month 3 and month 27 after initiation of supplementation. | The percentage of patients that maintain no evidence of disease activity (NEDA-3) in the time between month 3 and month 27 after initiation of supplementation. NEDA-3 is defined as a binary composite consisting of absence of confirmed relapses, no new or enlarged lesions on brain MRI and no confirmed disability progression. For relapses to be confirmed, they need to be accompanied by an increase of at least 0.5 points on the EDSS or 2 points in one of the EDSS functional system scores, or at least 1 point in two or more of the EDSS functional system scores. Confirmed disability progression is defined as an increase in the EDSS score compared to EDSS at month 3 which is of at least 1 point (or 0.5 points if the baseline EDSS \>5.5) and is sustained for three months (measured at month 12 and confirmed at month 15 or measured at month 24 and confirmed at month 27 or measured at a relapse evaluation prior to or at month 24 and confirmed at the next visit or the latest at month 27). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized relapse rate evaluated at month 27 | The time between month 3 and month 27 after initiation of supplementation. | Defined as the total number of confirmed relapses experienced during the intervention for each patient divided by years of exposure to the intervention and excluding the first three months for both outcome and exposure. |
| Total (cumulative) number of new or enlarged T2-weighted/FLAIR brain lesions per scheduled yearly MRI evaluated at month 27 | The time between month 3 and month 27 after initiation of supplementation. | New or enlarged brain lesions are evaluated at month 15 and compared to month 3 and at month 27 and compared to month 15; results from unscheduled MRIs between month 3 and month 27 are also considered. |
| Serum neurofilament light chain (sNfL) | Evaluated longitudinally at months 0, 3, 15 and 27. | — |
| Percentage of patients with disability improvement confirmed at 3 months | The time between month 3 and month 27 after initiation of supplementation. | Confirmed disability improvement is defined as a reduction in EDSS (expanded disability status scale) score compared to EDSS at month 3 which is of at least 1 point (or 0.5 points if the baseline EDSS \>5.5). The EDSS score ranges from 0 to 10 with 0 indicating no neurological disability and 10 indicating death from MS. Measured at month 12 and confirmed at month 15 or measured at month 24 and confirmed at month 27. |
| The time to onset of disability worsening confirmed at 3 months | The time between month 3 and month 27 after initiation of supplementation. | Confirmed disability worsening is defined as an increase in the EDSS (expanded disability status scale) score compared to EDSS at month 3 which is of at least 1 point (or 0.5 points if the baseline EDSS \>5.5). The EDSS score ranges from 0 to 10 with 0 indicating no neurological disability and 10 indicating death from MS. Measured at month 12 and confirmed at month 15 or measured at month 24 and confirmed at month 27 or measured at a relapse evaluation prior to or at month 24 and confirmed at the next visit or the latest at month 27. |
| Cumulative change in EDSS score | The time between month 3 and month 24 after initiation of supplementation. | Calculated as area under the curve (AUC) for measured values of the EDSS (expanded disability status scale) score from month 3 to month 24. The EDSS score ranges from 0 to 10 with 0 indicating no neurological disability and 10 indicating death from MS. |
| Multiple Sclerosis Functional Composite (MSFC) | The time between month 0 and month 24 after initiation of supplementation. | A composite score used to assess neurological function by combining results from the Timed 25-Foot Walk (T25FW) test, the Nine-Hole Peg Test (9HPT) and the Symbol Digit Modalities Test (SDMT) evaluated at months 0, 12 and 24. |
| Symbol Digit Modalities Test (SDMT) | The time between month 0 and month 24 after initiation of supplementation. | A measure of cognitive function and especially processing speed - evaluated at months 0, 12 and 24. |
| California Verbal Learning Test-II (CVLT-II) | The time between month 0 and month 24 after initiation of supplementation. | A measure of verbal learning and memory - evaluated at months 0, 12 and 24. |
| Brief Visuospatial Memory Test - Revised (BVMR-R) | The time between month 0 and month 24 after initiation of supplementation. | A measure of visuospatial memory - evaluated at months 0, 12 and 24. |
| Intra-eye change in peripapillary retinal nerve fiber layer (RNFL) thickness | The time between month 0 and month 24 after initiation of supplementation. | Measured using Optical Coherence Tomography (OCT) at months 0, 12 and 24. |
| Intra-eye change in ganglion cell and inner plexiform layer (GCIPL) thickness | The time between month 0 and month 24 after initiation of supplementation. | Measured using Optical Coherence Tomography (OCT) at months 0, 12 and 24. |
| Modified Fatigue Impact Scale (MFIS-21) | The time between month 0 and month 24 after initiation of supplementation. | The MFIS-21 consists of a physical subscale (ranges from 0-36), a cognitive subscale (ranges from 0-40) and a psychosocial subscale (ranges from 0-8). The total MFIS-21 scale is computed by adding the scores from the physical, the cognitive and the psychosocial subscales. It ranges from 0-84 with higher scores indicating a greater impact from fatigue. MFIS-21 is evaluated longitudinally at months 0, 3, 6, 9, 12, 15, 18, 21, 24 and 27. |
| Multiple Sclerosis Quality of Life-54 (MSQOL-54) | The time between month 0 and month 24 after initiation of supplementation. | The MSQOL-54 questionnaire is used to calculate a physical health composite score and a mental health composite score. They both range from 0-100 with higher scores indicating better health/ higher quality of life. The questionnaire is administered at months 0, 12 and 24. |
| Brain-derived neurotrophic factor (BDNF) | The time between month 0 and month 27 after initiation of supplementation. | Brain-derived neurotrophic factor measured in platelet-free plasma samples using ELISA or mesoscale. Monitored longitudinally at months 0, 3, 15 and 27. |
| C-reactive protein (CRP) | The time between month 0 and month 27 after initiation of supplementation. | CRP measured in plasma (mg/L) as a biomarker of infection and systemic inflammation. Lower-limit of quantification: 0,4 mg/L. Values below 0,4 mg/L are imputed as 0,2 mg/L. Monitored longitudinally at months 0, 3, 15 and 27. |
| Triglycerides | The time between month 0 and month 27 after initiation of supplementation. | Plasma triglycerides (mmol/l) monitored longitudinally at months 0, 3, 15 and 27. |
| Non-HDL cholesterol | The time between month 0 and month 27 after initiation of supplementation. | Non-HDL cholesterol calculated as total cholesterol minus HDL cholesterol (mmol/l). Monitored longitudinally at months 0, 3, 15 and 27. |
| C-peptide | The time between month 0 and month 27 after initiation of supplementation. | Proinsulin C-peptide (pmol/l) measured in plasma. Monitored longitudinally at months 0, 3, 15 and 27. |
| Fasting glucose | The time between month 0 and month 27 after initiation of supplementation. | Plasma glucose (mmol/l). Participants abstain from eating and drinking after 22.00 the day before. Only water is allowed. Monitored longitudinally at months 0, 3, 15 and 27. |
| 8-iso-prostaglandin F2α and other F2-isoprostanes | The time between month 0 and month 27 after initiation of supplementation. | F2-isoprostanes with a specific focus on 8-iso-prostaglandin F2α measured in morningurine or blood samples as a marker of oxidative stress-related lipid oxidation. Monitored longitudinally at months 0, 3, 15 and 27. |
| 8-oxo-dG | The time between month 0 and month 27 after initiation of supplementation. | 8-oxo-dG (8-Oxo-2'-deoxyguanosine) measured in blood or morningurine samples as a marker of oxidative stress-related DNA damage. Monitored longitudinally at months 0, 3, 15 and 27. |
| Fecal lipocalin | The time between month 0 and month 27 after initiation of supplementation. | Lipocalin measured in fecal samples as a sensitive biomarker of intestinal inflammation. Monitored longitudinally at months 0, 3, 15 and 27. |
| Microbiota profiling of fecal samples | The time between month 0 and month 27 after initiation of supplementation. | Microbiota profiling of fecal samples using molecular biology methods including but not limited to sequencing and flowcytometric analyses. Monitored longitudinally at months 0, 3, 15 and 27. |
| Serum and fecal metabolomics | The time between month 0 and month 27 after initiation of supplementation. | Targetted and untargetted liquid-chromatography mass-spectrometry-based metabolomics to measure diet-, host- and microbial-derived metabolites. Targetted analyses aim to quantify indole-3-propionic acid and its metabolites (biomarker of compliance as well as absorptive and metabolic capacity), other bacterial- and host metabolites of tryptophan as well as short-chain fatty acids. Monitored longitudinally at months 0, 3, 15 and 27. |
Countries
Denmark
Contacts
CONTACTJette Lautrup Frederiksen, MD, dr.med, professor
CONTACTMoschoula Passali, MSc, PhD
PRINCIPAL_INVESTIGATORJette Lautrup Frederiksen, MD, dr.med, professor
Copenhagen University Hospital, Rigshospitalet-Glostrup
Outcome results
None listed