A Trial of Bile Acid Supplementation in Patients With Multiple Sclerosis

• Tauroursodeoxycholic Acid (Drug), also known as Taurolite: Participants will be given 1 gram of Tauroursodeoxycholic acid twice daily in the form of four 250mg capsules.
• Placebo oral capsule (Drug): Participants will be given four capsules of the placebo twice daily.

Primary outcomes

• Number of Participants With at Least One Treatment-related Adverse Event [16 weeks]: Safety and tolerability will be assessed based on treatment-related adverse events in the two arms.
• Number of Total Treatment-related Adverse Events [16 weeks]: Safety and tolerability will be assessed based on treatment-related adverse events in the two arms.
• Incidence of Treatment-related Adverse Events (AE) [16 weeks]: Safety and tolerability will be assessed based on treatment-related adverse events in the two arms. AE incidence will be measured as total number of events per 1000 exposure years.

Secondary outcomes

• Change in Fasting Bile Acid Levels in Plasma [Baseline to 16 weeks]: The change of targeted bile acid levels over the course of 16 weeks (duration of the study) is reported. Bile acid levels (ng/mL) were log transformed before analysis to approximate normal distribution. Units are log(levels) per 16 weeks. Values are derived from linear mixed-effects models.
• Change in Microbiome Alpha-diversity Measured by Shannon Index at the End of the Study [Baseline to 16 weeks]: Change in Shannon index of the gut microbiota between baseline and end of study (16 weeks). Shot-gun metagenomic sequencing in first morning stool specimen was utilized to derive the microbiome composition. Higher values of the index indicate more diversity in the microbial community. The minimum value the Shannon index can take is 0 (no diversity). There is no upper limit to the index.
• Change in Flow Cytometric Assessments of Peripheral Blood Mononuclear Cells (PBMCs) [Baseline to 16 weeks]: Change in flow cytometric assessments over the course of 16 weeks (duration of the study). Cells are expressed as ratios of their parent types. Units reported as change in the ratio per 16 weeks. Values are derived from linear mixed-effects models.
• Change in Quality of Life Based on Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument [Baseline to 16 weeks]: Change in physical and mental health scores as assessed using the Multiple Sclerosis Quality of Life-54 (MSQOL-54) instrument over the course of 16 weeks (duration of the study). This 54-item instrument generates 12 subscales along with two summary scores, and two additional single-item measures. Two summary scores - physical health and mental health - are derived from a weighted combination of scale scores. Higher scores suggest a better quality of life. Scores can range from 0 to 100.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Diagnosis of Progressive MS based on Lublin Criteria
* Low bile acid levels identified using targeted metabolomics analysis
* On the same therapy for the past 6 months and not expected to switch therapy in the next 6 months
* No relapse in the past 3 months

Exclusion Criteria:

* No previous history of liver disease or cholecystectomy
* No stage IV/V chronic kidney disease or other severe metabolic derangements (e.g. poorly controlled thyroid disease or diabetes)
* BMI < 15 kg/m2 and BMI > 40 kg/m2
* Female patients who are pregnant or nursing, or not willing to use contraception
* Chronic antibiotic use
* Corticosteroid treatment within the past 30 days
* Known history of other neuroinflammatory, neurodegenerative or systemic autoimmune disease

Participant flow

Outcome results

• Number of Participants With at Least One Treatment-related Adverse Event (Primary), Count of participants, Participants: TUDCA Treatment 10; Placebo Oral Capsule 7
• Change in Fasting Bile Acid Levels in Plasma (Secondary), Mean, log(levels[ng/mL]) per 16 weeks: TUDCA Treatment 0.44 (-0.14 to 1.02); Placebo Oral Capsule 0.48 (-0.13 to 1.09)
• Change in Microbiome Alpha-diversity Measured by Shannon Index at the End of the Study (Secondary), Mean, score on a scale: TUDCA Treatment -0.15 (-0.47 to 0.18); Placebo Oral Capsule 0.06 (-0.3 to 0.41)
• Change in Flow Cytometric Assessments of Peripheral Blood Mononuclear Cells (PBMCs) (Secondary), Mean, parent cell ratio per 16 weeks: TUDCA Treatment -1.34 (-4.63 to 1.96); Placebo Oral Capsule 3.05 (-1.88 to 7.98)
• Change in Quality of Life Based on Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument (Secondary), Mean, score on a scale: TUDCA Treatment -0.15 (-4.37 to 4.07); Placebo Oral Capsule 0.01 (-4.7 to 4.71)
• Number of Total Treatment-related Adverse Events (Primary), Number, total treatment-related adverse events: TUDCA Treatment 11; Placebo Oral Capsule 8
• Incidence of Treatment-related Adverse Events (AE) (Primary), Number, total events per 1000 exposure years: TUDCA Treatment 1218; Placebo Oral Capsule 1061

Adverse events

Time frame: 16 weeks

Serious adverse events by term

Other adverse events by term

• Results publication: Ladakis DC, Harrison KL, Smith MD, Solem K, Gadani S, Jank L, Hwang S, Farhadi F, Dewey BE, Fitzgerald KC, Sotirchos ES, Saidha S, Calabresi PA, Bhargava P. Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease. Med. 2025 Mar 14;6(3):100522. doi: 10.1016/j.medj.2024.09.011. Epub 2024 Oct 23. PMID 39447576

• Study Protocol and Statistical Analysis Plan (PDF, 2021-01-11)

• Pavan Bhargava, MBBS, MD, Principal investigator, Johns Hopkins University