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

Lynn R Webster,1 Martin E Hale,2 Tadaaki Yamada,3 James E Wild4 1PRA Health Sciences, Salt Lake City, UT, USA; 2Gold Coast Research LLC, Plantation, FL, USA; 3Shionogi, Inc., Florham Park, NJ, USA; 4Upstate Clinical Research Associates, Williamsville, NY, USACorrespondence: Lynn R WebsterPRA Health Sciences, Salt Lake City, UT, USATel +1 801 269-8200Email lrwebstermd@gmail.comPurpose: 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.Clinicaltrials.gov Registration: COMPOSE-1: NCT01965158; COMPOSE-2: NCT01993940; COMPOSE-3: NCT01965652.Keywords: opioid-related disorders, opioid analgesics, naldemedine, renal insufficiency, constipation; chemically induced