Tight Control Management in Perianal Crohn's Disease (PLACE-PCD)

January 14, 2022 updated by: Mak Wing Yan, Chinese University of Hong Kong

A Prospective Longitudinal Study on the Effect of Tight Control Management on Perianal Crohn's Disease

Perianal Crohn's disease (pCD) affects around one-third of patients with Crohn's disease (CD) during their disease course. It represents a distinct disease phenotype and causes significant morbidity, often requiring multiple surgical interventions. However, treatment of pCD is still challenging and unsatisfactory. Only approximately one-third of pCD patients responded to biologic treatment. Overall, medical therapy with anti-TNF could only achieve prolonged remission in 30-40% of pCD cases. At the same time, surgical treatment could only lead to a favourable outcome in around 50% of patients with a higher recurrence rate in patients with complex than in simple fistulae. Recently, combination of optimal medical therapy with surgical therapy (drainage of sepsis and insertion of seton), with radiological guidance, has been suggested as the standard management so as to improve the outcomes of complex pCD.

Magnetic resonance imaging (MRI) is considered to be the gold standard imaging technique for perianal CD. It can visualise the anal sphincter and the pelvic floor muscles, as well as the fistula tracts and abscesses. Previous studies using MRI to monitor treatment response to anti-TNF revealed that radiological healing lagged behind clinical remission by a median of 12 months and that long-term maintenance therapy is probably required to prevent recurrence despite a clinically healed external opening. Therefore, we hypothesize that serial monitoring with MRI is important.

Recently, there has been some advance in the surgical treatment of perianal Crohn's disease. FiLaCTM uses a radial-emitting disposable laser fibre for endofistular therapy. Recent systemic review and meta-analysis showed that the primary success rate was 73.3% (11/15) in patients with perianal Crohn's fistula.

There has been breakthrough in the management of luminal Crohn's disease. The CALM study has showed that timely escalation of anti-TNF on the basis of clinical symptoms combined with biomarkers in patients with luminal Crohn's disease resulted in better clinical and endoscopic outcomes than symptom-driven decision alone. It is unsure whether this approach is also applicable to patients with perianal Crohn's disease.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

Perianal Crohn's disease (pCD) affects around one-third of patients with Crohn's disease (CD) during their disease course. It represents a distinct disease phenotype and causes significant morbidity, often requiring multiple surgical interventions. The presence of pCD causes significant burden to patients. The risk of developing perianal fistulae depends on disease location and is most commonly seen in colonic disease with rectal involvement. Perianal fistulae have been reported in 12% of subjects with small intestinal CD, 15% with ileocolonic CD, 41% with colonic CD without rectal involvement and 92% of those with colonic CD with rectal involvement. Persistently high CRP level > 31 was recently found to be independently associated with subsequent development of perianal fistula in CD patients. Besides, male gender, those who have a younger age of onset of CD, non-Caucasians and Sephardic (as opposed to Ashkenazi) Jews are all at higher risk of developing pCD.

However, treatment of pCD is still challenging and unsatisfactory. Antibiotics including metronidazole and ciprofloxacin, thiopurines and other immunomodulators failed to show radiological healing of anal fistulas. Approximately one-third of pCD patients responded to biologic treatment. The ACCENT II trial is the first double blind RCT that demonstrates the benefit of infliximab maintenance in fistulising Crohn's disease. At week 54, complete absence of draining fistulae was noted in 36% of patients in the infliximab maintenance group, compared to 19% in the placebo group. (p=0.009) There are also evidence that maintenance infliximab therapy could reduce hospitalisation, surgeries and procedures in fistulising Crohn's disease. In the CHARM study, 30% of patients with fistulae treated with adalimumab had complete fistulae closure, and this increased to 33% at 56 weeks compared with 13% in the placebo group. However, the risk of recurrence is high. Only 34% of patients remained free of relapse after one year of cessation.

Up till now, there are still no clear predictors, which can predict the response to anti-TNF therapy except the presence of proctitis. Presence of proctitis has been shown to be a poor predictor of response to anti-TNF therapy. Recently, A.J. Yarur et al. reported that patients with pCD who achieved remission had higher infliximab trough level compared to those with active fistulae [15.8 vs. 4.4 lg/mL, respectively (P < 0.0001)], and those who developed anti-infliximab antibodies had a lower chance of achieving fistula healing (OR: 0.04 [95%CI: 0.005-0.3], P < 0.001). An infliximab level of ≥10.1 µg/mL is associated with fistula healing [OR: 3.9 (95%CI: 1.34-11.8) P = 0.012]. Another, retrospective study by Davidov et. al, showed that infliximab levels at week 2 and 6 were significantly associated with fistula response at week 14 and 30. Infliximab levels of 9.25µg/mL at week 2 and 7.25 µg/mL at week 6 could best predict response to treatment.

Overall, medical therapy with anti-TNF could only achieve prolonged remission in 30-40% of pCD cases. At the same time, surgical treatment could only lead to a favourable outcome in around 50% of patients with a higher recurrence rate in patients with complex than in simple fistulae. Recently, combination of optimal medical therapy with surgical therapy (drainage of sepsis and insertion of seton), with radiological guidance, has been suggested as the standard management so as to improve the outcomes of complex pCD. An earlier study in 2003 revealed that the combination of seton placement and infliximab results in an earlier initial response (100% vs. 82.6%, p=0.014), lower recurrence rates (44% vs. 79%, p=0.001) and longer time to relapse (13.5 months vs. 3.6 months, p=0.0001) than infliximab alone. Further studies in Japan and France evaluating the efficacy of combination of seton insertion and infliximab also yielded positive results with higher chance of fistulae closure. A recent systemic review and meta-analysis of 24 studies by Yassin et al. revealed that combination therapy led to higher complete remission rate compared with single therapy (52% vs. 43%).33 Overall, long-term infliximab therapy with combined medical and surgical management produced clinical remission in 36-58%.

Magnetic resonance imaging (MRI) is considered to be the gold standard imaging technique for perianal CD. It can visualise the anal sphincter and the pelvic floor muscles, as well as the fistula tracts and abscesses. Previous studies using MRI to monitor treatment response to anti-TNF revealed that radiological healing lagged behind clinical remission by a median of 12 months and that long-term maintenance therapy is probably required to prevent recurrence despite a clinically healed external opening. Therefore, investigators hypothesize that serial monitoring with MRI is important.

Recently, there has been some advance in the surgical treatment of perianal Crohn's disease. FiLaCTM uses a radial-emitting disposable laser fibre for endofistular therapy. Recent systemic review and meta-analysis showed that the primary success rate was 73.3% (11/15) in patients with perianal Crohn's fistula.

There has been breakthrough in the management of luminal Crohn's disease. The CALM study has showed that timely escalation of anti-TNF on the basis of clinical symptoms combined with biomarkers in patients with luminal Crohn's disease resulted in better clinical and endoscopic outcomes than symptom-driven decision alone. It is unsure whether this approach is also applicable to patients with perianal Crohn's disease.

Therefore, investigators hypothesize that more proactive treatment with treating to target "Radiological healing on MRI" is associated with better outcome and the combination of examination under anesthesia with drainage of perianal abscess and together with FiLaCTM of the fistula will lead to better outcome.

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Not Applicable

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
        • The Chinese University of Hong Kong

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

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18 years old
  • Confirmed diagnosis of perianal Crohn's disease
  • On biologics or will start biologics

Exclusion Criteria:

  • Patients who have perianal fistula due to causes other than Crohn's disease
  • Patients who have allergic reaction / contraindications to anti-TNF
  • Patients who have active cancer
  • Patients who have contraindications for MRI
  • Known pregnancy

For patients who refuse to participate in the tight monitoring arm, they will be consented and recruited to the control arm for comparison.

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

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Tight control arm
Patients in the tight control arm will have additional FiLAC treatment within 24 months if the anatomy of the fistula is favourable. MRI pelvis will be performed at baseline and every 6 months. Biologic dosage will be adjusted according to MRI pelvis findings.
Diagnostic test: MRI pelvis
MRI pelvis monitoring every 6 months; FiLAC to treat fistula tract within 24 months if the anatomy of the fistula is favourable
Other Names:
  • FiLAC
NO_INTERVENTION: Control arm
Patients in the control arm will have management according to physician own decision.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the disease activity in patients with perianal Crohn's disease
Time Frame: 24 months
Change in the proportion of patients with perianal Crohn's disease achieving clinical remission under tight monitoring using MRI guidance compared to standard care
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of pCD patients achieving closure of external fistula opening with FiLAC
Time Frame: 24 months
Number of patients achieving closure of external fistula opening after FiLaC treatment
24 months
Proportion of pCD patients requiring proctectomy, defunctioning surgery
Time Frame: 24 months
Proportion of pCD patients requiring proctectomy, defunctioning surgery
24 months
Number of surgeries required for perianal Crohn's disease
Time Frame: 24 months
Number of surgeries required for perianal Crohn's disease in patients undergoing tight monitoring and that in the control group
24 months
Side effects profile
Time Frame: 24 months
Number of patients with treatment-related adverse events in the tight monitoring model
24 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with adverse events associated with FiLAC treatment
Time Frame: 24 months
Number of patients with adverse events associated with FiLAC treatment
24 months

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: Wing Yan Mak, MRCP, Prince of Wales Hospital

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)

July 1, 2019

Primary Completion (ACTUAL)

January 12, 2022

Study Completion (ANTICIPATED)

June 30, 2024

Study Registration Dates

First Submitted

February 27, 2019

First Submitted That Met QC Criteria

March 1, 2019

First Posted (ACTUAL)

March 4, 2019

Study Record Updates

Last Update Posted (ACTUAL)

January 18, 2022

Last Update Submitted That Met QC Criteria

January 14, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PLACE-PCD_Protocol_20200909 v6

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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.

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