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| Name | Class |
|---|---|
| Helse Nord | INDUSTRY |
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Although biologic therapy have revolutionized the treatment of Spondyloarthrtitis (SpA), many patients do not experience complete relief of SpA related complaints.
It has been established that patients with SpA have an altered composition of microorganisms (microbiota) in the gut compared to healthy controls, and that this correlates to disease activity and respons to therapy.
The goal of this randomized double-blind study is to evaluate the efficacy of fecal microbiota transplantation (FMT) in patients with axial SpA with a suboptimal effect of biologic therapy.
The main questions it aims to answer are:
Participants will receive a single treatment in the form of an enema with either donor FMT or placebo at baseline. The primary endpoint will be evaluated after 90 days, but efficacy and safety will be monitored from baseline until 365 days.
Axial Spondyloarthritis (axSpA) is a chronic inflammatory disease affecting the sacroiliac joints (SIJ) and the spine.
The approach to treatment of axSpA is a combination of patient education, with a focus on exercise and lifestyle, and a medical treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line medical treatment, providing symptom relief for a large portion of the patients. For patients with inadequate response, or intolerance, to NSAIDs, biological (TNFi and IL17i) or targeted synthetic (JAKi) disease modifying drugs (b/ts-DMARDs) are considered a second-line treatment option and provide excellent efficacy for many patients. However, a substantial portion of the patients experience active disease despite this second-line therapy.
The cause of the disease is multifactorial, and both genetic and environmental factors contribute in the pathogenesis. Patients with axSpA have a higher prevalence of inflammatory bowel disease (IBD) than the background population, i.e. Crohn's disease and ulcerative colitis. However, inflammation in the gut is also demonstrated in 50-70% of patients without symptoms of IBD, and this inflammation is believed to be of importance in the development of the disease.
The human gut microbiota is the collection of microbes in the intestines. The composition of the microbiota is the result of many factors and have evolved over time to form a mutually beneficial relationship to both humans and microorganisms. Normally there is a balance and a stability in this composition, but in many conditions an imbalance, termed dysbiosis, has been demonstrated. This is also the case in axSpA, and the extent of this dysbiosis also relates to disease activity and to response to therapy.
Fecal microbiota transplantation (FMT) is a method used to alter the microbiota composition by transferring microbes from a healthy individual to a recipient. In several conditions this has both proven the ability to alter the microbiota and to provide symptom relief , e.g. clostridium difficile infections, ulcerative colitis and irritable bowel syndrome.
Given the potential role of the microbiota in the pathogenesis of axSpA, we wish to evaluate whether replacing the microbiota in patients with inadequate response to biologic therapy with FMT can be efficacious in providing a state of inactive disease and symptom relief.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Donor A FMT | Experimental | Active treatment contain 60g of feces from a single healthy, screened donor. The feces is combined with glycerol and saline to a total volume of 440 ml in an enema bag. Each participant will only receive a single treatment at baseline. |
|
| Donor B FMT | Experimental | Active treatment contain 60g of feces from a single healthy, screened donor. The feces is combined with glycerol and saline to a total volume of 440 ml in an enema bag. Each participant will only receive a single treatment at baseline. |
|
| Donor C FMT | Experimental | Active treatment contain 60g of feces from a single healthy, screened donor. The feces is combined with glycerol and saline to a total volume of 440 ml in an enema bag. Each participant will only receive a single treatment at baseline. |
|
| Placebo/autologous FMT | Placebo Comparator | Placebo treatment will be processed identically to active treatment, but with paritcipants own stool. The patients in the placebo group will consequently receive an enema with 60g of their own feces combined with glycerol and saline as a single treatment at baseline. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| FMT | Drug | Active FMT |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Minimal Clinically Important Improvement | Proportion of patients that meet the criteria of Minimal Clinically Important Improvement in the donor FMT (dFMT) versus the autologous FMT (aFMT) group at day 90 after treatment. Minimal Clinically Important Improvement is defined by a decrease of ≥1,1 in ASDAS-CRP | 90 days |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse events | The proportion of patients experiencing any adverse events from baseline util day 90 and day 365 | Day 0-90 and day 91-365 |
| Ankylosing Spondylitis Disease Activity Score (ASDAS)20 |
| Measure | Description | Time Frame |
|---|---|---|
| Exploratory endpoint | Changes in taxonomy and function of the microbiome, the immune system, metabolome and gut epithelial barrier in participants with vs without treatment success to dFMT and aFMT | baseline and day 90 |
| Exploratory endpoint |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Gunnstein Bakland, MD PhD | Contact | +4795860791 | gunnstein.bakland@unn.no | |
| Peter Johnsen, MD PhD | Contact | peter.holger.johnsen@unn.no |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital North Norway | Recruiting | Tromsø | 9038 | Norway |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22265264 | Result | Baraliakos X, Braun J. Spondyloarthritides. Best Pract Res Clin Rheumatol. 2011 Dec;25(6):825-42. doi: 10.1016/j.berh.2011.11.006. | |
| 32433595 | Result | Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020 Jun;30(6):492-506. doi: 10.1038/s41422-020-0332-7. Epub 2020 May 20. |
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There is not an IPD established.
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| ID | Term |
|---|---|
| D000089183 | Axial Spondyloarthritis |
| D013167 | Spondylitis, Ankylosing |
| D064806 | Dysbiosis |
| D025241 | Spondylarthritis |
| D013166 | Spondylitis |
| D001168 | Arthritis |
| D009140 | Musculoskeletal Diseases |
| D013122 | Spinal Diseases |
| D007592 | Joint Diseases |
| ID | Term |
|---|---|
| D025242 | Spondylarthropathies |
| D001847 | Bone Diseases |
| D000844 | Ankylosis |
| D010335 | Pathologic Processes |
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A blinded, randomized, placebo-controlled, parallel-group, single-center, superiority, phase III clinical trial. Participants randomized til active treatment will receive FMT from one of three donors. Allocation will be random in blocks of 9 (Donor A: Donor B : Donor C : Placebo 2:2:2:3).
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A person will be responsible for the Randomization and Allocation (RAP) procedure, and will be the only person not blinded to randomization and treatment. This person will, however, be blinded for the patient´s identity.
| Placebo |
| Drug |
The placebo treatment will be prepared based on the patients' fecal samples (autologous). |
|
Change in the dFMT vs aFMT group from baseline
| baseline, day 30, day 60 and day 90 |
| Bath Ankylosing Spondylitis Disease Activity Index | Change in the dFMT vs aFMT group from baseline | baseline, day 30, day 60 and day 90 |
| Bath Anykylosing Spondylitis Funtional Index | Change in the dFMT vs aFMT group from baseline | baseline, day 30, day 60 and day 90 |
| Patient global assessment | Change in the dFMT vs aFMT group from baseline | baseline, day 30, day 60 and day 90 |
| VAS spinal pain | Change in the dFMT vs aFMT group from baseline | baseline, day 30, day 60 and day 90 |
| Modified Fatigue Impact Scale | Change in the dFMT vs aFMT group from baseline | baseline and day 90 |
| RAND-36 | Change in the dFMT vs aFMT group from baseline | baseline and day 90 |
| Maastricht Ankylosing Spondylitis Enthesitis Score | Change in the dFMT vs aFMT group from baseline | baseline and day 90 |
| The 66/68 Joint Count Score | Change in the dFMT vs aFMT group from baseline | baseline and day 90 |
| Bath Ankylosing Spondylitis Metrology Index | Change in the dFMT vs aFMT group from baseline | baseline and day 90 |
| Ankylosing Spondylitis Disease Activity Score (ASDAS)40 | Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 |
| Bath Ankylosing Spondylitis Disease Activity Index | Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 |
| Bath Anykylosing Spondylitis Funtional Index | Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 |
| Patient global assessment | Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 |
| VAS spinal pain | Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 |
| Modified Fatigue Impact Scale | Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 |
| RAND-36 | Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 |
Differences in baseline taxonomy and function of the microbiome, the immune system, metabolome and gut epithelial barrier in participants with vs without treatment success to dFMT and aFMT
| baseline |
| 30480772 | Result | Imdad A, Nicholson MR, Tanner-Smith EE, Zackular JP, Gomez-Duarte OG, Beaulieu DB, Acra S. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev. 2018 Nov 13;11(11):CD012774. doi: 10.1002/14651858.CD012774.pub2. |
| 29615661 | Result | Bazin T, Hooks KB, Barnetche T, Truchetet ME, Enaud R, Richez C, Dougados M, Hubert C, Barre A, Nikolski M, Schaeverbeke T. Microbiota Composition May Predict Anti-Tnf Alpha Response in Spondyloarthritis Patients: an Exploratory Study. Sci Rep. 2018 Apr 3;8(1):5446. doi: 10.1038/s41598-018-23571-4. |
| 29100842 | Result | Johnsen PH, Hilpusch F, Cavanagh JP, Leikanger IS, Kolstad C, Valle PC, Goll R. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol. 2018 Jan;3(1):17-24. doi: 10.1016/S2468-1253(17)30338-2. Epub 2017 Nov 1. |
| 32173258 | Result | Breban M, Beaufrere M, Glatigny S. The microbiome in spondyloarthritis. Best Pract Res Clin Rheumatol. 2019 Dec;33(6):101495. doi: 10.1016/j.berh.2020.101495. Epub 2020 Mar 12. |
| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D001850 | Bone Diseases, Infectious |
| D007239 | Infections |