PMID- 29545635 OWN - NLM STAT- MEDLINE DCOM- 20190806 LR - 20190806 IS - 1572-0241 (Electronic) IS - 0002-9270 (Linking) VI - 113 IP - 5 DP - 2018 May TI - Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. PG - 735-745 LID - 10.1038/s41395-018-0026-7 [doi] AB - OBJECTIVES: Two identical, phase 3, randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation (IBS-C). METHODS: Adults meeting Rome III criteria for IBS-C were randomized (1:1:1) to placebo or plecanatide (3 or 6 mg) for 12 weeks. The primary efficacy end point was the percentage of overall responders (patients reporting >/=30% reduction from baseline in worst abdominal pain plus an increase of >/=1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for >/=6 of 12 treatment weeks). Safety was assessed by adverse events (AEs). RESULTS: Overall, 2189 individuals were randomized across the two studies and 1879 completed the studies. Demographic and baseline characteristics were similar across treatment groups and between studies. The percentage of overall responders in Study 1 was 30.2% and 29.5% for plecanatide 3 and 6 mg, respectively, vs. 17.8% placebo (P < 0.001 for each dose vs. placebo), and in Study 2 was 21.5% (P = 0.009) and 24.0% (P < 0.001) for plecanatide 3 and 6 mg, respectively, compared to 14.2% for placebo. The percentage of sustained efficacy responders (overall responders plus weekly responders for >/=2 of last 4 weeks of the 12-week treatment period) was significantly greater for both doses of plecanatide vs. placebo across both studies. All secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements compared with placebo. The most common AE was diarrhea (3 mg, 4.3%; 6 mg, 4.0%; placebo, 1.0%). Discontinuation due to diarrhea was infrequent (3 mg, 1.2%; 6 mg, 1.4%; placebo, 0). CONCLUSIONS: Plecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability. FAU - Brenner, Darren M AU - Brenner DM AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Fogel, Ronald AU - Fogel R AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Dorn, Spencer D AU - Dorn SD AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Krause, Richard AU - Krause R AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Eng, Paul AU - Eng P AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Kirshoff, Robert AU - Kirshoff R AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Nguyen, Anhthu AU - Nguyen A AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Crozier, Robert A AU - Crozier RA AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Magnus, Leslie AU - Magnus L AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. FAU - Griffin, Patrick H AU - Griffin PH AD - Division of Gastroenterology and Hepatology, Northwestern University-Feinberg School of Medicine, Chicago, iL, USA. Clinical Research institute of Michigan, Chesterfield, Mi, USA. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. WR-Clinsearch, Chattanooga, TN, USA. Synergy Pharmaceuticals inc, New York, NY, USA. daggerDeceased: Paul Eng. LA - eng PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20180315 PL - United States TA - Am J Gastroenterol JT - The American journal of gastroenterology JID - 0421030 RN - 0 (Gastrointestinal Agents) RN - 0 (Natriuretic Peptides) RN - 0 (Placebos) RN - 7IK8Z952OK (plecanatide) CIN - Ann Intern Med. 2018 Jul 17;169(2):JC11. PMID: 30014100 MH - Abdominal Pain/*drug therapy/etiology MH - Adult MH - Aged MH - Aged, 80 and over MH - Constipation/*drug therapy/etiology MH - Defecation/drug effects MH - Diarrhea/chemically induced/epidemiology MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Female MH - Gastrointestinal Agents/*administration & dosage/adverse effects MH - Humans MH - Irritable Bowel Syndrome/complications/*drug therapy MH - Male MH - Middle Aged MH - Natriuretic Peptides/*administration & dosage/adverse effects MH - Placebos/administration & dosage MH - Treatment Outcome MH - Young Adult EDAT- 2018/03/17 06:00 MHDA- 2019/08/07 06:00 CRDT- 2018/03/17 06:00 PHST- 2017/11/10 00:00 [received] PHST- 2018/01/19 00:00 [accepted] PHST- 2018/03/17 06:00 [pubmed] PHST- 2019/08/07 06:00 [medline] PHST- 2018/03/17 06:00 [entrez] AID - 10.1038/s41395-018-0026-7 [doi] PST - ppublish SO - Am J Gastroenterol. 2018 May;113(5):735-745. doi: 10.1038/s41395-018-0026-7. Epub 2018 Mar 15.