Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| South-Eastern Norway Regional Health Authority | OTHER |
| Haukeland University Hospital | OTHER |
| St. Olavs Hospital | OTHER |
| University Hospital of North Norway |
Not provided
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ACHIM by gastroduodenoscopy | Experimental | 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. |
|
| Placebo by gastroduodenoscopy | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| "ACHIM" as solute (10^9 intestinal microbes/ml) | Drug | 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. |
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| • Change from baseline to week 12 in Faecal incontinence quality of life scale | Fecal Incontinence Quality-of-Life Scale is a validated patients reported outcome divided in four subscales all rated from 1-4 (5,6) by 1 having lowest quality of life. Change=(week12 score-baseline score) | baseline to weeks 12 |
| • Change from baseline to week 12 in UCLA GIT score item reflux |
Inclusion Criteria:
Exclusion Criteria:
Medical Conditions
Cardiovascular diseases, any of the following
Lung disease with impaired respiratory function, any of the following
Significant pulmonary hypertension, any of the following
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
Chronic liver disease or gastro-intestinal condition, any of the following
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.
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Anna-Maria Hoffmann-Vold, MD, PhD | Oslo University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Haukeland University Hospital | Bergen | Norway | ||||
| Oslo University Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27941129 | Background | Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, Distler O, Clements P, Cutolo M, Czirjak L, Damjanov N, Del Galdo F, Denton CP, Distler JHW, Foeldvari I, Figelstone K, Frerix M, Furst DE, Guiducci S, Hunzelmann N, Khanna D, Matucci-Cerinic M, Herrick AL, van den Hoogen F, van Laar JM, Riemekasten G, Silver R, Smith V, Sulli A, Tarner I, Tyndall A, Welling J, Wigley F, Valentini G, Walker UA, Zulian F, Muller-Ladner U; EUSTAR Coauthors. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017 Aug;76(8):1327-1339. doi: 10.1136/annrheumdis-2016-209909. Epub 2016 Nov 9. | |
| 25372804 |
Not provided
Not provided
The investigators plan to publish the protocol and statistical analysis plan separately. The IPD will be published according to relevant legislation and as required by publishing authority.
Not known yet.
Not known yet.
Not provided
Not provided
| ID | Term |
|---|---|
| D012595 | Scleroderma, Systemic |
| ID | Term |
|---|---|
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012871 | Skin Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000069467 | Fecal Microbiota Transplantation |
| ID | Term |
|---|---|
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
Not provided
Not provided
| OTHER |
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.
Not provided
Not provided
Masking will apply for the whole duration of study until end of study defined as week 20 visit for the last participant.
|
| • 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 |
The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The reflux scale is scored on a Visual Analog Scale from 0 (better) to 3 (worse) . Change=(week12 score-baseline score) |
| baseline to week 12 |
| • Change from baseline to week 12 in UCLA GIT score item fecal soilage | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The fecal soilage scale is scored on a Visual Analog Scale from 0 (better) to 3 (worse) . Change=(week12 score-baseline score) | baseline to week 12 |
| • Change from baseline to week 12 in UCLA GIT score item constipation | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The constipation 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 emotional wellbeing | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The emotional wellbeing scale is scored on a Visual Analog Scale from 0 (better) to 3 (worse) . Change=(week12 score-baseline score) | baseline to week 12 |
| • Change from baseline to week 12 in UCLA GIT score item social participation | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The social participation scale is scored on a Visual Analog Scale from 0 (better) to 3 (worse) . Change=(week12 score-baseline score) | baseline to week 12 |
| • Change from baseline to week 12 in • Change from baseline to week 12 in HAQ-DI scores | The HAQ-DI is a patient reported outcome measuring generic health status and quality of life scale ranging from 0 to 3, with no difficultie (scale 0) up to major difficulties (scale 3). Change=(week12 score-baseline score) | baseline to week 12 |
| • Change from baseline to week 12 in VAS Fatigue scale | The fatigue scale measures fatigue representing how the participant feel, along a visual analogue line that extends between "not at all tired" (0) to "extremely tired" (10). Change=(week12 score-baseline score) | baseline to week 12 |
| • Change from baseline to week 12 in ScleroId score | The ScleroId has 10 SSc specific questionnes all along a visual analogue line that extends between "none" (0) to "extreme" (10) with a maximum score of 100. Change=(week12 score-baseline score) | baseline to week 12 |
| • Change from baseline to weeks 2, 6 and 12 in overall faecal microbiome composition measured by 16sRNA based methods | 16sRNA based methods measure the fecal microbiota composition and will be assessed at 4 timepoints. Changes from baseline to week 2,6 and 12 will be assessed. | baseline to week 2, 6 and 12 |
| • Change from baseline to week 12 in saliva, skin and urine microbiome measured by 16sRNA based methods | 16sRNA based methods measure the microbiota composition and will be assessed at 4 timepoints. Changes from baseline to week 2,6 and 12 will be assessed. | baseline to week 12 |
| • Change from baseline to weeks 2, 6 and 12 in immunoglobulin bound fraction of the overall faecal microbiome | 16sRNA based methods measure the fecal microbiota composition which is Ig coated and will be assessed at 4 timepoints. Changes from baseline to week 2,6 and 12 will be assessed. | • Baseline up to week 2, 6 and 12 |
| • 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 | In a subgroup of patients SmartPill technology assesses gastrointestinal transit time. Chenges will be assessed frombaseline to week 12 | Baseline to week week 12 |
| • 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 | Blood samples will be assessed for changes from baseline to weeks 6 and 12 | baseline to week 6 and 12 |
| • 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 | Tissue samples will be assessed from skin and intestines and changes from baseline to weeks 2 and 12 determined | Baseline to week 2 and 12 |
| • Change from baseline to week 12 in skin properties evaluated by elastography and ultrasonographic skin thickness | Elastography assess skin properties and will be assessed in a subset of patients at baseline and week 12 | week 12 to week 12 |
| • Change from baseline to week 12 in Health-related Quality of Life assessed by EQ-5D | The EQ-5D is a generic health status and quality of life scale. The respondents evaluate their overall health status using the visual analogue scalend scales of 1-3 with higher values having worse health. Change=(week12 score-baseline score) | baseline to week 12 |
| • 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 | 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), the bloting from 0-3. Change=(week20 score-week 12 score) | week 12 to 20 and 36 |
| • 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 | 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=(week20 score-week 12 score) | week 12 to 20 and 36 |
| • 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 | See endpoints explained above for the different outcome measures and explanations | week 12 to 20 and 36 |
| • 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 | 16sRNA based methods measure the microbiota composition and will be assessed at week 12, 20 and partly 36. Changes from to week 12 to week 20 and in a subset to week 36 will be assessed. | week 12 to 20 and 36 |
| • Assess change of saliva, skin and urine microbiome measured by 16sRNA based methods from week 12 through week 20 in all participants | 16sRNA based methods measure the microbiota composition and will be assessed at week 12 and 20. Changes from week 12 to week 20 will be assessed. | week 12 to 20 |
| • 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 | Blood samples will be assessed for changes from week 12 to week 20 and 36 in a subset | week 12 to 20 and 36 |
| • 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 | The UCLA GIT score is a validated patient reported outcome measure capturing and grading GI symptoms related to SSc. The reflux scale is scored on a Visual Analog Scale from 0 (better) to 3 (worse) . Change=(week20 score-week 12 score) and assess changes in association with øsophagus biopsies | week 12 to 20 |
| • 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 | The EQ-5D is a generic health status and quality of life scale. The respondents evaluate their overall health status using the visual analogue scalend scales of 1-3 with higher values having worse health. Change=(week20 and 36 score-week 12 score) | week 12 to 20 and 36 |
| Oslo |
| Norway |
| University hospital of North Norway | Tromsø | Norway |
| St. Olavs hospital, Trondheim university hospital | Trondheim | Norway |
| Background |
| Hansi N, Thoua N, Carulli M, Chakravarty K, Lal S, Smyth A, Herrick A, Ogunbiyi O, Shaffer J, Mclaughlin J, Denton C, Ong V, Emmanuel AV, Murray CD. Consensus best practice pathway of the UK scleroderma study group: gastrointestinal manifestations of systemic sclerosis. Clin Exp Rheumatol. 2014 Nov-Dec;32(6 Suppl 86):S-214-21. Epub 2014 Nov 5. |
| 28761687 | Background | Volkmann ER, Hoffmann-Vold AM, Chang YL, Jacobs JP, Tillisch K, Mayer EA, Clements PJ, Hov JR, Kummen M, Midtvedt O, Lagishetty V, Chang L, Labus JS, Molberg O, Braun J. Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts. BMJ Open Gastroenterol. 2017 Apr 1;4(1):e000134. doi: 10.1136/bmjgast-2017-000134. eCollection 2017. |
| 23323867 | Background | van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037. Epub 2013 Jan 16. |
| 31337728 | Background | Staley C, Kaiser T, Vaughn BP, Graiziger C, Hamilton MJ, Kabage AJ, Khoruts A, Sadowsky MJ. Durable Long-Term Bacterial Engraftment following Encapsulated Fecal Microbiota Transplantation To Treat Clostridium difficile Infection. mBio. 2019 Jul 23;10(4):e01586-19. doi: 10.1128/mBio.01586-19. |
| 29860912 | Background | Juul FE, Garborg K, Bretthauer M, Skudal H, Oines MN, Wiig H, Rose O, Seip B, Lamont JT, Midtvedt T, Valeur J, Kalager M, Holme O, Helsingen L, Loberg M, Adami HO. Fecal Microbiota Transplantation for Primary Clostridium difficile Infection. N Engl J Med. 2018 Jun 28;378(26):2535-2536. doi: 10.1056/NEJMc1803103. Epub 2018 Jun 2. No abstract available. |
| 19714600 | Background | Khanna D, Hays RD, Maranian P, Seibold JR, Impens A, Mayes MD, Clements PJ, Getzug T, Fathi N, Bechtel A, Furst DE. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. Arthritis Rheum. 2009 Sep 15;61(9):1257-63. doi: 10.1002/art.24730. |
| 21724699 | Background | Khanna D, Furst DE, Maranian P, Seibold JR, Impens A, Mayes MD, Clements PJ, Getzug T, Hays RD. Minimally important differences of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. J Rheumatol. 2011 Sep;38(9):1920-4. doi: 10.3899/jrheum.110225. Epub 2011 Jul 1. |
| 22108748 | Background | Dehli T, Martinussen M, Mevik K, Stordahl A, Sahlin Y, Lindsetmo RO, Vonen B. Translation and validation of the Norwegian version of the fecal incontinence quality-of-life scale. Scand J Surg. 2011;100(3):190-5. doi: 10.1177/145749691110000310. |
| 30665723 | Background | Yang Y, Qiu L, Wang L, Xiang X, Tang Y, Li H, Yan F. Quantitative Assessment of Skin Stiffness Using Ultrasound Shear Wave Elastography in Systemic Sclerosis. Ultrasound Med Biol. 2019 Apr;45(4):902-912. doi: 10.1016/j.ultrasmedbio.2018.11.015. Epub 2019 Jan 18. |
| 31594647 | Background | Benno P, Norin E, Midtvedt T, Hellstrom PM. Therapeutic potential of an anaerobic cultured human intestinal microbiota, ACHIM, for treatment of IBS. Best Pract Res Clin Gastroenterol. 2019 Jun-Aug;40-41:101607. doi: 10.1016/j.bpg.2019.03.003. Epub 2019 Apr 29. |
| 22468996 | Background | Jorup-Ronstrom C, Hakanson A, Sandell S, Edvinsson O, Midtvedt T, Persson AK, Norin E. Fecal transplant against relapsing Clostridium difficile-associated diarrhea in 32 patients. Scand J Gastroenterol. 2012 May;47(5):548-52. doi: 10.3109/00365521.2012.672587. Epub 2012 Apr 2. |
| 39900089 | Derived | Fretheim H, Barua I, Bakland G, Dhainaut A, Halse AK, Carstens MN, Didriksen H, Midtvedt O, Lundin KEA, Aabakken L, Sarna VK, Zare HK, Khanna D, Distler O, Midtvedt T, Baekkevold ES, Olsen IC, Domanska D, Pesonen ME, Molberg O, Hoffmann-Vold AM. Faecal microbiota transplantation in patients with systemic sclerosis and lower gastrointestinal tract symptoms in Norway (ReSScue): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Rheumatol. 2025 May;7(5):e323-e332. doi: 10.1016/S2665-9913(24)00334-5. Epub 2025 Jan 31. |
| 34168032 | Derived | Hoffmann-Vold AM, Fretheim HH, Sarna VK, Barua I, Carstens MN, Distler O, Khanna D, Volkmann ER, Midtvedt O, Didriksen H, Dhainaut A, Halse AK, Bakland G, Pesonen M, Olsen I, Molberg O. Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome (ACHIM) in patients with systemic sclerosis: study protocol for the randomised controlled phase II ReSScue trial. BMJ Open. 2021 Jun 24;11(6):e048541. doi: 10.1136/bmjopen-2020-048541. |