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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
220
Two capsules are taken every morning and two capsules are taken every evening for 27 consecutive months. Placebo capsules are taken orally.
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.
Glostrup Hospital
Glostrup Municipality, Denmark
RECRUITINGNo evidence of disease activity (NEDA)
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).
Time frame: The time between month 3 and month 27 after initiation of supplementation.
Annualized relapse rate evaluated at month 27
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.
Time frame: The time between month 3 and month 27 after initiation of supplementation.
Total (cumulative) number of new or enlarged T2-weighted/FLAIR brain lesions per scheduled yearly MRI evaluated at month 27
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.
Time frame: The time between month 3 and month 27 after initiation of supplementation.
Serum neurofilament light chain (sNfL)
Time frame: Evaluated longitudinally at months 0, 3, 15 and 27.
Percentage of patients with disability improvement confirmed at 3 months
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.
Time frame: The time between month 3 and month 27 after initiation of supplementation.
The time to onset of disability worsening confirmed at 3 months
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.
Time frame: The time between month 3 and month 27 after initiation of supplementation.
Cumulative change in EDSS score
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.
Time frame: The time between month 3 and month 24 after initiation of supplementation.
Multiple Sclerosis Functional Composite (MSFC)
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.
Time frame: The time between month 0 and month 24 after initiation of supplementation.
Symbol Digit Modalities Test (SDMT)
A measure of cognitive function and especially processing speed - evaluated at months 0, 12 and 24.
Time frame: The time between month 0 and month 24 after initiation of supplementation.
California Verbal Learning Test-II (CVLT-II)
A measure of verbal learning and memory - evaluated at months 0, 12 and 24.
Time frame: The time between month 0 and month 24 after initiation of supplementation.
Brief Visuospatial Memory Test - Revised (BVMR-R)
A measure of visuospatial memory - evaluated at months 0, 12 and 24.
Time frame: The time between month 0 and month 24 after initiation of supplementation.
Intra-eye change in peripapillary retinal nerve fiber layer (RNFL) thickness
Measured using Optical Coherence Tomography (OCT) at months 0, 12 and 24.
Time frame: The time between month 0 and month 24 after initiation of supplementation.
Intra-eye change in ganglion cell and inner plexiform layer (GCIPL) thickness
Measured using Optical Coherence Tomography (OCT) at months 0, 12 and 24.
Time frame: The time between month 0 and month 24 after initiation of supplementation.
Modified Fatigue Impact Scale (MFIS-21)
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.
Time frame: The time between month 0 and month 24 after initiation of supplementation.
Multiple Sclerosis Quality of Life-54 (MSQOL-54)
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.
Time frame: The time between month 0 and month 24 after initiation of supplementation.
Brain-derived neurotrophic factor (BDNF)
Brain-derived neurotrophic factor measured in platelet-free plasma samples using ELISA or mesoscale. Monitored longitudinally at months 0, 3, 15 and 27.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
C-reactive protein (CRP)
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.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
Triglycerides
Plasma triglycerides (mmol/l) monitored longitudinally at months 0, 3, 15 and 27.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
Non-HDL cholesterol
Non-HDL cholesterol calculated as total cholesterol minus HDL cholesterol (mmol/l). Monitored longitudinally at months 0, 3, 15 and 27.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
C-peptide
Proinsulin C-peptide (pmol/l) measured in plasma. Monitored longitudinally at months 0, 3, 15 and 27.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
Fasting glucose
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.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
8-iso-prostaglandin F2α and other F2-isoprostanes
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.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
8-oxo-dG
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.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
Fecal lipocalin
Lipocalin measured in fecal samples as a sensitive biomarker of intestinal inflammation. Monitored longitudinally at months 0, 3, 15 and 27.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
Microbiota profiling of fecal samples
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.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
Serum and fecal metabolomics
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.
Time frame: The time between month 0 and month 27 after initiation of supplementation.
Jette Lautrup Frederiksen, MD, dr.med, professor
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