SAN DIEGO – The investigational oral drug, naldemedine, was found effective in treating opioid-induced constipation (OIC) in patients with noncancer chronic pain, according to results of two identically designed phase III trials (COMPOSE I and II). Naldemedine achieved durable efficacy and consistent safety, with a low incidence of gastrointestinal side effects, and importantly did not compromise or interfere with the analgesic effect of opioids.
In both studies, the drug met the primary endpoint and significantly improved all secondary endpoints. Improved frequency of spontaneous bowel movements (SBMs) was observed for at least 9 weeks out of the 12 weeks (the primary endpoint) in 47.6% of naldemedine-treated patients, compared with 34.6% of placebo patients in COMPOSE I. In COMPOSE II, 52.5% versus 33.6%, respectively, had improved frequency of SMB for at least 9 out of 12 weeks.
“Improvement with naldemedine was seen early and was durable, with no evidence of opiate withdrawal. This is good news for patients with OIC, given the significant impact this condition can have and the difficulty they can have in finding a safe and effective treatment,” said presenting author Dr. Martin Hale, an orthopedic surgeon and pain management specialist. He presented results of both trials at the annual Digestive Disease Week.
Naldemedine is a naltrexone-based, once-daily, oral, peripherally acting mu-opioid–receptor antagonist being developed by Shionogi. The fact that it is not centrally acting suggests that its side effect profile would be acceptable. Opiates work on mu receptors, reducing GI motility and fluid secretion, resulting in OIC.
“Laxatives have limited efficacy for OIC and do not address the underlying problem,” Dr. Hale of Gold Coast Research, Plantation, Fla., said. Thus, better treatments are needed.
Study details
Both studies were 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. COMPOSE I included 547 patients, and COMPOSE II, 553 patients. To be included, patients had to be on opioid therapy for at least 3 months and on a stable dose of opioids for at least 4 weeks. They had to have noncancer pain accompanied by OIC.
Patients were randomized in a 1:1 ratio to oral naldemedine 0.2 mg with or without food versus placebo. “Being able to take the drug with food makes it more acceptable to patients,” Dr. Hale noted.
Responses were observed early in the course of the 12-week trial and remained durable. Naldemedine treatment significantly improved the frequency of SBMs per week, compared with placebo (P less than .0001 in both studies), and SBMs without straining per week from baseline to the last 2 weeks of the study (P = .0003 in COMPOSE I and P = .0011 in COMPOSE II).
Adverse events were similar across all four arms of both studies. Treatment-related adverse events were reported in about 48% of patients across both trials. Major adverse cardiovascular events (MACE) of concern occurred in 1 patient in treated with naldemedine and 1 in the placebo group. “MACE is not relevant with this drug,” Dr Hale told listeners.
Abdominal pain and diarrhea were the only treatment-related adverse events reported in greater than 5% of patients treated with naldemedine versus placebo. Abdominal pain was reported in 6.3% of the treated groups in COMPOSE I and 5.2% of the treated group in COMPOSE II versus 1.8% and 2.9%, respectively, in the placebo groups. Diarrhea was reported in 6.6% of the naldemedine patients in COMPOSE I and in 8.9% in COMPOSE II, compared with 2.9% and 1.8%, respectively, on placebo. Nausea was reported in 4.8% of naldemedine-treated patients in both trials, compared with 2.6% and 3.3%, respectively, in the placebo arms.
“Most treatment-emergent adverse events were mild or moderate. Back pain and flatulence were rare,” he commented.
Two scales were used to measure opiate withdrawal: Clinical Opiate Withdrawal Scale (COWS) and Subjective Opiate Withdrawal Score (SOWS). The graph curves were superimposable for naldemedine and placebo at all time points, showing that naldemedine did not interfere with the analgesic effect of opioids.
The study was funded by Shionogi, Florham Park, N.J.