Dexmecamylamine Hydrochloride

We evaluated the efficacy and tolerability of the nicotinic channel modulator dexmecamylamine for overactive bladder.

This was a randomized, double-blind, placebo controlled trial in 768 randomized subjects. Those with at least a 6-month history of overactive bladder were randomized to 0.5, 1 or 2 mg dexmecamylamine or placebo in a ratio of 1:1:1:2, respectively. Subjects completed a 3-day diary before each visit associated with the 12-week treatment period. They were required to have 8 or more micturitions per day and 3 or more urinary urge incontinent episodes per day if overactive bladder wet at the end of a placebo run-in period. Co-primary end points for the study included a change from baseline 1) in micturition frequency per 24 hours at week 12 and 2) in urge urinary incontinence episodes per 24 hours at week 12. Secondary end points were voided volume, nocturia episodes, OABq (Overactive Bladder Questionnaire) and urgency questionnaire.

Dexmecamylamine (2 mg) produced a statistically significant decrease in micturition frequency (p = 0.03) but did not produce a statistically significant decrease in urge incontinence (wet) episodes (p = 0.38). Secondary end points, including volume voided in the 1 mg group only, CGI-I (Clinical Global Impression of Improvement), visual analog scale urgency impact, intensity and severity, were statistically significant at week 12 for the 2 mg dose. Dexmecamylamine was well tolerated in this subject population with a low incidence of discontinuations due to adverse effects. Constipation, dry mouth and urinary tract infection showed a dose dependent increase in frequency.

Dexmecamylamine does not appear to offer an enhanced therapeutic profile for the treatment of overactive bladder relative to current therapies.

To evaluate the neuronal nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy in patients with major depressive disorder (MDD) and inadequate response to prior antidepressant treatment.

Study 004 (D4130C00004) and Study 005 (D4130C00005) comprised an 8-week open-label antidepressant (SSRI/SNRI) treatment period followed by an 8-week randomised, active treatment with twice-daily TC-5214 (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo, adjunct to ongoing SSRI/SNRI. Primary efficacy endpoint was change in MADRS total score from randomisation (Week 8) to treatment end (Week 16). Secondary endpoints included MADRS response and remission, and changes in SDS and HAM-D-17-item scores. Safety and tolerability were monitored throughout.

Studies 004 and 005 randomised 640 and 696 patients, respectively, to TC-5214 or placebo. No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end. The most commonly reported adverse events (> 10%) with TC-5214 were constipation, dizziness and dry mouth.

TC-5214 adjunct to antidepressant was generally well tolerated. However, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy.