Study No: Title: Rationale: . Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: BRL /621 Title: A randomized, double-blind, placebo-controlled trial of intermittent treatment with /day and 20mg/day versus placebo in Canadian women with Premenstrual Dysphoric Disorder Rationale: This clinical trial evaluated the efficacy of intermittent luteal-phase administration of paroxetine (10mg and 20mg) versus placebo in the treatment of PMDD. Phase: IV Study Period: May to Nov Study Design: This was randomized, double-blind, placebo-controlled, three-arm parallel group study comparing intermittent luteal-phase treatment with /day and 20mg/day with placebo Centres: Four centers in Canada Indication: Premenstrual Dysphoric Disorder (PMDD) Treatment: Paroxetine 10mg, 20mg, or placebo daily for 24 weeks during luteal phases of the menstrual cycle Objectives: To evaluate the efficacy of intermittent treatment with paroxetine (10mg/day and 20mg/day) administered during the luteal phase of the menstrual cycle only, in the PMDD population. Primary Outcome/Efficacy Variable: The primary efficacy variable for this study was the percent change from baseline in the luteal phase visual analogue scale for irritability (VAS-Irritability score) at study endpoint. Secondary Outcome/Efficacy Variable: Secondary efficacy variables were as follows: The percent change from baseline in the luteal phase score at study endpoint, for each of the following VAS items: depressed mood, tension, affective lability, mood swings, bloatedness, breast tenderness, and lack of energy and food cravings. The raw change from baseline in the luteal phase score at study endpoint, for each of the following VAS items: irritability, depressed mood, tension, affective lability, mood swings, bloatedness, breast tenderness, lack of energy and food cravings. The overall proportion of responders at study endpoint as determined by a 50% reduction from baseline, for each of the Irritability, Depressed mood, Tension and Affective Lability VAS items individually. The overall proportion of responders as determined by a score of 1 (very much improved) or 2 (much improved) on the global improvement item of the Clinical Global Impression (observer-rated) at study endpoint. The change from baseline to study endpoint in the PMTS-O (observer-rated) total score. The change from baseline to study endpoint in the CGI (observer-rated) severity of illness score. The change from baseline to study endpoint in the three Sheehan Disability Scale (SDS) scores (i.e. Work, Social Life/Leisure Activities & Family Life/Home Responsibilities) Patient Evaluation of Study Medication at study endpoint. Statistical Methods: Sample size determination was based on detecting a 35% change from baseline to study endpoint for the primary efficacy variable, VAS-Irritability. A sample size of 26 evaluable subjects in each of the three study arms provided 90% power for each comparison between placebo and paroxetine (10mg and 20mg), given a normal significance level of 5%. This accounted for adjusting for multiple (2) comparisons. The estimated standard deviation was SD=38.5. Allowing for a 20% attrition rate, 99 subjects were targeted for recruitment in order to obtain 33 subjects per treatment arm. Each paroxetine group (i.e. 10mg intermittent treatment and 20mg intermittent treatment) was compared with placebo at study endpoint using two-tailed statistical tests. The effect of interactions (e.g., treatment by centre) was assessed at the 10% level of significance. All other hypothesis tests were assessed at the nominal 5% level of significance (actual significance level of 2.5% adjusting for multiple comparisons). No statistical comparisons were made between the two paroxetine treatment arms. Study Population: Female subjects at least 18 years in age were considered eligible if they experienced regular menstrual cycles, used an adequate form of non-hormonal contraception, and had a diagnosis according to DSM-IV criteria A-C for PMDD which was present at least 1 year and symptoms present in at least 10 menstrual cycles. At least one of the four core symptoms had to be prominent (irritability, depressed mood, tension or affective lability), and

2 the severity of these symptoms had to be rated 50% higher during the luteal phase compared with the follicular phase, as confirmed by the two reference cycles. The subject had to have a baseline luteal phase Clinical Global Impression severity of illness score of 3 Patients were excluded if they were taking oral contraception, breast-feeding, pregnant or planning to become pregnant during the study period. Patients were also excluded if they met the DSM-IV criteria for any Axis 1 disorder, deemed a suicidal risk, had a history of SSRI use for premenstrual symptoms, taking ongoing medication which could affect PMDD symptomatology, had clinically significant abnormality screening blood tests, or had a baseline MADRS score of >10 during the follicular phase of the menstrual cycle. Placebo Paroxetine 10mg Paroxetine 20mg Number of Subjects: Planned, N Randomised, N Completed, n (%) 22 (62.8) 25 (78.1) 23 (63.9) Total Number Subjects Withdrawn, N (%) 13 (37.1) 7 (21.9) 13 (36.1) Withdrawn due to Adverse Events n (%) 2 (5.7) 2 (6.3) 4 (11.1) Withdrawn due to Lack of Efficacy n (%) 1 (2.97) 0 0 Withdrawn for other reasons n (%) 10 (28.6) 5 (15.6) 9 (25.0) Demographics placebo N (ITT) Females Mean Age, years (SD) 34.6 (5.6) 38.3 (3.8) 36.5 (6.0) White, n (%) 32 (97.0) 31 (100.0) 34 (97.0) Age at onset of PMDD, years (SD) 25.7 (8.1) 29.5 (7.7) 28.5 (8.1) Primary Efficacy Results: (ITT Population) Irritability placebo (N=33) (n=31) (n=35) Median Baseline (mm) Median % change from baseline Difference between treatments % Confidence Interval (-42.3, 9.9) (-51.3, -6.2) p-value Secondary Outcome Variable(s) placebo (N=33) (n=31) (n=35) Depressed Mood Median Baseline (mm) Median % change from baseline Difference between treatments % Confidence Interval (-47.3, 8.6) (-50.0, -0.9) Tension Median Baseline (mm) Median % change from baseline Difference between treatments % Confidence Interval (-36.2, 17.4) (-46.3, 8.7) Affective Lability Median Baseline (mm) Median % change from baseline Difference between treatments % Confidence Interval (-65.6, 0.4) (-79.2, -10.6) Mood Swings Median Baseline (mm)

3 Median % change from baseline Difference between treatments % Confidence Interval (-56.6, 4.8) (-73.3, -1.9) Bloatedness Median Baseline (mm) Median % change from baseline Difference between treatments % Confidence Interval (-38.3, 13.7) (-51.6, 0.2) Breast Tenderness Median Baseline (mm) Median % change from baseline Difference between treatments % Confidence Interval (-31.1, 27.4) (-54.3, 10.2) Lack of Energy Median Baseline (mm) Median % change from baseline Difference between treatments % Confidence Interval (-19.9, 56.2) (-16.9, 53.9) Food Craving Median Baseline (mm) Median % change from baseline Difference between treatments % Confidence Interval (-43.0, 8.2) (-60.5, -4.3) SDS work life Median % change from baseline Difference between treatments % Confidence Interval (-2.20, 0.93) (-2.50, 0.23) SDS social life Median % change from baseline Difference between treatments % Confidence Interval (-2.49, 0.91) (-3.10, -0.25) SDS family life Median % change from baseline Difference between treatments % Confidence Interval (-2.94, 0.44) (-3.26, -0.22) Proportion(%) with 50% reduction from baseline Irritability Odds ratio (compared with placebo) % Confidence Interval 0.81, , Depressed Mood Odds ratio (compared with placebo) % Confidence Interval 0.72, , 8.69 Tension Odds ratio (compared with placebo) % Confidence Interval 0.50, , Affective Lability Odds ratio (compared with placebo) % Confidence Interval - - Mood Swings N/A N/A N/A Bloatedness N/A N/A N/A Breast Tenderness N/A N/A N/A Lack of Energy N/A N/A N/A

4 Food Craving N/A N/A N/A PMTS-O N/A N/A N/A CGI-I N/A N/A N/A CGI-S N/A N/A N/A PESM N/A N/A N/A Safety Results: (Safety Population): All adverse events occurring after administration of the first dose of study medication. Serious adverse events which occur during the clinical study or within 30 days or five half lives, whichever is the longer of receiving the last dose of study medication, whether or nor related to study drug, must be reported. Most Frequent Adverse Events On-therapy Placebo N=33 N=31 Subjects with any AE(s), n (%) 28 (85.0) 25 (81.0) 29 (83.0) Nausea 9 (27) 8 (26) 19 (54) Dry Mouth 3 (9) 5 (16) 6 (17) Fatigue 1 (3) 5 (16) 9 (26) Decreased Appetite 2 (6) 4 (13) 3 (9) Influenza Symptoms 3 (9) 4 (13) 1 (3) Common Cold 7 (21) 3 (10) 3 (9) Insomnia 1 (3) 3 (10) 1 (3) Weight gain 1 (3) 3 (10) 1 (3) Constipation 2 (6) 3 (10) 0 (0) Dizziness 1 (3) 2 (6) 3 (9) Yawning 0 (0) 2 (6) 3 (9) Diarrhea 2 (6) 1 (3) 3 (9) Decreased Libido 3 (9) 0 (0) 3 (9) Light-headed 0 (0) 0 (0) 3 (9) Heartburn 0 (0) 0 (0) 3 (9) Cold Symptoms 0 (0) 2 (6) 2 (6) Headache 3 (9) 1 (3) 2 (6) Gastric Upset 2 (6) 0 (0) 0 (0) Lower abdomen 2 (6) 0 (0) 0 (0) Sore throat 2 (6) 0 (0) 1 (3) Tiredness 2 (6) 1 (3) 0 (0) Dysmenorrhea 2 (6) 1 (3) 2 (6) Pain in leg(s) 2 (6) 0 (0) 0 (0) Headache 2 (6) 0 (0) 1 (3) Back pain 2 (6) 1 (3) 2 (6) Dullness of emotions 2 (6) 1 (3) 0 (0) Serious Adverse Events On Therapy n (%) [n considered by the investigator to be related to study medication] Placebo N=33 N=31 N=35 N=35 Subjects with any SAE(s), n (%) 0 1 (3) [0] 0 Tonsillitis 0 1 (3) [0] 0 Subjects with any fatal SAE(s), n (%) Conclusion: Subjects in the 20mg paroxetine group had statistically greater percentage of change from baseline in the luteal phase VAS-Irritability score compared to placebo. The 10mg paroxetine arm failed to achieve statistical significance compared to placebo. AEs were reported by 29 (83%) subjects in the 20mg paroxetine group, 25 (81%) subjects in the 10mg group, and 28 (85%) subjects in the placebo group. The most common AEs ( 5% in either paroxetine group and at least twice the rate of placebo) were nausea, fatigue, decreased appetite, insomnia, weight gain, dizziness, yawning, heartburn, light-headedness, and cold symptoms. There was 1 serious adverse event: 1 case of tonsillitis in the group. There were no fatal events.

5 Publications: No publication Date Updated: 01-Dec-2005