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

Ananthakrishnan AN, Luo C, Yajnik V, Khalili H, Garber JJ, Stevens BW, Cleland T, Xavier RJ. Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases. Cell Host Microbe. 2017 May 10;21(5):603-610.e3. doi: 10.1016/j.chom.2017.04.010. — View Citation

Aniwan S, Park SH, Loftus EV Jr. Epidemiology, Natural History, and Risk Stratification of Crohn's Disease. Gastroenterol Clin North Am. 2017 Sep;46(3):463-480. doi: 10.1016/j.gtc.2017.05.003. Epub 2017 Jul 19. — View Citation

Billiet T, Cleynen I, Ballet V, Ferrante M, Van Assche G, Gils A, Vermeire S. Prognostic factors for long-term infliximab treatment in Crohn's disease patients: a 20-year single centre experience. Aliment Pharmacol Ther. 2016 Oct;44(7):673-83. doi: 10.1111/apt.13754. Epub 2016 Aug 9. — View Citation

Boschetti G, Garnero P, Moussata D, Cuerq C, Preaudat C, Duclaux-Loras R, Mialon A, Drai J, Flourie B, Nancey S. Accuracies of serum and fecal S100 proteins (calprotectin and calgranulin C) to predict the response to TNF antagonists in patients with Crohn's disease. Inflamm Bowel Dis. 2015 Feb;21(2):331-6. doi: 10.1097/MIB.0000000000000273. — View Citation

Guidi L, Marzo M, Andrisani G, Felice C, Pugliese D, Mocci G, Nardone O, De Vitis I, Papa A, Rapaccini G, Forni F, Armuzzi A. Faecal calprotectin assay after induction with anti-Tumour Necrosis Factor alpha agents in inflammatory bowel disease: Prediction of clinical response and mucosal healing at one year. Dig Liver Dis. 2014 Nov;46(11):974-9. doi: 10.1016/j.dld.2014.07.013. Epub 2014 Aug 2. — View Citation

Hansen JJ, Sartor RB. Therapeutic Manipulation of the Microbiome in IBD: Current Results and Future Approaches. Curr Treat Options Gastroenterol. 2015 Mar;13(1):105-20. doi: 10.1007/s11938-014-0042-7. — View Citation

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

Kiss LS, Szamosi T, Molnar T, Miheller P, Lakatos L, Vincze A, Palatka K, Barta Z, Gasztonyi B, Salamon A, Horvath G, Toth GT, Farkas K, Banai J, Tulassay Z, Nagy F, Szenes M, Veres G, Lovasz BD, Vegh Z, Golovics PA, Szathmari M, Papp M, Lakatos PL; Hungarian IBD Study Group. Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn's disease. Aliment Pharmacol Ther. 2011 Oct;34(8):911-22. doi: 10.1111/j.1365-2036.2011.04827.x. Epub 2011 Aug 24. — View Citation

Lewis JD, Chen EZ, Baldassano RN, Otley AR, Griffiths AM, Lee D, Bittinger K, Bailey A, Friedman ES, Hoffmann C, Albenberg L, Sinha R, Compher C, Gilroy E, Nessel L, Grant A, Chehoud C, Li H, Wu GD, Bushman FD. Inflammation, Antibiotics, and Diet as Environmental Stressors of the Gut Microbiome in Pediatric Crohn's Disease. Cell Host Microbe. 2015 Oct 14;18(4):489-500. doi: 10.1016/j.chom.2015.09.008. Erratum In: Cell Host Microbe. 2017 Aug 9;22(2):247. — View Citation

Louis E, Mary JY, Vernier-Massouille G, Grimaud JC, Bouhnik Y, Laharie D, Dupas JL, Pillant H, Picon L, Veyrac M, Flamant M, Savoye G, Jian R, Devos M, Porcher R, Paintaud G, Piver E, Colombel JF, Lemann M; Groupe D'etudes Therapeutiques Des Affections Inflammatoires Digestives. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012 Jan;142(1):63-70.e5; quiz e31. doi: 10.1053/j.gastro.2011.09.034. Epub 2011 Sep 22. — View Citation

Perez-Brocal V, Garcia-Lopez R, Vazquez-Castellanos JF, Nos P, Beltran B, Latorre A, Moya A. Study of the viral and microbial communities associated with Crohn's disease: a metagenomic approach. Clin Transl Gastroenterol. 2013 Jun 13;4(6):e36. doi: 10.1038/ctg.2013.9. — View Citation

Reinisch W, Wang Y, Oddens BJ, Link R. C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn's disease: a post-hoc analysis from ACCENT I. Aliment Pharmacol Ther. 2012 Mar;35(5):568-76. doi: 10.1111/j.1365-2036.2011.04987.x. Epub 2012 Jan 18. — View Citation

Roseth AG, Aadland E, Grzyb K. Normalization of faecal calprotectin: a predictor of mucosal healing in patients with inflammatory bowel disease. Scand J Gastroenterol. 2004 Oct;39(10):1017-20. doi: 10.1080/00365520410007971. No abstract available. — View Citation

Sartor RB, Wu GD. Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. Gastroenterology. 2017 Feb;152(2):327-339.e4. doi: 10.1053/j.gastro.2016.10.012. Epub 2016 Oct 18. — View Citation

Shaw KA, Bertha M, Hofmekler T, Chopra P, Vatanen T, Srivatsa A, Prince J, Kumar A, Sauer C, Zwick ME, Satten GA, Kostic AD, Mulle JG, Xavier RJ, Kugathasan S. Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease. Genome Med. 2016 Jul 13;8(1):75. doi: 10.1186/s13073-016-0331-y. — View Citation

Silverstein MD, Loftus EV, Sandborn WJ, Tremaine WJ, Feagan BG, Nietert PJ, Harmsen WS, Zinsmeister AR. Clinical course and costs of care for Crohn's disease: Markov model analysis of a population-based cohort. Gastroenterology. 1999 Jul;117(1):49-57. doi: 10.1016/s0016-5085(99)70549-4. — View Citation

Sipponen T, Savilahti E, Karkkainen P, Kolho KL, Nuutinen H, Turunen U, Farkkila M. Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti-TNF-alpha therapy for Crohn's disease. Inflamm Bowel Dis. 2008 Oct;14(10):1392-8. doi: 10.1002/ibd.20490. — View Citation

Wagner J, Maksimovic J, Farries G, Sim WH, Bishop RF, Cameron DJ, Catto-Smith AG, Kirkwood CD. Bacteriophages in gut samples from pediatric Crohn's disease patients: metagenomic analysis using 454 pyrosequencing. Inflamm Bowel Dis. 2013 Jul;19(8):1598-608. doi: 10.1097/MIB.0b013e318292477c. — View Citation

* 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