Ankylosing Spondylitis, Arthritis, Axial Spondyloarthritis, Dysbiosis, Joint Diseases, Musculoskeletal Diseases, Spinal Disease, Spondylitis, Spondyloarthritis
Conditions
Keywords
Axial Spondyloarthritis, Microbiome, Fecal Microbiota Transplantation, Microbiota, FMT, RCT
Brief summary
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: * Can FMT reduce disease activity in axial SpA? * Can FMT alleviate pain and reduce fatigue in axial SpA? * Is the composition of microorganisms restored to normal in patients with SpA after a treatment with FMT? 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.
Detailed description
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. In the Microspa study, we aim to evaluate whether fecal microbiota transplantation (FMT) can induce clinical remission and symptom relief in patients with axial spondyloarthritis who have shown an inadequate response to biologic therapy. Microspa 2 is a parallel trial that retains the overall design of the original study, with adjustments made to the eligibility criteria and primary and secondary endpoints. All other components-including outcome measures, sample size, randomization strategy, and statistical analysis plan-remain unchanged. In Microspa 2, eligible participants include patients who are biologic-naïve or who have previously used biologic therapy but discontinued treatment. Patients currently receiving biologic therapy are excluded. The primary endpoint is the proportion of patients in the donor FMT group compared to the autologous FMT group who initiate immunomodulatory treatment within 90 days following the intervention. An additional secondary endpoint is the proportion of patients initiating immunomodulatory treatment within 365 days post-intervention.
Interventions
DRUGFMT
Active FMT
DRUGPlacebo
The placebo treatment will be prepared based on the patients' fecal samples (autologous).
Sponsors
University Hospital of North Norway
Helse Nord
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
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.
Intervention model description
A blinded, randomized, placebo-controlled, parallel-group, single-center, superiority, phase II clinical trial. Participants randomized to 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).
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Axial Spondyloarthritis according to the ASAS classification criteria * Active disease defined as ASDAS ≥2.1 with elevated CRP ≥3 OR active inflammation on MRI within the last 3 months * Onset of axial SpA within last 10 years * Unsatisfactory relief of NSAIDs * On stable immunomodulatory treatment (TNFi, IL17i or JAKi) the last 3 months OR without immunomodulatory treatment last 3 months
Exclusion criteria
* Planned dose adjustment or change in immunomodulatory treatment the next 90 days * Disease or disorder with life expectancy of ≤5 years * Severe immune deficiency (acquired, congenital og du to medication) * Previous treatment with FMT * Regular use of opioids with the exception of codeine and tramadol * Any specific diagnosis that could explain or contribute to the patients back pain (e.g. tumor, fracture, infection or degenerative disease) * Inflammatory spinal disease other than axSpA * Severe psychiatric disorder, alcohol- or drug abuse * Active inflammatory bowel disease * Microscopic colitis, diverticulitis or ileus * Active psoriasis * Fibromyalgia * Abdominal surgery excluding appendectomy, cholecystectomy, hysterectomy, caesarian section, sapling-ooforectomy and hernia surgery * Malignant disease excluding basalioma and melanoma stage 1 * Conditions with expected necessary treatment with antibiotics during the study period, e.g. periodontitis end ischemic digital ulcers * Treatment with antibiotics 12 weeks prior to study entry * Pregnancy, lactation or planned pregnancy within the next 3 months * Contraindications for rectal catheter insertion * Planned rehabilitation program the next 90 days * Limited ability to comply with protocol requirements, including biobank participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Minimal Clinically Important Improvement | 90 days | 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 (FMT - Fecal Microbiota Transplantation). Minimal Clinically Important Improvement is defined by a decrease of ≥1,1 in ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | Day 0-90 and day 91-365 | The proportion of patients experiencing any adverse events from baseline util day 90 and day 365 |
| Assessment in Spondyloarthritis International Society (ASAS)20 | baseline, day 30, day 60 and day 90 | Improvement of at least 20% in 3 out of four domains without worsening of 20% or more in the remaining domain. Change in the dFMT vs aFMT group from baseline |
| Bath Ankylosing Spondylitis Disease Activity Index (BASDAI, 0-10) | baseline, day 30, day 60 and day 90 | Higher score indicates more active disease. Change in the dFMT vs aFMT group from baseline |
| Bath Ankylosing Spondylitis Funtional Index (BASFI, 0-10) | baseline, day 30, day 60 and day 90 | Higher score indicating more severe disease impact. Change in the dFMT vs aFMT group from baseline |
| Patient global assessment of disease (PGA, 0-10) | baseline, day 30, day 60 and day 90 | Patient's evaluation of disease impact. Higher score indicating worse disease. Change in the dFMT vs aFMT group from baseline |
| VAS spinal pain (Visual Analogue Scale, 0-10) | baseline, day 30, day 60 and day 90 | Patient's evaluation of pain on av visual analogue scale. Higher score indicating worse pain. Change in the dFMT vs aFMT group from baseline |
| Modified Fatigue Impact Scale (0-84) | baseline and day 90 | Higher score indicating greater impact of fatigue on daily life. Change in the dFMT vs aFMT group from baseline |
| RAND-36 (Quality-of-life measure) | baseline and day 90 | Change in the dFMT vs aFMT group from baseline |
| Maastricht Ankylosing Spondylitis Enthesitis Score (MASES, 0-13) | baseline and day 90 | Higher score indicating more widespread pain. Change in the dFMT vs aFMT group from baseline |
| The 66/68 Joint Count Score | baseline and day 90 | Indicating number of swollen and tender joints. Change in the dFMT vs aFMT group from baseline |
| Bath Ankylosing Spondylitis Metrology Index (BASMI) | baseline and day 90 | Indicating restricted mobility. Change in the dFMT vs aFMT group from baseline |
| Ankylosing Spondylitis Disease Activity Score (ASDAS)40 | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 | Improvement of at least 40% in 3 out of four domains without worsening of 20% or more in the remaining domain.Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline |
| Bath Anykylosing Spondylitis Funtional Index (BASFI, 0-10) | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 | Higher score indicating more severe disease impact. Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline |
| Patient global assessment (PGA, 0-10) | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 | Patient's evaluation of disease impact. Higher score indicating worse disease. Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline |
| VAS spinal pain (0-10) | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 | Patient's assessment of spinal pain og visual scale. Higher score indicates more pain. Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline |
| RAND-36 | baseline and day 30, day 60, day 90, day 180, day 270 and day 365 | Quality-of-life measure. Long term change that includes the extended open labeled follow up in the dFMT vs aFMT group from baseline |
Countries
Norway
Contacts
CONTACTGunnstein Bakland, MD PhD
CONTACTPeter Johnsen, MD PhD
Outcome results
None listed