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

May 30, 2023 updated by: Siew Chien NG, Chinese University of Hong Kong

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

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.

Study Overview

Status

Terminated

Conditions

Detailed 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.

Study Type

Observational

Enrollment (Actual)

13

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
      • Hong Kong, Hong Kong
        • Prince of Wales Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Consecutive CD subjects who visit Prince of Wales Hospital in Hong Kong

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chinese University of Hong Kong

Investigators

  • Principal Investigator: Siew Chien Ng, Prof, Chinese University of Hong Kong

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 18, 2019

Primary Completion (Actual)

August 29, 2022

Study Completion (Actual)

August 29, 2022

Study Registration Dates

First Submitted

June 20, 2019

First Submitted That Met QC Criteria

June 20, 2019

First Posted (Actual)

June 21, 2019

Study Record Updates

Last Update Posted (Actual)

June 1, 2023

Last Update Submitted That Met QC Criteria

May 30, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CD MiRES

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Crohn Disease

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Bahamas

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe