Naldemedine Improves Patient-Reported Outcomes of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain in the COMPOSE Phase 3 Studies

Abstract

Objective: Opioid-induced constipation is among the most common side effects associated with opioid use in patients with chronic non-cancer pain, and it can have a significant negative impact on health-related quality of life (QOL). This analysis evaluated the effect of naldemedine 0.2 mg on patient-reported outcomes in three phase 3 clinical studies.

Methods: COMPOSE-1 and COMPOSE-2 were identical randomized, double-blind, placebo-controlled, parallel-group studies of 12 weeks' duration, allowing data to be integrated (n=1095). COMPOSE-3 was similar in design, but of 52 weeks' duration (n=1241). Patients were adults with chronic non-cancer pain who had been treated with opioid analgesics for ≥3 months and experiencing opioid-induced constipation. Patient-reported outcomes included Patient Assessment of Constipation Symptoms (PAC-SYM; 12 questions assessed on a 5-point Likert scale), PAC-QOL (28 questions assessed on a 5-point Likert scale), and Subject Global Satisfaction (measured on a 7-point Likert scale). The proportion of patients achieving a ≥1.5 improvement in PAC-SYM and PAC-QOL was calculated. The correlation between change in PAC-SYM and PAC-QOL scores and frequency of bowel movements was also explored.

Results: The proportion of PAC-SYM and PAC-QOL responders was significantly higher for naldemedine than for placebo at all assessed time points in COMPOSE-1/COMPOSE-2 (p<0.005 for both) and COMPOSE-3 (p<0.005 and p<0.0001, respectively). There was a statistically significant correlation between improvement in PAC-SYM/PAC-QOL and frequency of bowel movements at all time points (p≤0.0002). The majority of patients treated with naldemedine reported markedly or moderately improved satisfaction with constipation and abdominal symptoms on the Subject Global Satisfaction questionnaire.

Discussion: Naldemedine treatment was associated with a rapid and sustained clinically relevant improvement in patient-reported outcomes, indicating improvement in opioid-induced constipation-related symptoms and QOL.

Clinicaltrialsgov registration: NCT01965158, NCT01993940, NCT01965652.

Keywords: gastrointestinal tract; minimal clinically important difference; mu opioid receptor; patient satisfaction; quality of life.

Conflict of interest statement

Michael Camilleri has provided scientific advice to Shionogi and has received a research grant from AstraZeneca in the field of opioid-induced constipation. Martin Hale was a clinical trial investigator, consultant to Shionogi Inc. and received a stipend for review of the clinical study report. Bart Morlion was a clinical trial site investigator for Shionogi Inc.; a consultant for Astellas Pharma Europe Ltd, Boehringer Ingelheim International, Boston Scientific, Bayer, Lilly, Reckitt Benckiser, Grünenthal, Mundipharma International, TEVA Pharmaceuticals Europe, GSK Consumer Healthcare, and Kyowa Kirin; and a speaker for Mundipharma International, Pfizer Inc, Shionogi Inc., Kyowa Kirin, and Procter and Gamble Company. Jan Tack has provided scientific advice to Allergan, Kyowa Kirin, Shionogi, and Shire, has been a speaker for Allergan and Kyowa Kirin, and has received a research grant from Kyowa Kirin related to opioid-induced constipation. Lynn Webster has provided scientific advice to Arbor Pharmaceuticals and BDSI; has worked on advisory boards for BDSI, Ensysce Biosciences, Neurana, and Salix; has received travel expenses from BDSI, Ensysce Biosciences, Elysium, Neurana, and Salix; has received personal fees for consultation from Bonti, Charleston Labs, Daiichi Sankyo, Depomed, Egalet, Elysium, Indivior, Insys Therapeutics, Inspirion Therapeutics, Kempharm, Mallinckrodt Pharmaceuticals, Merck, Pain Therapeutics, Pernix, Pfizer, Shionogi, Teva, Trevena, Trevi, and Vallon, outside the submitted work. James Wild received a stipend from Shionogi Inc. for review of the clinical study report. The authors report no other conflicts of interest in this work.

© 2021 Camilleri et al.

Figures

Figure 1

Proportion of patients achieving ≥1.5-point decrease in PAC-SYM scores from (A) integrated COMPOSE-1 and COMPOSE-2 data; (B) COMPOSE-3 data. ap<0.0001 for naldemedine vs placebo; bp<0.005 for naldemedine vs placebo.

Figure 2

Proportion of patients achieving ≥1.5-point decrease in PAC-QOL scores from (A) integrated COMPOSE-1 and COMPOSE-2 data; (B) COMPOSE-3 data. ap<0.0001 for naldemedine vs placebo; bp<0.005 for naldemedine vs placebo.

Figure 3

Frequency distribution of Subject Global Satisfaction scores for (A) integrated COMPOSE-1 and COMPOSE-2 data and (B) COMPOSE-3 data.