Fecal Microbiota Transplantation After Autologous HSCT in Patients With Multiple Sclerosis

Study Overview
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Brief Summary
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The hypothesis of the study is that according to modern data, the pathogenesis of multiple sclerosis is inextricably linked to the patient's microbiota. Therefore, transplantation of a normal fecal microbiota (FMT) can improve the outcome of autologous hematopoietic stem cell transplantation (autoHSCT) by increasing the disease-free period and disease progression suspension for at least 5 years after transplantation, which meets the NEDA (No Evidence of Disease Activity) criteria, satisfying the current trends of clinical neurology.

Detailed Description
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AutoHSCT may be a method of choice to treat patients with refractory forms of multiple sclerosis, taking into account the insufficient efficacy of first line therapy, lack of availability (government approval) and high cost of monoclonal antibodies as a second line drugs. In this setting, according to the safety-efficiency ratio the most appropriate are reduced intensity conditioning regimens in autoHSCT. In 75% of cases for refractory forms of multiple sclerosis it is possible to achieve 5 years remission with transplant mortality less than 1%. In recent years, it is quite clear that gut microbiota abnormalities may be one of mechanisms for autoimmune diseases development. Therefore, the correction of gut dysbiosis through FMT from a healthy donor can improve the effectiveness of basic therapies. Currently, FMT is a rapidly developing method of treating intestinal infections associated with multi-resistant bacteria, based on the replacement of the recipient's microbiota by the donor's microbiota.

Official Title
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Allogeneic Fecal Microbiota Transplantation as a Consolidation Treatment After Autologous Hematopoietic Stem Cell Transplantation in Patients With Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Biological: allogeneic fecal microbiota


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis: Multiple sclerosis (Relapsing-Remitting, Secondary-Progressive, Primary-Progressive) AutoHSCT Signed informed consent No second tumors No severe concurrent illness 1.0-6.5 points by EDSS Disease duration less than 20 years Disease progression on 1 and/or 2 line therapy (1 point EDSS 1.0-6.0 and 0,5 point EDSS 6.0-6.5) Exclusion Criteria: Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50% Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted Respiratory distress >grade I Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits Creatinine clearance < 60 mL/min Uncontrolled bacterial or fungal infection at the time of enrollment Requirement for vasopressor support at the time of enrollment Karnofsky index <30% Pregnancy Somatic or psychiatric disorder making the patient unable to sign informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AutoHSCT + FMT<br>AutoHSCT with reduced intensity condition regimen (RIC). FMT starting D+60 up to D+120 via po capsules: 30 capsules with fecal transplant divided in two consecutive days (more accurate capsules amount is according to patients body weight) | Biological: allogeneic fecal microbiota<br>* All patients receive autoHSCT with RIC (Cyclophosphamide, Antithymocyte globulin, Rituximab). After immune system reconstitution (approximately starting D+60 up to D+120), patients will receive FMT from healthy donor via po capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate effectiveness of autoHSCT in combination with FMT in patients with refractory multiple sclerosis | Multiple sclerosis progression free survival | 365 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate overall survival after autoHSCT in combination with FMT in patients with refractory multiple sclerosis | Overall survival | 365 days | 
| To evaluate adverse effects after FMT in immunocompromised patients | Toxicity based NCI CTCAE ver.5.0, including analysis of severe bacterial, fungal and viral infections incidence | 365 days | 
| Quality of life status 1 | Multiple sclerosis-specific questionnaire - HADS (Hospital Anxiety and Depression Scale) before and after autoHSCT: 0-7 points - normal; 8-10 - subclinically expressed anxiety/depression; 11-21 - clinically expressed anxiety/depression | 365 days | 
| Quality of life status 2 | Multiple sclerosis-specific questionnaire - EDSS (Expanded Disability Status Scale) before and after autoHSCT: 0 points - Normal neurologic exam; 1.0-1.5 - No disability, minimal signs in one or two Functional Systmes (FS); 2.0-2.5 - Minimal disability in one or two FS; 3.0-3,5 - Moderate disability in one FS, fully ambulatory; 4.0-4.5 - Fully ambulatory without aid. Able to walk without aid or rest some 500 or 300 meters; 5.0-5.5 - Ambulatory without aid or rest for about 200 or 100 meters; 6.0 - Intermittent assistance required to walk about 100 meters; 6.5 - Constant bilateral assistance required to walk about 20 meters; 7.0-7.5 - Unable to walk beyond about 5 meters or more than a few steps; 8.0 - Essentially restricted to bed, but may be out of bed itself; 8.5 - Essentially restricted to bed; 9.0 - Helpless bed patient; can communicate and eat; 9.5 - Totally helpless bed patient; unable to communicate effectively or eat/swallow; 10 - Death due to MS | 365 days | 
| Evaluation of Immune system reconstitution after autoHSCT 1 | CD4+/CD8+ x10^9/l level before and after autoHSCT + FMT | 365 days | 
| Evaluation of Immune system reconstitution after autoHSCT 2 | Regulatory T-cells (CD4+CD25+CD127low, cell/mm^3) level before and after autoHSCT + FMT | 365 days | 
| Impact of autoHSCT on brain structure anatomy | MRI 3 Tesla | 365 |