AD7.2.3.3.6.1                                21-Item HAMD

 

The LOCF analyses showed p values of less than 0.05 favoring drug over placebo at six, seven, and eight weeks for 150 mg/d and favored placebo over drugs at two weeks for 300 mg/d.  The OC analysis showed p values of less than 0.05 favoring drug over placebo at no time.  The only robust differences were seen in the LOCF and OC analyses at two weeks when placebo favored 300 mg/d drug.  Seventy-six of 146 (52%) 150 mg/d patients, 74 of 144 (51%) 300 mg/d patients, and 59 of 148 (40%) placebo patients were considered treatment responders at time of discontinuation.  A Pearson chi-square analysis comparing the proportion of responders across the treatment groups showed a trend toward a difference between the three treatment groups (X²=5.5, df=2, p=0.063).

 

AD7.2.3.3.6.3                                HAMD-Item #1

 

The LOCF analyses showed p values of less than 0.05 favoring drug over placebo at no time for 150 mg/d or 300 mg/d.  The OC analysis showed p values of less than 0.05 favoring drug over placebo at no time for 150 mg/d and at four 4 weeks for 300 mg/d.  Had the sponsor corrected their analysis for multiple-comparisons, no significant differences would have been demonstrated at any time point.

 

AD7.2.3.3.6.4                                CGI-S

 

The LOCF analyses showed p values of 0.05 or less favoring drug over placebo at one week for 150 mg/d and at no time for 300 mg/d.  The OC analysis showed p values of 0.05 or less favoring drug over placebo at one week for 150 mg/d and at four weeks for 300 mg/d.  At two weeks the OC analysis showed placebo favoring 300 mg/d drug.  Had the sponsor corrected their analysis for multiple-comparisons, no significant differences would have been demonstrated at any time.

 

AD7.2.3.3.6.5                                CGI-I

 

The LOCF analyses showed p values of 0.05 or less favoring drug over placebo at seven and eight weeks for 150 mg/d.  At one and two weeks the LOCF analysis showed placebo at no time for 150 mg/d and at four weeks for 300 mg/d.  At one week the OC analysis showed placebo favoring 300 mg/d drug.  Had the sponsor corrected their analysis for multiple-time point comparisons, no significant differences would have been demonstrated at any time point.  Seventy-seven of 146 (53%) 150 mg/d patients, 72 of 144 (50%) 300 mg/d patients, and 61 of 148 (41%) placebo patients were considered treatment responders at time of discontinuation.  A Pearson chi-square analysis comparing the proportion of responders across the treatment groups showed no significant differences between the groups (X²=4.27, df=2, p=0.118).

 

AD7.2.3.3.6.6                                MADRS

 

The LOCF analyses showed p values of less than 0.05 favoring drug over placebo at six, seven, and eight weeks for 150 mg/d and at no time for 300 mg/d.  The OC analysis showed p values of less than 0.05 favoring drug over placebo at no time for 150 mg/d or 300 mg/d.  Seventy-five of 146 (51%) 150 mg/d patients, 76 of 144 ((53%) 300 mg/d patients, and 59 of 148 (40%) placebo patients were considered treatment responders at time of discontinuation.  A Pearson chi-square analysis comparing the proportion of responders across the treatment groups showed a trend toward a difference between the three treatment groups (X²=5.90, df=2,   p=0.052).

 

AD7.2.3.4                                Conclusions

 

The parametric analyses show inconsistent results across outcome measures and no clear evidence of an expected dose-response relationship.  Had there been statistical correction for multiple-time-point or multiple-dose testing, then the data in favor of efficacy of either dose or bupropion sustained-release tested would be even weaker.

 

 

Bupropion SR Clinical Review Addendum for Protocol         8

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