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

Sponsor
Chinese University of Hong Kong (Other)
Overall Status
Enrolling by invitation
CT.gov ID
NCT03861689
Collaborator
(none)
40
Enrollment
1
Location
2
Arms
60
Anticipated Duration (Months)
0.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Diagnostic Test: MRI pelvis
 N/A

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 Design

Study Type:
Interventional
Anticipated Enrollment :
40 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Prospective Longitudinal Study on the Effect of Tight Control Management on Perianal Crohn's Disease
Actual Study Start Date :
Jul 1, 2019
Actual Primary Completion Date :
Jan 12, 2022
Anticipated Study Completion Date :
Jun 30, 2024

Arms and Interventions

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.

    Outcome Measures

    Primary Outcome Measures

    1. Change in the disease activity in patients with perianal Crohn's disease [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

    Secondary Outcome Measures

    1. Number of pCD patients achieving closure of external fistula opening with FiLAC [24 months]

      Number of patients achieving closure of external fistula opening after FiLaC treatment

    2. Proportion of pCD patients requiring proctectomy, defunctioning surgery [24 months]

      Proportion of pCD patients requiring proctectomy, defunctioning surgery

    3. Number of surgeries required for perianal Crohn's disease [24 months]

      Number of surgeries required for perianal Crohn's disease in patients undergoing tight monitoring and that in the control group

    4. Side effects profile [24 months]

      Number of patients with treatment-related adverse events in the tight monitoring model

    Other Outcome Measures

    1. Number of patients with adverse events associated with FiLAC treatment [24 months]

      Number of patients with adverse events associated with FiLAC treatment

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 The Chinese University of Hong Kong Hong Kong Hong Kong

    Sponsors and Collaborators

    • Chinese University of Hong Kong

    Investigators

    • Principal Investigator: Wing Yan Mak, MRCP, Prince of Wales Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Mak Wing Yan, Assistant Professor, Chinese University of Hong Kong
    ClinicalTrials.gov Identifier:
    NCT03861689
    Other Study ID Numbers:
    • PLACE-PCD_Protocol_20200909 v6
    First Posted:
    Mar 4, 2019
    Last Update Posted:
    Jan 18, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Mak Wing Yan, Assistant Professor, Chinese University of Hong Kong
    Perianal Crohn's disease
    MRI
    Additional relevant MeSH terms:
    Crohn Disease
    Inflammatory Bowel Diseases
    Fistula

    Study Results

    No Results Posted as of Jan 18, 2022