A Renal Impairment Subgroup Analysis of the Safety and Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain Receiving Opioid Therapy

Abstract

Purpose: Naldemedine, an oral, peripherally acting μ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), is renally excreted. This subgroup analysis integrated data from 3 Phase 3 trials (COMPOSE-1, COMPOSE-2, COMPOSE-3) to evaluate the safety and efficacy of naldemedine in patients with renal impairment (RI).

Patients and methods: Patients age 18-80 years with chronic non-cancer pain (CNCP) and OIC received oral naldemedine 0.2 mg or placebo once daily. RI subgroups consisted of patients with normal function (baseline glomerular filtration rate ≥90 mL/min/1.73 m2), mild (≥60 to <90 mL/min/1.73 m2), and moderate (≥30 to <60 mL/min/1.73 m2) RI. Safety assessments based on ≤12 weeks of treatment from all 3 studies included incidence of treatment-emergent adverse events (TEAEs). Efficacy was based on the proportion of responders in COMPOSE-1 and COMPOSE-2 only, defined as ≥3 spontaneous bowel movements (SBMs)/week and a ≥1-SBM/week increase from baseline for ≥9 of 12 weeks and ≥3 of the last 4 weeks.

Results: In total, 2328 patients were included in this analysis. The incidence of TEAEs was similar in the naldemedine and placebo groups (overall, 47.1% vs 45.6%; normal, 44.6% vs 43.6%; mild RI, 49.0% vs 44.7%; moderate RI, 46.6% vs 55.9%). GI-related TEAEs occurred more frequently in the naldemedine group versus placebo (overall, 21.8% vs 13.8%; normal, 21.6% vs 12.5%; mild RI, 22.6% vs 14.7%; moderate RI, 18.0% vs 14.2%). A significantly greater proportion of patients in the naldemedine 0.2 mg group were responders versus the placebo group (overall, 50.1% vs 34.1%, P<0.0001; normal, 52.0% vs 39.3%; mild RI, 48.3% vs 30.3%; moderate RI, 52.5% vs 31.7%).

Conclusion: This integrated analysis confirmed that OIC treatment with naldemedine 0.2 mg was generally well tolerated and effective in patients with CNCP and mild or moderate RI. Safety and efficacy results were consistent with the overall population.

Clinicaltrialsgov registration: COMPOSE-1: NCT01965158; COMPOSE-2: NCT01993940; COMPOSE-3: NCT01965652.

Keywords: constipation; chemically induced; naldemedine; opioid analgesics; opioid-related disorders; renal insufficiency.

Conflict of interest statement

LR Webster affiliated with PRA Health Sciences reports consultation and/or advisory board as well as travel expenses from BDSI, Ensysce, Inspirion, Alcobra, Bonti, Charleston Laboratories, Daiichi Sankyo, Depomed, Egalet, Elysium, Indivior, Insys, Kempharm, Mallinckrodt, Neurana, Pain Therapeutics, Pernix, Pfizer, Salix, Shionogi, Teva, and Trevena. He is also a consultant for Merck, Trevi, Vallon, and Vector. ME Hale affiliated with Gold Coast Research LLC was a consultant to and a principal investigator for Shionogi Inc. and received a stipend for review of the clinical study report. T Yamada is an employee of Shionogi Inc. who may or may not own stock options. JE Wild affiliated with Upstate Clinical Research Associates, received a stipend from Shionogi Inc. for review of the clinical study report. The authors report no other conflicts of interest in this work.

© 2020 Webster et al.

Figures

Figure 1

Study designs. Abbreviation: R, randomization.

Figure 2

Incidence of abdominal pain (A), diarrhea (B), nausea (C), and vomiting (D) by eGFR at baseline (COMPOSE-1/COMPOSE-2/COMPOSE-3 safety population). Abbreviations: eGFR, estimated glomerular filtration rate; NAL, naldemedine, RI, renal impairment.

Figure 3

Proportion of responders by eGFR at baseline (COMPOSE-1/COMPOSE-2 intent-to-treat population). *P value for the overall population calculated by Cochran-Mantel-Haenszel test; no statistical analyses were performed for subgroup comparisons. Abbreviations: eGFR, estimated glomerular filtration rate; NAL, naldemedine, RI, renal impairment.

Figure 4

Difference of proportion of responders by eGFR at baseline (COMPOSE-1/COMPOSE-2 intent-to-treat population). Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; NAL, naldemedine; PBO, placebo; RI, renal impairment.