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

Hale, M.; Wild, James; Reddy, Jyotsna; Yamada, Tadaaki; Ferreira, Juan Camilo Arjona

doi:10.1016/s2468-1253(17)30105-x

Cited by 102 publications

(198 citation statements)

References 15 publications

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“…A new oral PAMORA, naldemedine, which has also demonstrated good efficacy and tolerability in a large clinical trial program [33][34][35], has recently been approved by the FDA and is currently undergoing licensing application at the EMA.…”

Section: Secretagoguesmentioning

confidence: 99%

Medical Therapy of Constipation: Current Standards and Beyond

Andresen

Layer²

2018

Visc Med

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Chronic constipation is a very common medical problem with relevant impact on the patients' quality of life. Modern definitions recognize constipation as a polysymptomatic disorder, including various aspects of disturbed defecation. Current guidelines recommend a stepwise approach in the management of chronic constipation. Isolated or concomitant evacuation disorders should be identified and may need differential/additional treatment. Baseline measures include lifestyle components and bulking agents. The next step recommends treatment with conventional laxatives. In refractory patients, modern medical therapies, such as the prokinetic prucalopride or the secretagogues linalotide or lubiprostone, may be used effectively. For patients with opioid-induced constipation, the modern concept of peripherally acting µ-opioid antagonists has shown to successfully improve this increasing medical problem and even to potentially increase survival time in terminally ill patients on opioid therapy. Prolonged-released oral naloxone (in fixed combination with oxycodone), oral naloxegol or naldemedine, and subcutaneous methylnaltrexone have all demonstrated good efficacy and tolerability in the treatment of opioid-induced constipation. To adequately apply stepwise treatment algorithms, a simple tool to identify treatment failure may improve patient care.

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Section: Secretagoguesmentioning

confidence: 99%

Medical Therapy of Constipation: Current Standards and Beyond

Andresen

Layer²

2018

Visc Med

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“…A total of 7715 patients with 4100 AEs were reported in 26 RCTs . Overall, there were significantly increased AEs in patients given PAMORA (RR, 1.10; 95% CI, 1.06–1.15; P < 0.00001; Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Crossover and cluster RCTs were excluded to avoid heterogeneity. We regarded SBM (defined as a bowel movement without a rescue laxative taken within the past 24 h) as the same disease concept as a rescue‐free bowel movement (defined as a bowel movement where no laxatives were used during the prior 24 h).…”

Section: Methodsmentioning

confidence: 99%

Peripherally acting μ‐opioid antagonist for the treatment of opioid‐induced constipation: Systematic review and meta‐analysis

Nishie

Yamamoto

Yamaga³

et al. 2019

J of Gastro and Hepatol

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Background and Aim Opioid‐induced constipation (OIC) is a frequent adverse event (AE) that impairs patients' quality of life (QOL). Peripherally acting μ‐opioid receptor antagonists (PAMORAs) have been recognized as a treatment option for OIC, but the effect consistent across the studies has not been evaluated. Methods We conducted a quantitative meta‐analysis to explore the efficacy of PAMORA for OIC (registered with PROSPERO: CRD42018085298). We systematically searched randomized controlled trials (RCTs) in Medline, Embase, and Central databases. Change from baseline in spontaneous bowel movements, pooled proportion of responders, QOL, and AEs were calculated and compared with results in placebo cases. Results We included 31 RCTs with 7849 patients. A meta‐analysis revealed that patients under PAMORA therapy had considerably improved spontaneous bowel movement from baseline compared with those given placebo (20 RCTs; mean difference, 1.43; 95% confidence interval [CI], 1.18–1.68; n = 5622) and more responded (21 RCTs; risk ratio [RR], 1.81; 95% CI, 1.55–2.12; n = 4821). Moreover, QOL of patients receiving PAMORA was significantly better (8 RCTs; mean difference, −0.22; 95% CI, −0.28 to −0.17; n = 2884). AEs were increased significantly in the PAMORA group (26 RCTs; RR, 1.10; 95% CI, 1.06–1.15; n = 7715), especially in gastrointestinal disorders, whereas serious AEs were not significant (17 RCTs; RR, 1.04; 95% CI, 0.85–1.28; n = 5890). Conclusion Peripherally acting μ‐opioid receptor antagonist has been shown to be effective and durable for patients with OIC and is the only drug with confirmed evidence in meta‐analysis. The possibility of publication bias was the limitation of this study.

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“…[14][15][16] Additionally, 0.2 mg naldemedine is the approved therapeutic dose in the United States. The renal and hepatic impairment studies were designed in accordance with US FDA Guidance for Industry (Pharmacokinetics in Patients With Impaired Renal Function and Pharmacokinetics in Patients With Impaired Hepatic Function, respectively) as described below.…”

Section: Methodsmentioning

confidence: 99%

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

Fukumura

Yamada

Yokota

et al. 2019

Clinical Pharm in Drug Dev

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Naldemedine is a peripherally acting μ-opioid-receptor antagonist for the treatment of opioid-induced constipation. Two phase 1 single-dose studies investigated the pharmacokinetics and safety of a 0.2-mg oral dose of naldemedine in subjects with renal impairment (mild, n = 9; moderate, n = 9; severe, n = 6; and end-stage renal disease, n = 8) or hepatic impairment (mild or moderate, n = 8 each) and demographically matched healthy subjects with normal renal and hepatic function (n = 8, both studies). Pharmacokinetic assessments indicate that dose adjustments for naldemedine are not necessary for subjects with any degree of renal impairment or for subjects with mild or moderate hepatic impairment. In subjects with renal impairment compared with healthy subjects with normal renal function, the geometric mean ratios of naldemedine area under the concentration-time curve (AUC 0-inf ) ranged from 82.8% (90%CI 69.5% to 98.6%) to 137.8% (90%CI 114.0% to 166.5%). Renal clearance decreased with reduced renal function (normal function 1.3 L/h; mild impairment 1.1 L/h; moderate impairment 1.0 L/h; severe impairment 0.5 L/h), and only 2.7% of naldemedine was removed by hemodialysis. In subjects with hepatic impairment compared with healthy subjects with normal hepatic function, the geometric mean ratio of AUC 0-inf ranged from 82.8% (90%CI 65.7% to 104.5%) to 105.2% (90%CI 83.4% to 132.6%). Naldemedine was well tolerated in both healthy subjects and subjects with renal or hepatic impairment, and reported adverse events were generally consistent with the known safety profile.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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

Cited by 102 publications

References 15 publications

Medical Therapy of Constipation: Current Standards and Beyond

Medical Therapy of Constipation: Current Standards and Beyond

Peripherally acting μ‐opioid antagonist for the treatment of opioid‐induced constipation: Systematic review and meta‐analysis

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

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