Jyotsna Bk Reddy

Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials

BACKGROUND Opioid-induced constipation is a frequent side-effect of opioid treatment, and standard interventions have limited or inconsistent efficacy. This study assessed the efficacy and safety of naldemedine, a peripherally acting μ-opioid receptor antagonist, for the treatment of opioid-induced constipation in patients with chronic non-cancer pain. METHODS We report two double-blind, randomised, placebo-controlled trials in adults with chronic non-cancer pain and opioid-induced constipation. The first (COMPOSE-1) was done in 68 outpatient sites in seven countries and the second (COMPOSE-2) at 69 outpatient sites in six countries; both studies were done in Europe and the USA. Eligible patients were aged 18-80 years, did not use laxatives, and had a stable opioid regimen for treatment of chronic non-cancer pain with a total daily dose averaging at least 30 mg (morphine equivalent) for at least 1 month before screening. Patients were randomly assigned (1:1) to receive either oral naldemedine 0·2 mg or matching placebo once a day for 12 weeks. Randomisation was stratified by average total daily opioid dose (30-100 mg and >100 mg equivalents of oral morphine sulphate). The primary endpoint was proportion of responders. A responder had at least three spontaneous bowel movements (SBMs) per week with an increase from baseline of at least one SBM per week for at least 9 weeks of the 12-week treatment period including at least three of the last 4 weeks. Efficacy endpoints were analysed by intention to treat and the safety population included all patients who received at least one dose of study drug. These trials have both been completed and are registered with ClinicalTrials.gov, numbers NCT01965158 and NCT01993940. FINDINGS In COMPOSE-1, 547 patients were recruited between Aug 29, 2013, and Jan 22, 2015, and were randomly assigned to receive naldemedine (n=274) or placebo (n=273). Patients for COMPOSE-2 were recruited between Nov 4, 2013, and June 9, 2015; 553 patients were randomly assigned to receive naldemedine (n=277) or placebo (n=276). Five patients were enrolled at more than one site, so were excluded from the intention-to-treat population (COMPOSE-1: one per group; COMPOSE-2: one in the naldemedine group, two from the placebo group), with intention-to-treat group sizes of 273 in the naldemedine group and 272 in the placebo group in COMPOSE-1, and 276 in the naldemedine group and 274 in the placebo group in COMPOSE-2. The proportion of responders in both trials was significantly higher with naldemedine than with placebo in COMPOSE-1 (130 responders [47·6%] of 273 in the naldemedine group vs 94 responders [34·6%] of 272 in the placebo group, difference 13·0% [95% CI 4·8-21·3]; p=0·002) and in COMPOSE-2 (145 [52·5%] of 276 vs 92 [33·6%] of 274, difference 18·9% [10·8-27·0]; p<0·0001). Incidence of adverse events with naldemedine was similar to placebo (COMPOSE-1: 132 [49%] of 271 in the naldemedine group vs 123 [45%] of 272 in the placebo group; COMPOSE-2: 136 [50%] of 271 vs 132 [48%] of 274). Treatment-related adverse events were noted in 59 (22%) of 271 patients in the naldemedine group and 45 (17%) of 272 in the placebo group in COMOPOSE-1, and in 54 (20%) of 271 patients in the naldemedine group and 31 (11%) of 274 in the placebo group of COMPOSE-2; the between-group differences were largely due to gastrointestinal disorders, which were more common with naldemedine than placebo (COMPOSE-1: 40 [15%] patients in the naldemedine group vs 18 [7%] in the placebo group; COMPOSE-2: 42 [16%] vs 20 [7%]). INTERPRETATION Naldemedine treatment led to a significantly higher responder rate than did placebo and was generally well tolerated. These results support that naldemedine could be a new option for the treatment of opioid-induced constipation in patients with chronic non-cancer pain. FUNDING Shionogi & Co, Ltd.

W1784 Should Plastic or Metallic Stents Be Chosen for Bilateral Stenting in Malignant Hilar Obstruction? a Meta-Analysis and Systematic Review of Risks

bubbles. The sizes of the RFA-induced areas were not significantly different between the single-step and multi-step methods. [Conclusions] The present results demonstrate that increased intrahepatic pressure causes microbubbles, thus suggesting that some risk of dissemination due to RFA exists. Therefore, RFA should be performed while adjusting intrahepatic pressure to avoid generating microbubbles. From this perspective, the multistep LeVeen method is suitable for treatment.

Impact of Endoscopist's Experience On Success Rate of En-Bloc and En Bloc-Cure of Large Colorectal Polyps By Endoscopic Submucosal Dissection: A Meta-Analysis and Systematic Review

Impact of Endoscopist’s Experience On Success Rate of En-Bloc and En Bloc-Cure of Large Colorectal Polyps By Endoscopic Submucosal Dissection: A Meta-Analysis and Systematic Review Srinivas R. Puli, Yasuo Kakugawa, Takuji Gotoda, Jyotsna Bk Reddy, Daphne Antillon, Yutaka Saito, Mainor R. Antillon Background: Endoscopic submucosal dissection (ESD) has emerged as an alternative to surgery for the resection of large (O 2 cm) colorectal polyps. ESD is a technically demanding procedure. From published data, it is not clear how endoscopists’ experience affects successful en-block resection of large colonic polyps. Aim: To evaluate how endoscopists experience in performing ESD affects the proportion of successful en-block resection of large colonic polyps. Method: Study Selection Criteria: Studies using ESD technique to resect large colonic polyps were selected. Successful cure en-block resection was defined as margins free polyp resection. Data collection & extraction: Articles were searched in Medline, Japanese language literature, and Cochrane control trial registry. Two reviewers independently searched and extracted data. Statistical Method: Summary estimates are expressed as pooled proportions. Studies were grouped into !100 ESD’s performed and O 100 ESD’s performed. First, the individual study proportions of successful resection are transformed into a quantity using Freeman-Tukey variant of the arcsine square root transformed proportion. The pooled proportion is calculated as the back-transform of the weighted mean of the transformed proportions, using inverse arcsine variance weights for the fixed effects model and DerSimonian-Laird weights for the random effects model. Results: Initial search identified 2,120 reference articles, in which, 389 relevant articles were selected and reviewed. Data was extracted from 13 studies (N Z 1,080) which met the inclusion criteria. 9 Studies had !100 ESD’s (N Z 394) and 4 studies had O100 ESD’s (N Z 686). The mean size of the polyps was 30.65 SE 2.88 mm. The pooled proportions are shown in table 1. The fixed effect model was not used because of the heterogeneity among studies. The publication bias calculated by BeggMazumdar bias indicator for successful en-bloc resection gave a Kendall’s tau b value of -0.22 (p Z 0.32) and the same for successful cure en-block resection was -0.23 (p Z 0.25). Conclusion: ESD is an innovative technique for resection of large colonic polyps that offers an alternative to surgery. Our meta-analysis shows that the success rate for both en-bloc and en-bloc cure improves with O100 ESDs. Endoscopist’s experience significantly improves the success rates of this technique to treat large colorectal polyps.