Gut Microbiota Transplantation in Systemic Sclerosis

Study Overview
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Brief Summary
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Systemic Sclerosis (SSc) is a progressive multi-organ disorder with high disease burden. Life expectancy in SSc is reduced by 25-40 years, mainly due to cardiopulmonary and gastro-intestinal (GI) disease involvement; and a very poor response to available treatment. Aiming to improve treatment for SSc, the ReSScue project will determine the therapeutic potential of standardized, cultivated gut microbiome transplantation (GMT), and assess the mechanisms by which this novel intervention strategy works. This approach is rationalized by studies indicating that skewed gut microbiomes could act as major, environmental risk factors in SSc; and thereby be rational targets for therapeutic manipulation. ReSScue is set up as a 4 months randomized double blind trial involving the University Hospital in Oslo. Trial participants will be recruited from the population-based, nationwide SSc cohort. Intervention will be by GMT or placebo. Primary end point is changes in SSc-related GI parameters , while secondary outcomes include safety, explorative clinical parameters, changes in oral, skin and gut microbiomes, and in immune cell phenotypes.

Detailed Description
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This is a randomized, double blind clinical trial testing intervention by standardized GMT. The study cohort will include 10 SSc patients with GI symptoms. Evaluation of end points is at 16 weeks. The trial is set up with six study visits. Patient recruitment, eligibility screening and retrieval of informed consent will be performed at OUS before inclusion. At visit 1, and 6 patients will undergo clinical examination, PFTs, at all visits clinical examination and sampling of biological material.

Official Title
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Reduce Disease Activity in Systemic Sclerosis by Transplantation of an Anaerobically Cultivated Human Intestinal Microbiota, a Controlled Interventional Pilot Trial

Conditions
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Scleroderma, Systemic

Intervention / Treatment
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* Biological: Anaerobically Cultivated Human Intestinal Microbiota
* Biological: Anaerobically Cultivated medium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fulfillment of the 2013 SSc classification criteria Objective GI involvement and provide informed consent. Exclusion Criteria: Severe organ dysfunction (and risk of procedure related complications Recent exposure to antibiotics

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ACHIM<br>Anaerobically Cultivated Human Intestinal Microbiota | Biological: Anaerobically Cultivated Human Intestinal Microbiota<br>* 30ml ACHIM will be administrated at week 0 and 2 with 14 days apart<br>|
| Placebo Comparator: Placebo<br>Anaerobically Cultivated medium | Biological: Anaerobically Cultivated medium<br>* 30ml medium will be administrated at week 0 and 2 with 14 days apart<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical SSc-related GI parameters | The investigators apply a patient-reported outcome measure; the validated UCLA Scleroderma Clinical Trial Consortium GIT 2.0 (UCLA GIT score 2.0) Instrument. The instrument includes seven multi-item scales: diarrhea, reflux, distention/bloating, fecal soilage, constipation, emotional well-being, and social functioning. Items are scored on a 0-3 range, and a lower value indicates a better health related quality of life. The Total GIT Score is a composite score that includes the total sum of all subgroups except constipation divided by 6. The Total GIT Score ranges from 0-3, and a lower value indicates a better health related quality of life. | The change in the UCLA GIT score from baseline to week 16 will be evaluated. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical SSc activity | Explore the effect of GMT on known clinical outcome measures. The investigators base these assessments on the validated SSc disease activity index which includes a set value for active disease and a definition of change. | The investigators will assess all the SSc disease activity index measures at study start and week 16 . | 
| Gut microbiome composition changes | It is unknown how the gut microbiome composition changes after GMT and how long these changes persist. We will investigate these aspects, as well as the mechanisms by which ACHIM exert its effects. Specifically, the investigators will address how the intestinal IgA binding to gut commensals and other bacteria is regulated. | The investigators will assess the gut microbiome weekly from study start to week 16. | 
| Incidence of Treatment-Emergent Adverse Events (Safety) | We define an adverse event as any untoward medical occurrence that may arise during the study period. The study investigator will fill out a safety form at each study visit (week, 0, 2, 4, 8, 12 and 16). The following questions will be asked: Hospital admission or contact with primary physician since last visit and reason why. Diarrhea, constipation, stomach pain, nausea, vomiting or fever since last study visit. Use of antibiotics since last visit. | Explore safety of GMT intervention at each study visit (week 0, 2, 4, 8,12 and 16) | 
| Tissue architecture changes | Explore effects of GMT on tissue architecture in gut and skin, and on immune cell distribution in blood. | The investigators will analyse tissue architeure in the gut at week 0. 2 and 16. The skin tissue archtecture at week 0 and 16. The immune cell distribution in blood at week 0, 2, 4, 8, 12 and 16. | 
| Clinical SSc-related GI parameters | The investigators apply a patient-reported outcome measure; the validated UCLA Scleroderma Clinical Trial Consortium GIT 2.0 (UCLA GIT score 2.0) Instrument. The instrument includes seven multi-item scales: diarrhea, reflux, distention/bloating, fecal soilage, constipation, emotional well-being, and social functioning. Items are scored on a 0-3 range, and a lower value indicates a better health related quality of life. The Total GIT Score is a composite score that includes the total sum of all subgroups except constipation divided by 6. The Total GIT Score ranges from 0-3, and a lower value indicates a better health related quality of life. | The change in the UCLA GIT score from baseline will be evaluated at each study visit (week 0,2,4,8 and 12). |