Clinical Trial Result Information

Title of Study:
A Placebo- and Paroxetine-Controlled Study of Efficacy and Safety.

Fast Facts:

Protocol number:	BN16430
Sponsor:	Roche Laboratories Inc
Company division:	Pharmaceutical
Product name:	NK1 Inhibitor
Generic name:	NK1 Inhibitor
Phase of development:	II
Therapeutic area, approved indication:	Major Depressive Disorder (MDD)
Date of report:	12/1/2005

Clinical study summary:
This double-blind, randomized study compared the effect of RO0675930, paroxetine and placebo on the symptoms of major depressive disorder. Patients were randomized to receive either RO0675930 200 mg or 400 mg, paroxetine 20 mg or placebo; all drugs were given orally, once daily for 6 weeks.

Study center(s) :
20 centers in the USA

Objectives:
The primary objective was to evaluate the efficacy of two doses of RO0675930 compared with placebo in the treatment of patients with symptoms of major depressive disorder (MDD).

Methodology:
Patients were randomized at baseline without a lead-in period to one of 4 treatment groups; placebo, paroxetine 20 mg, RO0675930 200 mg or RO0675930 400 mg. Efficacy was assessed at weeks 1, 2, 3, 4 and at the end of treatment. Adverse events were followed up until they resolved, returned to baseline status or stabilized; they were also evaluated 7 and 14 days after treatment had discontinued. Serious adverse events were followed for 28 days after cessation of treatment. Patient self-evaluation of sexual function was performed at week 4 and at the end of treatment. Heart rate and blood pressure were recorded weekly. Clinical laboratory assessments and ECGs were assessed at week 3 and at the end of treatment.

Number of patients (planned/analyzed):
445

Diagnosis and main criteria for inclusion:
Patients 18-65 years-of-age with a DSM-IV primary diagnosis of major depressive disorder and a MADRS score of ≥ 25.

Test product, dose and mode of administration or test procedure:
RO0675930 200 mg capsules

Duration of treatment:
6 weeks.

Reference therapy, dose and mode of administration or reference procedure:
Paroxetine (Paxil) 20 mg tablets over-encapsulated by Roche.

Criteria for evaluation (efficacy, safety):
Primary: Change from baseline in the HAMD 17-item scale total score at the end of treatment (week 6 or the time of withdrawal from treatment).
Secondary: Change from baseline in the HAMD 17-item scale total score at weeks 1, 2, 3 and 4. Change from baseline in the Bech Melancholia scale total score at the end of treatment and at weeks 1, 2, 3 and 4. Change from baseline in the MADRS total score at the end of treatment.

Safety: Adverse events, sexual function, clinical laboratory tests, vital signs, body weights and physical examination, ECGs.

Statistical methods:
Efficacy variables were analyzed for the ITT population using OC and LOCF values. Inferential statistics were applied to compare each dose of RO0675930 and placebo. Comparisons between RO0675930 and placebo or paroxetine were performed based on description statistics. Mean change from baseline variables were analyzed using analysis of covariance. Comparisons significant at the 0.05 level after adjustment for multiple comparisons were noted. The proportion of patients achieving a dichotomous response was analyzed using Cochran-Mantel-Haenszel test. All safety data was summarized using descriptive statistics.

Summary (efficacy, safety, other results):
Efficacy: Analysis of the primary endpoint (change from baseline in the HAMD 17-item scale) showed no statistical differences in patients treated with RO0675930 or paroxetine when compared with the placebo controls. Analysis of the secondary endpoints (Bech Melancholia scale and MADRS) also showed no differentiation between groups receiving active treatment or placebo.

Safety: During the treatment period, a slightly higher incidence of AEs was observed in the RO0675930 groups compared with placebo. The highest incidence of AEs was seen with paroxetine treatment. Somnolence, fatigue and flatulence were all observed at a higher rate in the active treatment groups. A range of gastrointestinal and psychiatric disorders were observed with paroxetine, in particular, nausea was observed at an incidence of 21%, compared with 11% in both of the RO0675930-treated groups and 7% in the placebo controls. Adverse events related to sexual dysfunction were observed at a higher incidence with paroxetine than in groups receiving RO0675930 or placebo. Upon discontinuation of treatment, the incidence of AEs remained higher among paroxetine patients than among placebo, with the lowest incidence seen in the two groups previously treated with RO0675930. Signs associated with paroxetine withdrawal included dizziness, nausea and non-specific psychiatric disorders.

All other safety measures (ECGs, vital signs, clinical laboratory assessments) were comparable among the four groups.

Conclusions:
Daily oral doses of 200 mg or 400 mg RO0675930 showed no improvement in depression over placebo in patients with MDD. Clinical improvement in patients taking the active control (paroxetine) could also not be differentiated from the placebo group; hence, the overall results of this study are judged to be inconclusive. Underlying the failure of this trial was a high placebo response observed in the three itemized rating scales. RO0675930 was well tolerated and the overall incidence of adverse events was similar among RO0675930-treated and placebo patients. Discontinuation of treatment with RO0675930 was not associated with an increase in adverse events compared with placebo, whereas discontinuation of treatment with paroxetine resulted in a higher incidence of symptoms than placebo, particularly dizziness and nausea. All other safety measures were comparable among the four groups