Summary

• The company cannot recommend any practices, procedures or usage that deviate from the approved labeling.
• Please refer to the local labeling for relevant information regarding dose increase or dose interval reduction of REMICADE for the treatment of ulcerative colitis (UC).
• Among the 229 REMICADE–treated patients in the Active Ulcerative Colitis Trial (ACT) extension studies, 16 patients who entered the extension study and received REMICADE 5 mg/kg increased their dose to 10 mg/kg. Of these 16 UC patients, 12 patients completed the extension, 1 each was lost to follow-up or withdrew consent, and 2 patients discontinued due to adverse events (n=1 worsening UC; n=1 adenocarcinoma of the lung).¹
• In a randomized, multicenter, open-label phase 3 trial in 60 pediatric patients with moderately-to-severely active UC, patients who lost response during the maintenance phase were able to increase the REMICADE dose and/or frequency. Of the 45 patients who were randomized from 60 pediatric patients in the trial, 23 patients stepped up therapy, with more patients stepping up in the every 12 week group compared to the every 8 week group (n=14/23 vs n=9/22), and most patients stepping up by week 22 (n=18/23; 78.3%).²
• A total of 15 of the 45 randomized pediatric patients discontinued maintenance treatment with 11 of these patients in the group who stepped up therapy. Among patients that stepped up and had data at week 54, 9 of 10 patients demonstrated improvement in disease activity.²

CLINICAL DATA

ACT Clinical Trials Extension

Reinisch et al (2012)¹ evaluated the effects of REMICADE treatment on long-term efficacy, safety, and quality of life in patients who entered the ACT 1 and ACT 2 extension studies after the main ACT studies. In the studies, dose adjustments were allowed, including dose increase from 5 to 10 mg/kg.

Study Design/Methods

• The efficacy of REMICADE in moderate-to-severely active UC was demonstrated in 2 large clinical studies, the ACT 1 and ACT 2 clinical trials. Patients received a 3-dose induction regimen of REMICADE at weeks 0, 2, and 6, followed by maintenance treatment every 8 weeks.
• Patients were eligible to continue into the extension and receive up to 3 additional years of therapy if they demonstrated benefit from REMICADE treatment during the 54-week ACT 1 study or the 30-week ACT-2 study and in the opinion of the investigator, could benefit from continued treatment. Patients were also required to have completed their main study therapy and evaluations through weeks 46 and 54 for ACT 1 and through weeks 22 and 30 for ACT 2 and were not allowed to receive experimental medication for UC after the main study was completed.
• During the extension, patients continued to receive the blinded treatment that they were randomized to in the main study. Study sites began to unblind treatment after the week 54 (ACT 1) and extension week 24 (ACT 2) analyses were completed.
• The first extension study infusion (extension week 0 [E0]) for patients was at week 54 in ACT 1 patients and week 30 in ACT 2 patients.
• After all sites were unblinded, patients receiving 5 or 10 mg/kg of REMICADE continued in that arm and received open-label REMICADE 5 or 10 mg/kg every 8 weeks (however, placebo patients were discontinued from the study upon unblinding).
  • Patients receiving the 10 mg/kg REMICADE dose were allowed to decrease to
    5 mg/kg.
  • Patients receiving 5 mg/kg could increase to 10 mg/kg for subsequent infusions if response was lost and with physician discretion.
• During the extension studies, patients were allowed to continue stable doses of conventional concomitant UC medications. Dose adjustments of these products, and additions or discontinuation of these products were allowed as needed.
• REMICADE treatment for patients continued for a maximum of 3 years (E152) or until REMICADE was commercially available in that country post-marketing authorization. Patients were evaluated every 8 weeks up to E152.

Results

• A total of 291 patients entered the long-term extension study of the ACT trials (n=229 REMICADE-treated patients from either the 5 mg/kg or the 10 mg/kg groups in ACT 1 or ACT 2; n=62 placebo).
• Among the 229 REMICADE–treated patients in the ACT extension studies, 16 patients who entered the extension study and received REMICADE 5 mg/kg increased their dose to 10 mg/kg.
  • Of these 16 patients, 12 patients completed the extension, 1 each was lost to follow-up or withdrew consent, and 2 patients discontinued due to adverse events (n=1 worsening UC; n=1 adenocarcinoma of the lung).
• Additionally, 2 patients who entered the extension study and received REMICADE 10 mg/kg decreased their dose to 5 mg/kg, but then increased back to 10 mg/kg dose and completed the study.

Pediatric Ulcerative Colitis Phase 3 Trial

Hyams et al (2012)², in a randomized, multicenter, open-label phase 3 trial, evaluated the efficacy and safety of induction and maintenance therapy with REMICADE in 60 pediatric patients (ages 6-17 years old) with moderately to severely active UC who had failed conventional therapy. In the trial, patients who lost response during the maintenance phase were able to increase the REMICADE dose and/or frequency.

Study Design/Methods

• REMICADE 5 mg/kg, in an induction regimen at weeks 0, 2, and 6, was given to patients with active UC who had not responded or tolerated conventional therapy, including 5-aminosalicylic acid compounds, 6-mercaptopurine or azathioprine, or oral or intravenous (IV) corticosteroids.
• Responders at week 8 were randomized equally to maintenance REMICADE every 8 or 12 weeks and followed for efficacy through week 54 and safety through week 62. Patients receiving every 8 week therapy received REMICADE up to week 46 and in the every 12 week group they received REMICADE until week 42.
• Patients who lost response during the maintenance phase were able to increase the REMICADE dose and/or frequency:
  • 5 mg/kg every 8 weeks increased to 10 mg/kg every 8 weeks
  • 5 mg/kg every 12 weeks who lost response within 8 weeks of the previous REMICADE infusion increased to 10 mg/kg every 8 weeks
  • 5 mg/kg every 12 weeks who lost response between 8 and 12 weeks after the previous REMICADE infusion increased to 5 mg/kg every 8 weeks
• Patients who were nonresponders at week 8 did not receive further REMICADE.
• Before enrolling, patients receiving UC treatments were required to be on stable doses. Patients receiving oral or IV corticosteroids or immunomodulators could taper their dose during the study if needed. Other UC-specific medical therapies were required to remain stable.

Results

• A total of 60 patients (median age: 14.5 years; median Mayo score: 8.0; median Pediatric Ulcerative Colitis Activity Index [PUCAI] score: 55.0) were included in the trial, with 53.3% (n=32/60) of patients being female, 76.7% of patients with extensive disease, and a median disease duration among patients of 1.4 years.
• At baseline, 53.3% (n=32/60) of patients were receiving 1 or more immunomodulatory agents (6-mercaptopurine, azathioprine, methotrexate, aminosalicylates, antibiotics), and 61.7% (n=37/60) of patients were receiving oral or parenteral corticosteroids (excluding budesonide).
• Among 60 enrolled patients, 45 were randomized at week 8 to receive REMICADE every 8 weeks (n=22) or every 12 weeks (n=23).
• Of the 45 randomized patients, 23 patients stepped up therapy with more patients stepping up in the every 12 week group compared to every 8 week group (n=14/23 vs n=9/22). Most patients stepped up by week 22 (n=18/23; 78.3%).
• In the every 12 week group, of the 14 patients who stepped up: 8 patients stepped up to 10 mg/kg every 8 weeks and 6 patients to 5 mg/kg every 8 weeks.
• Overall, 15 of the 45 randomized patients discontinued maintenance treatment, with 11 of these patients in the group who stepped up therapy. Among those who stepped up, 7 patients (30.4%) discontinued maintenance treatment because of an adverse event, 3 patients (13.0%) for unsatisfactory therapeutic effect, and 1 patient (4.3%) for other reasons.
• Among patients that stepped up and had data at week 54, 9 of 10 patients demonstrated improvement in disease activity, which was defined as a decrease of ≥2 points in their partial Mayo score. It is noted that these patients might have altered their concomitant UC medications.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 31 August 2023.

Summarized in this response are relevant data from a study extension of a pivotal clinical trial program in the treatment of adult patients with moderately to severely active UC (ACT clinical trials extension) and a pivotal pediatric phase 3 clinical trial in patients 6-17 years old with moderately to severely active UC.