Targacept, Inc. has reported positive results from a double blind, placebo controlled phase II clinical trial of mecamylamine hydrochloride as an augmentation treatment for major depression. The trial (n=184) evaluated the effects of mecamylamine taken with citalopram hydrobromide, a treatment combination known as Tridmac, in patients who did not respond adequately to citalopram alone. is a commonly prescribed treatment for depression marketed as Celexa in the US.
On one of two primary endpoints in the trial, patients receiving Tridmac showed greater improvement on symptoms of depression, as measured by group mean change from baseline on the Hamilton Depression Rating Scale (HAM-D), than patients receiving placebo with continued citalopram therapy. This result was statistically significant on an intent to treat basis (p=0.041) and showed a strong trend on a per protocol basis (p=0.059). HAM-D is a commonly used 17-item scale that evaluates depressed mood and other symptoms of depression and anxiety.
The result on the trial's other primary endpoint, achievement of remission, favoured the Tridmac group over the placebo group, although this result did not reach statistical significance. In addition, the trial included five other rating scales as secondary measures. The results on all five rating scales favoured the Tridmac group over the placebo group with statistical significance (p<0.05) on a per protocol basis. On an intent to treat basis, the results on three of the five rating scales were statistically significant.
"The Tridmac study indicates the potential for a new treatment option for the millions of patients suffering from major depression for whom current treatment modalities are inadequate. The large-scale StarD trial funded by The National Institute of Mental Health has clearly demonstrated both this significant societal need and the value of combining treatments," commented Ranga Krishnan M.D., chairman of department of psychiatry, Duke University Medical Center.
"We are very pleased with the outcome of our Tridmac trial. These results add to the large body of clinical and scientific evidence supporting the promise of NNRs as therapeutic targets for treating depression and other mood disorders. They also reflect the breadth of our pipeline of NNR Therapeutics, with Tridmac representing a potential late-stage opportunity as a treatment for depression in addition to our clinical candidates in development for cognitive disorders and pain," commented J. Donald deBethizy, Ph.D., president and chief executive officer of Targacept. "Our near-term objectives include defining plans for further development in our depression program following dialogue with the Food and Drug Administration," deBethizy added.
Tridmac was generally well tolerated in the trial. There was one serious adverse event reported in each of the Tridmac and placebo groups. In the Tridmac group, a patient experienced an upper respiratory tract infection and irregular heartbeat and discontinued participation in the trial.
Targacept intends to present the full data from the trial at an appropriate scientific forum.
The Tridmac trial included two phases and was conducted at one site in the US and nine sites in India under an Investigational New Drug Application and the analogous Indian regulatory process. In the first phase, patients with a diagnosis of Major Depressive disorder (n=450) were given open label citalopram hydrobromide over six weeks and evaluated based on their improvement on two scales HAM-D and the clinical global impression subscale for severity of illness (CGI-SI) to determine the extent of any response. Partial and non-responders based on scores on the two scales at the end of the six-week dosing period (HAM-D = 14 and CGI-SI = 4) were enrolled in the second phase (n=184), which was double blind and placebo-controlled. In the second phase, patients received either mecamylamine or placebo, together with continued citalopram therapy, for an additional eight weeks. Patients in the mecamylamine dose group initially received 5mg daily, titrating up to 10mg over the dosing period at the clinician's discretion based on tolerability and therapeutic response. The primary endpoints of the trial were group mean change from baseline and achievement of remission, in each case as measured by HAM-D and compared to continued citalopram therapy plus placebo. The secondary outcome measures for the trial included rating scales to assess symptoms of depression and anxiety, disability, irritability, global improvement or severity of illness. Data from the trial were evaluated on both an intent to treat and per protocol basis. The intent to treat data set (n=160) includes all patients who received at least one dose of blinded study medication and were assessed using HAM-D at least once post baseline. The per protocol data set (n=151) includes patients who were at least 80 per cent compliant with the dosing regimen called for by the protocol and were assessed using HAM-D at the end of the dosing period.
Major depression is a severe psychiatric mood disorder. It is characterized by a wide range of symptoms that cause significant impairment in the ability to work, study, sleep, eat, and enjoy once pleasurable activities. These symptoms include persistent despondence, loss of interest in normal activities, changes in appetite, difficulty in sleeping, agitation, apathy or feelings of guilt.