Allan Olson

Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial

BACKGROUND We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohns disease who respond to a single infusion of infliximab. METHODS 573 patients with a score of at least 220 on the Crohns disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat. FINDINGS 335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohns disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups. INTERPRETATION Patients with Crohns disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.

Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease

BACKGROUND & AIMS The effect of different treatment regimens on antibody responses to infliximab and their clinical significance was examined by using data from ACCENT I. METHODS Patients with Crohns disease (n = 573) received 5 mg/kg infliximab (week 0) and then were randomly assigned to blinded infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo (group I), 5 mg/kg infliximab (group II), or 5 mg/kg infliximab at weeks 2 and 6, followed by 10 mg/kg thereafter (group III). At week 14 or later, patients losing response could cross over to episodic infliximab treatment increased by 5 mg/kg. Samples for antibody determination were collected before the first infusion and at weeks 14, 22, 54, 62, 72, and, if applicable, before and after crossover. RESULTS Through week 72, antibodies to infliximab were detected in 30%, 10%, and 7% of groups I, II, and III, respectively (P < 0.0001). Patients receiving immunomodulators had a lower incidence of antibodies compared with patients receiving infliximab alone (10% and 18%, respectively; P = 0.02). Antibodies were associated with a 12% absolute increase in infusion reactions but no increase in serious infusion reactions or serum sickness-like reactions. In the overall population, similar proportions of antibody-positive and antibody-negative patients achieved clinical response (64% and 62%, respectively; P = NS) or clinical remission (41% and 39%, respectively; P = NS) at week 54. Notably, 86% of patients responded to retreatment, and 63% were in clinical response at week 54; however, fewer antibody-positive group I patients attained clinical remission (31%) compared with those who were antibody negative (37%) or antibody inconclusive (54%) (P = NS). CONCLUSIONS Reduced antibody formation and greater clinical benefit were observed with an induction regimen followed by maintenance treatment compared with a single dose followed by episodic retreatment in Crohns disease patients treated with infliximab.

Colectomy Rate Comparison After Treatment of Ulcerative Colitis With Placebo or Infliximab

BACKGROUND & AIMS The efficacy of infliximab for treating patients with ulcerative colitis has been established. METHODS The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan-Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo. RESULTS Eighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy. CONCLUSIONS Patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo.

Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD‐subgroup analyses across four randomized trials

Background  Benefits and risks of concomitant immunomodulators and maintenance infliximab in inflammatory bowel disease (IBD) patients have not been adequately evaluated.

Factors associated with the development of intestinal strictures or obstructions in patients with Crohn's disease

OBJECTIVE:Theoretical concern exists that rapid luminal healing in Crohns disease (CD) with therapies like infliximab increases the risk of intestinal stenosis, stricture, or obstruction (SSOs).METHODS:Data were analyzed from the ongoing observational TREAT (the Crohns Therapy, Resource, Evaluation, and Assessment Tool) Registry and ACCENT I (A Crohns Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) study. Investigators reported SSOs as adverse events or serious adverse events.RESULTS:In TREAT, SSOs occurred at a significantly higher rate in patients treated with infliximab compared with patients who received other treatments only (1.95 events/100 patient-years vs 0.99 events/100 patient-years; p < 0.001). Using multivariable analyses, however, infliximab therapy was not associated with SSO development. CD severity at the time of event onset (hazard ratio (HR) = 2.35, 95% confidence internal (CI) 1.35–4.09); CD duration (HR = 1.02, 95% CI 1.00–1.04); ileal disease (HR = 1.56, 95% CI 1.04–2.36); and new corticosteroid use (HR = 2.85, 95% CI 1.23–6.57) were associated with SSOs. In ACCENT I, no increase in SSOs was reported in patients who received infliximab maintenance therapy compared with those who received episodic therapy, despite higher median cumulative infliximab exposure. Additionally, there was no increase in SSO development with rapid mucosal healing (healing at week 10).CONCLUSIONS:Although unadjusted analyses suggested that patients who received infliximab were twice as likely to develop SSOs, multivariable analysis adjusting for other factors demonstrated that only disease duration, disease severity, ileal disease, and new corticosteroid use were significantly associated with SSO development.

The effects of infliximab therapy on health-related quality of life in ulcerative colitis patients

OBJECTIVES:The impact of infliximab induction and maintenance therapy on health-related quality of life (HRQL) was evaluated in patients with ulcerative colitis (UC).METHODS:In two placebo-controlled, double-blind studies (the Active Ulcerative Colitis Trials 1 and 2 [ACT 1 and 2]), 728 patients were randomized to placebo or infliximab 5 mg/kg or 10 mg/kg. Infusions were administered at weeks 0, 2, 6, and every 8 wk thereafter, up to week 22 (ACT 2) or 46 (ACT 1). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-Item Short Form Health Survey physical and mental component summary (PCS and MCS, respectively) scores were analyzed.RESULTS:Baseline scores for the pooled patient population indicated substantial impairment in HRQL. Improvement at week 8 in the total IBDQ score was significantly greater in the infliximab 5-mg/kg (40, P < 0.001) and 10-mg/kg (36, P < 0.001) groups compared with the placebo group (28). Improvement at week 8 was also significantly greater in the infliximab 5- and 10-mg/kg groups for the PCS (6.8 and 5.9, respectively) and MCS (5.9 and 6.4, respectively) compared with placebo (PCS = 3.7, MCS = 3.0, P < 0.01 for all comparisons). Continued benefit was seen at weeks 30 and 54 with infliximab maintenance therapy (P < 0.001 for all comparisons). Improvement in total IBDQ score correlated significantly (P < 0.001) with improvement in both PCS and MCS scores, and Mayo score.CONCLUSIONS:Infliximab therapy substantially improved HRQL in patients with UC. This benefit was sustained through 1 yr with maintenance infliximab therapy.

Unemployment and disability in patients with moderately to severely active Crohn's disease.

Goals: Unemployment and disability rates in Crohns disease patients from the ACCENT I trial were assessed. Factors associated with employment and disability status were explored. Background: Limited data regarding unemployment and disability status in patients with active Crohns disease are available. Study: Baseline data were used to assess unemployment and disability rates. Logistic regression analysis examined factors that were associated with employment and disability status. Analysis of variance was used to compare quality of life. Results: The baseline full-and part-time employment rates were 48% and 13%, respectively, with 39% of patients unemployed and 25% receiving disability compensation. Only 14% of 225 unemployed patients felt well enough to work if a job were available. Younger age, female gender, shorter disease duration, and prior bowel resection predicted a higher likelihood of unemployment. Younger age and female gender also predicted a higher likelihood of not being employed full-time. Prior bowel resection predicted a higher likelihood of receiving disability compensation. Quality of life (Inflammatory Bowel Disease Questionnaire, Short Form-36) scores were significantly higher in employed patients. Conclusions: Patients with moderately to severely active Crohns disease had low employment and high disability rates. Given their economic importance, assessment of these outcomes should be integrated into future evaluations of therapy, including clinical trials.

Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis

BACKGROUND Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. METHODS We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score ≤2, with no subscore >1) at 8 weeks. RESULTS The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of ≥3 points and ≥30% and decrease in rectal-bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The most common adverse events overall were anemia and headache. CONCLUSIONS In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.).

Response and remission are associated with improved quality of life, employment and disability status, hours worked, and productivity of patients with ulcerative colitis

Background: Impairment of health‐related quality of life, employment, and productivity has been documented in patients with moderate to severe ulcerative colitis. Methods: Using prospectively collected data from the Active Ulcerative Colitis Trials 1 and 2, we examined the impact of clinical response or remission, as defined using the Mayo score, on health‐related quality of life, employment, disability, productivity, and hours worked per week. These analyses were based on observed data and included all 728 patients, regardless of their randomized treatment group (i.e., placebo and infliximab patients were grouped for analysis). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36‐Item Short Form (SF‐36) scores among nonresponders, responders, and patients in remission were compared. In addition, changes in employment, disability status, productivity, and hours worked per week of patients in clinical remission and patients not in clinical remission were compared. Results: Ulcerative colitis patients in clinical response or remission had significantly improved IBDQ and SF‐36 scores at week 30 compared with those of nonresponders (P < 0.001). Among those not employed at baseline, including those receiving disability compensation, greater percentages of patients in remission at week 30 were employed (20.6%) and not receiving disability compensation (58.8%) than were those not in remission (8.3% and 20.0%, respectively; P < 0.05 for both comparisons). At week 30, improvements from baseline in productivity and both actual and fully productive hours worked per week were greater for patients in remission compared with those not in remission (P < 0.05 for all three comparisons). Conclusions: These results confirm the validity of response and remission as defined using the Mayo score.

Endoscopic and histologic evidence of persistent mucosal healing and correlation with clinical improvement following sustained infliximab treatment for Crohn's disease.

ABSTRACT Objectives: The long-term effect of infliximab on endoscopic and histologic disease activity and expression of inflammatory markers was assessed in Crohns disease patients who received infliximab as episodic or scheduled maintenance therapy over 54 weeks (ACCENT I). Methods: All patients received infliximab 5 mg/kg at week 0 and at week 2 were then randomized as responders or nonresponders to placebo or infliximab (5 or 10 mg/kg). Patients received placebo or infliximab 5 mg/kg at weeks 2 and 6 followed by placebo or infliximab (5 or 10 mg/kg) every 8 weeks or episodically on loss of response. Crohns Disease Activity Index (CDAI), Crohns Disease Endoscopic Index of Severity (CDEIS), Inflammatory Bowel Disease Questionnaire (IBDQ), and colonic and ileal Global Histologic Disease Activity (CGHAS and IGHAS) scores were determined at weeks 0, 10, and 54. Tumor necrosis factor-alpha (TNF‐α), gelatinase B, infliximab, tenascin, clusters of differentiation marker 68 (CD68), and intercellular adhesion molecule‐1 (ICAM‐1) were detected in mucosal biopsies by immunohistochemistry. Results: At baseline, CDEIS significantly correlated with CGHAS only. Further at baseline, both CDEIS and the worst CGHAS or IGHAS, were significantly correlated with CD68, ICAM‐1, and gelatinase B expression. At week 10, improvement in CGHAS only, correlated significantly with better CDAI, CDEIS, and IBDQ scores. Improvements in CDEIS and GHAS at week 10 correlated with reductions in gelatinase B and CD68, whereas only GHAS improvement correlated with decreased TNF‐α expression. At week 54, decreased gelatinase B expression continued to correlate with improved CDEIS and GHAS while decreased CD68 and TNF-α expression correlated with GHAS and CDEIS improvement, respectively. Conclusions: Endoscopic and histologic evidence of mucosal healing was associated with a sustained reduction in the expression of inflammatory markers. Infliximab-induced improvement in the clinical signs and symptoms of Crohns disease was associated with endoscopic and histologic evidence of sustained mucosal healing.