Clinical trial NCT04300426: Safety and Efficacy of Anaerobic Cultivated Human Intestinal Microbiome Transplantation in Systemic Sclerosis (ReSScue)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Systemic Sclerosis
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: South-Eastern Norway Regional Health Authority
name: Haukeland University Hospital
name: St. Olavs Hospital
name: University Hospital of North Norway
First posted: 2020-03-09
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: • 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
timeFrame: baseline to week 12
Secondary outcomes:
measure: • Safety and tolerability assessed by adverse event (AE) monitoring, physical examination and clinical laboratory testing from baseline to the end of the study period
timeFrame: • Over the study period of 20 (+16) weeks
measure: • Change from baseline to week 12 in total UCLA GIT score
timeFrame: baseline, week 6 and week 12.
measure: • Change from baseline to week 12 in UCLA GIT score item diarrhea
timeFrame: baseline to week 12
measure: • Change from baseline to week 12 in UCLA GIT score item bloating
timeFrame: baseline to week 12
Other outcomes:
measure: • Change from baseline to week 12 in Faecal incontinence quality of life scale
timeFrame: baseline to weeks 12
measure: • Change from baseline to week 12 in UCLA GIT score item reflux
timeFrame: baseline to week 12
measure: • Change from baseline to week 12 in UCLA GIT score item fecal soilage
timeFrame: baseline to week 12
measure: • Change from baseline to week 12 in UCLA GIT score item constipation
timeFrame: baseline to week 12
measure: • Change from baseline to week 12 in UCLA GIT score item emotional wellbeing
timeFrame: baseline to week 12
measure: • Change from baseline to week 12 in UCLA GIT score item social participation
timeFrame: baseline to week 12
measure: • Change from baseline to week 12 in • Change from baseline to week 12 in HAQ-DI scores
timeFrame: baseline to week 12
measure: • Change from baseline to week 12 in VAS Fatigue scale
timeFrame: baseline to week 12
measure: • Change from baseline to week 12 in ScleroId score
timeFrame: baseline to week 12
measure: • Change from baseline to weeks 2, 6 and 12 in overall faecal microbiome composition measured by 16sRNA based methods
timeFrame: baseline to week 2, 6 and 12
measure: • Change from baseline to week 12 in saliva, skin and urine microbiome measured by 16sRNA based methods
timeFrame: baseline to week 12
measure: • Change from baseline to weeks 2, 6 and 12 in immunoglobulin bound fraction of the overall faecal microbiome
timeFrame: • Baseline up to week 2, 6 and 12
measure: • Change from baseline to week 12 in gastrointestinal transit time and contractions evaluated by SmartPill technology along with registration of stool frequency and consistency by Bristol Stool Scale
timeFrame: Baseline to week week 12
measure: • Change from baseline to weeks 6 and 12 in peripheral blood B cell and T cells (as evaluated by receptor sequencing, proteomics and cellular phenotyping) and content of soluble molecules
timeFrame: baseline to week 6 and 12
measure: • Change from baseline to weeks 2 and 12 in the architecture and cellular composition of duodenal biopsy specimens (including characterization of cellular surface markers, proteomics, metabolomics and immune cell receptor sequencing
timeFrame: Baseline to week 2 and 12
measure: • Change from baseline to week 12 in skin properties evaluated by elastography and ultrasonographic skin thickness
timeFrame: week 12 to week 12
measure: • Change from baseline to week 12 in Health-related Quality of Life assessed by EQ-5D
timeFrame: baseline to week 12
measure: • Change from week 12 through week 20 in all participants, and up to week 36 in a subset of participants in UCLA GIT score item diarrhea or bloating, depending which was the worst symptom at the baseline evaluated separately for each patient
timeFrame: week 12 to 20 and 36
measure: • Follow changes of UCLA total GIT score from week 12 through week 20 in all participants, and up to week 36 in a subset of participants
timeFrame: week 12 to 20 and 36
measure: • Follow changes in mean of HAQ-DI; VAS Fatigue; ScleroId score; and patient reported global assessment from week 12 through week 20 in all participants, and up to week 36 in a subset of participants
timeFrame: week 12 to 20 and 36
measure: • Assess changes of overall faecal microbiome composition measured by 16sRNA based methods from week 12 through week 20 in all participants, and up to week 36 in a subset of participants
timeFrame: week 12 to 20 and 36
measure: • Assess change of saliva, skin and urine microbiome measured by 16sRNA based methods from week 12 through week 20 in all participants
timeFrame: week 12 to 20
measure: • Assess change in peripheral blood B cell and T cells and content of soluble molecules from week 12 through week 20 in all participants, and up to week 36 in a subset of participants
timeFrame: week 12 to 20 and 36
measure: • Assess changes in upper GIT scores from week 12 to 20 and determine potential associations to the architecture and cellular composition of oesophagus biopsy specimens
timeFrame: week 12 to 20
measure: • Assess change from week 12 to 20 in Health-related Quality of Life assessed by EQ-5D from week 12 through week 20 in all participants, and up to week 36 in a subset of participants
timeFrame: week 12 to 20 and 36
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Tromsø
country: Norway
facility: University hospital of North Norway
city: Trondheim
country: Norway
facility: St. Olavs hospital, Trondheim university hospital
Study officials:
affiliation: Oslo University Hospital
name: Anna-Maria Hoffmann-Vold, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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