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A Phase 2b, Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain.

ABSTRACT: This study evaluated the efficacy and safety of oral naldemedine 0.1?mg, 0.2?mg, or 0.4?mg once daily in patients who had opioid-induced constipation (OIC) and maintained a stable laxative regimen.This four-week, phase 2b, randomized, double-blind placebo-controlled trial (clinicaltrials.gov identifier NCT01443403) enrolled patients on long-term opioid therapy for chronic noncancer pain with OIC. The primary efficacy end point was change in weekly spontaneous bowel movement (SBM) frequency from baseline to the last two weeks of treatment. Secondary end points included the proportion of SBM responders (patients with??3 SBMs/week and an increase of??1 SBM/week from baseline over the last 2 weeks of treatment). Safety parameters assessed included adverse events, effects on analgesia, and opioid withdrawal symptoms.Overall, 244 patients were randomized 1:1:1:1 to naldemedine 0.1?mg, 0.2?mg, 0.4?mg, or placebo. Baseline patient characteristics were comparable. Weekly SBM frequency was significantly higher with naldemedine 0.2?mg (3.37, P?=?0.0014) and 0.4?mg (3.64, P?=?0.0003), but not with 0.1?mg (1.98, P?=?0.3504), vs placebo (1.42). The proportion of SBM responders was significantly higher with naldemedine 0.2?mg (71.2%, P?=?0.0005) and 0.4?mg (66.7%, P?=?0.003), but not with 0.1?mg (52.5%, P?=?0.1461), vs placebo (39.3%). Treatment-emergent adverse events were generally mild to moderate in severity; incidences increased with naldemedine dose. No clinically meaningful changes in other safety parameters were observed.Naldemedine 0.2?mg once daily is the optimal dose for future confirmatory trials in OIC.

SUBMITTER: Webster LR

PROVIDER: S-EPMC5914456 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A Phase 2b, Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain.

Webster Lynn R LR Yamada Tadaaki T Arjona Ferreira Juan Camilo JC

Pain medicine (Malden, Mass.) 20171201 12

<h4>Objective</h4>This study evaluated the efficacy and safety of oral naldemedine 0.1 mg, 0.2 mg, or 0.4 mg once daily in patients who had opioid-induced constipation (OIC) and maintained a stable laxative regimen.<h4>Methods</h4>This four-week, phase 2b, randomized, double-blind placebo-controlled trial (clinicaltrials.gov identifier NCT01443403) enrolled patients on long-term opioid therapy for chronic noncancer pain with OIC. The primary efficacy end point was change in weekly spontaneous bo ...[more]

PMID: 28371937

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Project description:ObjectivesThis multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain.MethodsAdults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24 μg or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (≥1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (≥3 SBMs per week) for at least 9 of the 12 treatment weeks.ResultsIn total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7 h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3%; placebo, 2.8%) were related to lubiprostone.ConclusionsLubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain.

Project description:PurposeAn oral formulation of methylnaltrexone has been developed for treating opioid-induced constipation (OIC). This manuscript examines the impact of oral methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, on opioid analgesia.MethodsThis Phase III, randomized, double-blind, placebo-controlled trial, evaluated changes in pain intensity scores (0= no pain to 10= worst possible pain) and opioid use in adults with chronic noncancer pain. Patients taking ≥50 mg/day oral morphine equivalent dose (MED) for ≥14 days before screening with less than three rescue-free bowel movements/week received oral methylnaltrexone 150 mg/day (n=201), 300 mg/day (n=201), 450 mg/day (n=200), or placebo (n=201) once daily for 4 weeks followed by 8 weeks of oral methylnaltrexone as needed.ResultsThe primary condition requiring opioid use was back pain (68.2% of 803 patients). Baseline pain intensity scores were similar among treatment groups (mean range, 6.2-6.4) and remained stable throughout the 4-week double-blind (mean range, 6.1-6.5) and 8-week as needed (mean range, 6.3-6.5) periods. Baseline mean MED was comparable between oral methylnaltrexone 150 mg (200.0 mg/day), methylnaltrexone 450 mg (218.0 mg/day), and placebo (209.7 mg/day), but was slightly higher in the oral methylnaltrexone 300-mg group (252.6 mg/day). Nonsignificant, minimal changes in mean MED were observed after 4 weeks of treatment (214.5-235.6 mg/day) and at the end of the as needed phase (202.3-234.9 mg/day). The percentage of patients who initiated new opioid medications during the 4-week, once-daily dosing period was generally similar among the oral methylnaltrexone 150-mg, 300-mg, and 450-mg groups (44.8%, 43.3%, and 35.0%, respectively), the oral methylnaltrexone combined group (41.0%), and the placebo group (39.8%). The most common newly initiated opioid medications during this once-daily period were oxycodone (oral methylnaltrexone groups combined, 14.6%; placebo, 12.4%) and morphine (oral methylnaltrexone combined, 10.1%; placebo, 7.0%).ConclusionOral methylnaltrexone does not elicit opioid withdrawal or interfere with opioid analgesia.

Dataset Information

A Phase 2b, Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain.

Publications

A Phase 2b, Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain.

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