The primary purpose of this study is to evaluate the efficacy and safety of 2 maintenance regimens of ustekinumab administered subcutaneously to patients with moderately to severely active Crohn\'s disease who responded to treatment with intravenous ustekinumab in studies CNTO1275CRD3001 and CNTO1275CRD3002, compared to subcutaneously administered placebo.
BACKGROUND: Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.
METHODS: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150).
RESULTS: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.
CONCLUSIONS: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).
BACKGROUND: In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported.
METHODS: UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding.
RESULTS: A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed.
CONCLUSIONS: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.
BACKGROUND & AIMS: We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn's disease (CD).
METHODS: We performed an endoscopy substudy of 334 patients with moderate to severe CD participating in 3 randomized controlled phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline time point of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomly assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary end point was change in the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy.
RESULTS: Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline time point until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P = .012). Results were similar among patients in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P = .176 and for every 8 weeks, a reduction of 3.1; P = .107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis.
CONCLUSIONS: In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab. (ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355).
BACKGROUND: Crohn's disease (CD) is a chronic inflammatory bowel disease affecting a growing number of people in the U.S. The goal of treatment is to achieve and maintain remission, thereby avoiding costly hospitalizations and/or surgeries associated with significant economic burden for patients (pts) and payers. Ustekinumab (UST) was approved for treatment of moderately‐to‐severely active CD in the U.S. in 2016. However, evidence of its impact on healthcare costs from CD‐related hospitalizations and surgeries remains limited. OBJECTIVE: To assess healthcare costs for CD‐related hospitalizations and surgeries in pts initiated with either placebo (PBO) or UST 90 mg q8w in the IM‐UNITI long‐term extension (LTE) study over a period of 2 years. METHODS: Eligible CD pts were first enrolled in the UNITI‐1&2 IV induction studies. Clinical responders were then randomized 1:1:1 in the IM‐UNITI maintenance study to PBO, UST 90 mg q12w, or UST 90 mg q8w. All pts completing week 44 were eligible to enter the LTE study. Only the pts on PBO or UST 90 mg q8w (FDA approved dosing regimen, UST hereafter) in the LTE study were analyzed. Number of pts with a CD‐related hospitalization and/or surgery was recorded. Mean annual costs for CD‐related hospitalizations and surgeries were obtained from the literature, and adjusted to 2018 U.S. dollars. Number needed to treat (NNT) and per‐pt‐per‐year (PPPY) costs were calculated. RESULTS: 103 UST and 82 PBO pts from the IM‐UNITI LTE study were analyzed. In 2 years, UST pts had fewer CD‐related hospitalizations without surgery (hospitalizations hereafter, 3.9% vs. 11.0% for PBO) and CD‐related surgeries with or without hospitalization (surgeries hereafter, 3.9% vs. 11.0% for PBO). The NNT was 14 to avoid either a CD‐related hospitalization or a surgery for UST pts. UST pts had PPPY cost reduction of $1,103 and $2,113 in CD‐related hospitalizations and surgeries, relative to PBO, respectively. Overall, UST pts had total PPPY cost reduction of $3,216 for healthcare costs from CD‐related hospitalizations and surgeries compared to PBO. The 103 UST pts had total cost reduction of $662,459 from fewer CD‐related hospitalizations and surgeries over 2 years. CONCLUSIONS: UST reduced the costs associated with CD‐related hospitalizations and surgeries in moderately‐to‐severely active CD pts in the IM‐UNITI LTE study over the course of 2 years. Results are likely conservative as only single events per pt were recorded and placebo treated pts in maintenance were induced with UST prior to rerandomization.
Introduction: Ustekinumab (UST) is a well‐established therapy in Crohn's disease (CD) and psoriatic diseases. Recently presented phase 3 data showed that UST was safe and effective in ulcerative colitis (UC). Phase 3 induction and maintenance studies of UST in CD (UNITI, IMUNITI) and UC (UNIFI) had similar designs, which allows for integrated analysis across both inflammatory bowel disease (IBD) indications. Aims &Methods: We present an analysis of integrated safety data of UST in IBD. Data from 6 phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year of follow‐up. In phase 3, CD and UC pts received a single IV placebo (PBO) or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8 or q12 wks). Concomitant immunomodulators (IMM) and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes through 1 year are presented as the number of pts with events per 100 pt‐years (PY) of follow‐up Results: At induction baseline (2370 pts in pooled phase 3 IBD studies), median age was 38.0 years, 46.9% were receiving corticosteroids, 30.8% were receiving IMM, 53.0% had failed biologics, and 37.1% were naive to biologics. In phase 3 IBD studies, through Wk8 of PBO‐controlled induction, 1582 pts were treated with UST. Pts with ≥1 event (PBO vs UST) were 55.8% vs 53.9% with AEs, 6.2% vs 4.4% with SAEs, 19.9% vs 19.3% with infections, and 1.3% vs 1.1% with serious infections. Through 1 year in pooled phase 2/3 IBD studies, 2574 pts were treated with UST with 1733 PY. The number of patients per 100 PY with AEs (PBO 165.99 vs UST 118.32), SAEs (27.50 vs 21.23), infections (80.31 vs 64.32), serious infections (5.53 vs 5.02), malignancies including non‐melanoma skin cancer (NMSC) (0.50 vs 0.81), and discontinuations of study agent because of an AE (13.41 vs 7.73) were similar between UST and PBO. The most frequently occurring AEs (excluding diseases under study) were arthralgia (PBO 16.93 vs UST 16.56), headache (16.43 vs 16.50), nausea (13.25 vs 11.94), and abdominal pain (14.59 vs 11.54), and infections were nasopharyngitis (16.26 vs 18.11) and upper respiratory tract infection (11.40 vs 11.36). Results were similar for the CD and UC studies separately (Table shows key safety events). (Table Presented) [Number of pts with key safety events through 1 year of treatment per 100 PY of follow‐up (number of patients with events) in phase 2/3 CD &UC studies] Regarding serious infections, the CD‐specific manifestation of anal abscess occurred in PBO 2.02 and UST 0.90 pts per 100 PY in CD pts. When CD‐specific events were excluded, overall rates of serious infections were similar between UC and CD populations. In pooled phase 2/3 studies, the only malignancy (excluding NMSC) reported in >1 UST‐treated pt was prostate cancer; no lymphomas were reported through 1 year. Two pts receiving UST (0.12 per 100 PY; both had UC) died from events that investigators considered to be unrelated to study agent (esophageal varices hemorrhage and acute respiratory failure during thyroid surgery). Conclusion: The safety profile of UST in pts with UC and across integrated IBD indications through 1 year was favorable and consistent with the established safety profile in pts with CD and psoriatic disease.
BACKGROUND & AIMS: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown.
METHODS: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs).
RESULTS: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline.
CONCLUSIONS: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355.
INTRODUCTION: Theoretical risks of biologic agents remain under study.
OBJECTIVE: The aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials.
METHODS: Patients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn's disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs]).
RESULTS: Among 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2-128.7) versus 129.4 (120.9-138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2-101.5] vs. 115.3 [109.9-121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3-125.9] vs. 107.3 [102.0-112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3-0.7] vs. 0.3 [0.0-1.1]), malignancies (0.4 [0.2-0.6] vs. 0.2 [0.0-0.8]), and deaths (0.1 [0.0-0.3] vs. 0.0 [0.0-0.4]) were rare across indications.
CONCLUSIONS: Ustekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications.
TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355.
BACKGROUND AND AIMS: Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported.
METHODS: At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits.
RESULTS: Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0-152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%].
CONCLUSIONS: Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355.
BACKGROUND: Ustekinumab is currently approved globally in Crohn's disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn's disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses. METHODS: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or ~6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received ≥1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient‐years of follow‐up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time‐to‐event analyses for serious adverse events and serious infections were also performed. RESULTS: Through 1 year, 2574 patients received ustekinumab (1733 patient‐years of follow‐up). The number of patients with adverse events per 100 patient‐years (placebo 165.99 [95% CI, 155.81‐176.67] vs ustekinumab 118.32 [95% CI, 113.25‐123.55]), serious AEs (27.50 [95% CI, 23.45‐32.04] vs 21.23 [95% CI, 19.12‐23.51]), infections (80.31 [95% CI, 73.28‐87.84] vs 64.32 [95% CI, 60.60‐68.21]), serious infections (5.53 [95% CI, 3.81‐7.77] vs 5.02 [95% CI, 4.02‐6.19]), and malignancies excluding nonmelanoma skin cancer (0.17 [95% CI, 0.00‐0.93] vs 0.40 [95% CI, 0.16‐0.83]) were similar between placebo and ustekinumab. CONCLUSIONS: The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications. CLINICALTRIALS.GOV NUMBERS: NCT00265122; NCT00771667; NCT01369329; NCT01369342; NCT01369355; NCT02407236.
BACKGROUND AND AIMS: Comparative effectiveness have become increasingly important to help position therapies for inflammatory bowel disease. We compared the efficacy and rapidity of onset of action of infliximab vs. ustekinumab induction therapy for moderate to severe biologic‐naïve Crohn's disease (CD) using patient‐level data from randomized controlled trials. METHODS: This was a post‐hoc analysis of two large CD clinical trial programs which included data on 420 biologic‐naïve CD patients. Differences in proportions of patients achieving week 6 clinical remission (CR), clinical response, and normalization of calprotectin were compared. Multivariate logistic regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline co‐variates. RESULTS: At week 6, a comparable number of patients achieved CR with infliximab as compared to patients treated with ustekinumab (44.9% vs. 37.9%, aOR 1.22 (95%CI 0.79‐1.89)). Similarly, at week 6 clinical response rates were not significantly different (58.4% infliximab vs. 54.9% ustekinumab, aOR 1.25 (95%CI 0.82‐1.90)). No significant difference was observed between treatment groups for achieving week 6 fecal calprotectin <250 mcg/L in those with elevated values at baseline (42.3% infliximab vs. 34.7% ustekinumab, aOR 1.34 (95%CI 0.79‐2.28)). Similar results were seen for all analyses done within the propensity matched cohort. CONCLUSIONS: Based on this post‐hoc analysis, infliximab and ustekinumab appear to have similar efficacy and speed of onset in patients with Crohn's disease who are biologic‐naive.
The primary purpose of this study is to evaluate the efficacy and safety of 2 maintenance regimens of ustekinumab administered subcutaneously to patients with moderately to severely active Crohn\'s disease who responded to treatment with intravenous ustekinumab in studies CNTO1275CRD3001 and CNTO1275CRD3002, compared to subcutaneously administered placebo.
