Indole-3-PROpionic Acid Clinical Trials - Multiple Sclerosis

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).

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.

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.

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.

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.

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.

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.

A measure of cognitive function and especially processing speed - evaluated at months 0, 12 and 24.

A measure of verbal learning and memory - evaluated at months 0, 12 and 24.

A measure of visuospatial memory - evaluated at months 0, 12 and 24.

Measured using Optical Coherence Tomography (OCT) at months 0, 12 and 24.

Measured using Optical Coherence Tomography (OCT) at months 0, 12 and 24.

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.

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 measured in platelet-free plasma samples using ELISA or mesoscale. Monitored longitudinally at months 0, 3, 15 and 27.

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.

Plasma triglycerides (mmol/l) monitored longitudinally at months 0, 3, 15 and 27.

Non-HDL cholesterol calculated as total cholesterol minus HDL cholesterol (mmol/l). Monitored longitudinally at months 0, 3, 15 and 27.

Proinsulin C-peptide (pmol/l) measured in plasma. Monitored longitudinally at months 0, 3, 15 and 27.

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.

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 (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.

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 using molecular biology methods including but not limited to sequencing and flowcytometric analyses. Monitored longitudinally at months 0, 3, 15 and 27.

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.

Tertiary efficacy outcome related to multiple sclerosis. Progression is defined as an increase in the EDSS score compared to the 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.

Tertiary efficacy outcome related to multiple sclerosis. A measure of walking ability, including speed, co-ordination and balance - evaluated at month 0, month 12 and month 24.

Tertiary efficacy outcome related to multiple sclerosis. A measure of finger dexterity - evaluated at months 0, 12 and 24.

Tertiary efficacy outcome related to multiple sclerosis. Monitored longitudinally in serum samples at months 0, 3, 15 and 27.

Tertiary efficacy outcome related to multiple sclerosis. Monitored longitudinally in serum samples at months 0, 3, 15 and 27.

Tertiary efficacy outcome related to multiple sclerosis. Measured longitudinally in serum samples at months 0, 3, 15 and 27.

Tertiary efficacy outcome related to multiple sclerosis. WPAI results are expressed as impairment percentages where higher percentages indicate greater impairment and lower productivity. Evaluated at months 0, 12 and 24.

Exploratory outcome related to metabolic health. HbA1c (IFCC, mmol/mol) measured in whole blood. Estimated average glucose values (mmol/l) are also calculated automatically from HbA1c by our laboratory. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to metabolic health. Plasma cholesterol (mmol/l). Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to metabolic health. Plasma high-density lipoprotein (HDL) (mmol/l). Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to metabolic health. Plasma low-density lipoprotein (LDL) (mmol/l). Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to metabolic health. Plasma very low-density lipoproteins (mmol/l). Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to metabolic health. BMI calculated as weight (kg)/ height (m)^2. Monitored longitudinally at months 0, 12, and 24. Height is only measured at baseline with longitudinal changes in BMI reflecting changes in weight.

Exploratory outcome related to metabolic health. The distance (cm) from the lower back to the highest point of the abdomen while in a supine position as a measure of visceral obesity. Monitored longitudinally at months 0, 12 and 24.

Exploratory outcome related to metabolic health. Calculated as an average of two measurements and expressed in cm. Monitored longitudinally at months 0, 12 and 24.

Exploratory outcome related to metabolic health. Calculated as an average of two measurements and expressed in cm. Monitored longitudinally at months 0, 12 and 24.

Exploratory outcome related to metabolic health. Monitored longitudinally at months 0, 12 and 24.

Exploratory outcome related to metabolic health. Blood pressure (mm Hg) defined as the lowest value obtained across three measurements. Monitored longitudinally at months 0, 12 and 24.

Exploratory outcome related to metabolic health. Resting heart rate defined as the lowest value obtained across three measurements while sitting in a relaxed position. Monitored longitudinally at month 0, 12 and 24.

Exploratory outcome related to systemic inflammation. Monitored longitudinally in platelet-free plasma at months 0, 3, 15 and 27.

Exploratory outcome related to systemic inflammation. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to systemic inflammation. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to systemic inflammation. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to systemic inflammation. Soluble urokinase plasminogen activator receptor (suPAR) monitored longitudinally in blood samples at months 0, 3, 15 and 27.

Exploratory outcome related to systemic inflammation. Monitored longitudinally in blood samples at months 0, 3, 15 and 27.

Exploratory outcome related to systemic inflammation. Gene expression analyses monitored longitudinally in buffycoat samples collected at months 0, 3, 15 and 27.

Exploratory outcome related to oxidative stress. Protein carbonyls measured in blood or morningurine samples as a marker of protein oxidation. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to oxidative stress. Malondialdehyde monitored longitudinally in blood or morningurine samples at months 0, 3, 15 and 27.

Exploratory outcome monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Self-reported (questionnaire) gastrointestinal symptoms of bloating, pain, rumbling, flatulence, constipation, hard stools and diarrhea evaluated using a visual analogue scale as well as a question on the frequency of defecation. Monitored longitudinally at months 0, 12 and 24.

Exploratory outcome related to gastrointestinal function. Classification of stool consistency using the Bristol Stool Chart. Numerical scale ranging from 1 (separate hard lumps) to 7 (liquid consistency with no solid pieces) with one-unit increments. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Measurement of transit time through the digestive system using a so-called maize test. Participants consume 100 grams of sweet maize in the morning between 5.30-10.00 while still in a fasting state. The exact date and time of consumption is registered and so is the exact date and time when maize is observed for the first time in feces. Transit time is expressed as the difference between the ingestion and fecal excretion timepoints in hours. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Evaluation of endogenous antibody-coating of fecal microbes (bacteria, viruses etc) as well as the ability of fecal microbes to be bound by disease-related and other antibodies. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Lipopolysaccharide (LPS, endotoxin) and LPS-binding protein, capsular polysaccharides or other bacterial polysaccharides measured in blood samples as a biomarker of bacterial translocation across the intestinal epithelium. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Measurements of intestinal fatty acid binding protein in blood samples as a biomarker of enterocyte damage. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Measurement of pre-haptoglobin 2 in blood samples as a biomarker of intestinal permeability. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Measurement of citrulline in blood samples as a biomarker of intestinal function. Monitored longitudinally at months 0, 3, 15 and 27.

Exploratory outcome related to gastrointestinal function. Calprotectin measured in fecal samples as a biomarker of intestinal inflammation. Monitored longitudinally at months 0, 3, 15 and 27.

A safety outcome. Study participants are asked whether they have experienced any positive or negative effects and whether they believe they have been given IPA or placebo. Evaluated at months 3, 12, 15, 24 and 27.

A safety outcome. Interviews with the aim of uncovering any side effects or adverse events. Results are registered using the REDCap instrument "CDISC|CDASHIG v2.1|Adverse Events". Evaluated at months 3, 12, 15, 24 and 27.

A safety outcome. Total leucocytes, basophils, eosinophils, lymphocytes, monocytes, neutrophils as well as the joint group of metamyelo-, myelo- and promyelocytes. All counted in whole blood samples (x10^9/l). Monitored at months 0, 3, 15 and 27.

A safety outcome. Thrombocytes measured in whole blood (x 10^9/L). Monitored at months 0, 3, 15 and 27.

A safety outcome. Hemoglobin measured in whole blood (mmol/l). Monitored at months 0, 3, 15 and 27.

A safety outcome. Plasma alanine transaminase (ALT, U/l) measured as a biomarker of liver function. Monitored at months 0, 3, 15 and 27.

A safety outcome. Plasma aspartate aminotransferase (U/l) also known as aspartate transaminase measured as a biomarker of liver and muscle damage. Monitored at months 0, 3, 15 and 27.

A safety outcome. Lactate dehydrogenase measured in plasma (U/l). Monitored at months 0, 3, 15 and 27.

A safety outcome. Bilirubins measured in plasma (µmol/L) as a biomarker of liver function. Monitored at months 0, 3, 15 and 27.

A safety outcome. Alkaline phosphatase (U/l) as a biomarker of liver function. Monitored at months 0, 3, 15 and 27.

A safety outcome. Thyroid-stimulating hormone measured in plasma (mU/L) as a biomarker of thyroid function. Monitored at months 0, 3, 15 and 27.

A safety outcome. Monitored in blood samples as a biomarker of thyroid function at months 0, 3, 15 and 27.

A safety outcome. Monitored in blood samples as a biomarker of thyroid function at months 0, 3, 15 and 27.

A safety outcome. Albumin measured in plasma (g/L). Monitored at months 0, 3, 15 and 27.

A safety outcome. Coagulation factors II, VII and X (INR) measured in citrate plasma as a biomarker of coagulation. Monitored at months 0, 3, 15 and 27.

A safety outcome. Plasma creatinine (µmol/L) as a biomarker of kidney function. Monitored at months 0, 3, 15 and 27.

A safety outcome. Estimated glomerular filtration rate (eGFR/ 1,73m² (ml/min)) as a biomarker of kidney function. Monitored at months 0, 3, 15 and 27.

A measure of compliance. Evaluated longitudinally at months 3, 12, 15, 24 and 27.

Information on potential confounders or effect modifiers. The questionnaire is administered at months 0, 12 and 24.

Information on potential confounders or effect modifiers. A food frequency questionnaire (FFQ) regarding dietary habits and food consumption during the past year is administered at months 0, 12 and 24.

Information on potential confounders or effect modifiers. Measurement of fatty acids, vitamins, minerals, amino acids and food-derived DNA in blood, urine and fecal samples. Monitored at months 0, 3, 15 and 27.

Information on potential confounders or effect modifiers. The Major Depression Inventory (MDI) score ranges from 0 to 50 with higher scores suggesting higher degrees of depression. Evaluated at months 0, 12 and 24.

Information on potential confounders or effect modifiers. The global Pittsburgh Sleep Quality Index (PSQI) score is calculated. It ranges from 0 to 21 with higher scores indicating worse sleep quality. Evaluated at months 0, 12 and 24.