·         Females who were pregnant, breast-feeding, or unwilling to employ appropriate contraceptive methods during the study.

·         History within one year of alcohol or substance abuse

·         Receipt of fluoxetine or an investigational drug within four weeks of the treatment phase, receipt of an MAOI drug or protriptyline within two weeks of the treatment phase, or receipt of any other psychoactive drug within one week of the treatment phase.

·         History of treatment with bupropion

·         Incapable of spontaneous conversation or activity

·         Active suicidality

 

7.2.2.2.3             Planned Study Conduct/Dosing Plan

 

Following one week of single-blind b.i.d. placebo washout, this trial was an eight week, parallel, double blind study; patients  were randomly assigned to receive placebo or one of four dose levels of bupropion sustained-release.  Patients were randomized in blocks of five, with equal chances of receiving any of the five treatments.  Medication consisted of identically-appearing tablets containing either placebo, 50 mg, or 150 mg bupropion sustained-release.  Each patient received each week a carton with ten blister cards containing six tablets.  They were instructed to take three tablets each morning and three each evening and to return the blister cards with all unused tablets.  On this schedule, patients either received placebo b.i.d., 50 mg bupropion sustained-release b.i.d., 100 mg bupropion sustained-release b.i.d., 150 mg bupropion sustained-release b.i.d., or 200 mg bupropion sustained-release b.i.d.  Patients in the latter two groups were titrated to their study doses by the fourth and eighth days, respectively.  Patients who experienced intolerable adverse effects from their assigned dose were to be discontinued from the trial.  Except for chloral hydrate that was permitted as a supplement in the first two weeks of the study, concomitant medications intended for psychoactive purposes were not permissible during the study.  Compliance was assessed by weekly review of the blister cards.

 

7.2.2.2.4             Efficacy Assessments

 

The 17-item HAMD, 28-item HAMD, the CGI-S, and the CGI-I constituted the efficacy measures and were performed at each weekly visit.  A screening occurred at the onset of placebo washout.  A baseline (Day 0) visit occurred one week later at which time participating patients were randomly assigned to receive treatment.  The remaining visits occurred at one week intervals over the following eight weeks.

 

7.2.2.2.5             Safety Assessments

 

Safety assessments included physical examinations, clinical laboratory tests, electrocardiograms at the discretion of the individual investigators, and an adverse experience probe by investigators.

 

7.2.2.2.6             Analysis/Plan

 

The sponsor designated the following a priori efficacy parameters: 17-item HAMD score, 28-item HAMD score, HAMD depressed mood item #1, CGI-S rating, and CGI-I rating.  The analyses were performed using observed scores and last observed carried forward scores.  Parametric analysis and non-parametric “responder” analysis was specified for the data.

 

7.2.2.3                  Study Conduct/Outcome

 

7.2.2.3.1             Patient Disposition

 

A total of 602 patients constituted the baseline sample and the intent-to-treat sample (those patients receiving at least one dose of their assigned medication and having at least one efficacy assessment after baseline) constituted

 

 

Bupropion Sustained-Release Clinical Review               18

 

 

 

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