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

Crohn Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06051253
• Other study ID #: 20220573
• Status: Recruiting
• Phase: Phase 4
• Start date: November 1, 2023
• Est. completion date: June 30, 2027

Study information

• Verified date: May 2024
• Source: Asan Medical Center
• Contact: Byong Duk Ye, MD, PhD
• Phone: 82-2-3010-3181
• Email: bdye[@]amc.seoul.kr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 86
• Est. completion date: June 30, 2027
• Est. primary completion date: June 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 80 Years

Eligibility

• Inclusion Criteria:

1. Age: 19-80 years

2. Subjects diagnosed with perianal fistulizing Crohn's disease based on clinical, endoscopic, histological, and radiologic findings, etc.

3. Subjects naive to both biological drugs (anti-TNFs, anti-integrin, anti-IL12/23, etc.) and investigational new drugs

4. Subjects with at least one draining perianal fistula

5. Subjects not responding to two or more conventional treatments (antibiotics, drainage, immunosuppressants, etc.)

6. 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:

1. In cases where written informed consents cannot be provided by the study subjects or the subjects' legally acceptable representative

2. Subject with a probability of receiving bowel surgery within 12 weeks after baseline, decided by investigators

3. Subjects with temporary or permanent stoma

4. Subjects with short bowel syndrome

5. Subjects not eligible due to significant bowel strictures or intra-abdominal abscesses

6. 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

7. Subjects with enterovaginal fistula, enterocutaneous fistula, or enteroenteric fistula

8. Subjects previously exposed to biologics (anti-TNFs, anti-integrin, anti-IL12/23, etc.) or investigational new drugs

9. Subjects with a history of hypersensitivity to monoclonal antibody

10. 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)

11. 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

12. 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

13. 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

14. Subjects positive for anti-HCV antibody

15. Subjects with a history of infection with HIV or subject positive for HIV Ag

16. Subjects positive for Clostridioides difficile toxin assay or Clostridioides difficile culture assay

17. Subjects with a heart disease of NYHA Class III/IV

18. Subjects with current or previous demyelinating disease

19. 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.

20. Subjects with symptoms or signs of active infection or with a history of treatment for infection within 8 weeks

21. Subjects with a history of organ transplantation

22. Pregnant or lactating women

23. Non-Korean ethnicity according to a family tree

24. Subjects decided to be not eligible for the study by investigators

Related Conditions & MeSH terms

• Crohn Disease
• Fistula
• Infliximab
• Therapeutic Drug Monitoring

Intervention

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 mg/kg, the next doses are fixed to 10 mg/kg.
• 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.

Locations

Country	Name	City	State
Korea, Republic of	Asan Medical Center	Seoul

Sponsors (1)

Lead Sponsor	Collaborator
Asan Medical Center

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (19)

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. — View Citation

Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010 Apr 15;362(15):1383-95. doi: 10.1056/NEJMoa0904492. — View Citation

Davidov Y, Ungar B, Bar-Yoseph H, Carter D, Haj-Natour O, Yavzori M, Chowers Y, Eliakim R, Ben-Horin S, Kopylov U. Association of Induction Infliximab Levels With Clinical Response in Perianal Crohn's Disease. J Crohns Colitis. 2017 May 1;11(5):549-555. doi: 10.1093/ecco-jcc/jjw182. — View Citation

Gionchetti P, Dignass A, Danese S, Magro Dias FJ, Rogler G, Lakatos PL, Adamina M, Ardizzone S, Buskens CJ, Sebastian S, Laureti S, Sampietro GM, Vucelic B, van der Woude CJ, Barreiro-de Acosta M, Maaser C, Portela F, Vavricka SR, Gomollon F; ECCO. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 2: Surgical Management and Special Situations. J Crohns Colitis. 2017 Feb;11(2):135-149. doi: 10.1093/ecco-jcc/jjw169. Epub 2016 Sep 22. Erratum In: J Crohns Colitis. 2022 Aug 16;: — View Citation

Hindryckx P, Jairath V, Zou G, Feagan BG, Sandborn WJ, Stoker J, Khanna R, Stitt L, van Viegen T, Shackelton LM, Taylor SA, Santillan C, Mearadji B, D'Haens G, Richard MP, Panes J, Rimola J. Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn's Disease. Gastroenterology. 2019 Nov;157(5):1233-1244.e5. doi: 10.1053/j.gastro.2019.07.027. Epub 2019 Jul 20. — View Citation

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. — View Citation

Ordas I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2012 Oct;10(10):1079-87; quiz e85-6. doi: 10.1016/j.cgh.2012.06.032. Epub 2012 Jul 17. — View Citation

Papamichael K, Rakowsky S, Rivera C, Cheifetz AS, Osterman MT. Association Between Serum Infliximab Trough Concentrations During Maintenance Therapy and Biochemical, Endoscopic, and Histologic Remission in Crohn's Disease. Inflamm Bowel Dis. 2018 Sep 15;24(10):2266-2271. doi: 10.1093/ibd/izy132. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Regueiro M, Mardini H. Treatment of perianal fistulizing Crohn's disease with infliximab alone or as an adjunct to exam under anesthesia with seton placement. Inflamm Bowel Dis. 2003 Mar;9(2):98-103. doi: 10.1097/00054725-200303000-00003. — View Citation

Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004 Feb 26;350(9):876-85. doi: 10.1056/NEJMoa030815. — View Citation

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. — View Citation

Vande Casteele N, Ferrante M, Van Assche G, Ballet V, Compernolle G, Van Steen K, Simoens S, Rutgeerts P, Gils A, Vermeire S. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015 Jun;148(7):1320-9.e3. doi: 10.1053/j.gastro.2015.02.031. Epub 2015 Feb 24. — View Citation

Yan X, Zhu M, Feng Q, Yan Y, Peng J, Xu X, Xu A, Ran Z. Evaluating the effectiveness of infliximab on perianal fistulizing Crohn's disease by magnetic resonance imaging. Gastroenterol Rep (Oxf). 2019 Feb;7(1):50-56. doi: 10.1093/gastro/goy036. Epub 2018 Oct 24. — View Citation

Yarur AJ, Kanagala V, Stein DJ, Czul F, Quintero MA, Agrawal D, Patel A, Best K, Fox C, Idstein K, Abreu MT. Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn's disease. Aliment Pharmacol Ther. 2017 Apr;45(7):933-940. doi: 10.1111/apt.13970. Epub 2017 Feb 17. — View Citation

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. — View Citation

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. Lancet. 2019 Apr 27;393(10182):1699-1707. doi: 10.1016/S0140-6736(18)32196-2. Epub 2019 Mar 28. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of participants in clinical remission	Clinical remission is defined as no draining perianal fistula on gentle finger compression by a surgeon, without a seton. To be classified as clinical remission, participants should show no draining perianal fistula on gentle finger compression by a surgeon, without a seton at both week 50 and week 54.	Both week 50 and 54
Primary	Change of the MAGNIFI-CD (Magnetic Resonance Novel Index for Fistula Imaging in Crohn's Disease) score	MAGNIFI-CD = 3 x Number of fistula tract (3 levels) + 2 x Hyperintensity of primary tract on post-contrast T1-weighted images (2 levels) + 2 x Dominant feature (3 levels) + 2 x Fistula length (3 levels) + 2 x Extension (3 levels) + 1 x Inflammatory mass (6 levels).; Range of values: 0 ~ 25 High values mean more active perianal fistula	Week 54
Secondary	Proportion of participants in clinical response	Clinical response is defined as 50% or more decrease of the number of draining fistula or of draining amount on gentle finger compression by a surgeon, without a seton.	Week 54
Secondary	The proportion of patients with MAGNIFI-CD (Magnetic Resonance Novel Index for Fistula Imaging in Crohn's Disease) score of 0	MAGNIFI-CD = 3 x Number of fistula tract (3 levels) + 2 x Hyperintensity of primary tract on post-contrast T1-weighted images (2 levels) + 2 x Dominant feature (3 levels) + 2 x Fistula length (3 levels) + 2 x Extension (3 levels) + 1 x Inflammatory mass (6 levels).; Range of values: 0 ~ 25 High values mean more active perianal fistula	Week 54
Secondary	Biochemical remission	The proportion of patients with biochemical remission (CRP [C-reactive protein] < 0.6 mg/dL)	Week 54
Secondary	The median level of infliximab	Infliximab level is measured by the the Quantum Blue® Infliximab assay measure and is expressed as mcg/mL. In each group, infliximab trough levels of week 22, 30, 38, 46 and 54 are summarized and median value with interquartile ranges are calculated. Between two groups, those median values are compared.	Week 22, 30, 38, 46 and 54
Secondary	Change of IBDQ (Inflammatory Bowel Disease Questionnaire) score	The IBDQ (Inflammatory Bowel Disease Questionnaire) gives a possible score range of 32 to 224, where a higher score indicates better health-related quality of life. IBDQ is measured at week 14 and week 54.	Week 54
Secondary	The proportion of patients with safety issues (adverse events)	Comparing the proportions of patients having any adverse events, serious adverse events, serious infections, and all types of adverse events	Week 54