Faecal Analyses in Rheumatoid Arthritis Therapy (FART)

• ClinicalTrials.gov Identifier: NCT03775824
• Recruitment Status: Completed
• First Posted: December 14, 2018
• Last Update Posted: September 16, 2019
• Sponsor: Region Skane
• Information provided by (Responsible Party): Kristofer Andreasson, Region Skane

Tracking Information

• First Submitted Date: December 11, 2018
• First Posted Date: December 14, 2018
• Last Update Posted Date: September 16, 2019
• Actual Study Start Date: August 1, 2016
• Actual Primary Completion Date: November 1, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 19, 2018)

• Intestinal gut flora in rheumatoid arthritis [ Time Frame: Analysis made at study start/baseline ]
  Intestinal gut flora based on DNA-based microbial analysis of fecal samples
• Change in gut flora [ Time Frame: Change from baseline Dysbiosis Index Score at 6 months ]
  Change in Dysbiosis Index Score at follow up compared to baseline. The Dysbiosis Index Score measures degree of intestinal dysbiosis on a scale from 1 to 5, where 5 indicates dysbiosis. The Index has been extensively described at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029765/
• Change in disease activity/treatment response at follow up [ Time Frame: Change from baseline DAS-28 at 6 months ]
  Change in Disease Activity Score 28 (DAS-28), an established index of disease activity in rheumatoid arthritis between 0-10, where 10 equals maximum activity.

Original Primary Outcome Measures (submitted: December 11, 2018)

• Intestinal gut flora in rheumatoid arthritis [ Time Frame: Analysis made at study start/baseline ]
  Intestinal gut flora based on DNA-based microbial analysis of fecal samples
• Change in gut flora [ Time Frame: Change from baseline Dysbiosis Index Score at 6 months ]
  Change in intestinal gut flora assessed by Dysbiosis Index Score at follow up compared to baseline
• Change in disease activity/treatment response at follow up [ Time Frame: Change from baseline DAS-28 at 6 months ]
  Change in rheumatoid arthritis disease activity based on Disease Activity Score 28 (DAS-28), a Composite index of disease activity between 0-10, where 10 equals maximum activity

Current Secondary Outcome Measures (submitted: December 19, 2018)

• Adherance to immunosuppressive therapy [ Time Frame: Analysis made at 6 months follow up ]
  Is the patient still prescribed the same immunosuppressant compared to baseline?
• Change in intestinal concentration Prevotella [ Time Frame: Change from baseline concentration at 6 months ]
  Alterations in intestinal concentrations of Prevotella bacteria according to polymerase chain reaction (PCR)-based analysis
• Change in intestinal concentration Lactobacillus [ Time Frame: Change from baseline concentration at 6 months ]
  Alterations in intestinal concentrations of Lactobacillus bacteria according to PCR-based analysis
• Change in intestinal concentration Clostridia [ Time Frame: Change from baseline concentration at 6 months ]
  Alterations in intestinal concentrations of Clostridia bacteria according to PCR-based analysis

Original Secondary Outcome Measures (submitted: December 11, 2018)

• Drug survival [ Time Frame: Analysis made at 6 months follow up ]
  Patient still taking drug at follow up
• Change in concentration of specific gut bacteria [ Time Frame: Change from baseline concentration at 6 months ]
  Alterations in intestinal concentrations of the following bacteria; Prevotella, Lactobacillus and Clostridia

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Faecal Analyses in Rheumatoid Arthritis Therapy
• Official Title: Faecal Analyses in Rheumatoid Arthritis Therapy: An Prospective Observational Study of the Intestinal Microbiome in Patients With Rheumatoid Arthritis Receiving Immunosuppressive Therapy

Brief Summary

This study evaluates the intestinal microbiome and disease activity in patients with rheumatoid arthritis receiving immunosuppressive therapy. Patients will be analysed at two time points in reference to two predefined primary endpoints:

• Changes in intestinal microbiome
• Response to therapy

The investigators want to evaluate if successful treatment of rheumatoid arthritis coincide with specific changes in the gut flora.

Detailed Description

Methotrexate (MTX) and tumor necrosis factor (TNF) -inhibitors are two efficient medications for the treatment of rheumatoid arthritis. In a substantial number of cases however, these medications remain ineffective. At present, the scientific community has limited understanding of why some patients are resistant to these medications. The purpose of this study is to understand if the gut flora may associate with treatment response.

Recent studies have associated rheumatoid arthritis with intestinal dysbiosis. Specifically, the bacteria Prevotella copri, has been associated with this disease, an observation that has been supported also by mechanistic studies. In patients receiving methotrexate, normalization of dysbiosis has been associated with successful treatment.

This study is of observational character and integrated in the routine clinical care of patients with rheumatoid arthritis at the Rheumatology Clinic, Skane University Hospital, Lund, Sweden. Study participants are asked to deliver blood and fecal sampling at two time-points together with clinical evaluation of disease activity. With an estimated inclusion of 50 patients, at least 20 responders and 20 non-responders are expected to be included and to be compared to each other.

If successful treatment response in rheumatoid arthritis is associated with specific alterations of the gut flora, these results may guide future studies on the impact of dysbiosis and probiotics on this disease.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples Without DNA

Description:

Faecal and blood samples from study participants are stored in a biorepository.

• Sampling Method: Non-Probability Sample

Study Population

This study encompasses consecutive patients with rheumatoid arthritis who by their physician at the Rheumatology Clinic, Skåne University Hospital, have been prescribed any of the predefined drugs.

Patients who are willing to comply with the study protocoll are included.

The study population is consequently not a sample, but encompasses a majority of patients being prescribed theses medications at our University clinic.

• Condition: Rheumatoid Arthritis

Intervention

• Drug: MTX start
  Patient prescribed MTX s.c. or p.o. because of active rheumatoid arthritis
  Other Name: MTX
• Drug: TNF start
  Patient prescribed TNF-inhibitor because of active rheumatoid arthritis
  Other Name: TNF

Study Groups/Cohorts

• MTX start
  Patients with active rheumatoid arthritis who are either naive to methotrexate, or have not used this medicine in the last year and who are about to start therapy with methotrexate i.v. or s.c.
  Intervention: Drug: MTX start
• TNF start
  Patients with active rheumatoid arthritis who are either naive to TNF-inhibitors, or have not used this medicine in the last year and who are about to start therapy with any of the following (biosimilars included); infliximab, adalimumab, etanercept, certolizumab or golimumab
  Intervention: Drug: TNF start

Publications *

• Andréasson K, Alrawi Z, Persson A, Jönsson G, Marsal J. Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease. Arthritis Res Ther. 2016 Nov 29;18(1):278.
• Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015 Aug;21(8):895-905. doi: 10.1038/nm.3914. Epub 2015 Jul 27.
• Pianta A, Arvikar SL, Strle K, Drouin EE, Wang Q, Costello CE, Steere AC. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest. 2017 Aug 1;127(8):2946-2956. doi: 10.1172/JCI93450. Epub 2017 Jun 26.

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: December 11, 2018): 50
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: June 1, 2019
• Actual Primary Completion Date: November 1, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Rheumatoid arthritis according to the 2010 classification criteria
• About to start methotrexate or TNF-inhibitor because of active disease

Exclusion Criteria:

• Failure to understand protocol
• A history of alcohol abuse
• Concomitant inflammatory bowel disease
• Any history of diverticulitis
• A history of failure to comply with prescribed medication
• Ongoing biological therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT03775824
• Other Study ID Numbers: FART1
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Kristofer Andreasson, Region Skane
• Study Sponsor: Region Skane
• Collaborators: Not Provided

Investigators

• Principal Investigator: Kristofer Andréasson, MD PhD; Skane University Hospital

• PRS Account: Region Skane
• Verification Date: September 2019