A Safety and Efficacy Study of 26489112 in Patients With Treatment-Resistant Major Depressive Disorder

This is a randomized (patients assigned to treatment groups by chance), double-blind
(neither the study physician nor the patient will know the identification of treatment
assigned), active- and placebo-controlled study to assess the efficacy and safety of
26489112 in adult patients with treatment-resistant major depressive disorder (MDD). The
active control used in the study is venlafaxine extended-release [XR], an antidepressant
drug used to treat patients with MDD. A target of 150 patients will be randomly assigned
(like flipping a coin) to 1 of 3 treatment groups with approximately 50 patients planned per
treatment group. This study consists of a screening phase of up to 4 weeks, a 6-week
double-blind treatment phase, and a safety follow-up period that includes a 1-week taper
phase (described below). During the screening phase, patients who meet entry criteria for
the study will be tapered off their current psychotropic medications (medications affecting
the mind or mood or other mental processes) prior to randomization in the double-blind
treatment phase of the study. In the double-blind treatment phase, patients will be randomly
assigned to receive either 2 capsules of 26489112, venlafaxine XR (the active comparator),
or placebo (a sugar pill) once daily for 6 weeks. Upon completion of the double-blind
treatment phase or when patients discontinue study drug at any time point during the
double-blind treatment phase, study medication will be tapered and/or discontinued in a
blinded manner over a 1-week period. A Data Monitoring Committee (DMC) made up of
individuals not involved in the conduct of the study will monitor safety during the study.
The primary outcome measure will be the change from baseline to end point (after 6 weeks of
treatment or at the time of early withdrawal from the study) in the total score from the
Montgomery-Asberg Depression Rating Scale (MADRS, a scale that physicians use to measure the
severity of depression in patients and changes in depression due to antidepressant
treatment). Patient safety will be monitored during the study by evaluating adverse events
(side effects) reported and findings from clinical laboratory test results, 12-lead
electrocardiograms (ECGs), vital sign measurements, body weight measurements and physical,
neurologic, and ophthalmologic examinations performed. Blood samples for assessing pre- and
post dose levels of 26489112 or venlafaxine will be obtained at protocol-specified time
points during the study. In addition, a blood sample will be obtained from all enrolled
patients at Visit 2 for pharmacogenomics research (research to help identify genetic markers
of response, to explain variability in the data, or to address emerging clinical issues).
Patients will receive double-blind treatment with 2 capsules of 26489112 (500 mg/day during
the first 3 weeks that may be increased up to 1000 mg/day by week 4), venlafaxine XR (75
mg/day during week 1 increased to 150 mg/day during weeks 2-6]), or placebo orally (by
mouth) with food once daily for 6 weeks. After 6 weeks, venlafaxine XR 150 mg/day will be
tapered to one 75 mg/day capsule for 1 week and patients receiving 26489112 or placebo will
be switched to 1 capsule of placebo for 1 week.