BACKGROUND & AIMS: With several options available for patients with moderate-severe ulcerative colitis (UC), rapidity of symptom resolution could be an important differentiator. We compared the efficacy and speed of onset of action of infliximab vs golimumab induction therapy using patient-level data from phase 3 trials (ACT-1, ACT-2, and PURSUIT-SC).
METHODS: We compared differences in proportions of patients who achieved the composite outcome of a rectal bleeding score=0 and stool frequency score ≤1 (patient-reported outcome 2 remission) at weeks 2 and 6 of treatment with standard-dose infliximab vs golimumab using logistic generalized estimating equation. Overall efficacy for inducing clinical remission (Mayo clinic score <3) was compared using logistic regression. Analyses were adjusted for sex, disease extent, baseline clinical and endoscopic severity, C-reactive protein, albumin, body weight and concomitant medications (immunomosuppressives, corticosteroids, and 5-aminsalicylates).
RESULTS: Trial populations were similar and no differences were observed among the placebo groups in the studies. A significantly higher proportion patients treated with infliximab than golimumab achieved patient-reported outcome 2 remission at week 2 (35% vs 30%; adjusted odds ratio [OR], 1.71; 95% CI, 1.15-2.55) and at week 6 (50.0% vs 38.9%; adjusted OR, 2.0; 95% CI, 1.40-2.94). Infliximab-treated patients were also significantly more likely to achieve clinical remission than golimumab-treated patients (adjusted OR, 3.01; 95% CI, 1.95-4.70), with consistent findings in patients with moderate or severe UC.
CONCLUSIONS: Based on a patient-level analysis of data from phase 3 trials, infliximab resolves symptoms more rapidly and has greater efficacy for inducing remission than golimumab in patients with moderate-to-severe UC.
Tofacitinib is an oral synthetic small-molecule inhibitor of Janus kinases, which are involved in the pathogenesis of various inflammatory diseases, representing a new therapeutic option for ulcerative colitis. The efficacy and safety of tofacitinib have been demonstrated in clinical trials in patients with moderate to severe ulcerative colitis, and it has recently been approved by the European Medicines Agency to treat this disease. This article reviews the most relevant characteristics of tofacitinib, its main differences from biological agents, the studies which demonstrate its efficacy in patients with ulcerative colitis, and its optimal use in different clinical situations.
BACKGROUND: Vedolizumab safety and efficacy have been established in many populations all over the world, but have never been studied in Japan. We report results from a Phase 3, randomized, double-blind, placebo-controlled study of vedolizumab in Japanese patients with active ulcerative colitis (UC).
METHODS: Patients with moderate-to-severe UC were enrolled into Cohort 1 (double-blinded) or Cohort 2 (open-label) in the induction phase. Cohort 1 was randomized 2:1 to receive 300 mg vedolizumab or placebo, while Cohort 2 received vedolizumab 300 mg only, at Weeks 0, 2, and 6. Patients from Cohorts 1 and 2 showing a clinical response to vedolizumab at Week 10 were randomized 1:1 to receive vedolizumab or placebo (double-blinded) at Week 14 and then every 8 weeks up to Week 54 as the maintenance phase. The primary endpoint was clinical response at Week 10, for the induction phase, and clinical remission at Week 60, for the maintenance phase.
RESULTS: A total of 292 patients were enrolled into the induction phase (246 in Cohort 1, 46 in Cohort 2); 83 patients achieved response to vedolizumab and were subsequently enrolled into the maintenance phase. Clinical response rates at Week 10 were 39.6% (65/164) and 32.9% (27/82) in the vedolizumab and placebo groups in Cohort 1, respectively (adjusted odds ratio [AOR] = 1.37, 95% CI 0.779-2.399; p = 0.2722). In the maintenance phase, clinical remission rate at Week 60 was significantly higher in the vedolizumab group, at 56.1% (23/41), versus 31.0% (13/42) for placebo (AOR = 2.88, 95% CI 1.168-7.108; p = 0.0210). Most adverse events were mild to moderate in intensity, and no deaths occurred during the study period.
CONCLUSIONS: Vedolizumab showed numerically greater efficacy compared with placebo as induction therapy, but the difference was not statistically significant. Vedolizumab was significantly superior to placebo as maintenance therapy in Japanese patients with UC. Vedolizumab has favourable safety and tolerability in these patients.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT02039505.
Background: We aimed to compare the effectiveness of vedolizumab (VDZ) to tumour necrosis factor (TNF)-antagonist therapy for ulcerative colitis (UC). Methods: Using a multicentre, US-based consortium of UC patients treated with VDZ or TNF-antagonist therapy, we performed propensity score matching (1:1) accounting for age, sex, prior UC-related hospitalisation within the previous year, disease extent, disease severity, steroid refractoriness or dependence, and prior TNF-antagonist failure. Treatment response was categorised using the physician global assessment. Using Cox proportional hazard models, we compared cumulative rates of clinical remission (complete resolution of UC-related symptoms), steroid-free remission (on steroids at baseline, tapered off, no repeat steroid prescription for 4 weeks), and endoscopic healing (Mayo endoscopic subscore of 0 or 1). Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported for VDZ compared with TNF-antagonist therapy. Results: The propensity score model accurately predicted treatment status (area under curve 0.73). Of 646 UC patients, 334 were included after matching (n = 167 VDZ,; 49% male; median age 36 years). After adjusting for concomitant steroid use, concomitant immunomodulator (azathioprine, 6-mercaptopurine, methotrexate) use, and number of prior TNF-antagonists used, VDZ-treated patients had statistically significant higher 12-month cumulative rates of clinical remission (54% vs. 37%; HR 1.54, 95% CI 1.08-2.18) and endoscopic healing (50% vs. 42%, HR 1.73, 95% CI 1.10-2.73). Cumulative 12-month rates for steroid-free remission were numerically higher for VDZ-treated patients, but not statistically significant (49% vs. 38%; HR 1.43, 95% CI 0.79-2.60), These findings were consistent when stratified by disease extent and prior TNF-antagonist exposure. Conclusions: After accounting for measurable disease and patientspecific characteristics that may impact biologic effectiveness, we observed that VDZ-treated UC patients had significantly higher 12-month cumulative rates of clinical remission and endoscopic healing, and numerically higher steroid-free remission rates, when compared with TNF-antagonist-treated patients. Randomised controlled trial data are needed to confirm these findings.
BACKGROUND & AIMS: This study compares the effectiveness and safety of infliximab and adalimumab in biologic-naive patients with ulcerative colitis (UC), in a nationwide register-based propensity score-matched cohort study.
METHODS: From 1719 adults with UC, between ages 15 and 75 years in Denmark treated with either infliximab or adalimumab as their first biologic agent, we compared rates of all-cause hospitalization, UC-related hospitalization, major abdominal surgery, and serious infections after a variable 2:1 propensity score matching, accounting for baseline clinical characteristics, disease severity, health care utilization, and use of UC-related medications.
RESULTS: As compared with infliximab-treated patients, adalimumab-treated patients had higher rate of all-cause hospitalization (hazard ratio [HR], 1.84; 95% CI, 1.18-2.85) and a trend toward higher rate of UC-related hospitalization (HR, 1.71; 95% CI, 0.95-3.07), particularly in a stratum of patients on concomitant immunomodulator therapy. However, risk of abdominal surgery (HR, 1.35; 95% CI, 0.62-2.94) was not different between the 2 treatment groups. Risk of serious infection requiring hospitalization was significantly higher in adalimumab-treated patients (HR, 5.11; 95% CI, 1.20-21.80).
CONCLUSIONS: In this nationwide propensity score matched-cohort study of biologic-naive adults with UC, use of adalimumab as first-line biologic over infliximab was associated with higher risk of hospitalization and serious infections, although risk of surgery was not different. In the absence of head-to-head trials, this evidence may assist patients, health care providers, purchasers, and policy makers to make informed decisions that may improve health care in UC.
<b>BACKGROUND: </b>The global phase 3 studies of golimumab [PURSUIT-SC and PURSUIT-maintenance (M)], an anti-tumor necrosis factor-α (anti-TNFα) antibody, have demonstrated clinical efficacy and safety as induction and maintenance therapies in patients with moderate to severely active ulcerative colitis (UC). This study aimed to evaluate the efficacy and safety of golimumab as maintenance therapy in the Japanese population.<b>METHODS: </b>In this phase 3, double-blind (DB), placebo-controlled, parallel group, randomized withdrawal study, 144 Japanese patients with moderately to severely active UC received golimumab doses of 200 mg (at week 0) and 100 mg (at week 2) subcutaneously during the 6-week open-label induction phase. Patients who responded to golimumab induction therapy entered the DB maintenance (M) phase and were randomized (1:1) to receive 100 mg of golimumab subcutaneous injection (SC) or placebo every 4 weeks for 52 weeks. The primary endpoint was clinical response through M-week 54; secondary endpoints included clinical remission and mucosal healing at M-week 30 and 54.<b>RESULTS: </b>Among induction responders, more patients on golimumab treatment (56.3%) maintained clinical response through M-week 54 versus the placebo group (19.4%). At both M-week 30 and 54, 50% golimumab-treated patients achieved clinical remission versus the placebo group (6.5%) and a higher proportion of patients on golimumab (59.4%) experienced mucosal healing than the placebo group (16.1%). Incidence of treatment-emergent adverse events was 96.9% in the golimumab group and 71% in the placebo group. Overall, the efficacy and safety results in this study were comparable with those observed in global studies.<b>CONCLUSIONS: </b>Golimumab SC treatment maintained clinical efficacy through week 54 among induction responders, and no new safety signals were observed in the patients with moderate to severely active UC.<b>Clinical Trial Registration: </b>The study is registered at ClinicalTrials.gov NCT01863771.
<b>BACKGROUND: </b>Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.<b>METHODS: </b>We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.<b>RESULTS: </b>In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.<b>CONCLUSIONS: </b>In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).
GOAL: To evaluate the efficacy of low-dose (3.5 mg/kg) infliximab for induction and maintenance treatment in Chinese patients with ulcerative colitis.
BACKGROUND: Treatment with 4 to 5 mg/kg of infliximab also proved to be effective in treating moderate to severe ulcerative colitis. At present there is no relevant study on the effectiveness of infliximab doses lower than 4 mg/kg in patients with ulcerative colitis.
STUDY: A prospective, randomized, double-blind, placebo-controlled, and single-centered study was designed. A total of 123 patients (from 17 provinces of China) with moderate to severe active ulcerative colitis despite treatment with concurrent drugs received placebo or low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab intravenously at weeks 0, 2, and 6 and then every 8 weeks through week 22. Patients were followed up for 30 weeks.
RESULTS: Overall, 73% and 78% of patients who received low-dose (3.5 mg/kg) and standard-dose (5 mg/kg) infliximab, respectively, had clinical responses at week 8, as compared with 37% of patients who received placebo (P<0.01 for both comparisons with placebo). The number of patients who received low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab with a clinical response at week 30 (63% and 66%, respectively) was more than the patients who received placebo (27%, P<0.01 for both comparisons).
CONCLUSIONS: Chinese patients with moderate to severe active ulcerative colitis treated with low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter were more likely to have a clinical response at weeks 8 and 30 than those who received placebo.
Six biologic agents are currently approved for the treatment of IBD: four anti-TNF agents (infliximab, adalimumab, golimumab and certolizumab pegol) and two anti-integrin agents (natalizumab and vedolizumab). In Crohn's disease and ulcerative colitis refractory to standard medications, treatment choice among available biologic agents can be challenging. Several parameters should be taken into account to help physicians through the decision-making process, including the comparative effectiveness and long-term safety profile, availability and labelling in the prescriber's country, international guidelines, and cost, as well as patient preferences (such as the route of administration). Herein, we provide practical insights on the use of biologic agents in IBD. The results of head-to-head trials between biologic agents are eagerly awaited to guide decision-making regarding the choice of first-line biologic agents and to determine whether switching within the same drug class or swapping (switching out of the drug class) is preferable after primary or secondary loss of response to the first biologic agent. In the near future, treatment algorithms might evolve with the launch of new drugs (such as ustekinumab, tofacitinib and etrolizumab) and the increased use of biosimilars.
With several options available for patients with moderate-severe ulcerative colitis (UC), rapidity of symptom resolution could be an important differentiator. We compared the efficacy and speed of onset of action of infliximab vs golimumab induction therapy using patient-level data from phase 3 trials (ACT-1, ACT-2, and PURSUIT-SC).
METHODS:
We compared differences in proportions of patients who achieved the composite outcome of a rectal bleeding score=0 and stool frequency score ≤1 (patient-reported outcome 2 remission) at weeks 2 and 6 of treatment with standard-dose infliximab vs golimumab using logistic generalized estimating equation. Overall efficacy for inducing clinical remission (Mayo clinic score <3) was compared using logistic regression. Analyses were adjusted for sex, disease extent, baseline clinical and endoscopic severity, C-reactive protein, albumin, body weight and concomitant medications (immunomosuppressives, corticosteroids, and 5-aminsalicylates).
RESULTS:
Trial populations were similar and no differences were observed among the placebo groups in the studies. A significantly higher proportion patients treated with infliximab than golimumab achieved patient-reported outcome 2 remission at week 2 (35% vs 30%; adjusted odds ratio [OR], 1.71; 95% CI, 1.15-2.55) and at week 6 (50.0% vs 38.9%; adjusted OR, 2.0; 95% CI, 1.40-2.94). Infliximab-treated patients were also significantly more likely to achieve clinical remission than golimumab-treated patients (adjusted OR, 3.01; 95% CI, 1.95-4.70), with consistent findings in patients with moderate or severe UC.
CONCLUSIONS:
Based on a patient-level analysis of data from phase 3 trials, infliximab resolves symptoms more rapidly and has greater efficacy for inducing remission than golimumab in patients with moderate-to-severe UC.
