Opioid-induced constipation (OIC) is a prevalent and debilitating side effect experienced by patients undergoing long-term opioid therapy. The COMPOSE-3 trial 1 was designed to assess the long-term safety and efficacy of naldemedine, a peripherally acting μ-opioid receptor antagonist, over a 52-week period, providing critical insights into its use in clinical practice.

Study design

The primary goal of COMPOSE-3 was to evaluate the long-term safety and efficacy of naldemedine in adults with chronic non-cancer pain who have been receiving a stable opioid dose for over a month and who have opioid-induced constipation. This trial aimed to establish whether naldemedine could be safely administered over an extended period without diminishing its efficacy or altering the primary analgesic treatment.

COMPOSE-3 was a multicenter, phase 3, double-blind, randomized, parallel-group trial involving 1246 participants. These participants were randomly assigned in a 1:1 ratio to receive either 0.2 mg of naldemedine or a matching placebo orally once per day for 52 weeks following a screening period of 14-28 days. Randomization was stratified based on the total mean daily opioid dose during the 14-day qualifying period, categorized into 30–100 mg and greater than 100 mg oral morphine sulfate equivalents.

Participants ranged in age from 18 to 80 years, all suffering from chronic non-cancer pain and stable opioid use, with a stratification based on total mean daily dose of opioid during the 14-consecutive-day qualifying period. This diverse population provided a broad basis for evaluating the effects of naldemedine across various demographics. The inclusion criteria ensured that all participants had experienced fewer than four spontaneous bowel movements per week during the qualification period, indicating moderate to severe OIC.

Results

The primary efficacy endpoint was the frequency of occurrence of adverse reactions, including the incidence of treatment-emergent adverse events (TEAEs), serious adverse events, and adverse events leading to treatment discontinuation. The trial's results were pivotal in understanding the long-term tolerability of naldemedine.

• Safety and tolerability: Naldemedine demonstrated a safety profile consistent with previous shorter-term studies. TEAEs were reported in 68.4% of the naldemedine group compared to 72.1% in the placebo group (difference of proportion: 23.6%; 95% confidence interval: 28.7 to 1.5;), showing no significant increase in adverse effects due to long-term treatment.
• Treatment discontinuations: TEAEs leading to discontinuation were slightly higher in the naldemedine group (6.3%) compared to the placebo group (5.8%), indicating that naldemedine was generally well tolerated.
• Gastrointestinal disorders: As expected with a drug targeting opioid receptors in the gut, gastrointestinal disorders were the most commonly reported adverse events. However, these did not lead to a significant increase in discontinuation rates, suggesting that they were manageable within the clinical context.

Adapted by Viatris from Webster et al, 2018

Clinical implications

The findings from COMPOSE-3 provide compelling evidence supporting the long-term use of naldemedine for managing OIC in patients with chronic non-cancer pain. Importantly, the trial confirmed that naldemedine does not interfere with opioid-mediated analgesia nor does it precipitate opioid withdrawal, addressing two critical concerns in OIC management.

The ability to use naldemedine over an extended period without significant safety concerns or loss of efficacy offers a viable long-term solution for patients suffering from OIC.

This study supports the addition of naldemedine to a patient’s laxative regimen should patients still experience OIC.

Conclusion

The COMPOSE 3 trial was a double-blind, randomized, parallel-group trial offering robust data on the long-term use of naldemedine for the management of OIC. By demonstrating sustained safety and efficacy over a one-year period, naldemedine provides a promising option for enhancing the quality of life in patients with chronic non-cancer pain undergoing long-term opioid therapy. For clinicians, incorporating naldemedine into treatment protocols can significantly mitigate one of the most challenging side effects of opioid therapy, thereby improving overall treatment outcomes.

NO-RIZM-2024-00002 | 11-2024