Summary

• The safety and efficacy of REMICADE were assessed in 2 randomized, double-blind, placebo-controlled studies, Present et al and ACCENT II (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen), in adult patients with fistulizing Crohn’s disease (CD) with fistula(s) that were of at least 3 months duration.^1-3
• Among the Present et al patients treated with REMICADE 5 mg/kg, 68% experienced at least a 50% reduction in the number of open fistulas for at least 2 consecutive follow-up visits; 55% of these patients experienced closure of all fistulas.³
• Among the ACCENT II week 14 responders, time to loss of response (primary endpoint) was longer for patients who received REMICADE 5 mg/kg maintenance therapy as compared to placebo maintenance (>40 weeks vs 14 weeks, respectively). Additionally, REMICADE 5 mg/kg maintenance therapy resulted in a significant decrease in disease activity and improvement in health-related quality of life compared to placebo maintenance.²
• Safety findings in ACCENT II were similar between patients receiving REMICADE 5 mg/kg and placebo maintenance therapy.²

PRODUCT LABELING

Please refer to the INDICATIONS AND USAGE and the DOSAGE AND ADMINISTRATION sections of the REMICADE Prescribing Information that are relevant to your request.

CLINICAL TRIAL DATA

Present et al

Present et al (1999)³ evaluated the safety and efficacy of REMICADE in a randomized, double-blind, placebo-controlled study of 94 fistulizing CD patients with fistula(s) that were of at least 3 months duration.

Study Design/Methods

• Patients received 3 doses of placebo, 5 mg/kg, or 10 mg/kg REMICADE at weeks 0, 2, and 6, and clinical response was evaluated up to 18 weeks.
• Concurrent use of stable doses of corticosteroids, 5-aminosalicylates (5-ASA), antibiotics, methotrexate (MTX), 6-mercaptopurine (6-MP) and/or azathioprine (AZA) was permitted.
• Fifty-two patients (55%) had multiple cutaneous draining fistulas, 90% had fistula(s) in the perianal area, and 10% had abdominal fistula(s).

Results

• Among patients treated with REMICADE 5 mg/kg, 68% experienced at least a 50% reduction in the number of open fistulas for at least 2 consecutive follow-up visits (P=0.002 vs placebo); 55% of these patients experienced closure of all fistulas (P=0.001 vs placebo).
• Of the 32 patients in the 10 mg/kg REMICADE group, 18 (56%) achieved a clinical response.
• The median time to onset of response in the REMICADE-treated group was 2 weeks, and the median duration of response was 12 weeks.
• Overall, more than 60 percent of patients in all the groups had adverse events.  The most common reactions in the REMICADE group were headache, abscess, upper respiratory tract infection, and fatigue.

ACCENT II

Sands et al (2004)^2,4 evaluated the safety and efficacy of long-term maintenance therapy with REMICADE in 306 patients with fistulizing CD in the ACCENT II trial.

Study Design/Methods

• The ACCENT II trial (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) was a multicenter, randomized, international trial.
• Patients not previously treated with REMICADE experiencing a single or multiple draining enterocutaneous fistulas of at least 3 months duration were enrolled.
• The objectives of this 1-year trial included: evaluation of the efficacy of a 3-dose induction regimen of REMICADE 5 mg/kg followed by REMICADE 5 mg/kg maintenance every 8 weeks as compared with a 3-dose induction regimen of REMICADE 5 mg/kg followed by placebo maintenance every 8 weeks; the effects of a maintenance regimen on disease remission and quality-of-life compared to a 3-dose induction regimen; and the long-term safety of REMICADE maintenance therapy.
• All patients received an initial induction regimen of REMICADE 5 mg/kg at weeks 0, 2, and 6. At week 14, patients were randomized based on clinical response, defined as a ≥50% reduction from baseline in the number of draining fistulas at both weeks 10 and 14, and received maintenance dosing with either REMICADE 5 mg/kg or placebo every 8 weeks.
• Patients who did not respond to the initial 3-dose induction regimen were randomized separately from patients who demonstrated a response at both weeks 10 and 14.
• Beginning at week 22, patients who responded to treatment but then lost their clinical benefit were eligible to cross over to treatment with REMICADE 5 mg/kg if receiving placebo, or to REMICADE 10 mg/kg if receiving REMICADE 5 mg/kg.
  • Concomitant CD medications were maintained at stable doses.
• The primary endpoint of the trial was the time from randomization until loss of response; analysis only included the week 14 responders.
• Secondary endpoints included the effectiveness of REMICADE in inducing complete fistula response (no draining fistulas), duration of fistula response, and health-related resource consumption.
• The effects of REMICADE maintenance treatment on disease activity and quality-of-life were also assessed using the Crohn’s Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ).

Results

• Among all randomized patients (282 of 306 initially enrolled), baseline characteristics across groups were similar. Disease duration ranged from 0.2-49.8 years.
• Patients were typical of a CD population with active fistulizing disease, with over half of all patients in each group exhibiting a CDAI score ≥150, and over 30% having a CDAI ≥220.
• The median number of draining fistulas was 2 for all groups (range, 1-11 draining fistulas). Fistula location was predominately perianal, followed by abdominal and rectovaginal.
• Greater than 90% of the patients had received previous immunosuppressive and antibiotic therapy. Baseline characteristics are depicted in Table: Baseline Characteristics of All Patients.

Week 14 Responders

Of the 282 evaluable patients at week 14, 195 (69%) demonstrated a clinical response to REMICADE 5 mg/kg. Among the week 14 responders, the median time to loss of response was significantly longer for patients who received REMICADE 5 mg/kg maintenance therapy than for patients who received placebo maintenance (>40 weeks vs 14 weeks, respectively; P<0.001).²

• At week 54, significantly more patients in the REMICADE 5 mg/kg maintenance group maintained response and achieved complete closure of all fistulas compared to the placebo maintenance group (46% vs 23%, P=0.001; and 36% vs 19%, P=0.009). REMICADE 5 mg/kg maintenance therapy also resulted in a significant decrease in disease activity and in significantly more patients achieving remission, as measured by change from baseline in the CDAI score, compared to the placebo maintenance group.
• REMICADE 5 mg/kg maintenance therapy also resulted in a significant improvement in health-related quality-of-life compared to placebo maintenance therapy, as assessed by changes in the IBDQ score. Study results for the week 14 responders are summarized in Table: Summary of Results Among Week 14 Responders.²

Among week 14 responders, when comparing the REMICADE 5 mg/kg maintenance group to placebo maintenance, significant differences were seen in both mean hospitalizations days per patient and mean number of hospitalizations (0.5 vs 2.5 days, P<0.05; 11% vs 31%, P<0.05; respectively). Additionally, significant differences were noted in the number of all surgeries/procedures, inpatient surgery/procedures, and major surgeries (65 vs 126, P<0.05; 7 vs 41, P<0.01; 2 vs 11, P<0.05, respectively).⁵

Week 14 Nonresponders

Patients who failed to respond to the 3-dose induction at week 14 were randomized in an identical manner but separately from responders.²

• Twenty-one percent (9/43) of patients who subsequently received REMICADE 5 mg/kg maintenance therapy responded compared to 16% (7/44) of those who received placebo maintenance, however, the findings were not statistically significant (P=0.6).

Safety

The most common adverse events were upper respiratory tract infection, abdominal pain, and headache, occurring in 23%-29% of all patients. The incidence of these events between the 2 treatment groups was similar.^2,4

• The overall incidence of serious adverse events and adverse events that led to discontinuation of study medication were higher in the placebo maintenance treatment group than in the REMICADE 5 mg/kg maintenance group.
• The most common serious adverse event was worsening of CD, reported in 6.4% of all patients and observed more frequently in the placebo maintenance group (9.7%) than the REMICADE 5 mg/kg maintenance group (2.9%).
• Serious infections occurred in 5% of patients.
  • Abscess, the only serious infection that was reported in more than 2 patients, occurred in 5 patients who received placebo maintenance and in 2 patients who received REMICADE 5 mg/kg.
  • Other notable serious infections included a case of cytomegalovirus in a placebo-treated patient, and a nocardial skin lesion in an REMICADE 5 mg/kg-treated patient.
  • No other opportunistic infections were reported.
• Intraabdominal abscesses occurred in 15% of all patients, 12% of patients in the REMICADE 5 mg/kg maintenance group and 17% of patients in the placebo maintenance group. The overall occurrence of intestinal obstruction and perforation was similar across treatment groups.

Of 258 patients who were assessed for the presence of antibodies to REMICADE, 17% developed antibodies to REMICADE. Antibody development was higher in patients who received placebo (21%) as compared with patients who received REMICADE 5 mg/kg maintenance therapy (13%).^2,4

• Approximately half (52%) of the patients had inconclusive results due to the presence of REMICADE in the serum, which can interfere with the assay.
• The proportion of patients developing antibodies to REMICADE was lower among patients receiving concomitant corticosteroids or immunomodulators.
• The proportion of patients achieving a clinical response was similar across the 3 antibody to REMICADE classification groups.
• Overall, the proportion of infusions that resulted in infusion reactions was 4% of REMICADE 5 mg/kg maintenance infusions and 1% of placebo infusions resulting in infusion reactions (P<0.001).
• In general, the reactions were not severe enough to warrant discontinuation of treatment, with only 1 patient experiencing a serious infusion reaction.
• Patients who were classified as antibody to REMICADE-positive were approximately 2-3 times more likely to experience an infusion reaction.
• The occurrence of delayed hypersensitivity was low.
  • Specifically, 5 patients (1.8%) experienced a delayed hypersensitivity reaction, which resulted in study discontinuation in 3 patients (n=2 REMICADE 5 mg/kg; n=1 placebo).

More patients who received REMICADE 5 mg/kg maintenance therapy than patients who received placebo maintenance developed new antinuclear antibodies (ANA) and anti-double stranded DNA (anti-dsDNA; 46% vs 18% and 23% vs 6%, respectively).^2,4

• One patient developed a lupus-like syndrome; however, results of ANA and dsDNA assessments were negative.
• Multiple sclerosis developed in 1 patient assigned to placebo maintenance approximately 1 month after a REMICADE infusion that was not study-related. No malignancies or deaths were reported through week 54.
• Two cases of malignancy were reported during long-term follow-up.
  • One patient, a 42-year-old male with a 20-year history of colonic CD, received a diagnosis of rectal carcinoma approximately 2 years after his last REMICADE infusion.
  • The second patient, a 36-year-old male with a 22-year history of ileal CD and perianal fistula, received a diagnosis of rectal adenocarcinoma approximately 19 months after his last (sixth) infusion.
• Two deaths were reported during long-term follow-up.
  • One patient, a 78-year-old female died of sepsis related to advanced CD approximately 9 months after her last (fourth) study infusion of REMICADE. Of note, the patient also received an infusion of REMICADE 7 months before her death.
  • The other patient, a 52-year-old male, died from multi-system organ failure 18 months after receiving the 3-dose induction regimen of REMICADE 5 mg/kg. This patient did not receive any additional REMICADE.
• Overall, there were no remarkable differences in safety between treatment groups.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 19 November 2024.

Summarized in this response are relevant data from pivotal clinical trials of REMICADE for the use of fistulizing Crohn’s disease.