Progressive Multiple Sclerosis
Conditions
Brief summary
This study aims to identify the safety and tolerability of bile acid supplementation in patients with progressive Multiple Sclerosis (MS). Participants will also be assessed for an impact of the bile acid on their immune system and gut microbiome. Half of the participants will receive the bile acid tauroursodeoxycholic acid (TUDCA) and half will receive placebo. The investigators believe participants who take TUDCA will have normalization of blood bile acid levels, a normalization of abnormal immune response and a normalization of the gut microbiome.
Interventions
Participants will be given 1 gram of Tauroursodeoxycholic acid twice daily in the form of four 250mg capsules.
DRUGPlacebo oral capsule
Participants will be given four capsules of the placebo twice daily.
Sponsors
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
Out of the 59 people that got enrolled, four (4) were lost to follow-up and did not come for a baseline visit, while one (1) was not eligible based on the screening visit assessments, ending up with 54 people.
Participants by arm
| Arm | Count |
|---|---|
| TUDCA Treatment Tauroursodeoxycholic acid (Taurolite) 250 mg four capsules by mouth, twice daily for 16 weeks.
Tauroursodeoxycholic Acid: Participants will be given 1 gram of Tauroursodeoxycholic acid twice daily in the form of four 250mg capsules. | 28 |
| Placebo Oral Capsule Placebo oral capsule four capsules by mouth, twice daily for 16 weeks.
Placebo oral capsule: Participants will be given four capsules of the placebo twice daily. | 26 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 6 |
Baseline characteristics
| Characteristic | Placebo Oral Capsule | Total | TUDCA Treatment |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 10 | 57 years STANDARD_DEVIATION 10 | 56 years STANDARD_DEVIATION 11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 54 Participants | 28 Participants |
| Sex: Female, Male Female | 16 Participants | 30 Participants | 14 Participants |
| Sex: Female, Male Male | 10 Participants | 24 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 21 |
| other Total, other adverse events | 9 / 26 | 7 / 21 |
| serious Total, serious adverse events | 1 / 26 | 0 / 21 |
Outcome results
Primary
Incidence of Treatment-related Adverse Events (AE)
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.
Time frame: 16 weeks
Population: All participants who received at least one dose of the intervention and came back for a follow-up visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TUDCA Treatment | Incidence of Treatment-related Adverse Events (AE) | 1218 total events per 1000 exposure years |
| Placebo Oral Capsule | Incidence of Treatment-related Adverse Events (AE) | 1061 total events per 1000 exposure years |
Primary
Number of Participants With at Least One Treatment-related Adverse Event
Safety and tolerability will be assessed based on treatment-related adverse events in the two arms.
Time frame: 16 weeks
Population: All participants who received at least one dose of the intervention and came back for a follow-up visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TUDCA Treatment | Number of Participants With at Least One Treatment-related Adverse Event | 10 Participants |
| Placebo Oral Capsule | Number of Participants With at Least One Treatment-related Adverse Event | 7 Participants |
Primary
Number of Total Treatment-related Adverse Events
Safety and tolerability will be assessed based on treatment-related adverse events in the two arms.
Time frame: 16 weeks
Population: All participants who received at least one dose of the intervention and came back for a follow-up visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TUDCA Treatment | Number of Total Treatment-related Adverse Events | 11 total treatment-related adverse events |
| Placebo Oral Capsule | Number of Total Treatment-related Adverse Events | 8 total treatment-related adverse events |
Secondary
Change in Fasting Bile Acid Levels in Plasma
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.
Time frame: Baseline to 16 weeks
Population: All participants who received at least one dose of the intervention and had at least two measurements of bile acid levels in plasma.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Glycocholic Acid | -0.02 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Lithocholic Acid | 0.75 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Cholic Acid | -0.4 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Taurochenodeoxycholic Acid | 0.05 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Glycodeoxycholic Acid | 0.1 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Taurocholic Acid | -0.23 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Glycochenodeoxycholic Acid | 0.3 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Taurodeoxycholic Acid | -0.31 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Glycolithocholic Acid | 0.9 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Taurolithocholic Acid | 0.15 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Deoxycholic Acid | 0.14 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Tauroursodeoxycholic Acid | 2.52 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Glycoursodeoxycholic Acid | 2.3 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Ursodeoxycholic Acid | 1.89 log(levels[ng/mL]) per 16 weeks |
| TUDCA Treatment | Change in Fasting Bile Acid Levels in Plasma | Chenodeoxycholic Acid | 0.44 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Ursodeoxycholic Acid | 0.37 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Chenodeoxycholic Acid | 0.48 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Cholic Acid | 0.58 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Deoxycholic Acid | 0.46 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Glycochenodeoxycholic Acid | -0.09 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Glycocholic Acid | -0.32 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Glycodeoxycholic Acid | 0.14 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Glycolithocholic Acid | 0.35 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Glycoursodeoxycholic Acid | 0.14 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Lithocholic Acid | 0.2 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Taurochenodeoxycholic Acid | -0.04 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Taurocholic Acid | -0.26 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Taurodeoxycholic Acid | 0.1 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Taurolithocholic Acid | 0.14 log(levels[ng/mL]) per 16 weeks |
| Placebo Oral Capsule | Change in Fasting Bile Acid Levels in Plasma | Tauroursodeoxycholic Acid | -0.22 log(levels[ng/mL]) per 16 weeks |
Secondary
Change in Flow Cytometric Assessments of Peripheral Blood Mononuclear Cells (PBMCs)
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.
Time frame: Baseline to 16 weeks
Population: All participants who received at least one dose of the intervention and had at least two blood draws that resulted in PBMC isolation were included in the analysis
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| TUDCA Treatment | Change in Flow Cytometric Assessments of Peripheral Blood Mononuclear Cells (PBMCs) | T helper memory cells | -1.34 parent cell ratio per 16 weeks |
| TUDCA Treatment | Change in Flow Cytometric Assessments of Peripheral Blood Mononuclear Cells (PBMCs) | Cytotoxic T memory cells | -1.9 parent cell ratio per 16 weeks |
| Placebo Oral Capsule | Change in Flow Cytometric Assessments of Peripheral Blood Mononuclear Cells (PBMCs) | T helper memory cells | 3.05 parent cell ratio per 16 weeks |
| Placebo Oral Capsule | Change in Flow Cytometric Assessments of Peripheral Blood Mononuclear Cells (PBMCs) | Cytotoxic T memory cells | 2.61 parent cell ratio per 16 weeks |
Secondary
Change in Microbiome Alpha-diversity Measured by Shannon Index at the End of the Study
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.
Time frame: Baseline to 16 weeks
Population: All participants who received at least one dose of the intervention and returned at least two stool kits were included in the analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| TUDCA Treatment | Change in Microbiome Alpha-diversity Measured by Shannon Index at the End of the Study | -0.15 score on a scale |
| Placebo Oral Capsule | Change in Microbiome Alpha-diversity Measured by Shannon Index at the End of the Study | 0.06 score on a scale |
Secondary
Change in Quality of Life Based on Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument
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.
Time frame: Baseline to 16 weeks
Population: All participants who received at least one dose of the intervention and completed at least two MSQOL questionnaires were included in the analysis
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| TUDCA Treatment | Change in Quality of Life Based on Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument | MSQOL - Physical Component | -0.15 score on a scale |
| TUDCA Treatment | Change in Quality of Life Based on Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument | MSQOL - Mental Component | -0.44 score on a scale |
| Placebo Oral Capsule | Change in Quality of Life Based on Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument | MSQOL - Physical Component | 0.01 score on a scale |
| Placebo Oral Capsule | Change in Quality of Life Based on Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument | MSQOL - Mental Component | 4.57 score on a scale |