UNITI-1
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A Study to Evaluate the Safety and Efficacy of Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease Who Have Failed or Are Intolerant to Tumor Necrosis Factor (TNF) Antagonist Therapy (UNITI-1)

Registro de estudios clinicaltrials.gov
Año 2011
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This study (UNITI-1) will compare the effects (both positive and negative) of an initial treatment with ustekinumab to placebo over 8 weeks, in patients with moderately to severely active Crohn\'s disease who have either failed or could not tolerate at least one TNF-antagonist medications in the past (specifically, infliximab, adalimumab, or certolizumab pegol).

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A multicentre, double-blind, placebo-controlled phase 3 study of ustekinumab, a human interleukins-12/23p40 mab, in moderate-severe Crohn's disease refractory to anti-tumour necrosis factor α: UNITI-1

Revista
Año 2016
Enlaces DOI www.cochranelibrary.com

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Background: IL 12 and 23 are implicated in the pathophysiology of Crohn's disease (CD). These pro‐inflammatory cytokines are blocked by UST. In a phase 2b study (CERTIFI),1 UST IV induction followed by surveillance colonoscopy (SC) maintenance was shown effective in moderate‐severe CD refractory to anti‐tumour necrosis factor (TNF) therapy. This phase 3 study examined efficacy and safety of IV UST induction in these patients (pts). Methods: Pts with moderate‐to‐severely active CD(CDAI 220‐450) who previously failed or were intolerant to at least 1 TNF antagonist were randomised (1:1:1) at Wk0 to a single dose of IV placebo (PBO), UST 130 mg, or weight‐based tiered UST dosing approximating 6 mg/kg (260mg [wt ≤ 55kg], 390 mg [wt > 55kg and ≤ 85 kg]), 520 mg [wt > 85 kg]). The primary endpoint was clinical response at week 6, defined as reduction from baseline in the CDAI score of ≥ 100 points; pts with baseline CDAI score ≥ 220 to ≤ 248 points were considered in clinical response if a CDAI score of <150 was present. At week 8, patients either transitioned to the IM‐UNITI maintenance study or were followed to week 20. Results: The 741 randomised pts had a history of TNF‐antagonist failure, with baseline median CDAI of 317, C‐reactive protein (CRP) of 9.9 mg/L, and prior disease duration of 10.1 years. Of these, 51% had previously failed ≥ 2 anti‐TNFs with 29.1%, 69.4%, and 36.4% of pts, respectively. Clinical response at week 6 (primary endpoint) was observed in 33.7% of the ∼6 mg/kg and 34.3% of the 130 mg UST groups vs 21.5% in the PBO group (p = 0.003 and 0.002, respectively). Clinical remission (CDAI < 150) at week 8 was observed in 20.9% of the ∼6 mg/kg group and 15.9% of the 130 mg UST group vs 7.3% on PBO (p < 0.001, p = 0.003, respectively). Clinical response at week 8 was seen in 37.8% of the ∼6 mg/kg and 33.5% of the 130 mg UST groups vs 20.2% on PBO (each p ≤ 0.001). Proportion of patients with 70‐pt CDAI response at week 6 was 43.8% of the ∼6 mg/kg and 46.1% of the 130 mg UST groups vs 30.4% on PBO (p = 0.002 and < 0.001, respectively), and at the first post‐baseline week 3 visit, 40.6% in ∼6mg/ kg and 38.4% in the 130 mg UST groups vs 27.1% on PBO (p = 0.001 and p = 0.009, respectively), the final major secondary endpoint. Both IV UST induction doses additionally resulted in significant improvements in CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ), C‐reactive protein (CRP), faecal lactoferrin, and calprotectin vs IV PBO. Proportions of pts with adverse events (AEs), serious adverse events (SAEs), and infections were similar in the UST and PBO groups. One opportunistic infection (listeria meningitis) was reported in the ∼6 mg/kg UST group. No malignancies, deaths, major adverse cardiovascular events, or TB occurred in UST‐treated pts through week 20. Conclusions: In pts with moderate‐to‐severe CD refractory to 1 or prior TNF‐antagonists, IV UST induced clinical response and remission and was well tolerated throughout induction, confirming the previous positive induction data from CERTIFI.

Estudio primario

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A multicenter, double-blind, placebo-controlled phase3 study of ustekinumab, a human IL-1-/-3p40 mab, in moderate-service Crohn's disease refractory to anti-TFNα: UNITI-1

Revista Inflammatory Bowel Diseases
Año 2016
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Background: Interleukins 12&23 are implicated in the pathophysiology of Crohn's disease (CD). These pro-inflammatory cytokines are blocked by ustekinumab (UST). In a previous Phase 2b study (CERTIFI),1 UST IV induction followed by SC maintenance was shown effective in moderate-severe CD refractory to anti-TNF therapy. This Phase 3 study examined the efficacy and safety of IV UST induction in these patients. Methods: Patients with moderate-severely active CD (CDAI 220-450) who previously failed or were intolerant to at least 1 TNF-antagonist were randomized (1:1:1) at Week (Wk) 0 to a single dose of IV placebo (PBO), UST 130 mg, or weight-based tiered UST dosing approximating 6 mg/kg (260mg [weight ≤55 kg], 390mg [weight >55 kg and ≤85 kg], 520mg [weight >85 kg]). The primary endpoint was clinical response at Wk6, defined as reduction from baseline in the CDAI score of >100 points; patients with baseline CDAI score >220 to <248 points were considered in clinical response if a CDAI score of <150 was present. At Wk8, patients either transitioned to the IM-UNITI maintenance study or were followed to Wk20. Results: The 741 randomized patients had a history of TNF-antagonist failure, with baseline median CDAI of 317, CRP of 9.9 mg/L, and prior disease duration of 10.1 years. Of these, 51% had previously failed ≥2 anti-TNFs with 29.1%, 69.4%, and 36.4% of patients, respectively, satisfying protocol criteria for primary nonresponse, secondary non-response, or intolerance to at least one TNF antagonist. Statistical significance was demonstrated for the primary and all 4 major secondary endpoints at both IV doses. Clinical response at Wk6 (primary endpoint) was observed in 33.7% of the ∼6 mg/kg and 34.3% of the 130 mg UST groups versus 21.5% in PBO (P = 0.003 and 0.002, respectively). Clinical remission (CDAI <150) at Wk8 was observed in 20.9% of the ∼6 mg/kg group and 15.9% of the 130 mg UST group versus 7.3% on PBO (P < 0.001, P = 0.003, respectively). Clinical response at Wk8 was seen in 37.8% of the ∼6 mg/kg and 33.5% of the 130 mg UST groups, versus 20.2% on PBO (each P ≤ 0.001). Proportion of patients with 70pt CDAI response at Wk6 was 43.8% of the ∼6 mg/kg and 46.1% of the 130 mg UST groups versus 30.4% in PBO (P = 0.002 and <0.001, respectively) and at the first post-baseline Wk3 visit, 40.6% in ∼6 mg/kg and 38.4% in the 130 mg UST groups versus 27.1% in PBO (P = 0.001 and P = 0.009, respectively), the final major secondary endpoint. Both IV UST induction doses additionally resulted in significant improvements in CDAI, IBDQ, CRP, fecal lactoferrin and calprotectin versus IV PBO. Proportions of patients with AEs, SAEs, and infections were similar in the UST and PBO groups. One opportunistic infection (listeria meningitis) was reported in the ∼6 mg/kg UST group. No malignancies, deaths, major adverse cardiovascular events, or TB occurred in UST-treated patients through Wk20. Conclusions: In a population of moderate-severe CD patients refractory to one or more prior TNF-antagonists, IV UST induced clinical response and remission and was well-tolerated throughout induction, confirming the previous positive induction data from the Phase 2b CERTIFI study.

Estudio primario

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Assessment of serum C-reactive protein, fecal lactoferrin, and fecal calprotectin in patients with moderate-severely active Crohns disease: Results from the IM UNITI maintenance study.

Revista Gastroenterology
Año 2016

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Estudio primario

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Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease.

Revista The New England journal of medicine
Año 2016
Enlaces Pubmed DOI

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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 .).

Estudio primario

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Ustekinumab improves general health status and disease-specific health related quality of life of patients with moderate to severe Crohn\'s disease: Results from the uniti and IMUNITI phase 3 clinical trials

Revista Gastroenterology
Año 2016

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Molecular response to ustekinumab in moderate-to-severe Crohn\'s disease by serum protein analysis: Results from uniti-1 induction, uniti-2 induction, and imuniti maintenance studies

Revista Gastroenterology
Año 2016

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981 - Fistula Healing in Pivotal Studies of Ustekinumab in Crohn's Disease

Revista 2017 DDW Abstracts
Año 2017
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The Effects of Ustekinumab on Health-related Quality of Life in Patients With Moderate to Severe Crohn's Disease

Revista Journal of Crohn's & colitis
Año 2018
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Background and Aims: We assessed the effect of ustekinumab on health‐related quality of life [HRQOL] in adults with Crohn's disease [CD]. Methods: Patients with moderately to severely active CD and inadequate response or intolerance to tumour necrosis factor antagonists [UNITI‐1, n = 741], or conventional therapy [UNITI‐2, n = 627] were randomised to placebo, ustekinumab 130 mg, or 6 mg/kg intravenous induction therapy. At Week 8, ustekinumab‐treated responders (Crohn's Disease Activity Index [CDAI] reduction ≥100 or CDAI <150 points) were re‐randomised to subcutaneous maintenance therapy [IM‐UNITI, n = 388] with placebo, ustekinumab 90 mg every 12 weeks [q12w], or ustekinumab 90 mg every 8 weeks [q8w], for 44 additional weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and 36‐item Short Form Health Survey [SF‐36] physical component summary [PCS] and mental component summary [MCS] scores were completed at induction baseline and Week 8, and at maintenance Weeks 20 and 44. Clinically meaningful improvement in IBDQ and PCS and MCS scores were evaluated. For all HRQOL outcomes, each ustekinumab dose and placebo were compared. Results: Induction baseline mean values of IBDQ, PCS, and MCS were similar across groups, but impaired relative to general population norms. At Week 8, ustekinumab induced greater improvement than placebo in both HRQOL scores. Significantly greater proportions of patients receiving ustekinumab 6 mg/kg or 130 mg had clinically meaningful IBDQ improvement [UNITI‐1: 54.8%, 46.9% versus 36.5%, respectively; UNITI‐2: 68.1%, 58.7% versus 41.1%, respectively; p <0.05, all comparisons]. Similarly, greater proportions of ustekinumab‐treated patients in both studies had clinically meaningful improvements in PCS and MCS as compared with placebo. At Week 44, improvements in IBDQ, PCS, and MCS scores were maintained with ustekinumab. Conclusions: Ustekinumab improved HRQOL in patients with moderately to severely active CD.

Estudio primario

No clasificado

Efficacy of Ustekinumab for Inducing Endoscopic Healing in Patients With Crohn's Disease.

Revista Gastroenterology
Año 2018
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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).

Estudio primario

No clasificado

Post HOC Analysis of the Impact of Ustekinumab Treatment on Specific Items of the Inflammatory Bowel Disease Questionnaire in the Uniti-1 & 2 Programs

Revista Gastroenterology
Año 2018
Enlaces DOI www.cochranelibrary.com
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Background: Previous analysis of the UNITI- I & 2 and IM-UNITI phase 3 trials have shown that ustekinumab (UST) treatment improves general health status and IBD-specific HRQOL in patients with moderate to severe Crohn's disease (CD) both as intravenous (IV) induction therapy as well as subcutaneous (SC) maintenance. We conducted a post-hoc analysis to assess which items of the disease related inflammatory bowel disease questionnaire (IBDQ) had the greatest impact on health-related quality of life (HRQOL) at baseline and the effect of UST on improving these items after induction therapy. Methods: Patients with moderately to severely active CD [defined by a CD Activity Index (CDAI) of 220-450) who had inadequate response or intolerance to TNF antagonists (UNITI-1, N=741) or to conventional therapy (UNITI-2, N=627) were randomized 1:1:1 to receive UST ~6mg/kg, UST 130mg or placebo (PBO) intravenously (IV) at week 0 and the IBDQ score was assessed at baseline and week 8. In this post-hoc analysis, items of the IBDQ with the greatest impact on HRQOL at baseline were defined as having a pooled mean score <3.5 [(scale 1 (worse) - 7 (better)] at baseline and were selected for the analysis. Changes in mean scores were measured at week 8 (UNITI-1&2) and compared to placebo. Results: At baseline of UNITI-1&2, 11 of 32 items in the IBDQ had mean scores <3.5 and were determined as having a marked impact on quality of life: loose stools, feeling relaxed, fatigue, feeling unwell, abdominal pain, energy, sleep, abdominal cramps, happy with life, leisure activities, and feeling frustrated (Table 1). By week 8 statistically significant improvements were seen for the majority of these items in the UST 130mg arm vs placebo and for all items in the ~6mg/Kg vs placebo in UNITI-1& 2 (Table 2.a-c). Moreover, greater improvements were seen in the TNF-antagonist naïve population of UNITI-2 which were all statistically significant in the ~6mg/Kg UST arm vs placebo. Conclusion: Specific items in the IDBQ including fatigue, sleep, loose stools, and items relating to emotional/social such as feeling unwell and impact on leisure activities had the greatest negative impact on QoL at baseline. A single IV induction dose of UST treatment significantly improved the mean scores in these QoL items in patients with moderate to severe CD patients. [Table Presented]

Estudio primario

No clasificado

Safety of ustekinumab in inflammatory bowel diseases: integrated safety analysis of results from phase 2 and 3 studies in crohn's disease and ulcerative colitis

Revista
Año 2019
Enlaces DOI www.cochranelibrary.com
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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.

Estudio primario

No clasificado

Effects of Ustekinumab on Histologic Disease Activity in Patients With Crohn's Disease.

Revista Gastroenterology
Año 2019
Enlaces Pubmed DOI
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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.

Estudio primario

No clasificado

Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn's Disease: An Integrated Analysis of Phase II/III Clinical Development Programs.

Revista Drug safety
Año 2019
Enlaces Pubmed DOI PubMed Central
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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.

Estudio primario

No clasificado

Safety of Ustekinumab in Inflammatory Bowel Disease: pooled Safety Analysis of Results from Phase 2/3 Studies

Revista Inflammatory bowel diseases
Año 2021
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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.