Efficacy and Safety of Fecal Microbiota Transplantation in Peripheral Psoriatic Arthritis

Psoriatic Arthritis Clinical Trial

— FLORA  

Official title:

Efficacy and Safety of Fecal Microbiota Transplantation (FMT) in Patients With Peripheral Psoriatic Arthritis: a 6-month, Double-Blind, Randomized, Placebo-Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03058900
• Other study ID #: OUH-DC-FLORA-01
• Status: Completed
• Phase: N/A
• Start date: May 16, 2017
• Est. completion date: June 2, 2020

Study information

• Verified date: December 2020
• Source: Odense University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

An abnormal intestinal microbiota may be the mediator of the common inflammatory pathways seen in psoriatic arthritis. This study will explore clinical aspects associated with modifying the intestinal microbiota by infusing fecal donor microbiota into the small intestine of psoriatic arthritis patients with a minimum of three swollen joints despite at least three months of methotrexate treatment.

Description:

Recent years have seen growing recognition of the complexity of the role of the microbiota in shaping the immune system and its potential effects for health and disease. In particular, the gut bacteria composition has been associated with the pathogenesis of autoimmune and inflammatory diseases. Intriguingly, presence of intestinal inflammation in psoriatic arthritis (PsA) patients has been documented in several studies. Also, in genetically predisposed patients reactive arthritis, which share some of the clinical manifestations of PsA, can be triggered by certain types of bacterial gut infections. Furthermore, a recent study has reported that several intestinal bacteria including Akkermansia and Ruminoccocus, which are known to play an important role in maintaining gut homeostasis, were practically absent in PsA patients. Mechanisms through which the microbiota may be involved in the pathogenesis of PsA include an abnormal activation of the gut-associated lymphoid tissue (GALT) and/or an altered mucosal permeability thus compromising the capacity of the intestine to provide adequate containment of luminal microorganisms and molecules. By conducting a double-blinded, randomized, placebo-controlled trial of a non-related donor fecal microbiota transplantation (FMT) infused into the small intestine, this study will reveal whether FMT is more effective than an identically appearing placebo (saline) in reducing disease activity in psoriatic arthritis patients presenting with a minimum of three swollen joints despite at least three months of methotrexate treatment (maximal tolerable dosis ≥ 15 mg/week). All patients will throughout the study continue their individual treatment with weekly methotrexate.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: June 2, 2020
• Est. primary completion date: June 2, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Diagnosis of psoriatic arthritis according to the Classification Criteria for Psoriatic Arthritis (CASPAR criteria).
• Presence of active peripheral psoriatic arthritis defined as = 3 swollen joints.
• Methotrexate (= 15mg/week (maximal tolerable dosage)) for a minimum of 3 months prior to study inclusion.

Exclusion Criteria:

• Other inflammatory rheumatic diseases than PsA.
• Current axial disease activity or severe peripheral joint activity demanding immediate change of treatment or contraindicating placebo treatment for 6 months.
• History of severe MTX toxicity or allergic reactions.
• Current biological treatment and biological treatment within the last 6 months.
• Inflammatory bowel disease, celiac disease, food allergy, or other intestinal diseases.
• Current cancer or severe chronic infections.
• Pregnant or breastfeeding women.
• Systemic and/or local intra-articular or peritendinous steroid injections within 3 months of inclusion.
• Non-MTX DMARD treatment within three months of inclusion.
• Antibiotics within 3 months of inclusion.
• Not wishing to participate or unsuited for project evaluation.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Psoriatic
• Psoriatic Arthritis

Intervention

Drug:
• Fecal microbiota transplantation (FMT)
One fecal microbiota transplantation is performed at baseline using gastroscopic guidance. The transplant consists of 50 g feces obtained from a healthy non-related donor. The donor feces is suspended into NaCl (0.9%) and glycerol (10%), and will be stored at minus 80 degrees celsius until use. The total volume of the suspension is 250 mL and its temperature will be 37 degrees celsius when infused into the small intestine of the recipient.

Other:
• Drug: Placebo (saline)
One identical appearing sham procedure is performed at baseline using gastroscopic guidance. 250 mL saline (NaCl 0.9%) is infused into the small intestine of the recipient.

Drug:
• Methotrexate (MTX)
Weekly methotrexate in maximum tolerable dosis

Locations

Country	Name	City	State
Denmark	Dept. of Rheumatology at Odense University Hospital	Odense
Denmark	Diagnostic Centre at Silkeborg Regional Hospital	Silkeborg

Sponsors (8)

Lead Sponsor	Collaborator
Odense University Hospital	Manufacturer Vilhelm Pedersen Foundation, Odense Patient Data Explorative Network, Region of Southern Denmark, The Danish Regions (Medicinpuljen), The Danish Rheumatism Association, The Psoriasis Association, Denmark, University of Southern Denmark

Country where clinical trial is conducted

Denmark, 

References & Publications (22)

Bruce B, Fries JF. The Health Assessment Questionnaire (HAQ). Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39):S14-8. — View Citation

Brusca SB, Abramson SB, Scher JU. Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity. Curr Opin Rheumatol. 2014 Jan;26(1):101-7. doi: 10.1097/BOR.0000000000000008. Review. — View Citation

Coates LC, Conaghan PG, Emery P, Green MJ, Ibrahim G, MacIver H, Helliwell PS. Sensitivity and specificity of the classification of psoriatic arthritis criteria in early psoriatic arthritis. Arthritis Rheum. 2012 Oct;64(10):3150-5. doi: 10.1002/art.34536. — View Citation

Eppinga H, Konstantinov SR, Peppelenbosch MP, Thio HB. The microbiome and psoriatic arthritis. Curr Rheumatol Rep. 2014 Mar;16(3):407. doi: 10.1007/s11926-013-0407-2. Review. — View Citation

Faria JR, Aarão AR, Jimenez LM, Silva OH, Avelleira JC. Inter-rater concordance study of the PASI (Psoriasis Area and Severity Index). An Bras Dermatol. 2010 Sep-Oct;85(5):625-9. — View Citation

Jacques P, Elewaut D. Joint expedition: linking gut inflammation to arthritis. Mucosal Immunol. 2008 Sep;1(5):364-71. doi: 10.1038/mi.2008.24. Epub 2008 Jul 9. Review. — View Citation

Kingsley GH, Kowalczyk A, Taylor H, Ibrahim F, Packham JC, McHugh NJ, Mulherin DM, Kitas GD, Chakravarty K, Tom BD, O'Keeffe AG, Maddison PJ, Scott DL. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012 Aug;51(8):1368-77. doi: 10.1093/rheumatology/kes001. Epub 2012 Feb 17. — View Citation

Klingberg E, Carlsten H, Hilme E, Hedberg M, Forsblad-d'Elia H. Calprotectin in ankylosing spondylitis--frequently elevated in feces, but normal in serum. Scand J Gastroenterol. 2012 Apr;47(4):435-44. doi: 10.3109/00365521.2011.648953. Epub 2012 Jan 10. — View Citation

Lindqvist U, Kristjánsson G, Pihl-Lundin I, Hagforsen E, Michaëlsson G. Patients with psoriatic arthritis have an increased number of lymphocytes in the duodenal mucosa in comparison with patients with psoriasis vulgaris. J Rheumatol. 2006 May;33(5):924-7. Epub 2006 Mar 15. — View Citation

Maksymowych WP, Mallon C, Morrow S, Shojania K, Olszynski WP, Wong RL, Sampalis J, Conner-Spady B. Development and validation of the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index. Ann Rheum Dis. 2009 Jun;68(6):948-53. doi: 10.1136/ard.2007.084244. Epub 2008 Jun 4. — View Citation

Morgan XC, Huttenhower C. Meta'omic analytic techniques for studying the intestinal microbiome. Gastroenterology. 2014 May;146(6):1437-1448.e1. doi: 10.1053/j.gastro.2014.01.049. Epub 2014 Jan 28. Review. — View Citation

Scarpa R, Manguso F, D'Arienzo A, D'Armiento FP, Astarita C, Mazzacca G, Ayala F. Microscopic inflammatory changes in colon of patients with both active psoriasis and psoriatic arthritis without bowel symptoms. J Rheumatol. 2000 May;27(5):1241-6. — View Citation

Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T, Cerundolo V, Pamer EG, Abramson SB, Huttenhower C, Littman DR. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013 Nov 5;2:e01202. doi: 10.7554/eLife.01202. — View Citation

Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, Marmon S, Neimann A, Brusca S, Patel T, Manasson J, Pamer EG, Littman DR, Abramson SB. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol. 2015 Jan;67(1):128-39. doi: 10.1002/art.38892. — View Citation

Smith MB, Kelly C, Alm EJ. Policy: How to regulate faecal transplants. Nature. 2014 Feb 20;506(7488):290-1. — View Citation

Statnikov A, Alekseyenko AV, Li Z, Henaff M, Perez-Perez GI, Blaser MJ, Aliferis CF. Microbiomic signatures of psoriasis: feasibility and methodology comparison. Sci Rep. 2013;3:2620. doi: 10.1038/srep02620. — View Citation

Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H; CASPAR Study Group. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006 Aug;54(8):2665-73. — View Citation

Toupin-April K, Barton J, Fraenkel L, Li L, Grandpierre V, Guillemin F, Rader T, Stacey D, Légaré F, Jull J, Petkovic J, Scholte-Voshaar M, Welch V, Lyddiatt A, Hofstetter C, De Wit M, March L, Meade T, Christensen R, Gaujoux-Viala C, Suarez-Almazor ME, Boonen A, Pohl C, Martin R, Tugwell PS. Development of a Draft Core Set of Domains for Measuring Shared Decision Making in Osteoarthritis: An OMERACT Working Group on Shared Decision Making. J Rheumatol. 2015 Dec;42(12):2442-7. doi: 10.3899/jrheum.141205. Epub 2015 Apr 15. Review. — View Citation

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. — View Citation

Van Praet L, Van den Bosch F, Mielants H, Elewaut D. Mucosal inflammation in spondylarthritides: past, present, and future. Curr Rheumatol Rep. 2011 Oct;13(5):409-15. doi: 10.1007/s11926-011-0198-2. — View Citation

Yeoh N, Burton JP, Suppiah P, Reid G, Stebbings S. The role of the microbiome in rheumatic diseases. Curr Rheumatol Rep. 2013 Mar;15(3):314. doi: 10.1007/s11926-012-0314-y. Review. — View Citation

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. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment failure	Proportion of patients in each group who experience treatment failure according to shared decision making between patient and rheumatologist defined as at least one of the following: Need for more than 1 intra-articular glucocorticoid injection due to disease activity.; Need for change to other conventional DMARDs (at the moment oral leflunomide, sulfasalazin or ciclosporin) according to the updated Danish guideline treatment due to disease activity.; Need for biologic treatment according to the updated Danish guideline treatment due to severe disease activity.	6 months (+/- 14 days)
Secondary	The Short Health Assessment Questionnaire (2-page HAQ)	Change from baseline in the Short Health Assessment Questionnaire (2-page HAQ).	Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	The Dermatology Life Quality Index (DLQI) Questionnaire	Change from baseline in the Dermatology Life Quality Index (DLQI).	Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	Patient Reported Gastrointestinal Side Effects	Change from baseline in gastrointestinal symptoms.	Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	Patient Reported Other Side Effects	Change from baseline in other (non-gastrointestinal) symptoms.	Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	The American College of Rheumatology (ACR) Response Criteria	Proportion of patients in each group achieving; ACR20 response criteria; ACR50 response criteria; ACR70 response criteria; A patient will be considered as improved according to the ACR20/50/70 response criteria if she/he has at least 20/50/70% improvement in the two following measures: Tender joint count (68) and swollen joint count (66), and at least 3 of the following 5 measures: Patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, Health Assessment Questionnaire (HAQ) score, acute phase reactant (CRP).	Baseline, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	The Psoriatic Arthritis Response Criteria (PsARC)	Proportion of patients in each group achieving PsARC response criteria. A patient will be considered as improved according to the PsARC response criteria if she/he has an improvement in either joint swelling or tenderness, and in any of 4 other measures: Patient global assessment of articular disease; physician global assessment of articular disease; joint pain or tenderness; joint swelling.	Baseline, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	The Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index	Change from baseline in SPARCC Enthesitis Index in the subset of patients who have enthesitis at baseline.	Baseline, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	The Psoriasis Area Severity Index (PASI)	Change from baseline in the Psoriasis Area Severity Index (PASI) in the subset of patients who have psoriasis at baseline.	Baseline, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	Dactylitis	Change from baseline in the number of digits affected with dactylitis in the subset of patients who have dactylitis at baseline.	Baseline, 3 months (+/- 7 days), 6 months (+/- 14 days)
Secondary	Number of Adverse Events	Number of adverse events in each group.	6 months (+/- 14 days)
Secondary	Number of Patients with Adverse Events	Number of patients with at least one adverse event in each group.	6 months (+/- 14 days)