Naloxegol oxalate is used for the management of opiate-induced constipation in patients with chronic non-cancer-related pain.
Safety and efficacy of naloxegol were established in 2 identical randomized, double-blind, placebo-controlled, phase 3 studies (KODIAC-04 and KODIAC-05) in 1352 patients (mean age of 52 years) with non-cancer-related pain and active opiate-induced constipation who had received an oral opiate analgesic (at a stable dosage equivalent to 30 mg to 1 g of morphine sulfate daily) for at least 4 weeks prior to study enrollment. Opiate-induced constipation was defined as fewer than 3 spontaneous bowel movements per week during the 4 weeks prior to screening, with at least 25% of spontaneous bowel movements associated with straining, hard or lumpy stools, and/or a sensation of incomplete evacuation or anorectal obstruction. Patients with suspected clinically important disruptions of the blood-brain barrier were not enrolled in the studies. Patients in the studies were randomized to receive naloxegol 12.5 or 25 mg once daily or placebo for 12 weeks. No laxatives or bowel-therapy regimens other than a ''rescue'' laxative regimen (up to three 10- to 15-mg doses of bisacodyl followed, if necessary, by one-time use of an enema for an episode of no bowel movements for 72 hours) were permitted during the studies. Back pain (56-57%) and arthritis (10%) were the most common indications for opiate analgesia in the 2 studies. Patients enrolled in the studies had received their current opiate analgesic for an average of 3.6-3.7 years. The mean baseline opiate dosage was equivalent to 136-140 mg of morphine sulfate daily.
Laxative use on at least one occasion within 2 weeks prior to study enrollment was reported by 71% of patients. Approximately 53-55% of patients enrolled in the studies had an inadequate response to laxatives prior to study enrollment. Inadequate response to laxatives was defined as laxative use on at least 4 of the previous 14 days with at least 1 of the following symptoms of moderate, severe, or very severe intensity: incomplete bowel movements, hard stool, straining, or sensation of needing to pass a bowel movement but being unable to do so. In the subgroup of patients with inadequate response to laxatives, 42-50% of patients reported daily use of laxatives, most frequently stool softeners (18-24%), stimulants (16-18%), and polyethylene glycol (5-6%), prior to enrollment. Combined use of 2 laxative classes was reported by 27-31% of these patients at any time during the 14 days prior to enrollment; the most commonly reported combination was stimulants and stool softeners (8-10%).
The primary end point of the studies was response, defined as 3 or more spontaneous bowel movements per week and a change from baseline of 1 or more spontaneous bowel movements per week for at least 9 of the 12 study weeks and at least 3 of the final 4 study weeks. Response to naloxegol 25 mg daily was superior to the placebo response in both studies; however, response to naloxegol 12.5 mg daily was superior to the placebo response in only one of the studies. Response rates for naloxegol 25 mg, naloxegol 12.5 mg, and placebo were 44, 41, and 29%, respectively, in KODIAC-04 and 40, 35, and 29%, respectively, in KODIAC-05.
Key secondary end points of the studies included time to first postdose spontaneous bowel movement, change from baseline in the mean number of days per week with 1-3 spontaneous bowel movements, and response rate in patients with an inadequate response to laxatives prior to study enrollment. On each of these 3 key secondary end points, naloxegol 25 mg daily was superior to placebo in both studies and naloxegol 12.5 mg daily was superior to placebo in KODIAC-04; statistical significance for secondary end points could not be established for the 12.5-mg dosage in KODIAC-05 since this study failed to established efficacy of the 12.5-mg dosage for the primary efficacy end point. In the subgroup of patients with an inadequate response to laxatives, response rates were 49, 43, and 29% in KODIAC-04 for naloxegol 25 mg, naloxegol 12.5 mg, and placebo, respectively, and 47 and 31% in KODIAC-05 for naloxegol 25 mg and placebo, respectively. In KODIAC-04, median times to first postdose spontaneous bowel movement were 6, 20, and 36 hours with naloxegol 25 mg, naloxegol 12.5 mg, and placebo, respectively. In KODIAC-05, median times to first postdose spontaneous bowel movement were 12 and 37 hours with naloxegol 25 mg and placebo, respectively. A spontaneous bowel movement occurred within 24 hours of the first dose in 61-70 or 58% of patients receiving naloxegol 25 or 12.5 mg, respectively.
Mean daily opiate dosages remained stable during the studies, and mean changes from baseline in pain intensity (as measured on a scale of 0-10) were small and not clinically important.