Efficacy and Safety of Formulation Switching Between SC Infliximab and IV Infliximab in Patients With CD

Study Overview
=================
Brief Summary
-----------------
The goal of this prospective, multicenter, open-label, randomized controlled, non-inferiority trial is to test efficacy and safety of formulation switching between subcutaneous (SC) infliximab and intravenous (IV) infliximab in patients with moderately to severely active Crohn's disease (CD). The primary endpoint of this study is deep remission at week 54. The main questions this study aims to answer are: Question-1) Is maintenance therapy with SC infliximab (120mg every 2 weeks) non-inferior to IV infliximab (5mg/kg every 8 weeks) in terms of deep remission at week 54? Question-2) Is maintenance therapy with SC infliximab (120mg every 2 weeks) non-inferior to IV infliximab (10mg/kg every 8 weeks) in terms of deep remission at week 54?

Detailed Description
-----------------
Remsima (CT-P13) is the first biosimilar of infliximab and its intravenous (IV) formulation has been used for patients with active Crohn's disease (CD). Recently, subcutaneous (SC) formulation of Remsima (Remsima SC) was developed and approved by the Korean FDA (Food and Drug Administration). However, until now, besides a registration trial, real-life experiences of Remsima SC is still limited and the efficacy and safety of switching from SC to IV Remsima is still unknown. In this study, patients with moderately to severely active CD who achieve clinical response to SC Remsima at week 30 (IV Remsima 5mg/kg at week 0 and 2, followed by SC Remsima 120mg every 2 weeks from week 6) will be randomly (1:1) assigned to IV Remsima group (Arm 2) or to continued SC Remsima group (Arm 3). Non-responders at week 30 will be allocated to Arm 1 (IV Remsima 10 mg/kg). The primary endpoint is the non-inferiority of Arm 3 compared with Arm 2 in terms of deep remission rate at week 54. The secondary endpoint is the non-inferiority of Arm 3 compared with Arm 1 in terms of deep remission rate at week 54. The non-inferiority margin is set as -20% and a total of 100 patients will be enrolled. Through this study, the investigators aim to provide the clinical evidence for selecting the most optimal formulation of infliximab according to therapeutic response among Korean patients with CD.

Official Title
-----------------
Efficacy and Safety of Formulation Switching Between Subcutaneous Infliximab and Intravenous Infliximab in Patients With Crohn's Disease

Conditions
-----------------
Crohn's Disease

Intervention / Treatment
-----------------
* Drug: Infliximab-Dyyb


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years or older Moderate to severe Crohn's disease (Crohn's disease activity index 220 to 450) Ileocolonic Crohn's disease (CD) with Simple Endoscopic Score for Crohn Disease ≥6 or ileal or colonic CD with with Simple Endoscopic Score for Crohn Disease ≥4 and ulcer score ≥1 in at least one segment Fecal calprotectin ≥250 µg/g or C-reactive protein≥0.5 mg/dL Patients who have never been to exposed to any biologic agent Patients who are non-responsive or intolerance to conventional therapy (corticosteroids, immunomodulators, or antibiotics, etc.) or contraindicated to conventional therapy Patients who gave a voluntary informed consent Exclusion Criteria: Patients who have a history of hypersensitivity to humanized proteins Patients ever treated with corticosteroids within 8 weeks of screening date a) Symptomatic intestinal stricture, b) Symptomatic anal stricture, c) Untreated intra-abdominal abscess, d) Untreated perianal abscess, e) Abdominal surgery within 6 months, f) Patients who are expected to require intestinal surgeries during study period - However, the following patients can be included: from baseline, 4 weeks or more after proper drainage of perianal abscess and from baseline, 8 weeks or more after proper drainage of intra-abdominal abscess Active tuberculosis. However, the following patients can be included: Patients who were diagnosed with tuberculosis, but were properly treated with anti-tuberculosis therapy according to the standard guidelines and who were confirmed to be cured. Latent tuberculosis infection (LTBI): Patients confirmed as having latent tuberculosis through medical history, physical examination, chest X-ray, PPD (Purified Protein Derivative) skin test or interferon gamma release assay (IGRA) by a pulmonology specialist. However, patients with LTBI who finished proper treatment for LTBI for 4 weks and who are going to complete LTBI treatment. HBsAg (Hepatitis B virus surface antigen)-positivity. Patients with negative HBsAg, but positive IgG anti-HBc (Immunoglobulin G anti-Hepatitis B core antibody) should be tested for HBV (hepatitis B virus) DNA real time quantitative PCR (polymerase chain reaction). If HBV DNA real time quantitative PCR ≥10 IU/mL should be excluded. Anti-HCV (hepatitis C virus) antibody-positivity History of HIV (human immunodeficiency virus) infection of positivity for anti-HIV Heart disease of NYHA (New York Heart Association) Class III/IV Active infection Malignancy (excluding skin basal cell carcinoma, skin squamous cell carcinoma, and uterine cervix cancer) or history of colonic or small bowel dysplasia within 5 years Pregnancy or lactating woman Patients who are not applying proper contraceptive measures and patients who do not have a plan for proper contraceptive measures for at least 6 months after the last dose of infliximab (oral, parenteral, or implantable hormonal contraceptives, diaphragm, condom, intra-uterine device, or abstinence are accepted as proper contraceptive methods. Patients who are decided to be not proper to be enrolled into the study by investigators.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: In this study, CD (Crohn's disease) patients who achieved clinical response at week 30 after to Remsima (CT-P13, a biosimilar of infliximab) SC (subcutaneous formulation) will be randomly (1:1) assigned to intravenous infliximab (Remsima) group (Arm 2) or to continued infliximab (Remsima) SC group (Arm 3). The primary endpoint of the study is the non-inferiority of Arm 3 compared with Arm 2 in terms of deep remission rate at week 54. Non-responder at week 30 will be allocated to Arm 1 (intravenous infliximab [Remsima] 10 mg/kg) and the secondary endpoint is the non-inferiority of Arm 3 compared with Arm 1 in terms of deep remission rate at week 54. Through this study, the investigators aim to provide the clinical evidence for selecting the most optimal formulation of infliximab according to therapeutic response among Korean patients with CD.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-response to SC infliximab at week 30 and switched to infliximab IV 10 mg/kg every 8 weeks<br>Patients with moderately to severely active Crohn's disease will be given IV (intravenous) infliximab 5 mg/kg at week 0 and 2. Then, they will be treated with SC (subcutaneous) infliximab every 2 weeks from week 6. At week 30. patients will be allocated to one of 3 arms according to their response to SC infliximab. [Arm 1] Non-responders at week 30: Switched to infliximab IV 10 mg/kg every 8 weeks | Drug: Infliximab-Dyyb<br>* Continued infliximab SC 120 mg every other week, if response to SC infliximab at week 30<br>* Other names: Infliximab;|
| Experimental: Response to SC infliximab at week 30 and then, switched to infliximab IV 5 mg/kg every 8 weeks<br>Patients with moderately to severely active Crohn's disease will be given IV (intravenous) infliximab 5 mg/kg at week 0 and 2. Then, they will be treated with SC (subcutaneous) infliximab every 2 weeks from week 6. At week 30. patients will be allocated to one of 3 arms according to their response to SC infliximab. [Arm 2] Response to SC infliximab at week 30 and then, randomly allocated to infliximab IV 5 mg/kg every 8 weeks | Drug: Infliximab-Dyyb<br>* Continued infliximab SC 120 mg every other week, if response to SC infliximab at week 30<br>* Other names: Infliximab;|
| Active Comparator: Response to SC infliximab at week 30 and then, continued infliximab SC 120 mg every 2 weeks<br>Patients with moderately to severely active Crohn's disease will be given IV (intravenous) infliximab 5 mg/kg at week 0 and 2. Then, they will be treated with SC (subcutaneous) infliximab every 2 weeks from week 6. At week 30. patients will be allocated to one of 3 arms according to their response to SC infliximab. [Arm 3] Response to SC infliximab at week 30 and then, randomly allocated to infliximab SC 120 mg every 2 weeks | Drug: Infliximab-Dyyb<br>* Continued infliximab SC 120 mg every other week, if response to SC infliximab at week 30<br>* Other names: Infliximab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Deep remission rate of Arm 3 compared with Arm 2 | Deep remission: all of these 3 criteria (1) CDAI (Crohn's disease activity index) <150, (2) SES-CD (Simple Endoscopic Score for Crohn's disease) ≤2, (3) No systemic corticosteroids use for at least 8 weeks before evaluation. CDAI can range from 0 to 600 and a higher value mean more clinically active disease. SES-CD is scored for 5 segments (ileum, right colon, transverse colon, left colon, and rectum) for (1) ulcer size, (2) % of ulcerated surface, (3) % of affected surface, and (4) the presence of stenosis. A higher value means a high endoscopic disease activity. The non-inferiority of Arm 3 compared with Arm 2 will be test and the non-inferiority margin will be set as -20%. | Week 54 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Deep remission rate of Arm 3 compared with Arm 1 | Deep remission: all of these 3 criteria (1) CDAI (Crohn's disease activity index)<150, (2) SES-CD (Simple Endoscopic Score for Crohn's disease) ≤2, (3) No systemic corticosteroids use for at least 8 weeks before evaluation. CDAI can range from 0 to 600 and a higher value mean more clinically active disease. SES-CD is scored for 5 segments (ileum, right colon, transverse colon, left colon, and rectum) for (1) ulcer size, (2) % of ulcerated surface, (3) % of affected surface, and (4) the presence of stenosis. A higher value means a high endoscopic disease activity. The non-inferiority of Arm 3 compared with Arm 1 will be test and the non-inferiority margin will be set as -20%. | Week 54 | 
| Corticosteroid-free endoscopic remission rate of each arm | All of these 2 criteria should be met to be classified as a corticosteroid-free endoscopic remitter: (1) SES-CD (Simple Endoscopic Score for Crohn's disease) ≤2, (2) No systemic corticosteroids use for at least 8 weeks before evaluation SES-CD is scored for 5 segments (ileum, right colon, transverse colon, left colon, and rectum) for (1) ulcer size, (2) % of ulcerated surface, (3) % of affected surface, and (4) the presence of stenosis. A higher value means a high endoscopic disease activity. | Week 54 | 
| Corticosteroid-free complete mucosal healing rate of each arm | All of these 2 criteria should be met to be classified as an achiever of corticosteroid-free complete mucosal healing: (1) No visible ulcers (including aphthous ulcers) in ileocolonoscopy, (2) No systemic corticosteroids use for at least 8 weeks before evaluation | Week 54 | 
| Corticosteroid-free clinical response (CDAI-70) rate of each arm | All of these 2 criteria should be met to be classified as a corticosteroid-free clinical responder (CDAI-70): (1) Reduction of CDAI (Crohn's disease activity index) 70 or more compared with the baseline, (2) No systemic corticosteroids use for at least 8 weeks before evaluation CDAI can range from 0 to 600 and a higher value mean more clinically active disease. | Week 54 | 
| Corticosteroid-free clinical response (CDAI-100) rate of each arm | All of these 2 criteria should be met to be classified as a corticosteroid-free clinical responder (CDAI-100): (1) Reduction of CDAI (Crohn's disease activity index) 100 or more compared with the baseline, (2) No systemic corticosteroids use for at least 8 weeks before evaluation CDAI can range from 0 to 600 and a higher value mean more clinically active disease. | Week 54 | 
| Corticosteroid-free clinical remission rate of each arm | All of these 2 criteria should be met to be classified as a corticosteroid-free clinical remitter: (1) CDAI (Crohn's disease activity index) < 150, (2) No systemic corticosteroids use for at least 8 weeks before evaluation CDAI can range from 0 to 600 and a higher value mean more clinically active disease. | Week 54 | 
| Corticosteroid-free biochemical remission rate of each arm | All of these 2 criteria should be met to be classified as a biochemical remitter: (1) Both fecal calprotectin<250 µg/g and serum CRP (C-reactive protein) <0.5 mg/dL, (2) No systemic corticosteroids use for at least 8 weeks before evaluation | Week 54 | 
| Rate of anti-drug antibody positivity in each arm | Proportion of patients with a positive anti-infliximab antibody compared with the baseline | Week 54 | 
| The proportion of patients with treatment-related adverse events | Comparing the proportions of patients having any adverse events, serious adverse events, serious infections, and all types of adverse events as assessed by CTCAE v6.0 | Week 54 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Infliximab, Crohn's disease, Biosimilar, Remsima, Subcutaneous, Intravenous