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Background Ustekinumab (UST) is an IL-12/23p40 antagonist used to treat pts with moderate-to-severe ulcerative colitis (UC). The ongoing UNIFI long-term extension (LTE) evaluates subcutaneous (SC) 90mg UST maintenance therapy, with efficacy (wk152) and safety (wk156) results reported here. Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (175 SC placebo [PBO]; 172 UST 90mg every 12 weeks [q12w]; 176 UST 90mg q8w). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Starting at wk56, randomized pts with UC worsening could adjust to q8w. Symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) was evaluated in randomized pts. Safety was evaluated for all 588 pts treated in the LTE, including the randomized and nonrandomized populations; 188 received PBO and 457 received UST. The nonrandomized population included responders to PBO induction and UST induction nonresponders at wk8 who received SC UST, responded 8 wks later and received UST 90mg q8w. Results Among all pts randomized to UST at maintenance baseline (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 55.2% were in symptomatic remission at wk152 (biologic naïve, 66.1%; biologic failures, 43.5%; Table 1); 96.4% (185/192) of pts in symptomatic remission at wk152 were corticosteroid-free. Overall, 20.1% (39/149 biologic failure, 16/149 biologic naïve) of pts who were randomized to UST and treated in the LTE discontinued treatment between wks44 and 156. Among randomized pts treated with UST in the LTE, 67.6% were in symptomatic remission at wk152; 76.4% of those in clinical remission at wk44 were in symptomatic remission at wk152; and 84.1% of pts with observed data at wk152 were in symptomatic remission. From maintenance wk0-156, combined UST and PBO pts had 1281.6 and 425.0 pt-years of follow-up, respectively; and safety events per 100 pt-years of follow-up for combined UST vs PBO were AEs: 235.81 vs 204.48, SAEs: 7.73 vs 7.53, and serious infections: 2.34 vs 2.35 (Table 2). From wks96-156, there were no reported deaths or major adverse cardiovascular events. One UST-treated pt with fair skin and a prior history of basal cell carcinoma (BCC) reported 2 BCC. One 90 mg q8w UST pt receiving concomitant 6-MP reported SAEs of neutropenic sepsis and oral herpes SAE; the latter events were considered potential opportunistic infections. The dose of 6-MP was reduced, pt recovered and continued UST. Conclusion The efficacy of UST in pts with UC was sustained through 3 years. No new safety signals were observed.

Background Ustekinumab (UST) is an IL12/23 blocker approved for use in Crohn’s disease and ulcerative colitis (UC). In the UNIFI maintenance study of patients (pts) with moderate-severe UC, >90% of the pts who achieved clinical response or remission at week (wk) 44 were able to eliminate corticosteroids, an important goal of therapy. In this analysis, we describe the corticosteroid-sparing effects of UST treatment through 3 years among pts who were treated in the UNIFI long-term extension (LTE). Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (SC placebo [PBO], n=175; UST 90mg every 12 wks [q12w], n=172; or UST 90mg q8w, n=176). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Based on the investigator’s clinical judgement of their UC disease activity, pts in the LTE were eligible to receive dose adjustment starting at wk56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). Pts in PBO or q8w groups were only eligible for dose adjustment or sham dose adjustment before unblinding. Efficacy was evaluated in randomized pts using symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0). During the maintenance study, all pts receiving corticosteroids at maintenance baseline were required to initiate tapering. Through wk152 of the LTE, symptomatic remission endpoints were calculated with treatment failure and missing data nonresponder imputation, and dose adjustment was not considered to be a treatment failure. Missing corticosteroid dose data was managed using last observation carried forward. Results Of the 284 pts in the randomized population who were treated with UST in the LTE, 139 were receiving corticosteroids at maintenance baseline. Of these, 91.4% (n=127) were no longer receiving corticosteroids at wk152. The average prednisone-equivalent corticosteroid dose among pts receiving corticosteroids at maintenance baseline in the q8w group was 15.4 mg/day at maintenance baseline and 1.7 mg/day at wks44 & 152. In the q12w group, average prednisone-equivalent doses were 15.4, 1.0, and 4.6 mg/day, respectively (Table 1). Corticosteroid-free symptomatic remission rates through wk152 are summarized in Table 2. Results were similar for the q8w and q12w maintenance doses. Of the UST-treated pts who were in symptomatic remission at wk152, 94.6% (88/93) in the q12w group and 98.0% (97/99) in the q8w group were corticosteroid-free. Conclusion UST maintenance therapy, with both q8w and q12w dosing regimens, was effective in reducing and eliminating the use of corticosteroids in pts with UC through 3 years. Through 3 years of treatment with UST, the majority of pts in symptomatic remission were corticosteroid free.

Background & Aims Antibiotic treatment is the standard care for patients with uncomplicated acute diverticulitis. However, this practice is based on low-level evidence and has been challenged by findings from 2 randomized trials, which did not include a placebo group. We investigated the non-inferiority of placebo vs antibiotic treatment for the management of uncomplicated acute diverticulitis. Methods In the selective treatment with antibiotics for non-complicated diverticulitis study, 180 patients hospitalized for uncomplicated acute diverticulitis (determined by computed tomography, Hinchey 1a grade) from New Zealand and Australia were randomly assigned to groups given antibiotics (n = 85) or placebo (n = 95) for 7 days. We collected demographic, clinical, and laboratory data and answers to questionnaires completed every 12 hrs for the first 48 hrs and then daily until hospital discharge. The primary endpoint was length of hospital stay; secondary endpoints included occurrence of adverse events, readmission to the hospital, procedural intervention, change in serum markers of inflammation, and patient-reported pain scores at 12 and 24 hrs. Results There was no significant difference in median time of hospital stay between the antibiotic group (40.0 hrs; 95% CI, 24.4–57.6 hrs) and the placebo group (45.8 hrs; 95% CI, 26.5–60.2 hrs) (P = .2). There were no significant differences between groups in adverse events (12% for both groups; P = 1.0), readmission to the hospital within 1 week (1% for the placebo group vs 6% for the antibiotic group; P = .1), and readmission to the hospital within 30 days (11% for the placebo group vs 6% for the antibiotic group; P = .3). Conclusions Foregoing antibiotic treatment did not prolong length of hospital admission. This result provides strong evidence for omission of antibiotics for selected patients with uncomplicated acute diverticulitis. ACTRN: 12615000249550.

Background The UNIFI maintenance study evaluated the safety and efficacy of subcutaneous (SC) ustekinumab (UST) in patients with moderately–severely active UC who had responded to IV UST induction. Previously, we reported that health-related quality of life (HRQoL) improvements achieved after UST induction were maintained through Week 44 with UST maintenance. Here, we evaluated HRQoL through Week 92 in patients who continued UST maintenance in the long-term extension (LTE). Methods Patients who completed the maintenance study were eligible to continue their maintenance treatment regimen (placebo [PBO], UST90mg q12w, or UST90mg q8w) in the LTE if the investigator thought they could benefit from continued treatment. PBO patients discontinued from the LTE after the maintenance study was unblinded. Per investigator discretion, patients could receive a single dose adjustment (UST q12w to q8w or UST q8w to q8w [sham dose adjustment]) starting at Week 56. The Inflammatory Bowel Disease Questionnaire (IBDQ) is a 32-item questionnaire with a total score ranging from 32 to 224. Higher scores indicate better HRQoL, a score ≥170 indicates remission, and a change ≥16 was defined as clinically meaningful. General health was assessed using SF-36. A change ≥5 points in physical and mental component scores was defined as clinically meaningful. In this analysis, patients who dose adjusted were considered treatment failures. Results Most patients who received UST in the LTE maintained the improvements in IBDQ and SF-36 that were achieved after induction (Tables 1 and 2) through Week 92. Overall, 158 of 284 patients (55.6%) who received UST were in IBDQ remission at Week 92, and 114 of 169 patients (67.5%) who were in IBDQ remission at maintenance baseline were in IBDQ remission at Week 92. Of the 284 patients, 179 (63.0%) achieved a ≥16-point improvement in IBDQ score from induction baseline to Week 92. Of 250 patients who achieved a ≥16-point improvement from induction baseline to maintenance baseline, 154(61.6%) maintained a ≥16-point improvement at both Weeks 44 and 92. For SF-36, 142 of 284 patients (50.0%) had a ≥5-point improvement from induction baseline to Week 92 in the physical component score, while 128 of 284 (45.1%) had a ≥5-point improvement in the mental component score. Conclusion The majority of patients who were treated with UST in the LTE generally maintained improvements in IBDQ and SF-36 scores that were achieved after IV induction.

Background Ustekinumab (UST) has been shown to induce and maintain clinical response and remission in moderate–severe UC patients in the UNIFI study. In the UNIFI maintenance study, the primary randomised population consisted of patients who were in clinical response 8weeks after UST induction treatment. Patients who had a delayed response to induction were also eligible for the maintenance study but were not included in the randomised analysis set. Here, we present the efficacy and safety of UST maintenance among delayed responders who were treated in the UNIFI long-term extension(LTE). Methods UNIFI was a single protocol of induction and randomised withdrawal maintenance studies in patients with moderate–severe UC who failed conventional or biologic therapy(including TNF antagonists and/or vedolizumab). Delayed responders were patients who were not in clinical response to UST IV induction at Week8 but achieved response at Week16 following a single UST90mg SC dose at Week8. These patients entered the maintenance study and continued to receive UST90mg SC q8w. Patients who completed Week44 evaluations were eligible to enter LTE continuing to receive UST90mg SC q8w. Efficacy in delayed responders to UST(who were treated in LTE) was evaluated over time through Week92 and safety through Week96. Results 116 delayed responders to UST induction were treated in the LTE, including 58 who had previously failed biologic therapy and 58 who had not failed biologic therapy, 54 of whom were bio-naïve. Symptomatic remission(defined as stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) rates in delayed responders to UST induction increased from maintenance baseline to Weeks 44 and 92 (Table 1). Similar trends were seen within the biologic failure subgroups; although, rates among patients who had not failed biologics (primarily bio-naïve) were greater than those of patients who had failed biologics. Among the 79.3% (n = 92/116) of delayed responders to UST in symptomatic remission at Week 92, 94.6% (n = 87/92) were corticosteroid free. Safety data for randomised and non-randomised patients treated in UNIFI LTE is in Table2. The safety profile for UST in delayed responders was generally similar to that observed among patients randomised to UST; no new safety signals were observed. Conclusion Delayed responders to UST treatment maintained symptomatic remission through Week 92 with UST90mg SC q8w and the majority did so in the absence of corticosteroids.

Background Ustekinumab (UST) is an IL12/23 blocker approved for Crohn’s disease and ulcerative colitis (UC). In the UNIFI maintenance study of patients with moderate–severe UC, >90% of the patients who achieved clinical response or remission at week 44 were able to eliminate corticosteroids, an important goal of therapy. In this analysis, we describe the corticosteroid (CS) sparing effects of UST treatment through week 92 among patients who were treated in the UNIFI long-term extension (LTE). Methods Responders to UST 8 weeks after IV induction entered the maintenance study and were randomised to UST 90mg SC (q12wks or q8wks) or PBO. Patients who did not respond to UST IV induction received a dose of UST 90mg SC at week 8 and were evaluated at week 16. Those in clinical response at week 16 (delayed responders), were not randomised on entry into the maintenance study and received UST 90mg q8wk. All patients who completed week 44 of the maintenance study were eligible to enter the LTE and continue to receive the same dose. Patients could receive UST dose adjustment during the LTE (q12wk to q8wk or q8wk to q8wk [sham dose adjustment]) from week 56 onward. Patients who remained on PBO were discontinued from the LTE after maintenance study unblinding. During the maintenance study, CS tapering was recommended for all patients receiving CS at maintenance baseline. At week 92 of the LTE, CS-free symptomatic remission rates and CS use were calculated using intention-to-treat analyses with a dose adjustment considered to be a treatment failure and with a dose adjustment not considered to be a treatment failure. Results Of the 284 patients in the randomised population who were treated with UST in the LTE, 139 were receiving CS at maintenance baseline. Of these, 92.8% (n = 129) were CS-free at week 92. CS-free symptomatic remission rates at week 92 are summarised in Table 1. Results were similar for the q8wk and q12wk maintenance doses. Of the UST-treated patients who were in symptomatic remission at week 92, 98.4% (182/185) were CS-free; similar results were seen when dose adjustment was not considered to be a treatment failure. Of the 116 delayed responders (non-randomised population) who continued to receive UST in the LTE, 92 patients were in symptomatic remission at week 92; of whom, 94.6% (87/92) were CS-free. Conclusion UST maintenance therapy, with both q8wk and q12wk dosing regimens, was effective in reducing and eliminating the use of CS in patients with UC. Nearly all patients in the LTE who were in symptomatic remission at week 92, were not taking steroids.

Background & Aims Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence. Methods We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a ≥70-point increase from baseline, and endoscopic recurrence (Rutgeerts score ≥i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point. Results A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: -1.3% to 15.5%; P =.097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; P

Background The UNIFI randomised-withdrawal maintenance study evaluated the safety and efficacy of subcutaneous (SC) ustekinumab (UST) in patients (patients) with moderately to severely active ulcerative colitis (UC) who had responded to intravenous (IV) UST during induction. We evaluated the efficacy of UST dose adjustment during the long-term extension (LTE). Methods At Week (Week) 0 of the 44 weeks maintenance study, 523 patients who had responded to IV UST induction were randomly assigned in a 1:1:1 ratio to placebo (PBO) SC, UST SC 90 mg q12w, or 90 mg q8w. Patients who completed the maintenance study were eligible to enter the LTE if the investigator thought they would benefit from continued treatment. PBO patients were discontinued from the LTE after the maintenance study was unblinded and the analysis was complete. Based on investigator’s clinical judgement of UC disease activity, patients in the LTE were eligible to receive dose adjustment starting at Week 56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). PBO patients were only eligible for dose adjustment before unblinding. Patients were assessed for symptomatic remission (SR), partial Mayo scores, and inflammatory markers ≥16 weeks after dose adjustment. Results Symptomatic remission was maintained through Week 92 among patients treated with UST regardless of dose adjustment in the LTE (Figure). Overall, 40 (28.4%) and 37 (25.9%) patients in the q12w and q8w groups, respectively, underwent dose adjustment (or sham dose adjustment) prior to Week 92 of the LTE. Among patients who received dose adjustment at Week 76 or before and had data ≥16 weeks after dose adjustment, symptomatic remission was observed in 70.0% in the q12w-to-q8w group and 71.4% in the q8w-to-q8w group, the majority of whom were in symptomatic remission at the time of the dose adjustment (Table). The safety profile of UST in patients who received dose adjustment was generally consistent with the overall safety profile of UST. Conclusion Patients may benefit from UST dose adjustment to q8w. However, the majority of UST-treated patients were in SR at the time of dose adjustment in this study. No new safety signals were observed among patients who dose adjusted.

Pregabalin is a treatment for peripheral neuropathic pain. Here, the authors discuss its safety and efficacy and highlight its advantages over other drugs currently available for treating this condition. Copyright © 2006 Wiley Interface Ltd

Edward Welchew BMJ Publishing Group, pounds sterling16.95, pp 133 ISBN 0 7279 0860 X Our approach to managing postoperative pain has changed fundamentally over the past decade. Previously, most patients were fortunate if they received two or three doses of intramuscular opioid after major surgery. This despite numerous publications describing the excessive incidence of severe pain after surgery. There were probably two catalysts for change. Firstly, the report of the Royal Colleges of Anaesthetists and Surgeons on Pain After Surgery was published in 1991. It recommended a change in our attitude to postoperative pain, improved education, and the safe introduction of new pain management techniques into British hospitals. In general this was well received, and most hospitals have responded to it. The second factor …