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

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

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.

Inclusion Criteria:

1. Participant must be 18 to 85 years of age inclusive, at the time of signing the informed consent.
2. Participants must have been clinically diagnosed with SSc by a rheumatologist having experience with the disease.
3. Participants must have disease characteristics that fulfill the 2013 ACR/EULAR classification criteria for SSc.
4. 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.
5. 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.
6. Male and female
7. 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

  1. Cardiovascular diseases, any of the following

     1. Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 month of Visit 1
     2. Myocardial infarction within 6 months of Visit 1
     3. Unstable cardiac angina within 6 months of Visit 1

  2. Lung disease with impaired respiratory function, any of the following

     1. Forced Vital Capacity (FVC) < 50% of expected reference value within 12 month of Visit 1
     2. Diffusing lung capacity for carbon monoxide (DLCO) < 40% of expected reference value within 12 month of Visit 1
     3. LTOT or lung-tx

  3. Significant pulmonary hypertension, any of the following

     1. Previous clinical or echocardiographic evidence of significant right heart failure
     2. History of right heart catheterisation showing a cardiac index ≤ 2 l/min/m²

  4. History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1

  5. Severe anemia with Hb < 8.0 g/l within 4 weeks prior to Visit 1. Repeat testing of Hb is allowed.

  6. Bleeding risk, any of the following

     1. History of hemorrhagic central nervous system (CNS) event within 12 months of Visit 1.
     2. Known genetic predisposition to bleeding
     3. Platelet counts < 50 x 109/l

  7. Chronic liver disease or gastro-intestinal condition, any of the following

     1. Primary biliary cholangitis
     2. Primary sclerosing cholangitis
     3. Decompensated chronic liver disease
     4. Inflammatory bowel disease
     5. Celiac disease treated for less than 12 months.

  8. Gastro-intestinal surgery performed within the within 12 months of Visit 1

  9. 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.

  10. Chronic renal insufficiency, with estimated Glomerular Filtration Rate (eGFR) < 30.

  11. Active digital ulcers within 4 weeks of Visit 1.

  12. Anaphylactic food allergy.

  13. Eating disorder diagnosed by a physician

  14. 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

  15. Any antibiotic therapy within 3 months of Visit 1

  16. Prednisone >10 mg/day or equivalent within 4 weeks prior to Visit 1

  17. Cyclophosphamide or rituximab treatment within 6 months prior to Visit 1

  18. 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

  19. 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.

  20. Need for full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors or heparin)

  21. Previous hematopoietic stem cell transplantation (HSCT) within 12 months of Visit 1, or HSCT planned within 12 months after Visit 1.

  22. Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit.

      Prior/Concurrent Clinical Study Experience

  23. Prior participation in FMT study in the last 12 months. Diagnostic assessments

  24. 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

  25. 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.