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

NCT04300426 | Completed Phase 2 DMC

• 1 other identifier: 2019-004400-35
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 4

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.

Conditions

Systemic Sclerosis

Outcome Measures

Primary Outcomes (1)

• • 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 Outcomes (4)

• • Safety and tolerability assessed by adverse event (AE) monitoring, physical examination and clinical laboratory testing from baseline to the end of the study period

  • Over the study period of 20 (+16) weeks

• • Change from baseline to week 12 in total UCLA GIT score

  baseline, week 6 and week 12.

• • Change from baseline to week 12 in UCLA GIT score item diarrhea

  baseline to week 12

• • Change from baseline to week 12 in UCLA GIT score item bloating

  baseline to week 12

Other Outcomes (25)

• • Change from baseline to week 12 in Faecal incontinence quality of life scale

  baseline to weeks 12

• • Change from baseline to week 12 in UCLA GIT score item reflux

  baseline to week 12

• • Change from baseline to week 12 in UCLA GIT score item fecal soilage

  baseline to week 12

Study Arms (2)

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.

Drug: "ACHIM" as solute (10^9 intestinal microbes/ml)

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.

Drug: "ACHIM" as solute (10^9 intestinal microbes/ml)

Interventions

"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.

Also known as: Fecal microbiota transplantation

ACHIM by gastroduodenoscopy; Placebo by gastroduodenoscopy

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Oslo University Hospital: lead
• South-Eastern Norway Regional Health Authority: collaborator
• Haukeland University Hospital: collaborator
• St. Olavs Hospital: collaborator
• University Hospital of North Norway: collaborator

Study Sites (4)

Haukeland University Hospital

Bergen, Norway

Location

Oslo University Hospital

Oslo, Norway

Location

University hospital of North Norway

Tromsø, Norway

Location

St. Olavs hospital, Trondheim university hospital

Trondheim, Norway

Location

Related Publications (14)

• 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.

  PMID: 27941129 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.

  PMID: 25372804 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.

  PMID: 28761687 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.

  PMID: 23323867 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.

  PMID: 31337728 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.

  PMID: 29860912 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.

  PMID: 19714600 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.

  PMID: 21724699 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.

  PMID: 22108748 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.

  PMID: 30665723 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.

  PMID: 31594647 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.

  PMID: 22468996 BACKGROUND

• 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.

  PMID: 39900089 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.

  PMID: 34168032 DERIVED

MeSH Terms

Conditions

Scleroderma, Systemic

Interventions

Fecal Microbiota Transplantation

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics

Study Officials

• Anna-Maria Hoffmann-Vold, MD, PhD

  Oslo University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Masking will apply for the whole duration of study until end of study defined as week 20 visit for the last participant.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: National PI

Model Details: 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.

Study Record Dates

• First Submitted: February 25, 2020
• First Posted: March 9, 2020
• Study Start: September 24, 2020
• Primary Completion: June 27, 2022
• Study Completion: June 27, 2022
• Last Updated: October 12, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Not known yet.
• Access Criteria: Not known yet.

Locations

NO (4)