Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy Exposure–efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn’s Disease Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Population pharmacokinetics‐pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Vedolizumab as induction and maintenance therapy for Crohn's disease. Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists Vedolizumab as induction and maintenance therapy for ulcerative colitis. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed. Association Between Ustekinumab Trough Concentrations and Clinical, Biomarker, and Endoscopic Outcomes in Patients With Crohn’s Disease
Background : Vedolizumab is a gut-selective & agr;4&bgr;7 integrin antagonist for the treatment of moderately to severely active Crohn 's disease ( CD ) . Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha ( TNF-&agr ; ) antagonist therapy ( TNF-naïve ) or who had discontinued TNF-&agr ; antagonist therapy because of inadequate response ( i.e. , primary nonresponse ) , loss of response , or intolerance ( collectively classified as the TNF-failure population ) . Methods : Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6 , 10 , and 52 and included clinical remission ( CD Activity Index [ CDAI ] score ⩽150 ) , enhanced clinical response ( ≥100-point decrease from baseline in CDAI score ) , durable clinical remission ( remission at ≥80 % of visits ) , and corticosteroid-free remission . Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received . Results : Among patients who responded to vedolizumab induction at week 6 , 48.9 % of TNF-naïve and 27.7 % of TNF-failure patients were in remission  with vedolizumab at week 52 ( versus 26.8 % and 12.8 % with  placebo ) . Clinical efficacy was similar between the different types of TNF-&agr ; antagonist failure or the number of prior TNF-&agr ; antagonists failed . Safety profiles were similar in both sub population s. Conclusions : Vedolizumab had increased efficacy  over placebo in CD patients irrespective of TNF-&agr ; antagonist treatment history . Overall , rates of response and remission were numerically higher in patients  receiving vedolizumab  as a first biologic than in patients who had experienced TNF failure Background and Aims A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [ UC ] or Crohn 's disease [ CD ] has been reported . Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data . Methods Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated . Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [ Caverage ] as exposure measure . Results Higher vedolizumab concentrations were associated with higher clinical remission rates ; the exposure-efficacy relationship was steeper for UC than CD . Unadjusted analyses overestimated the relationship , more so for CD . From covariate-adjusted models , average probability of remission at Week 6 increased by approximately 15 % for UC and 10 % for CD between Caverage values of 35 and 84 µg/ml [ 5th and 95th percentiles , respectively ] . On average , patients with higher albumin , lower faecal calprotectin [ UC only ] , lower C-reactive protein [ CD only ] , and no previous tumour necrosis factor-α [ TNFα ] antagonist use had a higher remission probability . Previous TNFα antagonist use had the greatest impact ; remission probability was approximately 10 % higher in treatment-naïve patients . Conclusions Higher vedolizumab  serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD . This relationship is affected by several factors , including previous TNFα antagonist use . Prospect i ve studies are needed to assess vedolizumab dose individualisation and optimisation 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 r and omly 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 result ed 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 Clinical Trials.gov number , NCT01647516 . ) BACKGROUND Etrolizumab is a humanised monoclonal antibody that selectively binds the β7 subunit of the heterodimeric integrins α4β7 and αEβ7 . We aim ed to assess etrolizumab in patients with moderately-to-severely active ulcerative colitis . METHODS In this double-blind , placebo-controlled , r and omised , phase 2 study , patients with moderately-to-severely active ulcerative colitis who had not responded to conventional therapy were recruited from 40 referral centres in 11 countries . Eligible patients ( aged 18 - 75 years ; Mayo Clinic Score [ MCS ] of 5 of higher [ or ≥6 in USA ] ; and disease extending 25 cm or more from anal verge ) were r and omised ( 1:1:1 ) to one of two dose levels of subcutaneous etrolizumab  ( 100 mg at weeks 0 , 4 , and 8 , with placebo at week 2 ; or 420 mg loading dose [ LD ] at week 0 followed by 300 mg at weeks 2 , 4 , and 8) , or matching placebo . The primary endpoint was clinical remission at week 10 , defined as MCS of 2 or less ( with no individual subscore of > 1 ) , analysed in the modified intention-to-treat population ( mITT ; all r and omly assigned patients who had received at least one dose of study drug , had at least one post-baseline disease-activity assessment , and had a central ly read screening endoscopic subscore of ≥2 ) . This study is registered with Clinical Trials.gov , number NCT01336465 . FINDINGS Between Sept 2 , 2011 , and July 11 , 2012 , 124 patients were r and omly assigned , of whom five had a endoscopic subscore of 0 or 1 and were excluded from the mITT population , leaving 39 patients in the etrolizumab 100 mg group , 39 in the etrolizumab 300 mg plus LD group , and 41 in the placebo group for the primary analyses . No patients in the placebo group had clinical remission at week 10 , compared with eight ( 21 % [ 95 % CI 7 - 36 ] ) patients in the etrolizumab 100 mg group ( p=0·0040 ) and four ( 10 % [ 0·2 - 24 ] ) patients in the 300 mg plus LD group ( p=0·048 ) . Adverse events occurred in 25 ( 61 % ) of 41 patients in the etrolizumab 100 mg group ( five [ 12 % ] of which were regarded as serious ) , 19 ( 48 % ) of 40 patients in the etrolizumab 300 mg plus LD group ( two [ 5 % ] serious ) , and 31 ( 72 % ) of 43 patients in the placebo group ( five [ 12 % ] serious ) . INTERPRETATION Etrolizumab was more likely to lead to clinical remission at week 10 than was placebo . Therefore , blockade of both α4β7 and αEβ7 might provide a unique therapeutic approach for the treatment of ulcerative colitis , and phase 3 studies have been planned . FUNDING Genentech BACKGROUND Ustekinumab , a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23 , was evaluated as an intravenous induction therapy in two population s with moderately to severely active Crohn 's disease .  Ustekinumab was also evaluated as subcutaneous maintenance therapy . METHODS We r and omly 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 r and omly 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 ; Clinical Trials.gov numbers , NCT01369329 , NCT01369342 , and NCT01369355 . ) BACKGROUND The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn 's disease . We aim ed to assess the efficacy and safety of risankizumab ( BI 655066 , Boehringer Ingelheim , Ingelheim , Germany ) , a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 , in patients with moderately-to-severely active Crohn 's disease . METHODS In this r and omised , double-blind , placebo-controlled phase 2 study , we enrolled patients at 36 referral sites in North America , Europe , and southeast Asia . Eligible patients were aged 18 - 75 years , with a diagnosis of Crohn 's disease for at least 3 months , assessed as moderate-to-severe Crohn 's disease at screening , defined as a Crohn 's Disease Activity Index ( CDAI ) of 220 - 450 , with mucosal ulcers in the ileum or colon , or both , and a Crohn 's Disease Endoscopic Index of Severity ( CDEIS ) of at least 7 ( ≥4 for patients with isolated ileitis ) on ileocolonoscopy scored by a masked central reader . Patients were r and omised 1:1:1 using an interactive response system to a double-blind investigational product , and stratified by previous exposure to TNF antagonists ( yes vs no ) . Patients received intravenous 200 mg risankizumab , 600 mg risankizumab , or placebo , at weeks 0 , 4 , and 8 . The primary outcome was clinical remission ( CDAI < 150 ) at week 12 ( intention-to-treat population ) . Safety was assessed in patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT02031276 . FINDINGS Between March , 2014 , and September , 2015 , 213 patients were screened , and 121 patients r and omised . At baseline , 113 patients ( 93 % ) had been previously treated with at least one tumour necrosis factor ( TNF ) antagonist ( which had failed in 96 [ 79 % ] ) . At week 12 , 25 ( 31 % ) of 82 risankizumab patients ( pooled 41 patients in 200 mg and 41 patients in 600 mg arms ) had clinical remission versus six ( 15 % ) of 39 placebo patients ( difference vs placebo 15·0 % , 95 % CI 0·1 to 30·1 ; p=0·0489 ) . Ten ( 24 % ) of 41 patients who received 200 mg risankizumab had clinical remission ( 9·0 % , -8·3 to 26·2 ; p=0·31 ) and 15 ( 37 % ) of 41 who received the 600 mg dose ( 20·9 % , 2·6 to 39·2 ; p=0·0252 ) . 95 ( 79 % ) patients had adverse events ( 32 in the placebo group , 32 r and omised to 200 mg risankizumab , 31 r and omised to 600 mg risankizumab ) ; 18 had severe adverse events ( nine , six , three ) ; 12 discontinued ( six , five , one ) ; 24 had serious adverse events ( 12 , nine , three ) . The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn 's disease . No deaths occurred . INTERPRETATION In this short-term study , risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn 's disease . Therefore , selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn 's disease . FUNDING Boehringer Ingelheim 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 r and omized , 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 Vedolizumab , an anti‐α4β7 integrin monoclonal antibody ( mAb ) , is indicated for treating patients with moderately to severely active ulcerative colitis ( UC ) and Crohn 's disease ( CD ) . As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease , underst and ing determinants of vedolizumab clearance may help to optimise dosing BACKGROUND & AIMS We analyzed data collected during the Active Ulcerative Colitis Trials ( ACT-1 and ACT-2 ) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis . METHODS We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2 ; efficacy data were collected at weeks 8 , 30 , and 54 ( for ACT-1 only ) . Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend , logistic regression , and receiver operating characteristic curve analyses . We also evaluated factors that affected the relationship between exposure and response . RESULTS Median serum concentrations of infliximab  at weeks 8 , 30 , and /or 54 were significantly higher in patients with clinical response , mucosal healing , and /or clinical remission than in patients who did not meet these response criteria . There were statistically significant relationships between quartile of  infliximab serum concentration and efficacy at these time points ( P < .01 ) . Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile , and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab  than patients in other quartiles . Although the relationship between exposure to infliximab and response varied among patients , approximate serum concentrations of 41 μg/mL infliximab at week 8 of induction therapy and 3.7 μg/mL at steady-state during maintenance therapy produced optimal outcomes in patients . CONCLUSIONS Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis ; however , complex factors determine the relationship between exposure to this drug and response . A prospect i ve evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies . Clinical trials.gov numbers : NCT00036439 and NCT00096655 BACKGROUND The efficacy of vedolizumab , an α4β7 integrin antibody , in Crohn 's disease is unknown . METHODS In an integrated study with separate induction and maintenance trials , we assessed intravenous vedolizumab therapy ( 300 mg ) in adults with active Crohn 's disease . In the induction trial , 368 patients were r and omly assigned to receive vedolizumab or placebo at weeks 0 and 2 ( cohort 1 ) , and 747 patients received open-label vedolizumab  at weeks 0 and 2 ( cohort 2 ) ; disease status was assessed at week 6 . In the maintenance trial , 461 patients who had had a response to vedolizumab  were r and omly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52 . RESULTS At week 6 , a total of 14.5 % of the patients in cohort 1 who received vedolizumab and 6.8 % who received placebo were in clinical remission ( i.e. , had a score on the Crohn 's Disease Activity Index [ CDAI ] of ≤150 , with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity ) ( P=0.02 ) ; a total of 31.4 % and 25.7 % of the patients , respectively , had a CDAI-100 response ( ≥100-point decrease in the CDAI score ) ( P=0.23 ) . Among patients in cohorts 1 and 2 who had a response to induction therapy , 39.0 % and 36.4 % of those assigned to vedolizumab every 8 weeks and every 4 weeks , respectively , were in clinical remission at week 52 , as compared with 21.6 % assigned to placebo ( P<0.001 and P=0.004 for the two vedolizumab groups , respectively , vs. placebo ) . Antibodies against vedolizumab developed in 4.0 % of the patients . Nasopharyngitis occurred more frequently , and headache and abdominal pain less frequently , in patients receiving vedolizumab than in patients receiving placebo . Vedolizumab , as compared with placebo , was associated with a higher rate of serious adverse events ( 24.4 % vs. 15.3 % ) , infections ( 44.1 % vs. 40.2 % ) , and serious infections ( 5.5 % vs. 3.0 % ) . CONCLUSIONS  Vedolizumab-treated patients with active Crohn 's disease were more likely than patients receiving placebo to have a remission , but not a CDAI-100 response , at week 6 ; patients with a response to induction therapy who continued to receive vedolizumab ( rather than switching to placebo ) were more likely to be in remission at week 52 . Adverse events were more common with vedolizumab . ( Funded by Millennium Pharmaceuticals ; GEMINI 2 Clinical Trials.gov number , NCT00783692 . ) BACKGROUND & AIMS : The efficacy and safety of vedolizumab , a humanized immunoglobulin G1 monoclonal antibody against the integrin & agr;4&bgr;7 , were demonstrated in multicenter , phase 3 , r and omized , placebo‐controlled trials in patients with moderately to severely active ulcerative colitis ( UC ) or Crohn 's disease . We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC , based on past exposure to anti – tumor necrosis factor‐&agr ; ( TNF ) antagonists . METHODS : We performed a post hoc analysis of data from the GEMINI 1 study , collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist ( naive to TNF antagonists ) and 367 patients with an inadequate response , loss of response , or intolerance to TNF antagonists ( failure of TNF antagonists ) . Predefined outcomes of GEMINI 1 were evaluated in these sub population s. RESULTS : At Week 6 , there were greater absolute differences in efficacy  between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists , although the risk ratios ( RRs ) for efficacy were similar for each group . Week 6 rates of response  to vedolizumab and placebo were 53.1 % and 26.3 % , respectively , among patients naive to TNF antagonists ( absolute difference , 26.4 % ; 95 % confidence interval [ CI ] , 12.4–40.4 ; RR , 2.0 ; 95 % CI , 1.3–3.0 ) ; these rates were 39.0 % and 20.6 % , respectively , in patients with failure of TNF antagonists ( absolute difference , 18.1 % ; 95 % CI , 2.8–33.5 ; RR , 1.9 ; 95 % CI , 1.1–3.2 ) . During maintenance therapy , the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists , for most outcomes . Week 52 rates of remission  with vedolizumab and placebo were 46.9 % and 19.0 % , respectively , in patients naive to TNF antagonists ( absolute difference , 28.0 % ; 95 % CI , 14.9–41.1 ; RR , 2.5 ; 95 % CI , 1.5–4.0 ) and 36.1 % and 5.3 % , respectively , in patients with failure of TNF antagonists ( absolute difference , 29.5 % ; 95 % CI , 12.8–46.1 ; RR , 6.6 ; 95 % CI , 1.7–26.5 ) . No differences in adverse events were observed among groups . CONCLUSIONS : Vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure . There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure . Clinical Trials.gov no : NCT00783718 BACKGROUND Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis . METHODS We conducted two integrated r and omized , double-blind , placebo-controlled trials of vedolizumab in patients with active disease . In the trial of induction therapy , 374 patients ( cohort 1 ) received  vedolizumab  ( at a dose of 300 mg ) or placebo intravenously at weeks 0 and 2 , and 521 patients ( cohort 2 ) received open-label  vedolizumab at weeks 0 and 2 , with disease evaluation at week 6 . In the trial of maintenance therapy , patients in either cohort who had a response to vedolizumab at week 6 were r and omly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks . A response was defined as a reduction in the Mayo Clinic score ( range , 0 to 12 , with higher scores indicating more active disease ) of at least 3 points and a decrease of at least 30 % from baseline , with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 . RESULTS Response rates at week 6 were 47.1 % and 25.5 % among patients in the vedolizumab group and placebo group , respectively ( difference with adjustment for stratification factors , 21.7 percentage points ; 95 % confidence interval [ CI ] , 11.6 to 31.7 ; P<0.001 ) . At week 52 , 41.8 % of patients who continued to receive vedolizumab every 8 weeks and 44.8 % of patients who continued to receive vedolizumab every 4 weeks were in clinical remission ( Mayo Clinic score ≤2 and no subscore > 1 ) , as compared with 15.9 % of patients who switched to placebo ( adjusted difference , 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [ 95 % CI , 14.9 to 37.2 ; P<0.001 ] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [ 95 % CI , 17.9 to 40.4 ; P<0.001 ] ) . The frequency of adverse events was similar in the vedolizumab and placebo groups . CONCLUSIONS Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis . ( Funded by Millennium Pharmaceuticals ; GEMINI 1 Clinical Trials.gov number , NCT00783718 . ) BACKGROUND In patients with Crohn 's disease , the efficacy of ustekinumab , a human monoclonal antibody against interleukin-12 and interleukin-23 , is unknown . METHODS We evaluated ustekinumab in adults with moderate-to-severe Crohn 's disease that was resistant to anti-tumor necrosis factor ( TNF ) treatment . During induction , 526 patients were r and omly assigned to receive intravenous ustekinumab ( at a dose of 1 , 3 , or 6 mg per kilogram of body weight ) or placebo at week 0 . During the maintenance phase , 145 patients who had a response to ustekinumab at 6 weeks underwent a second r and omization to receive subcutaneous injections of ustekinumab ( 90 mg ) or placebo at weeks 8 and 16 . The primary end point was a clinical response at 6 weeks . RESULTS The proportions of patients who reached the primary end point were 36.6 % , 34.1 % , and 39.7 % for 1 , 3 , and 6 mg of ustekinumab per kilogram , respectively , as compared with 23.5 % for placebo ( P=0.005 for the comparison with the 6-mg group ) . The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks . Maintenance therapy with ustekinumab , as compared with placebo , result ed in significantly increased rates of clinical remission ( 41.7 % vs. 27.4 % , P=0.03 ) and response ( 69.4 % vs. 42.5 % , P<0.001 ) at 22 weeks . Serious infections occurred in 7 patients ( 6 receiving ustekinumab ) during induction and 11 patients ( 4 receiving ustekinumab ) during maintenance . Basal-cell carcinoma developed in 1 patient receiving ustekinumab . CONCLUSIONS Patients with moderate-to-severe Crohn 's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab , as compared with placebo . Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy . ( Funded by Janssen Research and Development ; CERTIFI Clinical Trials.gov number , NCT00771667 . ) BACKGROUND 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 . METHODS We conducted three phase 3 , r and omized , 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 r and omly 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 r and omly 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 . RESULTS 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 . CONCLUSIONS 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 Clinical Trials.gov numbers , NCT01465763 , NCT01458951 , and NCT01458574 , respectively . BACKGROUND & AIMS There is an increasing need for new treatments for patients with Crohn 's disease ( CD ) in whom previous therapy with tumor necrosis factor ( TNF ) antagonists has failed . We performed a placebo-controlled , phase 3 , double-blind trial to evaluate the efficacy and safety of vedolizumab , an antibody against the integrin α4β7 , as induction therapy . METHODS Patients with moderately to severely active CD ( CD activity index [ CDAI ] score , 220 - 400 points ) were assigned r and omly to groups given vedolizumab ( 300 mg ) or placebo intravenously at weeks 0 , 2 , and 6 . The primary analysis involved 315 patients with previous TNF antagonist failure ( ie , an inadequate response to , loss of response to , or intolerance of ≥1 TNF antagonists ) ; we determined the proportion of patients in clinical remission ( CDAI , ≤150 points ) at week 6 . Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population ( N = 416 ) , which included patients naive to TNF antagonist therapy ( n = 101 ) . RESULTS Among patients who had experienced previous TNF antagonist failure , 15.2 % of those given vedolizumab and 12.1 % of those given placebo were in remission at week 6 ( P = .433 ) . At week 10 , a higher proportion of this population given vedolizumab  was in remission ( 26.6 % ) than those given placebo ( 12.1 % ) ( nominal P = .001 ; relative risk , 2.2 ; 95 % confidence interval , 1.3 - 3.6 ) . A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response ( ≥100-point decrease in CDAI score from baseline ) at week 6 than those given placebo ( 39.2 % vs 22.3 % ; nominal P = .001 ; relative risk , 1.8 ; 95 % confidence interval , 1.2 - 2.5 ) . Adverse event results were similar among all groups . CONCLUSIONS Vedolizumab was not more effective  than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed . The therapeutic benefits of vedolizumab in these patients were detectable at week 10 . Clinical Trials.gov number : NCT01224171 BACKGROUND & AIMS : Ustekinumab , an inhibitor of the p40 subunit of interleukins 12 and 23 , is an effective treatment for patients with Crohn 's disease ( CD ) . Trough concentrations of tumor necrosis factor ( TNF ) antagonists and presence of anti‐drug antibodies are associated with important clinical and endoscopic outcomes . We investigated associations between trough concentrations of ustekinumab and clinical , biomarker , and endoscopic outcomes of real‐world patients with CD . METHODS : We recruited 62 patients with CD who were either refractory or intolerant to TNF antagonists , treated with ustekinumab from April 2014 to September 2015 . Patients received 90 mg of ustekinumab subcutaneously at weeks 0 , 1 , and 2 during induction and 90 mg every 4 or 8 weeks during maintenance  . Clinical , biomarker , and endoscopic outcomes , trough concentrations of ustekinumab , and anti‐drug antibodies  were assessed at both week 10 postinduction therapy and at week 26 or later during maintenance therapy in a prospect i ve longitudinal patient cohort or at week 26 or later during maintenance therapy in a cross‐sectional patient cohort . Analysis was performed on data combined from both maintenance cohorts , which had similar outcomes at week 26 or later . A primary analysis determined if ustekinumab drug trough concentrations were associated with clinical response ( reduction in Harvey Bradshaw Index score of 3 or greater ) , clinical remission ( Harvey Bradshaw Index score < 5 ) , steroid‐free clinical remission , biomarker ( serum level of C‐reactive protein [ CRP ] or level of fecal calprotectin ) reduction , biomarker normalization ( serum level of CRP below 5 mg/L or level of fecal calprotectin below 200 & mgr;g/g ) , endoscopic response ( simple endoscopic score for CD reduced by 50 % or more ) , or endoscopic remission ( simple endoscopic score for CD of 2 or less ) . RESULTS : At week 26 or beyond , 80.7 % of patients had a clinical response , 66.1 % were in clinical remission , 50.0 % were in steroid‐free clinical remission , 58.9 % had an endoscopic response , and 19.6 % were in endoscopic remission . The mean trough concentration of ustekinumab at this time point was higher in patients with an endoscopic response ( 4.7 & mgr;g/mL ) than without ( 3.8 ug/mL ; P = .03 ) . An optimal ustekinumab threshold trough concentration at week 26 or later was found to be 4.5 & mgr;g/mL ( area under the curve , 0.67 ) . A greater proportion of patients with trough concentrations of ustekinumab above 4.5 & mgr;g/mL at week 26 or later had an endoscopic response ( 75.9 % ) than did patients with trough concentrations below this level ( 40.7 % ; P = .008 ) . Patients with trough concentrations of ustekinumab above 4.5 & mgr;g/mL at week 26 or later also had a lower mean level of CRP ( 12.6 mg/L ) than did patients with trough concentrations below this level ( mean level of CRP , 23.9 mg/L ; P = .04 ) . We did not detect antibodies against ustekinumab in any patient . CONCLUSIONS : Ustekinumab therapy was effective in patients with CD who had not responded to or were intolerant to treatment with a TNF antagonist . Maintenance trough concentrations of ustekinumab above 4.5 & mgr;g/mL at 26 weeks or later were associated with biomarker reduction and endoscopic response
Background and Aims We sought to analyze whether response to a second-line biologic varies depending on the reason for discontinuation of the primary anti-TNF agent ( primary non-response [ PNR ] , secondary loss of response [ LOR ] after initial response , or intolerance ) , through a systematic review and meta- analysis .