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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Observational
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT03994224
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Chinese University of Hong Kong
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Siew Chien Ng, Prof
Principal Investigator Affiliation Chinese University of Hong Kong
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Recruiting
Countries Hong Kong
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Crohn Disease, Perianal Crohn Disease
Additional Details

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.

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International Sites

Prince of Wales Hospital, Hong Kong, Hong Kong

Status

Recruiting

Address

Prince of Wales Hospital

Hong Kong, ,

Site Contact

Siew Chien Ng, PhD

jessicaching@cuhk.edu.hk

+852 35053524

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