Safety and Efficacy of Anaerobic Cultivated Human Intestinal Microbiome Transplantation in Systemic Sclerosis (ReSScue)

Study Overview
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Brief Summary
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This study evaluates the effect of intestinal microbiota therapy on gastro-intestinal symptoms in patients with systemic sclerosis (SSc). This is a mulicenter randomized controlled trial conducted at university hospitals in Oslo, Tromsø, Bergen and Trondheim in Norway. In part A1, half of the patients will receive active substance (intestinal microbiota cultured in the lab - ACHIM) in the small intestine twice by gastroduodenoscopy, the other half will receive placebo. The primary outcome will be measured on week 12 by patient reported outcome measures. In part A2, all participants receive ACHIM at week 12, with an 8 week follow-up for all. A step-wise follow-up will be done in part B up to 16 weeks after week 20 until the last participant finish week 20 visit, which is defined as end of study.The blind from the first intervention will not be opened before end of study.

Official Title
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Aiming to Reduce Disease-related Gastrointestinal Symptoms in Systemic Sclerosis by Repeat Intestinal Infusions of Anaerobic Cultivated Human Intestinal Microbiome (ACHIM); a Randomized, Double-blind Placebo-controlled 20 Week Study

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: ACHIM as solute (10^9 intestinal microbes/ml)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 to 85 years of age inclusive, at the time of signing the informed consent. Participants must have been clinically diagnosed with SSc by a rheumatologist having experience with the disease. Participants must have disease characteristics that fulfill the 2013 ACR/EULAR classification criteria for SSc. Participants must be able to understand and follow trial procedures including completion of questionnaires regarding Patient Reported Outcome measures, such as the Norwegian version of the UCLA GIT V2.0 score. Participants must have moderate to severe SSc-related lower GI symptoms at time of inclusion, as defined by UCLA GIT score values of ≥1.01 for bloating and/or ≥0.50 for diarrhea at the screening visit. Male and female Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: Medical Conditions Cardiovascular diseases, any of the following Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 month of Visit 1 Myocardial infarction within 6 months of Visit 1 Unstable cardiac angina within 6 months of Visit 1 Lung disease with impaired respiratory function, any of the following Forced Vital Capacity (FVC) < 50% of expected reference value within 12 month of Visit 1 Diffusing lung capacity for carbon monoxide (DLCO) < 40% of expected reference value within 12 month of Visit 1 LTOT or lung-tx Significant pulmonary hypertension, any of the following Previous clinical or echocardiographic evidence of significant right heart failure History of right heart catheterisation showing a cardiac index ≤ 2 l/min/m² History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1 Severe anemia with Hb < 8.0 g/l within 4 weeks prior to Visit 1. Repeat testing of Hb is allowed. Bleeding risk, any of the following History of hemorrhagic central nervous system (CNS) event within 12 months of Visit 1. Known genetic predisposition to bleeding Platelet counts < 50 x 109/l Chronic liver disease or gastro-intestinal condition, any of the following Primary biliary cholangitis Primary sclerosing cholangitis Decompensated chronic liver disease Inflammatory bowel disease Celiac disease treated for less than 12 months. Gastro-intestinal surgery performed within the within 12 months of Visit 1 Hepatic dysfunction, as defined as AST, ALT or bilirubin levels >3 times the Upper limit of normal range (x ULN) within 4 weeks prior to Visit 1. Repeat testing of AST, ALT and bilirubin are allowed in participants with no prior history of hepatic dysfunction. Chronic renal insufficiency, with estimated Glomerular Filtration Rate (eGFR) < 30. Active digital ulcers within 4 weeks of Visit 1. Anaphylactic food allergy. Eating disorder diagnosed by a physician Other diseases or conditions that may interfere with testing procedures (for example inability to conduct gastroduodenoscopy) or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial (for example severe GI symptoms due to other diseases than SSc). Prior/Concomitant Therapy Any antibiotic therapy within 3 months of Visit 1 Prednisone >10 mg/day or equivalent within 4 weeks prior to Visit 1 Cyclophosphamide or rituximab treatment within 6 months prior to Visit 1 Unstable background monotherapy with any of the following therapeutics; mycophenolate mofetil/sodium, methotrexate, azathioprine, tocilizumab, abatacept, leflunomide, tacrolimus, tofacitinib and cyclosporine A. Participants have to be on stable monotherapy with any of these medications for at least 6 months prior to visit 1 Combined therapy of two or more of the following therapeutics: mycophenolate mofetil/sodium, methotrexate, azathioprine, tocilizumab, abatacept, leflunomide, tacrolimus, tofacitinib and ciclosporine A within at least 8 weeks prior to visit 1. Need for full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors or heparin) Previous hematopoietic stem cell transplantation (HSCT) within 12 months of Visit 1, or HSCT planned within 12 months after Visit 1. Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit. Prior/Concurrent Clinical Study Experience Prior participation in FMT study in the last 12 months. Diagnostic assessments Abnormal coagulation parameters as defined as International normalised ratio (INR) >2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by >1.5 x ULN at Visit 1 Other Exclusions Women who are pregnant, nursing, or who plan to become pregnant while in the trial. (Women of child bearing potential should be tested with Hcg (urine or serum). Woman of child bearing potential if not using highly efficient contraception.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The 20-week study period consists of a 12-week induction phase (Part A1), with randomized, double-blind parallel group interventions by endoscopic infusions at weeks 0 and 2, and an 8-week maintenance phase (Part A2) where all participants receive one single open label endoscopic infusion on week 12. Additionally, all participants who complete the 20-week study period are followed for a maximum 16 weeks monitoring period (Part B) to obtain longer-term data on safety and durability of intervention effects.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACHIM by gastroduodenoscopy<br>Intestinal microbiota (acronym ACHIM - anaerobically cultured human intestinal microbiota) will be administered by gastroduodenoscope twice (given at baseline and study-week 2). Each with volume 30 ml, containing approximately 10^9 bacteria / ml. Primary outcome measured at week 12. At week 12 an open label administration of ACHIM to all participants. Thereafter an 8 (+16) week period observation. Blind from the first intervention will be maintained through-out the duration of the study. | Drug: ACHIM as solute (10^9 intestinal microbes/ml)<br>* Culture of intesinal microbiota originally derived from a healthy subject are administered to a person with presumed dysbiotic intestinal symptoms with an objective to treat these symptoms.<br>* Other names: Fecal microbiota transplantation;|
| Placebo Comparator: Placebo by gastroduodenoscopy<br>ACHIM culture media (no bacteria) will be administered by gastroduodenoscope twice (given at baseline and study-week 2). Each with volume 30 ml. Primary outcome measured at week 12. At week 12 an open label administration of ACHIM to all participants. Thereafter an 8 (+16) week period observation. Blind from the first intervention will be maintained through-out the duration of the study. | Drug: ACHIM as solute (10^9 intestinal microbes/ml)<br>* Culture of intesinal microbiota originally derived from a healthy subject are administered to a person with presumed dysbiotic intestinal symptoms with an objective to treat these symptoms.<br>* Other names: Fecal microbiota transplantation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Change from baseline to week 12 in UCLA GIT score item diarrhea or bloating, depending which was the worst symptom at baseline evaluated separately for each patient | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The bloating scale is scored on a Visual Analog Scale from 0 (better) to 3 (worse) and the diarrhea scale from 0 (better) to 2.5 (worse). Change=(week12 score-baseline score) | baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Safety and tolerability assessed by adverse event (AE) monitoring, physical examination and clinical laboratory testing from baseline to the end of the study period | • Registration of number of adverse events adverse event (AE), assessment of physical examination and clinical laboratory testing by standardized assessments and sampling | • Over the study period of 20 (+16) weeks | 
| • Change from baseline to week 12 in total UCLA GIT score | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The total scale is scored on a Visual Analog Scale from 0 (better) to 3 (worse). Change=(week12 score-baseline score) | baseline, week 6 and week 12. | 
| • Change from baseline to week 12 in UCLA GIT score item diarrhea | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The diarrhea scale is scored on a Visual Analog Scale from 0 (better) to 2.5 (worse) . Change=(week12 score-baseline score) | baseline to week 12 | 
| • Change from baseline to week 12 in UCLA GIT score item bloating | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The bloating scale is scored on a Visual Analog Scale from 0 (better) to 3 (worse) . Change=(week12 score-baseline score) | baseline to week 12 |