The primary objective of this Phase 2, single-blind study was to assess safety and tolerability of various doses, dosing strategies and dose escalations of TD-1211, an orally administered and peripherally selective mu opioid antagonist. Secondary objectives assessed efficacy of TD-1211. Ninety-five chronic non-cancer pain OIC patients were enrolled into six cohorts. The first four cohorts received 5mg once daily for either four or two days, respectively, followed by an increase in daily dose to either 10mg or 15mg for two weeks. Cohort five received 2mg once daily and cohort six received 2.5mg q6h, respectively, for two weeks without dose escalations. TD-1211 was generally well tolerated. For the combined data, irrespective of dose, the most common TEAEs (occurring ≥ 5%) were abdominal pain (14.7%), nausea (9.5%), flatulence (8.4%), diarrhea (6.3%), headache (6.3%), and abdominal distension (5.3%). During the 4-day and 2-day initiation periods, respectively, 9.4% and 18.8% of subjects reported GI-related AEs. All AEs were transient and resolved without sequelae. Across cohorts, the mean baseline spontaneous bowel movements (SBMs) and complete SBMs (CSBMs) ranged from 0.9 to 1.7 and 0.1 to 0.6, respectively. During Week 2, the 10mg and 15mg dose cohorts showed a mean change from baseline in SBM and CSBM frequency ranging from 3.3 to 5.4 SBMs/week and 2.8 to 4.4 CSBMs/week. The 2mg TD-1211 dose demonstrated minimal activity, with a mean increase from baseline during Week 2 of 1.8 SBMs and 0.7 CSBMs. The 2.5mg q6h regimen was clinically active, with a mean increase from baseline at Week 2 of 4.3 SBMs and 4.5 CSBMs. There were no reports of central opioid withdrawal during the study and no clinically relevant changes in ECGs, laboratory exams, or vital signs. These results support further development of a 5mg treatment initiation dose followed by maintenance therapy at up to 15mg QD.
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© 2013 Published by Elsevier Inc.
