TDM-based Infliximab Treatment for Active Perianal Fistulizing Crohn's Disease

Official title

Efficacy of Infliximab Treatment Based on TDM (Therapeutic Drug Monitoring) in Adult Patients With Active Perianal Fistulizing Crohn's Disease

Overview

This study will compare the efficacy and safety of TDM (therapeutic drug monitoring)-based infliximab (CT-P13, RemsimaTM) intravenous therapy compared with the standard infliximab (RemsimaTM) intravenous therapy for patients with active perianal fistulzing Crohn's disease.

Detailed description

The TDM-based group: At week 0,2, and 6, infliximab (RemsimaTM) is intravenously administered at a dose of 5 mg/kg. From week 14 to 46 (at week 14, 22, 30, 38, and 46), infliximab dose can be increased to 10 mg/kg, targeting trough level (TL) of infliximab 10 mcg/mL or over (If TL is 10 mcg/mL or over under treatment with 5 mg/kg infliximab, 5 mg/kg of infliximab is continued. If TL is lower than 10 mcg/mL, infliximab dose is increased to 10 mg/kg). Once infliximab dose was increased to 10 mg/kg, the next doses are fixed to 10 mg/kg.

The standard group: Infliximab (RemsimaTM) is intravenously administered at a dose of 5 mg/kg at week 0, 2, 6, 14, 22, 30, 38, and 46. Therapeutic dose monitoring (TDM, checking trough levels of infliximab) is performed at week 14, 22, 30, 38, and 46, but TDM results are not reflected in determining doses of infliximab.

The co-primary endpoints of the study will be 1) Clinical remission (both week 50 and week 54), 2) Changes of MAGNIFI-CD (Magnetic Resonance Novel Index for Fistula Imaging in Crohn's Disease) score compared with the baseline score (week 54)

Interventions

• Drug TDM-based infliximab intravenous therapy
  Infliximab (CT-P13, RemsimaTM) is intravenously given as an induction therapy at a dose of 5 mg/kg at week 0, 2, and 6. From week 14 to 46 (at week 14, 22, 30, 38, and 46), infliximab dose can be increased to 10 mg/kg, targeting trough level (TL) of infliximab 10 mcg/mL or over (If TL is 10 mcg/mL or over under treatment with 5 mg/kg infliximab, 5 mg/kg of infliximab is continued. If TL is lower than 10 mcg/mL, infliximab dose is increased to 10 mg/kg). Once infliximab dose was increased to 10 m
• Drug Standard infliximab intravenous therapy
  Infliximab (CT-P13, RemsimaTM) is intravenously administered at a dose of 5 mg/kg at week 0, 2, 6, 14, 22, 30, 38, and 46. Therapeutic dose monitoring (TDM, checking trough levels of infliximab) is performed at week 14, 22, 30, 38, and 46, but TDM results are not reflected in determining doses of infliximab.

Primary outcome measures

• Proportion of participants in clinical remission [Time frame: Both week 50 and 54]
• Change of the MAGNIFI-CD (Magnetic Resonance Novel Index for Fistula Imaging in Crohn's Disease) score [Time frame: Week 54]

Secondary outcome measures (6)

• Proportion of participants in clinical response [Time frame: Week 54]
• The proportion of patients with MAGNIFI-CD (Magnetic Resonance Novel Index for Fistula Imaging in Crohn's Disease) score of 0 [Time frame: Week 54]
• Biochemical remission [Time frame: Week 54]
• The median level of infliximab [Time frame: Week 22, 30, 38, 46 and 54]
• Change of IBDQ (Inflammatory Bowel Disease Questionnaire) score [Time frame: Week 54]
• The proportion of patients with safety issues (adverse events) [Time frame: Week 54]

Eligibility criteria

• Inclusion Criteria:

• Age: 19-80 years
• Subjects diagnosed with perianal fistulizing Crohn's disease based on clinical, endoscopic, histological, and radiologic findings, etc.
• Subjects naive to both biological drugs (anti-TNFs, anti-integrin, anti-IL12/23, etc.) and investigational new drugs
• Subjects with at least one draining perianal fistula
• Subjects not responding to two or more conventional treatments (antibiotics, drainage, immunosuppressants, etc.)
• Women with a childbearing potential: Those who agree to follow contraception during study drug administration and for at least 6 months from the last dosing of the study medication
• Exclusion Criteria:

• In cases where written informed consents cannot be provided by the study subjects or the subjects' legally acceptable representative
• Subject with a probability of receiving bowel surgery within 12 weeks after baseline, decided by investigators
• Subjects with temporary or permanent stoma
• Subjects with short bowel syndrome
• Subjects not eligible due to significant bowel strictures or intra-abdominal abscesses
• Subjects who received bowel surgery within 6 months of baseline or subjects who were admitted due to complications associated with bowel strictures or intra-abdominal abscesses within 3 months of baseline
• Subjects with enterovaginal fistula, enterocutaneous fistula, or enteroenteric fistula
• Subjects previously exposed to biologics (anti-TNFs, anti-integrin, anti-IL12/23, etc.) or investigational new drugs
• Subjects with a history of hypersensitivity to monoclonal antibody
• Subjects requiring corticosteroid therapy. However, if oral corticosteroid dose lower or equivalent to prednisolone 20 mg/day before baseline is given and tapering of oral corticoseroid from baseline is planned, that subjects can be included in the study. Oral corticoseroid is tapered at a schedule of prednisolone 5 mg/7 days (example: if the subject was on oral prednisolone 20 mg/day before baseline, oral prednisolone is tapered as follows: 15 mg/day x 7 days -> 10 mg/day x 7 days -> 5 mg/day x 7 days -> stopping of prednisolone)
• Subjects with active tuberculosis. However, if the subject has a history of tuberculosis, which was cured with standard anti-tuberculosis therapy according to the standard anti-tuberculosis treatment guidelines, that subject can be included
• Subjects with latent tuberculosis: Subjects determined to be positive for latent tuberculosis by the pulmonology specialist after history taking, physical examination, chest X-ray, and interferon gamma release assay during the screening period. However, even if positive for latent tuberculosis, if 4 week-treatment for latent tuberculosis is completed and if further treatment for latent tuberculosis is planned to be completed, that subject can be included
• Subjects positive for HBsAg. In cases of HBsAg (-), but with IgG Anti-HBc (+), real time quantitative PCR for HBV DNA is required. If HBV DNA is 10 IU/mL or over, that subject should be excluded
• Subjects positive for anti-HCV antibody
• Subjects with a history of infection with HIV or subject positive for HIV Ag
• Subjects positive for Clostridioides difficile toxin assay or Clostridioides difficile culture assay
• Subjects with a heart disease of NYHA Class III/IV
• Subjects with current or previous demyelinating disease
• Subject with a history of malignancy (excluding skin basal cell carcinoma, skin squamous cell carcinoma, and uterine cervix cancer) within 5 years or with a history of dysplasia of colon or small bowel within 5 years.
• Subjects with symptoms or signs of active infection or with a history of treatment for infection within 8 weeks
• Subjects with a history of organ transplantation
• Pregnant or lactating women
• Non-Korean ethnicity according to a family tree
• Subjects decided to be not eligible for the study by investigators

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

South Korea · 1 center

• Asan Medical Center — Seoul

Publications

• Park JJ, Yang SK, Ye BD, Kim JW, Park DI, Yoon H, Im JP, Lee KM, Yoon SN, Lee H; IBD Study Group of the Korean Association for the Study of the Intestinal Diseases. [Second Korean Guidelines for the Management of Crohn's Disease]. Korean J Gastroenterol. 2017 Jan 25;69(1):29-54. doi: 10.4166/kjg.2017.69.1.29. Korean. PMID 28135790
• Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. Gastroenterology. 2002 Apr;122(4):875-80. doi: 10.1053/gast.2002.32362. PMID 11910338
• Cheon JH, Kim YS, Ye BD, Lee KM, Kim YH, Kim JS, Han DS, Kim WH. Crohn's Disease Clinical Network and Cohort (CONNECT) Study: The First Step Toward Nationwide Multicenter Research of Crohn's Disease in Korea. Intest Res. 2014 Jul;12(3):173-5. doi: 10.5217/ir.2014.12.3.173. No abstract available. PMID 25349589
• Klag T, Goetz M, Stange EF, Wehkamp J. Medical Therapy of Perianal Crohn's Disease. Viszeralmedizin. 2015 Aug;31(4):265-72. doi: 10.1159/000434664. Epub 2015 Jul 29. PMID 26557835
• Park EJ, Song KH, Baik SH, Park JJ, Kang J, Lee KY, Goo JI, Kim NK. The efficacy of infliximab combined with surgical treatment of fistulizing perianal Crohn's disease: Comparative analysis according to fistula subtypes. Asian J Surg. 2018 Sep;41(5):438-447. doi: 10.1016/j.asjsur.2017.06.005. Epub 2017 Aug 26. PMID 28851611
• Yassin NA, Askari A, Warusavitarne J, Faiz OD, Athanasiou T, Phillips RK, Hart AL. Systematic review: the combined surgical and medical treatment of fistulising perianal Crohn's disease. Aliment Pharmacol Ther. 2014 Oct;40(7):741-9. doi: 10.1111/apt.12906. Epub 2014 Aug 13. PMID 25115149
• Ye BD, Pesegova M, Alexeeva O, Osipenko M, Lahat A, Dorofeyev A, Fishman S, Levchenko O, Cheon JH, Scribano ML, Mateescu RB, Lee KM, Eun CS, Lee SJ, Lee SY, Kim H, Schreiber S, Fowler H, Cheung R, Kim YH. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study. La PMID 30929895
• Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999 May 6;340(18):1398-405. doi: 10.1056/NEJM199905063401804. PMID 10228190

Identifiers

NCT: NCT06051253 · 20220573

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗