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LAS VEGAS -- An investigational opioid antagonist provided effective and durable relief from opioid-induced constipation in patients with chronic pain without interfering with analgesia, a randomized trial showed.

Patients treated with TD-1211 had as much as a threefold improvement in spontaneous bowel movements compared with placebo-treated patients, according to Lynn Webster, MD, of Lifetree Clinical Research in Salt Lake City, and colleagues.

Significantly more patients treated with any of three doses of TD-1211 met prespecified response criteria compared with the placebo group, with differences ranging from 50% to 80%. The improvement persisted for 3 weeks or longer in all three TD-1211 groups, Webster reported here at the American College of Gastroenterology meeting.

"We observed no treatment-related serious adverse events and no evidence of CNS penetration, interference with analgesia, or central withdrawal," said Webster. "A majority of patients reported their constipation was better or much better on treatment, and response to treatment was clinically meaningful."

TD-1211 is a peripherally selective, multivalent inhibitor of the mu-opioid receptor. The agent has been developed as a once-daily oral treatment to normalize bowel-movement frequency and quality. Clinical development has focused on opioid-induced constipation, a common and potentially debilitating side effect of opioid treatment for chronic pain.

Webster reported findings from a phase IIb clinical trial comparing three doses of TD-1211 versus placebo in patients with longstanding opioid-induced constipation.

The trial involved patients requiring regular opioid therapy for relief of noncancer pain. To qualify for the study, patients had to demonstrate five or fewer spontaneous bowel movements over a 2-week baseline evaluation, plus one or more additional symptoms of constipation during at least 25% of bowel movements.

Investigators randomized patients to placebo or to 5, 10, or 15 mg of TD-1211 and followed them for 5 weeks. Patients in all three TD-1211 groups began treatment with 5 mg/d, which was titrated upward after 4 days in the 10- and 15-mg groups.

The primary endpoint was the change from baseline in the weekly average of complete spontaneous bowel movements, assessed during weeks 2 through 5.

The trial results comprised 217 patients, who had a mean age of 49, an average 6-year duration of opioid-induced constipation, and an average of 1.1 to 1.2 spontaneous bowel movements weekly at baseline. Women accounted for 59% of the study population, and back pain was the most common indication for chronic opioid use (43% of patients).

Patients in the placebo group averaged 1.0 complete spontaneous bowel movements during weeks 2 through 5. That compared with an average of 1.6 in the 5-mg TD-1211 group (P=0.0413), 3.0 in the 10-mg group (P=0.0010), and 2.7 in the 15-mg group (P=0.0003).

The total number of spontaneous bowel movements per week (complete or otherwise) averaged 3.1 in the placebo group, 3.9 in the 5-mg TD-1211 group (P=0.0739), 4.5 in the 10-mg group (P=0.0038), and 4.9 in the 15-mg group (P=0.0003).

A prespecified responder analysis showed that significantly more patients in each TD-1211 group met criteria for response -- three or more spontaneous bowel movements per week plus an increase from baseline of at least one spontaneous bowel movement for 3 or more weeks:

• Placebo -- 39%
• 5 mg TD-1211 -- 59% (P=0.0401)
• 10 mg -- 61% (P=0.0222)
• 15 mg -- 70% (P=0.0016)

When the trial ended, a majority of patients in the TD-1211 groups (53% to 66%) described their constipation as better or much better, compared with 22% of the placebo group (P=0.0033 to P≤0.0001).

Webster reported that 38% of TD-1211 patients had at least one spontaneous bowel movement within 4 hours and 52% within 8 hours, compared with 10% and 17% of the placebo groups.

At baseline, 54% to 67% of patients in the four treatment groups had Bristol Stool Scale (BSS) scores consistent with "hard, dry." When the trial ended, 47% of the placebo group had BSS scores indicative of hard, dry stool versus 15% to 30% of patients in the three TD-1211 groups.

Treatment-emergent adverse events occurred in a similar proportion of patients in the four groups. Average daily pain scores did not change significantly in any of the groups, suggesting no decrement in pain relief.

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