Autoimmune Diseases, Relapsing Multiple Sclerosis
Conditions
Keywords
microbiome, multiple sclerosis, microbiota, gut
Brief summary
The proposed randomized, open label, with treat as usual control group (standard treatment or any disease modifying drugs), crossover phase II study will be conducted in 40 patients (n=20 per group) with the relapsing forms of multiple sclerosis according to the McDonald 2010 Criteria. Patients will be randomized into 2 intervention groups. One will receive the FMT from month 1 and for the first 6 months (early intervention group). On the other hand, the other group will be a control group during the first 6 months and will receive the FMT for the last 6 months of the study. Patients will be screened for eligibility based on MS diagnosis and EDSS and if eligible then consented. All qualified patients will not be currently or recently treated with high dose steroids.
Detailed description
At Visit 1, before FMT(fecal microbial transplantation), patients will be evaluated for their vital signs, medical history and concomitant medications. Also before transplantation, patient's stool will be collected to study their microbial profile, blood collected for analysis to evaluate cytokines levels as well as blood DNA bacteria and finally, urinalysis to assess gut permeability (baseline). Other assessments (prior to the first dose of therapy) include an Expanded Disability Status Scale (EDSS), pregnancy test (if applicable), physical exam and ECG. Blood samples are also taken at month 1 in order to establish a baseline for routine chemistry/hematology. After all these assessments FMT will be performed by a trained nurse via a rectal enema. FMT for the early intervention group will be at V1, 2, 2.1, 2.2, V3 and V4. FMT randomized to late intervention group will be V4, 5, 6, 6.1.6.2, 6.3 and V7 Both groups, at Visit 1, Visit 4 and Visit 7, patients will be instructed to drink lactulose solution and collect the urine throughout the previous night and first thing in the morning. A proper collecting bottle will be provided and will also undergo a contrast-enhanced brain MRI scan at Robarts Institute London Ontario. Those randomized to the Early Intervention group, will return to the clinic for visit 2, 1 month after the first FMT(fecal microbial transplantation). Another stool sample to evaluate the microbial before the second FMT will be collected and peripheral blood samples for cytokines and blood bacterial DNA analysis. Both groups this same routine procedure repeated at visits 2.1, 2.2, 3, 4, 5, 6, 6.1.6.2, 6.3 and visit 7. Another safety assessment 2 weeks after FMT is to review any adverse events that may have occurred. Both groups will have an MRI at M1, M6 and M12.
Interventions
DRUGFecal microbiota
fecal microbial transplantation
Sponsors
London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a prospective, cross-over, open label, randomized 1:1 early versus delayed groups, interventional \[FMT\] versus no interventional \[no FMT\] controlled trial to explore the effects of FMT from a healthy donor to RMS patients and investigate whether this can influence disease activity based on a panel of biological markers.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Have a confirmed diagnosis of relapsing MS defined by the 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis * Any disease duration will be accepted. * Have a baseline EDSS of = or \<7.0 * Older than 18 years of age. * Be able to attend all clinic appointments without interruption * Patients must be able to understand English sufficiently well to understand and comply with the clinic and medication schedules and procedures. * Be willing and able to give written informed consent * Negative blood pregnancy test at screening
Exclusion criteria
* Not meeting all of the above inclusion criteria * Pregnancy or breastfeeding * Current or recent \[in the last 90 days\] exposure to high dose corticosteroids * Ongoing use of antibiotics * Standard of care exclusions for MRI scans * Presence of a chronic intestinal disease e.g. Celiac, malabsorption, colonic tumor * Inability to provide informed written consent. * Immunosuppression from transplantation, HIV, cancer chemotherapy or ongoing use of any immunosuppressive agents. * Concomitant inflammatory diseases * Pregnant women * Any contra-indications for MRI. Participants are to be screened by a CMRTO (The College of Medical Radiation Technologists of Ontario) certified MRI Technologist in order to determine the MRI compatibility or exclusion of implantable/external devices according to the manufacturer's safety guidelines. The devises include cerebral aneurysm clips, neuro-stimulator, mechanical heart valves, cardiac stents, IUDs(intrauterine device), vena cava filters, shunts, embolization coils, cochlear implants, non-removable prosthesis/artificial limbs. Contraindications are pacemaker of defibrillator, shrapnel/metallic fragments, previous brain surgery, seizure, severe claustrophobia, weight or body index that will prevent a successful MRI study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | Within 6 months | Luminex test to evaluate the levels of 25 cytokines in peripheral blood pre-fecal transplant and post fecal transplant. Due to early termination of the trial, we didn't meet the number of participants required for statistical analysis; therefore, we analyzed the data pre and post FMT, rather than early and late intervention groups as originally planned. Due to the small sample size there was a large variation between cytokine levels of each participant for pre and post FMT, resulting in large standard deviations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate Effect of Fecal Microbial Transplantation in Gut Microbiome | Monthly for 6 months | PCR (polymerase chain reaction) to assess blood DNA bacteria |
| Evaluate Effect of Fecal Microbial Transplantation in Gut Permeability | Baseline, 6 months, 12 months | Urinalysis to evaluate lactulose and mannitol levels |
| Evaluate Treatment Clinical Safety: Neurological Exam Using the Expanded Disability Status Scale | Monthly for 6 months | Neurological exam using the Expanded Disability Status Scale |
| Evaluate Treatment Safety: MRI to Access Subclinical Disease Activity | Baseline, 6 months and 12 months | MRI to access subclinical disease activity |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Early Intervention Fecal microbiota via enema at Month 1, 2, 3. 4, 5 and month 6 along with stool, urine and blood collection. At months 7, 8, 9, 10, 11 and 12 only stool, urine and blood collection.
Fecal microbiota: fecal microbial transplantation | 4 |
| Late Intervention At months 1, 2, 3, 4, 5 and 6, stool, urine and blood collection. Fecal microbiota via enema at month 6, 7, 8, 9, 10, 11and 12 months along with stool, urine and blood collection.
Fecal microbiota: fecal microbial transplantation | 7 |
| Total | 11 |
Baseline characteristics
| Characteristic | Early Intervention | Late Intervention | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 6 Participants | 10 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 7 |
| other Total, other adverse events | 3 / 4 | 5 / 7 |
| serious Total, serious adverse events | 0 / 4 | 0 / 7 |
Outcome results
Primary
Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients
Luminex test to evaluate the levels of 25 cytokines in peripheral blood pre-fecal transplant and post fecal transplant. Due to early termination of the trial, we didn't meet the number of participants required for statistical analysis; therefore, we analyzed the data pre and post FMT, rather than early and late intervention groups as originally planned. Due to the small sample size there was a large variation between cytokine levels of each participant for pre and post FMT, resulting in large standard deviations.
Time frame: Within 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-13 | 0.091 ng/mL | Standard Deviation 0.186 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-2 | 0.016 ng/mL | Standard Deviation 0.017 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-10 | 0.026 ng/mL | Standard Deviation 0.024 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-21 | 0.042 ng/mL | Standard Deviation 0.031 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-15 | 0.030 ng/mL | Standard Deviation 0.038 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-4 | 0.428 ng/mL | Standard Deviation 0.426 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL17F | 0.082 ng/mL | Standard Deviation 0.076 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-23 | 8.778 ng/mL | Standard Deviation 8.549 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-17a | 0.018 ng/mL | Standard Deviation 0.018 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-5 | 0.023 ng/mL | Standard Deviation 0.021 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | MIP3 Alpha | 0.049 ng/mL | Standard Deviation 0.035 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-6 | 0.055 ng/mL | Standard Deviation 0.117 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-22 | 0.414 ng/mL | Standard Deviation 0.443 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-17E | 0.149 ng/mL | Standard Deviation 0.153 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IFN Gamma | 0.064 ng/mL | Standard Deviation 0.046 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-27 | 1.534 ng/mL | Standard Deviation 0.795 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-9 | 0.036 ng/mL | Standard Deviation 0.039 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-31 | 0.156 ng/mL | Standard Deviation 0.22 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-12p70 | 0.026 ng/mL | Standard Deviation 0.019 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | TNF alpha | 0.042 ng/mL | Standard Deviation 0.033 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-1 Beta | 0.013 ng/mL | Standard Deviation 0.011 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | TNF beta | 0.313 ng/mL | Standard Deviation 0.585 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | GM-CSF | 0.171 ng/mL | Standard Deviation 0.186 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-28a | 1.190 ng/mL | Standard Deviation 2.512 |
| Pre-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-33 | 0.123 ng/mL | Standard Deviation 0.097 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-28a | 1.704 ng/mL | Standard Deviation 2.499 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL17F | 0.093 ng/mL | Standard Deviation 0.148 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | GM-CSF | 0.261 ng/mL | Standard Deviation 0.524 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IFN Gamma | 0.078 ng/mL | Standard Deviation 0.07 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-10 | 0.024 ng/mL | Standard Deviation 0.026 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | MIP3 Alpha | 0.036 ng/mL | Standard Deviation 0.023 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-12p70 | 0.033 ng/mL | Standard Deviation 0.043 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-13 | 0.084 ng/mL | Standard Deviation 0.181 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-15 | 0.036 ng/mL | Standard Deviation 0.054 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-17a | 0.023 ng/mL | Standard Deviation 0.039 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-22 | 0.559 ng/mL | Standard Deviation 0.811 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-9 | 0.031 ng/mL | Standard Deviation 0.042 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-1 Beta | 0.013 ng/mL | Standard Deviation 0.013 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-33 | 0.086 ng/mL | Standard Deviation 0.114 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-2 | 0.016 ng/mL | Standard Deviation 0.024 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-21 | 0.040 ng/mL | Standard Deviation 0.043 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-4 | 0.425 ng/mL | Standard Deviation 0.38 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-23 | 10.906 ng/mL | Standard Deviation 16.971 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-5 | 0.028 ng/mL | Standard Deviation 0.026 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-6 | 0.056 ng/mL | Standard Deviation 0.129 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-17E | 0.203 ng/mL | Standard Deviation 0.342 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-27 | 1.792 ng/mL | Standard Deviation 1.322 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | IL-31 | 0.198 ng/mL | Standard Deviation 0.28 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | TNF alpha | 0.053 ng/mL | Standard Deviation 0.036 |
| Post-FMT | Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | TNF beta | 0.306 ng/mL | Standard Deviation 0.627 |
Secondary
Evaluate Effect of Fecal Microbial Transplantation in Gut Microbiome
PCR (polymerase chain reaction) to assess blood DNA bacteria
Time frame: Monthly for 6 months
Secondary
Evaluate Effect of Fecal Microbial Transplantation in Gut Permeability
Urinalysis to evaluate lactulose and mannitol levels
Time frame: Baseline, 6 months, 12 months
Secondary
Evaluate Treatment Clinical Safety: Neurological Exam Using the Expanded Disability Status Scale
Neurological exam using the Expanded Disability Status Scale
Time frame: Monthly for 6 months
Secondary
Evaluate Treatment Safety: MRI to Access Subclinical Disease Activity
MRI to access subclinical disease activity
Time frame: Baseline, 6 months and 12 months