Clinical Trial Result Information

Title of Study:
A placebo- and paroxetine-controlled study of efficacy and safety.

Fast Facts:

Protocol number:	BN16568
Sponsor:	Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	NK1 Inhibitor
Generic name:	NK1 Inhibitor
Phase of development:	II
Therapeutic area, approved indication:	Major Depressive Disorder
Date of report:	1/1/2006

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 50 mg, 200 mg or 400 mg, paroxetine 20 mg or placebo; all drugs were given orally, once daily for 6 weeks.

Study center(s) :
28 sites in Canada, Finland, Sweden and Australia.

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

Methodology:
Patients were randomized at baseline without a lead-in period to one of 5 treatment groups; placebo, paroxetine 20 mg, RO0675930 50 mg, 200 mg or 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):
456

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 50mg, 200 mg or 400mg once daily in the morning, with or immediately after breakfast

Duration of treatment:
6 weeks.

Reference therapy, dose and mode of administration or reference procedure:
Paroxetine (Paxil) 20 mg tablets over-encapsulated by Roche, once daily in the morning, with or immediately after breakfast

Criteria for evaluation (efficacy, safety):
Efficacy: 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 scale, 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 descriptive 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 control. 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 groups receiving active drug (paroxetine or RO0675930) compared with placebo. The most frequently reported adverse events were headache, fatigue, nausea, dry mouth, diarrhea, dizziness and somnolence. For some types of AEs, such as nausea, sexual dysfunction, dry mouth and hyperhidrosis, a higher incidence was observed in the paroxetine group compared with placebo and RO0675930 treated groups. Upon discontinuation of treatment, adverse events were observed with a higher incidence in the paroxetine group than in the RO0675930 200 and 400 mg groups and placebo; however, the incidence among the RO0675930 50 mg group was close to that observed for paroxetine. The main event seen on discontinuation in paroxetine patients was dizziness. All other safety measures (ECGs, vital signs, clinical laboratory assessments) were comparable among the five groups; they did not raise any safety concerns.

Conclusions:
Daily oral doses of 50 mg, 200 mg and 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 documented by the three itemized rating scales. RO0675930 was well tolerated and the overall incidence of adverse events was only slightly higher than that observed in the placebo control and slightly lower than that seen for paroxetine. During the two weeks following drug discontinuation, a greater incidence of adverse events were observed in the paroxetine group than in the placebo and RO0675930 200 and 400 mg groups; however, the RO0675930 50 mg group experienced an incidence of adverse events close to paroxetine during this phase. All other safety measures were comparable among the five groups.