Fecal Microbial Transplantation in Relapsing Multiple Sclerosis Patients

• Sponsor: Lawson Health Research Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03183869
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Actual Duration (Months): 17.1
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Autoimmune Diseases; Relapsing Multiple Sclerosis	Drug: Fecal microbiota	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• 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.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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Fecal Microbial Transplantation in Relapsing Multiple Sclerosis Patients
• Actual Study Start Date: Aug 24, 2017
• Actual Primary Completion Date: Nov 19, 2018
• Actual Study Completion Date: Jan 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Fecal microbiota; fecal microbial transplantation; Other Names: fecal microbial transplantation
Active Comparator: 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.	Drug: Fecal microbiota; fecal microbial transplantation; Other Names: fecal microbial transplantation

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Evaluate Effect of Fecal Microbial Transplantation in Gut Microbiome [Monthly for 6 months]

   PCR (polymerase chain reaction) to assess blood DNA bacteria

2. Evaluate Effect of Fecal Microbial Transplantation in Gut Permeability [Baseline, 6 months, 12 months]

   Urinalysis to evaluate lactulose and mannitol levels

3. Evaluate Treatment Clinical Safety: Neurological Exam Using the Expanded Disability Status Scale [Monthly for 6 months]

   Neurological exam using the Expanded Disability Status Scale

4. Evaluate Treatment Safety: MRI to Access Subclinical Disease Activity [Baseline, 6 months and 12 months]

   MRI to access subclinical disease activity

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	London Health Sciences Centre, University Hospital	London	Ontario	Canada	N6A 5A5

Sponsors and Collaborators

• Lawson Health Research Institute

Investigators

• Principal Investigator: Marcelo Kremenchutzky, MD, FRCP, London Health Science Centre

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 9, 2018

More Information

Publications

• Cantarel BL, Waubant E, Chehoud C, Kuczynski J, DeSantis TZ, Warrington J, Venkatesan A, Fraser CM, Mowry EM. Gut microbiota in multiple sclerosis: possible influence of immunomodulators. J Investig Med. 2015 Jun;63(5):729-34. doi: 10.1097/JIM.0000000000000192.
• Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012 Jun 8;336(6086):1268-73. doi: 10.1126/science.1223490. Epub 2012 Jun 6. Review.
• Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012 Feb;46(2):145-9. doi: 10.1097/MCG.0b013e318234570b.
• Kwon HK, Kim GC, Kim Y, Hwang W, Jash A, Sahoo A, Kim JE, Nam JH, Im SH. Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response. Clin Immunol. 2013 Mar;146(3):217-27. doi: 10.1016/j.clim.2013.01.001. Epub 2013 Jan 16.
• Lavasani S, Dzhambazov B, Nouri M, Fåk F, Buske S, Molin G, Thorlacius H, Alenfall J, Jeppsson B, Weström B. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One. 2010 Feb 2;5(2):e9009. doi: 10.1371/journal.pone.0009009.
• Mielcarz DW, Kasper LH. The gut microbiome in multiple sclerosis. Curr Treat Options Neurol. 2015 Apr;17(4):344. doi: 10.1007/s11940-015-0344-7.
• Miyake S, Kim S, Suda W, Oshima K, Nakamura M, Matsuoka T, Chihara N, Tomita A, Sato W, Kim SW, Morita H, Hattori M, Yamamura T. Dysbiosis in the Gut Microbiota of Patients with Multiple Sclerosis, with a Striking Depletion of Species Belonging to Clostridia XIVa and IV Clusters. PLoS One. 2015 Sep 14;10(9):e0137429. doi: 10.1371/journal.pone.0137429. eCollection 2015.
• Tremlett H, Fadrosh DW, Faruqi AA, Hart J, Roalstad S, Graves J, Lynch S, Waubant E; US Network of Pediatric MS Centers. Gut microbiota composition and relapse risk in pediatric MS: A pilot study. J Neurol Sci. 2016 Apr 15;363:153-7. doi: 10.1016/j.jns.2016.02.042. Epub 2016 Feb 20.
• Wang S, Xu M, Wang W, Cao X, Piao M, Khan S, Yan F, Cao H, Wang B. Systematic Review: Adverse Events of Fecal Microbiota Transplantation. PLoS One. 2016 Aug 16;11(8):e0161174. doi: 10.1371/journal.pone.0161174. eCollection 2016. Review.

• Responsible Party: Lawson Health Research Institute
• ClinicalTrials.gov Identifier: NCT03183869
• Other Study ID Numbers: MS-FMT-001
• First Posted: Jun 12, 2017
• Last Update Posted: Dec 2, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Lawson Health Research Institute: microbiome; multiple sclerosis; microbiota; gut
• Additional relevant MeSH terms: Multiple Sclerosis; Autoimmune Diseases; Sclerosis

Study Results

Participant Flow

Arm/Group Title	Early Intervention	Late Intervention
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	4	7
COMPLETED	0	2
NOT COMPLETED	4	5

Baseline Characteristics

Arm/Group Title	Early Intervention	Late Intervention	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	4	7	11
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 100%	6 85.7%	10 90.9%
>=65 years	0 0%	1 14.3%	1 9.1%
Sex: Female, Male (Count of Participants)
Female	3 75%	5 71.4%	8 72.7%
Male	1 25%	2 28.6%	3 27.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pre-FMT	Post-FMT
Arm/Group Description	Cytokine values before fecal microbial transplants. Fecal microbiota: fecal microbial transplantation	Cytokine values after fecal microbial transplants. Fecal microbiota: fecal microbial transplantation
Measure Participants	10	10
IL17F	0.082 (0.076)	0.093 (0.148)
GM-CSF	0.171 (0.186)	0.261 (0.524)
IFN Gamma	0.064 (0.046)	0.078 (0.070)
IL-10	0.026 (0.024)	0.024 (0.026)
MIP3 Alpha	0.049 (0.035)	0.036 (0.023)
IL-12p70	0.026 (0.019)	0.033 (0.043)
IL-13	0.091 (0.186)	0.084 (0.181)
IL-15	0.030 (0.038)	0.036 (0.054)
IL-17a	0.018 (0.018)	0.023 (0.039)
IL-22	0.414 (0.443)	0.559 (0.811)
IL-9	0.036 (0.039)	0.031 (0.042)
IL-1 Beta	0.013 (0.011)	0.013 (0.013)
IL-33	0.123 (0.097)	0.086 (0.114)
IL-2	0.016 (0.017)	0.016 (0.024)
IL-21	0.042 (0.031)	0.040 (0.043)
IL-4	0.428 (0.426)	0.425 (0.380)
IL-23	8.778 (8.549)	10.906 (16.971)
IL-5	0.023 (0.021)	0.028 (0.026)
IL-6	0.055 (0.117)	0.056 (0.129)
IL-17E	0.149 (0.153)	0.203 (0.342)
IL-27	1.534 (0.795)	1.792 (1.322)
IL-31	0.156 (0.220)	0.198 (0.280)
TNF alpha	0.042 (0.033)	0.053 (0.036)
TNF beta	0.313 (0.585)	0.306 (0.627)
IL-28a	1.190 (2.512)	1.704 (2.499)

2. Secondary Outcome

Title	Evaluate Effect of Fecal Microbial Transplantation in Gut Microbiome
Description	PCR (polymerase chain reaction) to assess blood DNA bacteria
Time Frame	Monthly for 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Evaluate Effect of Fecal Microbial Transplantation in Gut Permeability
Description	Urinalysis to evaluate lactulose and mannitol levels
Time Frame	Baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Evaluate Treatment Clinical Safety: Neurological Exam Using the Expanded Disability Status Scale
Description	Neurological exam using the Expanded Disability Status Scale
Time Frame	Monthly for 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Evaluate Treatment Safety: MRI to Access Subclinical Disease Activity
Description	MRI to access subclinical disease activity
Time Frame	Baseline, 6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 year - Nov2017 - Nov2018
Arm/Group Title	Early Intervention		Late Intervention
Arm/Group Description	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		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
All Cause Mortality
	Early Intervention		Late Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/7 (0%)
Serious Adverse Events
	Early Intervention		Late Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Early Intervention		Late Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		5/7 (71.4%)
Cardiac disorders
Hypertension	0/4 (0%)		1/7 (14.3%)
Ear and labyrinth disorders
Ear Infection	0/4 (0%)		1/7 (14.3%)
Gastrointestinal disorders
Nausea	3/4 (75%)		0/7 (0%)
Difficulty Swallowing	0/4 (0%)		1/7 (14.3%)
Reproductive system and breast disorders
Vaginal Yeast Infection	0/4 (0%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Hives	0/4 (0%)		1/7 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.