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The Effect of Fecal Microbiota Transplantation in Ankylosing Spondylitis (AS) Patients. (ASGUT)

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ClinicalTrials.gov Identifier: NCT03726645
Recruitment Status : Enrolling by invitation
First Posted : October 31, 2018
Last Update Posted : May 31, 2019
Sponsor:
Information provided by (Responsible Party):
Johanna Hiltunen, Hospital District of Helsinki and Uusimaa

Brief Summary:

Ankylosing spondylitis (AS) patients often have subclinical gut wall inflammation. Gut dysbiosis has been associated with both AS and Crohn disease, both of which have several features in common. Gut dysbiosis is associated with specific microbial profile in AS patients. Fecal microbiota transplantation (FMT) has been proved to be safe and effective treatment for recurrent Clostridium difficile infection, and the change in gut microbiota is shown to be long lasting. It has led to interest to study its effect on different inflammatory conditions associated with gut dysbiosis.

We hypothesize that dysbiosis in AS leads to inflammasome overactivation on gut mucosa. We aim to study the role of gut inflammation, gut microbiota and inflammasome activation in pathogenesis of AS, and the effect of FMT on these factors, as well as clinical activity, in AS patients.


Condition or disease Intervention/treatment Phase
Ankylosing Spondylitis Other: Fecal microbiota transplantation Early Phase 1

Detailed Description:
This is a double-blind placebo- controlled randomized pilot study with 20 patients with active AS from 2 Finnish outpatient clinics. An ileocolonoscopy will be performed to all patients. 10 patients will receive FMT with feces of one of two healthy donors, and 10 patients with their own feces during ileocolonoscopy. Ileal and colonic biopsies will be taken to assess gut wall inflammation and mucosal microbiota composition. Ileocolonoscopy will be controlled in 6 months in patients with macroscopic inflammatory lesions in the first colonoscopy. From mucosal biopsies we will assess intestinal mucosal structure, inflammasome activity, cytokine expression, and the mucin layer thickness and the amount of bacterial LPS (lipopolysaccharide), which are associated with mucosal integrity. Blood levels of zonulin and LPS as indicators of mucosal permeability and bacterial penetrance will be assessed. Fecal samples will be collected repeatedly to measure fecal calprotectin, and to assess the bacterial profile changes. From mucosal biopsies and fecal samples microbial DNA will be segregated and bacterial species sorted by rRNA- based sequence technique. Clinical activity of AS will be assessed in follow-up visits as well as repeated BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), BASFI (Bath Ankylosing Spondylitis Functional Index) and MASES (Maastricht Ankylosing Spondylitis Enthesitis Score) evaluations, and measurement of CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate). Follow-up time is 12 months.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: FMT type (donor/own feces) randomization is done by a study nurse.
Primary Purpose: Treatment
Official Title: The Role of Gut Microbiota in the Pathogenesis of Ankylosing Spondylitis (AS), and the Effect of Fecal Microbiota Transplantation on Gut Microbiota, Gut Wall Inflammation and Clinical Activity of AS
Actual Study Start Date : October 24, 2018
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020


Arm Intervention/treatment
Active Comparator: Study group
Allogeneic fecal microbiota transplantation (from donor)
Other: Fecal microbiota transplantation
Fecal microbiota transplantation

Placebo Comparator: Control group
Autologous fecal microbiota transplantation (own stool)
Other: Fecal microbiota transplantation
Fecal microbiota transplantation




Primary Outcome Measures :
  1. The effect of FMT (fecal microbiota transplantation) on the clinical activity of ankylosing spondylitis (AS) as assessed by change in BASDAI (Bath Ankylosing Spondylitis Disease Activity Index). [ Time Frame: 5 measurements within 12 months ]
    BASDAI scale 0-10 (the higher the score the more severe the symptoms). Decrease in BASDAI indicates positive outcome.


Secondary Outcome Measures :
  1. The effect of FMT on the clinical activity of AS as assessed by change in BASFI (Bath Ankylosing Spondylitis Functional Index). [ Time Frame: 5 measurements within 12 months. ]
    BASFI scale 0-10 (the higher the score the more severe the symptoms). Decrease in BASFI indicates positive outcome.

  2. The effect of FMT on the clinical activity of AS as assessed by change in MASES (Maastricht Ankylosing Spondylitis Enthesitis Score). [ Time Frame: 5 measurements within 12 months. ]
    MASES scale 0-13 (the higher the score the more severe the symptoms). Decrease in MASES indicates positive outcome.

  3. The effect of FMT on C-reactive protein (CRP) concentration. [ Time Frame: 7 measurements within 12 months. ]
    Change in inflammatory parameter CRP concentration indicates positive outcome.

  4. The effect of FMT on erythrocyte sedimentation rate (ESR) level. [ Time Frame: 7 measurements within 12 months. ]
    Change in inflammatory parameter ESR level indicates positive outcome.

  5. The effect of FMT on gut wall inflammation as assessed by change in fecal calprotectin (F-calpro) level. [ Time Frame: 7 measurements within 12 months. ]
    Change in fecal calprotectin level indicates positive outcome.

  6. The effect of FMT on gut microbiota composition in AS patients. [ Time Frame: 7 stool microbial analysis within 12 months. ]
    Change in gut microbiota composition evaluated by stool microbial analysis indicates positive outcome.

  7. Association between specific intestinal pathogens and disease activity as assessed by BASDAI score. [ Time Frame: 7 stool microbial samples and 5 BASDAI measurements within 12 months. ]
    BASDAI scale 0-10 (the higher the score the more severe the symptoms). Association between specific microbial profile and higher or lower disease activity assessed by BASDAI indicates a positive outcome.

  8. Association between specific intestinal pathogens and disease activity as assessed by CRP concentration. [ Time Frame: 7 stool microbial samples and 7 CRP measurements within 12 months. ]
    Association between specific intestinal pathogens and (higher or lower) CRP concentration compared to patients with different microbial profile indicates a positive outcome.

  9. Association between gut wall cytokine expression and disease activity as assessed by BASDAI score. [ Time Frame: Intestinal biopsies at baseline. ]
    BASDAI scale 0-10 (the higher the score the more severe the symptoms). Association between the level of cytokine expression and BASDAI score indicates a positive outcome.

  10. Association between gut wall inflammasome activity and disease activity as assessed by BASDAI score. [ Time Frame: Intestinal biopsies at baseline. ]
    BASDAI scale 0-10 (the higher the score the more severe the symptoms). Association between gut wall inflammation as assessed by inflammasome activity and disease activity as assessed by BASDAI score indicates a positive outcome.

  11. Association between gut wall cytokine expression and disease activity as assessed by CRP concentration. [ Time Frame: Intestinal biopsies at baseline. ]
    Association between gut wall inflammation as assessed by the level of cytokine expression and the disease activity as assessed by CRP concentration indicates a positive outcome.

  12. Association between gut wall inflammasome activity and disease activity as assessed by CRP concentration. [ Time Frame: Intestinal biopsies at baseline. ]
    Association between gut wall inflammation as assessed by inflammasome activity and disease activity as assessed by CRP concentration indicates a positive outcome.

  13. Association between F-Calpro level and disease activity as assessed by BASDAI score. [ Time Frame: 7 F-Calpro- measurements and 5 BASDAI measurements within 12 months. ]
    Calprotectin- level < 100 ug/l is considered as normal. BASDAI scale 0-10 (the higher the score the more severe the symptoms). Association between gut wall inflammation as assessed by F-Calpro level and disease activity as assessed by BASDAI score indicates a positive outcome.

  14. Association between F-Calpro level and disease activity as assessed by CRP concentration. [ Time Frame: 7 F-Calpro and CRP measurements within 12 months. ]
    Calprotectin- level < 100 ug/l is considered as normal. Association between gut wall inflammation as assessed by F-Calpro and disease activity as assessed by CRP concentration indicates a positive outcome.

  15. The effect of FMT on gut wall permeability as assessed by blood zonulin concentration. [ Time Frame: 5 measurements within 12 months. ]
    Change in zonulin concentration indicates a positive outcome.

  16. The effect of FMT on gut wall bacterial penetrance as assessed by lipopolysaccharide (LPS) concentration. [ Time Frame: 5 measurements within 12 months. ]
    Change in LPS concentration indicates a positive outcome.

  17. The effect of FMT on gastrointestinal symptoms as assessed by GSRS (The Gastrointestinal Symptom Rating Scale). [ Time Frame: 5 GSRS evaluations within 12 months. ]
    GSRS score scale 15-105. The higher the score the more severe the symptoms. Decrease in GSRS indicates a positive outcome.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of AS by either the 1984 New York criteria or the ASAS (Assessment of SpondyloArthritis International Society) criteria for axial spondyloarthritis.
  • Active disease measured by BASDAI > 4.
  • Availability of consecutive fecal samples over 1 year period.
  • Compliance to attend ileocolonoscopy and FMT procedure.

Exclusion Criteria:

  • Diagnosis of inflammatory bowel disease.
  • Antibiotic therapy within the last 3 months.
  • Use of any probiotics within the last 3 months.
  • Pregnancy.
  • Unability to provide a written consent.
  • Other reason which by the opinion of the investigator makes patient ineligible for the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03726645


Locations
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Finland
Hospital District of Helsinki and Uusimaa, Department of Rheumatology
Helsinki, Uusimaa, Finland, 00029
Sponsors and Collaborators
Hospital District of Helsinki and Uusimaa
Investigators
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Study Director: Kari K Eklund, PhD, MD Hospital District of Helsinki and Uusimaa

Publications:

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Responsible Party: Johanna Hiltunen, MD, Principal Investigator, Hospital District of Helsinki and Uusimaa
ClinicalTrials.gov Identifier: NCT03726645     History of Changes
Other Study ID Numbers: HospitalDHU/Rheumatology
First Posted: October 31, 2018    Key Record Dates
Last Update Posted: May 31, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Johanna Hiltunen, Hospital District of Helsinki and Uusimaa:
ankylosing spondylitis
fecal microbiota transplantation
intestinal mucosal immunity
dysbiosis
microbiome

Additional relevant MeSH terms:
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Spondylitis
Spondylitis, Ankylosing
Bone Diseases, Infectious
Infection
Bone Diseases
Musculoskeletal Diseases
Spinal Diseases
Spondylarthropathies
Spondylarthritis
Ankylosis
Joint Diseases
Arthritis