A Prospective Longitudinal Study of Fecal Microbiome and Calprotectin to Predict Response to Biological Therapy in Patients With CD

Crohn Disease Clinical Trial

Official title:

A Prospective Longitudinal Study of Fecal Microbiome and Calprotectin to Predict Response to Biological Therapy in Patients With Crohn's Disease

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03994224
• Other study ID #: CD MiRES
• Status: Terminated
• Start date: February 18, 2019
• Est. completion date: August 29, 2022

Study information

• Verified date: May 2023
• Source: Chinese University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Crohn's disease (CD) is a chronic relapsing-remitting systemic inflammatory disease, affecting any part of the gastrointestinal tract. Biological therapy with anti-tumor necrosis factor (TNF) alpha is the established treatment of choice for the management of moderate to severe Crohn's disease. However, its efficacy in an individual patient is the unpredictable and long-term outcome is still suboptimal. Identifying biomarkers which can predict treatment response is thus of utmost importance and can allow personalized management. In inflammatory bowel disease (IBD), altered fecal microbiota signatures have been consistently reported. Moreover, overall bacterial diversity is consistently decreased during intestinal inflammation. Fecal calprotectin (FC) is a calcium and zinc binding protein largely confined to the neutrophil granulocytes and macrophages and is a very sensitive marker for detection of inflammation in the gastrointestinal tract. C reactive protein (CRP) is an acute phase reactant. CD Patients with elevated baseline CRP levels responded to infliximab treatment better and early normalisation of CRP correlated with sustained long-term response to infliximab therapy. The investigators hypothesize that faecal microbial signatures in conjunction with faecal calprotectin and CRP may have a role in predicting response to biological therapy in CD patients.

Description:

Crohn's disease (CD) is a chronic relapsing-remitting systemic inflammatory disease, affecting any part of the gastrointestinal tract. Patients frequently present with abdominal pain, fever, and symptoms of bowel obstruction or diarrhea with passage of blood or mucus, or both. It can lead to significant morbidity and disability in some cases. Population-based studies revealed that up to 50% of CD patients required surgery within 10 years from diagnosis.Only 24% remain in remission over their lifetime disease course. Biological therapy with anti-tumor necrosis factor (TNF) alpha is the established treatment of choice for the management of moderate to severe Crohn's disease. However, its efficacy in an individual patient is the unpredictable and long-term outcome is still suboptimal. Almost one-third of CD patients showed no response to anti-TNF and two-thirds do not achieve remission.The rate of loss of response after 1 year of infliximab therapy ranges between 23% and 46%.4 Identifying biomarkers which can predict treatment response is thus of utmost importance and can allow personalized management. Several biomarkers have been identified in predicting treatment response. C reactive protein (CRP) is an acute phase reactant with a short half-life of only 19 hours. CD Patients with elevated baseline CRP levels (>3mg/L) responded to infliximab treatment better and early normalisation of CRP correlated with sustained long-term response to infliximab therapy. Similar results were shown in adalimumab therapy. CD patients who had achieved normalisation of CRP (<3mg/L) at both week 4 and week 12 were less likely to discontinue adalimumab and had sustained clinical benefit. Fecal calprotectin (FC) is a calcium and zinc binding protein largely confined to the neutrophil granulocytes and macrophages and is a very sensitive marker for detection of inflammation in the gastrointestinal tract. FC levels dropped significantly in CD patients who responded to infliximab therapy. A decrease in FC level after therapy has been demonstrated to be associated with clinical, endoscopic and histological improvements. Moreover, a study has demonstrated that combination of CRP and FC represented a good predictor of relapse of CD among patients on anti-metabolite therapy after infliximab was stopped. In inflammatory bowel disease , altered fecal microbiota signatures have been consistently reported which included a reduction in biodiversity with lower proportions of Firmicutes and increases in Proteobacteria and Bacteroidetes phylum members.Moreover, overall bacterial diversity is consistently decreased during intestinal inflammation. Besides, CD patients have richer fungal species and higher microbiome diversities in mucosal biopsies. Several fungal species, including Candida spp., Gibberella moniliformis, Alternaria brassicicola and Cryptococcus neoformans, are increased in tissues from CD patients. CD patients may harbor increased numbers of bacteriophages in inflamed tissue and feces, though no specific viruses have been associated with human IBDs to date. Few studies have studied the longitudinal changes in the gut microbiome with drug treatment in IBD. Shaw et al. characterized 19 children with CD and 4 with ulcerative colitis (UC), showing that dysbiosis at baseline correlated with the degree of inflammatory burden of luminal disease. An improvement in fecal diversity was seen with clinical response in UC but not CD.Restoration of gut diversity has been reported previously with anti-TNF therapy. However, a more diverse microbiome has not been previously shown to be predictive of treatment response in children. Recent study by the Massachusetts group including 85 IBD patients (43 UC, 42 CD) who initiated treatment with vedolizumab revealed that baseline microbiome was significantly higher and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Patients achieving remission at week 14 demonstrated persistency in the microbial composition at both week 30 and week 54, suggesting that attainment of remission at week 14 is associated with durable changes in microbiomes. Thus, early changes in microbiome could help identify patients who will likely to achieve and maintain response to treatment. The investigators hypothesize that faecal microbial signatures in conjunction with faecal calprotectin and CRP may have a role in predicting response to biological therapy in CD patients.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: August 29, 2022
• Est. primary completion date: August 29, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Patients with moderate to severe Crohn's disease

1. Aged = 18 years old

2. Confirmed diagnosis of Crohn's disease according to established clinical, endoscopic and histological criteria

3. Moderate to severe Crohn's disease who are due to start biological therapy

4. Written informed consent obtained Subjects with perianal Crohn's disease

1. Aged = 18 years old

2. Confirmed diagnosis of Crohn's disease with perianal involvement according to established clinical, endoscopic and histological criteria

3. Subjects with active perianal Crohn's disease who are due to start biological therapy

4. Written informed consent obtained 4.2. Exclusion Criteria

1. Previous bowel surgery/ stoma

2. History of anti-TNF use in the last 3 months

3. Malignant disease within 5 years

4. Use of probiotics, prebiotics or antibiotics in the past 1 months

Related Conditions & MeSH terms

• Crohn Disease
• Perianal Crohn Disease

Locations

Country	Name	City	State
Hong Kong	Prince of Wales Hospital	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
Chinese University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

References & Publications (20)

Allez M, Karmiris K, Louis E, Van Assche G, Ben-Horin S, Klein A, Van der Woude J, Baert F, Eliakim R, Katsanos K, Brynskov J, Steinwurz F, Danese S, Vermeire S, Teillaud JL, Lemann M, Chowers Y. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohns Colitis. 2010 Oct;4(4):355-66. doi: 10.1016/j.crohns.2010.04.004. Epub 2010 Jun 29. — View Citation

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Jurgens M, Mahachie John JM, Cleynen I, Schnitzler F, Fidder H, van Moerkercke W, Ballet V, Noman M, Hoffman I, van Assche G, Rutgeerts PJ, van Steen K, Vermeire S. Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease. Clin Gastroenterol Hepatol. 2011 May;9(5):421-7.e1. doi: 10.1016/j.cgh.2011.02.008. Epub 2011 Feb 17. — View Citation

Karmiris K, Paintaud G, Noman M, Magdelaine-Beuzelin C, Ferrante M, Degenne D, Claes K, Coopman T, Van Schuerbeek N, Van Assche G, Vermeire S, Rutgeerts P. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease. Gastroenterology. 2009 Nov;137(5):1628-40. doi: 10.1053/j.gastro.2009.07.062. Epub 2009 Aug 5. — View Citation

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* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Asymptomatic Crohn's Disease patients	Defined as normal CRP level <10mg/l and no use of corticosteroid in the last 4 weeks.	2 years
Primary	Asymptomatic perianal Crohn's Disease patients	Defined as the absence of draining fistula on two consecutive visits according to Fistula Drainage Assessment.	2 years