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

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1 Studies 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.: 29060/688 Title: A Double-Blind, -Controlled, 3-Arm, Fixed-Dose Study of CR Continuous Treatment (12.5 mg/day and 25 mg/day) for Premenstrual Dysphoric Disorder Rationale: This study was designed to investigate the efficacy and safety of paroxetine controlled release (CR) in subjects with premenstrual dysphoric disorder (PMDD). Phase: III Study Period: 29 November November 2001 Study Design: This was a double-blind, placebo-controlled, 3-arm, fixed-dose study. Centers: This was a multicenter study carried out in 46 centers in Europe and South Africa, distributed as follows: 9 centers in the United Kingdom (UK); 8 each in the Netherlands and in Sweden; 6 in Norway; 4 each in Germany, Ireland, and South Africa; and 3 in Finland. Indication: Premenstrual dysphoric disorder Treatment: Subjects were randomized to one of three treatment arms (25 mg paroxetine CR, 12.5 mg paroxetine CR, or placebo) in a 1:1:1 ratio. Objective: The primary objective of this study was to compare the efficacy of continuous treatment with paroxetine CR (25 mg and 12.5 mg once daily (o.d.)) with that of placebo for the treatment of PMDD. The secondary objective of this study was to evaluate the safety of continuous treatment with paroxetine CR (25 mg and 12.5 mg o.d.) for the treatment of PMDD. Primary Outcome/Efficacy Variable: The primary measure of efficacy was the change from baseline in the mean luteal phase VAS-Mood score at the treatment cycle 3 LOCF endpoint. The mean luteal phase VAS score for each symptom was the mean of the last five days of the menstrual cycle, calculated for each subject. The VAS-Mood score was defined as the mean of luteal phase VAS scores for the four core PMDD symptoms: irritability, tension, depressed mood, and affective lability. Secondary Outcome/Efficacy Variables: The secondary measures of efficacy were: The change from baseline in the mean luteal phase VAS physical symptoms score at treatment cycle 3 LOCF endpoint; mean luteal phase score was the mean VAS physical symptom scores of the last 5 days of the menstrual cycle, calculated for each subject. The proportion of responders at the treatment cycle 3 LOCF endpoint, where response is defined as a 50% reduction from their baseline luteal phase VAS-Mood score. The proportion of responders at treatment cycle 3 LOCF endpoint, where response is defined as a mean luteal phase VAS-Mood score of less than or equal to their baseline mean follicular phase VAS-Mood score. The change from baseline in the area under the curve (AUC) for treatment cycles 1-3 in daily luteal phase VAS-Mood scores, adjusted for the total number of luteal days. The change from baseline in the individual items (work, social life, and family life) of the Sheehan Disability Scale (SDS) at the treatment cycle 3 LOCF endpoint. The change from baseline in the Premenstrual Tension Scale (observer rated) (PMTS-O) total score at the treatment cycle 3 LOCF endpoint. The change from baseline in the Clinical Global Impression (CGI)-Severity of Illness score at the treatment cycle 3 LOCF endpoint. The proportion of subjects who scored 1 (very much improved) or 2 (much improved) on the CGI-Global Improvement item at the treatment cycle 3 LOCF endpoint. The proportion of subjects who scored 1 (very much improved) or 2 (much improved) on the Patient Global Evaluation at treatment cycle 3 LOCF endpoint. Statistical Methods: Statistical inferences concerning the efficacy of paroxetine CR were made from the ITT population and PP population (for the primary variable only), using the LOCF dataset at treatment cycle 3. The primary variable, change from baseline in the mean luteal phase VAS-Mood score at treatment cycle 3 LOCF, was analyzed using parametric analysis of covariance. The model on which inference was based included terms for treatment group, center group, baseline score, and age. All hypothesis tests were two-sided. For the primary efficacy variable, hypothesis tests used a nominal 5% level of statistical significance and nominal 95% confidence intervals were presented for the treatment cycle 3 LOCF endpoint. 1

2 For the primary analysis, confidence intervals and significance tests were adjusted for two treatment comparisons using Hochberg s modification to the Bonferroni inequality. Secondary efficacy variables were analyzed using the model applied to the primary variable. Only the ITT population was analyzed for the secondary efficacy variables. No adjustments were made for multiple treatment comparisons; hypothesis tests used a 5% level of significance and 95% confidence intervals were presented. Continuous efficacy variables were analyzed using analysis of covariance techniques, with results presented as point estimates and 95% confidence intervals (nominal 95% confidence intervals for the primary efficacy variable) for the adjusted mean differences between each dose level of paroxetine CR and placebo. Categorical efficacy variables were analyzed using logistic regression techniques with results presented as adjusted odds ratios and 95% confidence intervals around the estimated odds ratios. The change from baseline in the CGI-Severity of Illness was analyzed using the Wilcoxon rank sum test, with results presented as median differences between treatments. Study Population: This study included female outpatients aged between 18 and 45 years whose menstrual cycles were regular (i.e., duration between 22 and 35 days), who had a diagnosis of PMDD according to Diagnostic and Statistical Manual Fourth Edition (DSM-IV) criteria (criteria A-C were to be fulfilled at visit 1 [screening] and criterion D in two consecutive reference cycles), whose PMDD had been present for at least the past year, and whose PMDD symptoms had been present in at least 9 out of 12 menstrual cycles. Number of Subjects: Planned, N Randomized, N Randomized (ITT),N Completed, 87 (74.4) 97 (78.9) 90 (76.3) Total Number Subjects Withdrawn, N (%) 30 (25.6) 26 (21.1) 28 (23.7) Withdrawn Due to Adverse Event, 19 (16.2) 13 (10.6) 7 (5.9) Withdrawn Due to Lack of Efficacy, 2 (1.7) 5 (4.1) 6 (5.1) Withdrawn for Other Reason, 9 (7.7) 8 (6.5) 15 (12.7) Demographics N (ITT) Females Mean Age, Years (SD) 36.7 (4.73) 37.1 (4.80) 36.5 (5.29) White, 117 (100.0) 121 (98.4) 118 (100.0) Primary Efficacy Results: Luteal Phase VAS-Mood Scores (ITT N for Baseline Baseline, Mean (SD) 48.0 (22.06) 55.1 (24.72) 57.9 (23.54) Adjusted Mean Change from Baseline at Treatment Cycle 3 LOCF (2.35) (2.12) (2.16) Endpoint (Standard Error [SE]) Difference in Adjusted Least Square (LS) Means Between CR and 95% CI for Treatment Difference , , 1.26 p-value for Treatment Difference Secondary Efficacy Results: Luteal Phase VAS Physical Symptoms Score at Treatment Cycle 3 LOCF Baseline, Mean (SD) 57.7 (26.64) 60.3 (27.86) 63.1 (27.80) Adjusted Mean Change from Baseline (SE) (2.83) (2.58) (2.61) Difference in Adjusted LS Means Between CR and % CI for Treatment Difference , , 1.97 Subjects Responding (50% Reduction from Baseline Mean Luteal Phase VAS-Mood Score) at Treatment Cycle 3 LOCF 2

3 N Responders, 68 (70.8) 77 (67.5) 63 (56.3) Adjusted Odds Ratio for Treatment Comparison Adjusted 95% CI for Treatment Comparison 1.10, , 2.83 Subjects Responding (Return to a Score of Baseline Mean Follicular Phase VAS-Mood Score) at Treatment Cycle 3 LOCF N Responders, 23 (24.2) 17 (14.8) 15 (13.8) Adjusted Odds Ratio for Treatment Comparison Adjusted 95% CI for Treatment Comparison 0.95, , 2.49 AUC Luteal Phase VAS-Mood Score for Treatment Cycles 1-3 (ITT Baseline, Mean (SD) 38.5 (17.89) 44.0 (19.96) 46.6 (18.97) Adjusted Mean Change from Baseline (SE) (1.57) (1.41) (1.51) Difference in Adjusted LS Means Between CR and % CI for Treatment Difference , , SDS Work Item Score at Treatment Cycle 3 LOCF Endpoint (ITT Baseline, Mean (SD) 5.4 (2.72) 5.3 (2.51) 5.5 (2.75) Adjusted Mean Change from Baseline (SE) (0.29) (0.26) (0.26) Difference in Adjusted LS Means Between CR and % CI for Treatment Difference -1.84, , 0.03 SDS Social/Leisure Item Score at Treatment Cycle 3 LOCF Baseline, Mean (SD) 6.2 (2.60) 5.8 (2.56) 6.5 (2.38) Adjusted Mean Change from Baseline (SE) (0.29) (0.27) (0.28) Difference in Adjusted LS Means Between CR and % CI for Treatment Difference -2.49, , SDS Family/Home Item Score at Treatment Cycle 3 LOCF Baseline, Mean (SD) 7.0 (2.34) 6.7 (2.37) 7.1 (2.33) Adjusted Mean Change from Baseline (SE) (0.31) (0.29) (0.30) Difference in Adjusted LS Means Between CR and % CI for Treatment Difference -2.56, , PMTS-O Total Score at Treatment Cycle 3 LOCF Endpoint (ITT Baseline, Mean (SD) 22.4 (5.68) 22.3 (5.97) 22.6 (5.47) Adjusted Mean Change from Baseline (SE) (0.80) (0.73) (0.75) Difference in Adjusted LS Means Between CR and % CI for Treatment Difference -6.62, , CGI-Severity of Illness Score at Treatment Cycle 3 LOCF Baseline, Mean (SD) 4.7 (0.94) 4.8 (1.04) 4.7 (1.19) Mean Change from Baseline Difference in Medians Between CR and -1-1 Subjects Responding on the CGI-Global Improvement Item (Score 1 or 2) at Treatment Cycle 3 LOCF Endpoint (ITT 3

4 N Responders, 68 (71.6) 70 (61.4) 47 (41.6) Adjusted Odds Ratio for Treatment Comparison Adjusted 95% CI for Treatment Comparison 2.13, , 4.00 Subjects Responding on the Patient Global Evaluation Item (Score of 1 or 2) at Treatment Cycle 3 LOCF Endpoint (ITT N Responders, 61 (64.9) 56 (50.0) 41 (38.0) Adjusted Odds Ratio for Treatment Comparison Adjusted 95% CI for Treatment Comparison 1.84, , 2.94 Safety Results: On-therapy adverse events (AEs) were defined as all AEs where the onset date was on or after the first day of treatment and before or on the last day of treatment. All serious adverse events (SAEs) are presented, including those that occurred on treatment or within 30 days following the end of treatment Most Frequent Adverse Events for ITT Population - On-Therapy N Subjects with any AE(s) 96 (82.1) 92 (74.8) 76 (64.4) Nausea 33 (28.2) 14 (11.4) 8 (6.8) Headache 27 (23.1) 20 (16.3) 15 (12.7) Asthenia 21 (17.9) 21 (17.1) 5 (4.2) Insomnia 18 (15.4) 7 (5.7) 1 (0.8) Sweating 16 (13.7) 8 (6.5) 0 Infection 13 (11.1) 7 (5.7) 8 (6.8) Dizziness 12 (10.3) 11 (8.9) 6 (5.1) Libido Decreased 12 (10.3) 14 (11.4) 4 (3.4) Constipation 10 (8.5) 3 (2.4) 1 (0.8) Tremor 8 (6.8) 1 (0.8) 1 (0.8) Increased Appetite 7 (6.0) 2 (1.6) 1 (0.8) Somnolence 7 (6.0) 4 (3.3) 0 Diarrhoea 6 (5.1) 3 (2.4) 3 (2.5) Dysmenorrhoea 3 (2.6) 9 (7.3) 10 (8.5) Sinusitis 3 (2.6) 1 (0.8) 8 (6.8) Serious Adverse Events for ITT Population - On-Therapy (Treatment Phase) [n considered by the investigator to be related to study medication] N (ITT) Subjects with Non-Fatal SAEs, (0.8) Myalgia (0.8) [0] Subjects with Fatal SAEs, Serious Adverse Events for ITT Population - On-Therapy (Follow-Up Phase) [n considered by the investigator to be related to study medication] N (ITT) Subjects with Non-Fatal SAEs, 1 (2.0) 0 0 Infection 1 (2.0) [0] 0 0 Vertigo 1 (2.0) [0] 0 0 Subjects with Fatal SAEs,

5 Conclusion: See publication below. Publications: Yonkers KA, Bellew KM, Rolfe TE, Perera PD. Pooled Analysis of Three Large Clinical Trials in the Treatment of PMDD. 156th Annual Meeting of the American Psychiatric Association; 2003; NR677 controlled release is effective in treating premenstrual dysphoric disorder: a pooled analysis of three trials. Yonkers, Kimberly A. MD, Hunter, Brian N. PhD, Bellew, Kevin M. MS, Rolfe, Timothy E. MSc, Steiner, Meir MD PhD, and Heller, Vicki L. MD 51st Annual Clinical Meeting of the American College of Obstetricians and Gynecologists 4/26/2003 New Orleans, LA; USA Pooled analysis of three multi-centre double-blind placebo-controlled clinical trials with paroxetine controlled-release (cr) in the treatment of premenstrual dysphoric disorder. Hunter, Brian, Bellew, Kevin M, and Perera, Philip D International Congress of the World Federation of Biological Psychiatry 2/9/2004 Sydney; Australia Date Updated: 08-Mar