Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial The Effects of Infliximab Therapy on Health-Related Quality of Life in Ulcerative Colitis Patients Combination of direct and indirect evidence in mixed treatment comparisons. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Infliximab for acute, not steroid-refractory ulcerative colitis: a randomized pilot study Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Predictors of early response to infliximab in patients with ulcerative colitis Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial Response and remission are associated with improved quality of life, employment and disability status, hours worked, and productivity of patients with ulcerative colitis Infliximab in the Treatment of Severe, Steroid-Refractory Ulcerative Colitis: A Pilot Study Infliximab for refractory ulcerative colitis or indeterminate colitis: an open‐label multicentre study
Objective The aim of this study was to assess the efficacy and safety of adalimumab ( ADA ) , a recombinant human monoclonal antibody against tumour necrosis factor α ( TNF ) , for the induction of clinical remission in anti-TNF naïve patients with moderately to severely active ulcerative colitis . Methods This 8-week , multicentre , r and omised , double-blind , placebo-controlled study ( NCT00385736 ) , conducted at 94 centres in North America and Europe , enrolled ambulatory adult patients with Mayo score of ≥6 points and endoscopic subscore of ≥2 points despite treatment with corticosteroids and /or immunosuppressants . Under the original study protocol , 186 patients were r and omised ( 1:1 ) to subcutaneous treatment with ADA160/80 ( 160 mg at week 0 , 80 mg at week 2 , 40 mg at weeks 4 and 6 ) or placebo . Subsequently , at the request of European regulatory authorities , the protocol was amended to include a second induction group ( ADA80/40 : 80 mg at week 0 , 40 mg at weeks 2 , 4 and 6 ) . The primary efficacy endpoint was clinical remission ( Mayo score ≤2 with no individual subscore > 1 ) at week 8 , assessed in 390 patients r and omised ( 1:1:1 ) to ADA160/80 , ADA80/40 , or placebo . Safety was assessed in all enrolled patients . Patients , study site personnel , investigators , and the sponsor were blinded to treatment assignment . Results At week 8 , 18.5 % of patients in the ADA160/80 group ( p=0.031 vs placebo ) and 10.0 % in the ADA80/40 group ( p=0.833 vs placebo ) were in remission , compared with 9.2 % in the placebo group . Serious adverse events occurred in 7.6 % , 3.8 % and 4.0 % of patients in the placebo , ADA80/40 , and ADA160/80 groups , respectively . There were two malignancies in the placebo group , none in the ADA groups . There were no cases of tuberculosis and no deaths . Conclusions ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and /or immunosuppressants . Clinical trial NCT00385736 OBJECTIVES : The impact of infliximab induction and maintenance therapy on health-related quality of life ( HRQL ) was evaluated in patients with ulcerative colitis ( UC ) . METHODS : In two placebo-controlled , double-blind studies ( the Active Ulcerative Colitis Trials 1 and 2 [ ACT 1 and 2 ] ) , 728 patients were r and omized to placebo or infliximab 5 mg/kg or 10 mg/kg . Infusions were administered at weeks 0 , 2 , 6 , and every 8 wk thereafter , up to week 22 ( ACT 2 ) or 46 ( ACT 1 ) . Changes in Inflammatory Bowel Disease Question naire ( IBDQ ) and Medical Outcomes Study 36-Item Short Form Health Survey physical and mental component summary ( PCS and MCS , respectively ) scores were analyzed . RESULTS : Baseline scores for the pooled patient population indicated substantial impairment in HRQL . Improvement at week 8 in the total IBDQ score was significantly greater in the infliximab 5-mg/kg ( 40 , P < 0.001 ) and 10-mg/kg ( 36 , P < 0.001 ) groups compared with the placebo group ( 28 ) . Improvement at week 8 was also significantly greater in the infliximab 5- and 10-mg/kg groups for the PCS ( 6.8 and 5.9 , respectively ) and MCS ( 5.9 and 6.4 , respectively ) compared with placebo ( PCS = 3.7 , MCS = 3.0 , P < 0.01 for all comparisons ) . Continued benefit was seen at weeks 30 and 54 with infliximab maintenance therapy ( P < 0.001 for all comparisons ) . Improvement in total IBDQ score correlated significantly ( P < 0.001 ) with improvement in both PCS and MCS scores , and Mayo score . CONCLUSIONS : Infliximab therapy substantially improved HRQL  in patients with UC . This benefit was sustained through 1 yr with maintenance infliximab therapy Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed 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 BACKGROUND & AIMS Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-α . Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled , double-blind trial . METHODS Ulcerative colitis long-term remission and maintenance with adalimumab 2 ( ULTRA 2 ) was a r and omized , double-blind , placebo-controlled trial to evaluate the efficacy of adalimumab in induction and maintenance of clinical remission in 494 patients with moderate-to-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants . Patients were stratified based on prior exposure to TNF-α antagonists ( either had or had not been previously treated with anti-TNF-α ) and r and omly assigned to groups given adalimumab 160 mg at week 0 , 80 mg at week 2 , and then 40 mg every other week or placebo . Primary end points were remission at weeks 8 and 52 . RESULTS Overall rates of clinical remission at week 8 were 16.5 % on adalimumab and 9.3 % on placebo ( P = .019 ) ; corresponding values for week 52 were 17.3 % and 8.5 % ( P = .004 ) . Among anti-TNF-α naïve patients , rates of remission at week 8 were 21.3 % on adalimumab and 11 % on placebo ( P = .017 ) ; corresponding values for week 52 were 22 % and 12.4 % ( P = .029 ) . Among patients who had previously received anti-TNF agents , rates of remission at week 8 were 9.2 % on adalimumab and 6.9 % on placebo ( P = .559 ) ; corresponding values for week 52 were 10.2 % and 3 % ( P = .039 ) . Serious adverse events occurred in 12 % of patients given adalimumab or placebo . Serious infections developed in 1.6 % of patients given adalimumab and 1.9 % given placebo . In the group given adalimumab , 1 patient developed squamous cell carcinoma and 1 developed gastric cancer . CONCLUSIONS Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants Objective Therapeutic alternatives for patients with acute ulcerative colitis in whom steroids would usually be contraindicated are rare . The antibody to tumor necrosis factor alpha , infliximab , has shown to be effective in the treatment of steroid-refractory ulcerative colitis in pilot studies . We therefore evaluated whether infliximab can achieve remission in patients with acute ulcerative pancolitis who were not steroid-refractory . Methods and design Patients were eligible if they had acute disease with a modified Truelove and Witts activity score of more than 10 for at least 2 weeks and if they were currently not receiving immunomodulators or more than 10 mg/day prednisolone . Patients were r and omly assigned to receive either three intravenous infusions of infliximab at 5 mg/kg ( group A ) or high-dose prednisolone ( 1.5 mg/kg body weight ) daily for 2 weeks , followed by 1 mg/kg for 1 week , followed by a weekly reduction of 5 mg ( group B ) . Therapy success was defined as clinical response in terms of a decrease of more than 5 points from the baseline score and to less than 10 points total after 3 weeks as well as after 13 weeks . Results Thirteen patients ( seven women , six men ) were r and omized ( six for group A and seven for group B ) . The median baseline activity scores were 13.5 ( 12–18 ) in group A and 14.0 ( 11–18 ) in group B. Five of six patients in group A and six of seven patients in group B showed therapy success after 3 weeks as well as after 13 weeks . Conclusions Infliximab could be effective in the treatment of acute moderate or severe ulcerative colitis . The obtained data call for larger controlled trials BACKGROUND & AIMS Despite treatment with corticosteroids , severe to moderately severe attacks of ulcerative colitis have a high colectomy rate . We intended to find a rescue therapy other than cyclosporin A , which imposes a high risk of side effects and cyclosporine-related mortality . METHODS This was a r and omized double-blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment . Patients were r and omized to infliximab/placebo  either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on day 3 or on day 6 - 8 if they fulfilled index criteria on day 5 - 7 for a severe or moderately severe acute attack of ulcerative colitis . Results were analyzed according to the intention-to-treat principle . The primary end point was colectomy or death 3 months after r and omization . Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation .  RESULTS Forty-five patients were included ( 24 infliximab and 21 placebo ) . No patient died . Seven patients in the infliximab group and 14 in the placebo group had a colectomy ( P = .017 ; odds ratio , 4.9 ; 95 % confidence interval , 1.4 - 17 ) within 3 months after r and omization . No serious side effects occurred . Three patients in the placebo group required operation for septic complications . CONCLUSIONS Infliximab 4 - 5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment Background Our objective is to report the outcome of infliximab ( IFX ) in ulcerative colitis ( UC ) patients from a single center and to identify predictors of early clinical response . Methods The first 100 UC patients ( 45 female ; median age , 37.9 years ) who received IFX at a single center were included . Eighty‐four patients received 5 mg/kg IFX , and 37 patients received a 3‐dose IFX induction at weeks 0 , 2 , and 6 . The Mayo endoscopic subscore , assessed by sigmoidoscopy before inclusion , was 1 , 2 , and 3 in 5 % , 52 % , and 43 % of patients , respectively . Sixty percent had pancolitis , 63 % were on concomitant immunosuppressive therapy , 9 % were active smokers , 64 % had C‐reactive protein ≥5 mg/dL , and 44 % were pANCA+/ASCA−. Five patients received IFX because of severe acute colitis refractory to intravenous corticosteroids . Results Early complete and partial clinical responses were observed in 41 % and 24 % of patients . Patients with early clinical response were significantly younger than nonresponders ( median age , 35.7 versus 41.6 years , P = 0.041 ) . Patients who were pANCA+/ASCA− had a significantly lower early clinical response ( 55 % versus 76 % ; odds ratio [ OR ] = 0.40 ( 0.16–0.99 ) , P = 0.049 ) . Concomitant immunosuppressive therapy and the use of an IFX induction scheme did not influence early clinical response . Only 1 of 5 patients who received IFX for acute steroid‐refractory colitis required colectomy within 2 months . Conclusions IFX  is an efficient therapy in UC , as shown by 65 % early clinical response . A pANCA+/ASCA− serotype and an older age at first IFX infusion are associated with a suboptimal early clinical response . ( Inflamm Bowel Dis 2006 Background : Tumour necrosis factor production is increased in the mucosa of patients with active ulcerative colitis . The benefits of infliximab in Crohn ’s disease are established . We investigated its efficacy in ulcerative colitis . Methods : We conducted a r and omised placebo controlled trial of infliximab ( 5 mg/kg ) in the treatment of glucocorticoid resistant ulcerative colitis . Infusions were given at weeks 0 and 2 . Disease activity and quality of life were recorded over eight weeks of follow up . Remission was defined as an ulcerative colitis symptom score ( UCSS ) of ⩽2 and /or Baron score of 0 at week 6 . Patients not in remission were offered open label infliximab 10 mg/kg and review ed two weeks later . Results : After two weeks , there was no statistically significant difference between the infliximab and placebo groups in the proportion of patients with a Baron score of 0 ( 13 % ( 3/23 ) v 5 % ( 1/19 ) ( 95 % confidence interval ( CI ) −9 % to 24 % ) ; p=0.74 ) . After six weeks , remission ( UCSS ⩽2 ) rates were 39 % ( 9/23 ) versus 30 % ( 6/20 ) ( 95 % CI −19 to 34 % ; p=0.76 ) . The median improvement in UCSS was 3 for the infliximab group and 2.5 for the placebo group ( p=0.82 , Mann-Whitney U test ) . A Baron score of 0 was likely in either group ( 26 % ( 6/23 ) v 30 % ( 6/20 ) ( 95 % CI −30 % to 23 % ) ; p=0.96 ) . Improvement in the IBDQ and EuroQol was not significantly different between the groups ( p=0.22 and 0.3 , respectively , Mann-Whitney U test ) . Twenty eligible patients were given open labelled infusions . Remission was achieved in 3/11 ( 27 % ) patients initially treated with infliximab and in 1/9 ( 11 % ) patients treated with placebo . Conclusion : These data do not support the use of infliximab in the management of moderately active glucocorticoid resistant ulcerative colitis Background : Impairment of health‐related quality of life , employment , and productivity has been documented in patients with moderate to severe ulcerative colitis . Methods : Using prospect ively collected data from the Active Ulcerative Colitis Trials 1 and 2 , we examined the impact of clinical response or remission , as defined using the Mayo score , on health‐related quality of life , employment , disability , productivity , and hours worked per week . These analyses were based on observed data and included all 728 patients , regardless of their r and omized treatment group ( i.e. ,  placebo and infliximab patients were grouped for analysis ) . Changes in Inflammatory Bowel Disease Question naire ( IBDQ ) and Medical Outcomes Study 36‐Item Short Form ( SF‐36 ) scores among nonresponders , responders , and patients in remission were compared . In addition , changes in employment , disability status , productivity , and hours worked per week of patients in clinical remission and patients not in clinical remission were compared . Results : Ulcerative colitis patients in clinical response or remission had significantly improved IBDQ and SF‐36 scores at week 30 compared with those of nonresponders ( P < 0.001 ) . Among those not employed at baseline , including those receiving disability compensation , greater percentages of patients in remission at week 30 were employed ( 20.6 % ) and not receiving disability compensation ( 58.8 % ) than were those not in remission ( 8.3 % and 20.0 % , respectively ; P < 0.05 for both comparisons ) . At week 30 , improvements from baseline in productivity and both actual and fully productive hours worked per week were greater for patients in remission compared with those not in remission ( P < 0.05 for all three comparisons ) . Conclusions : These results confirm the validity of response and remission as defined using the Mayo score We report the experience of 11 patients ( of 60 planned patients ) enrolled in a double-blind ,  placebo-controlled  clinical trial of infliximab in patients with severe , active steroid-refractory ulcerative colitis . The study was terminated prematurely because of slow enrollment . Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5 , 10 , or 20 mg/kg body weight . The primary endpoint used in this study was treatment failure at 2 weeks after infusion . Treatment failure was defined as 1 ) unachieved clinical response as defined by a modified Truelove and Witts severity score , 2 ) increase in corticosteroid dosage , 3 ) addition of immunosuppressants , 4 ) colectomy , or 5 ) death . Safety evaluations included physical examination , clinical chemistry and hematology laboratory tests , and occurrence of adverse experiences . Four of 8 patients ( 50 % ) who received infliximab were considered treatment successes at 2 weeks , compared with none of 3 patients who received placebo . Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab . Infusion with infliximab produced no significant adverse events .  Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis Background : The efficacy of infliximab in ulcerative colitis ( UC ) and indeterminate colitis has been poorly assessed and preliminary results are conflicting
OBJECTIVE To compare the efficacy of adalimumab and infliximab for the treatment of moderate to severe ulcerative colitis using indirect treatment comparison meta- analysis .