Study No.: 29060/717 Title: A Double-Blind, Placebo-Controlled, 3-Arm, Fixed-Dose Study of CR Intermittent Dosing (12.5 mg and 25 mg) for Premenstrual Dysphoric Disorder Rationale: In most trials investigating the effect of serotonin reuptake inhibition in premenstrual dysphoric disorder (PMDD), the selective serotonin reuptake inhibitor (SSRI) has been administered continuously throughout the menstrual cycle. However, several recent trials, including study 29060/658 using paroxetine immediate release (IR), suggest that PMDD may be effectively treated by administration of an SSRI intermittently, during luteal phases only. Thus, the onset of action of SSRIs appears to be much shorter when used for PMDD than when used for depression, panic disorder, or obsessive compulsive disorder. This study was designed to compare the efficacy of intermittent dosing with controlled release (CR) paroxetine (12.5 mg and 25 mg) with that of placebo for the treatment of PMDD. Phase: III Study Period: 25 June 2001-09 October 2002 Study Design: This was a multicenter, randomized, double-blind, placebo-controlled, fixed dose, three-arm parallel group study. Centers: This was a multicenter study carried out in 53 centers distributed as follows: 10 centers in Canada, 11 in Sweden, 9 in the USA, 7 in the Netherlands, 6 in Norway, and 5 each in Finland and Germany. Indication: Premenstrual Dysphoric Disorder Treatment: Prior to randomization, subjects were required to meet the protocol-defined daily symptom visual analogue scales (VAS) entry criteria for two consecutive menstrual cycles. Subjects who failed to meet the VAS entry criteria during reference cycle 1 were, at the investigator s discretion, entered into an additional reference cycle 1(a) rather than being excluded from the study at this point. Subjects received no medication during reference cycle 1 or 1(a). Following reference cycle 1 or 1(a), eligible subjects entered reference cycle 2, where they received single-blind placebo medication. At the end of the reference phase, eligible subjects diagnosed as having PMDD according to DSM-IV criteria A to D (based on their daily VAS ratings) were randomized to receive one of three possible treatments (paroxetine CR 12.5 mg, paroxetine CR 25 mg, or placebo) in a 1:1:1 ratio for up to three double-blind treatment cycles (TCs). or placebo was administered orally once daily (morning) during the luteal phase of the subject s menstrual cycle. Subjects were instructed to start taking study medication at an estimated 14 days prior to the start of their next menstrual cycle and to stop taking study medication on the first day of menses. Objectives: The primary objective of this study was to compare the efficacy of intermittent dosing with paroxetine CR (12.5 mg and 25 mg) with that of placebo for the treatment of PMDD. The hypothesis to be tested was that paroxetine treatment results in a greater improvement in symptoms of PMDD compared with placebo treatment. The secondary objective was to evaluate the safety and tolerability of intermittent dosing with paroxetine CR (12.5 mg and 25 mg) for the treatment of PMDD. Primary Outcome/Efficacy Variable: The primary outcome measure was the change from baseline in mean luteal phase Visual Analogue Scale (VAS)-Mood score at the treatment cycle 3 last observation carried forward (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 efficacy measures included the following: Change from baseline in the mean luteal phase VAS Physical Symptoms score at the treatment cycle 3 LOCF endpoint. Mean luteal phase score is the mean of the last 5 days of the menstrual cycle, calculated for each subject. Change from baseline in the mean luteal phase VAS total score at the treatment cycle 3 LOCF endpoint (regulatoryrequested variable). Change from baseline in area under the curve (AUC) for treatment cycles 1 through 3 in daily luteal phase VAS Mood scores, adjusted for the total number of luteal days. 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. Change from baseline in the SDS total score at the treatment cycle 3 LOCF endpoint. Change from baseline in the observer-rated Premenstrual Tension Scale (PMTS-O) total score at the treatment cycle 3 LOCF endpoint. Change from baseline in the CGI severity of illness score at the treatment cycle 3 LOCF endpoint. Proportion of responders defined by a 50% reduction from their baseline luteal phase VAS-Mood score at the treatment cycle 3 LOCF endpoint. The proportion of responders defined by a mean luteal phase VAS-Mood score at the treatment cycle 3 LOCF 1
endpoint of less than or equal to their baseline mean follicular phase VAS-Mood score. The proportion of subjects who scored 1 or 2 (very much improved or much improved) on the CGI global improvement item at the treatment cycle 3 LOCF endpoint. The proportion of subjects who scored a 1 or 2 (very much improved or much improved, respectively) on the Patient Global Evaluation (PGE) (subject-rated) at the treatment cycle 3 LOCF endpoint. Statistical Methods: Statistical inferences concerning the efficacy of paroxetine CR were made from the intent-to-treat (ITT) population and per-protocol (PP) population (for the primary variable only), using the LOCF dataset at TC 3. The primary variable, change from baseline in the mean luteal phase VAS-Mood score at TC 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 (CIs) were presented for the TC 3 LOCF endpoint. For the primary analysis CIs and significance tests were adjusted for two treatment comparisons using Hochberg s modification to the Bonferroni inequality. Secondary efficacy variables were analyzed using a model including terms for treatment group, center group, baseline score, and age. 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% CIs were presented. Continuous efficacy variables were analyzed using analysis of covariance techniques, with results presented as point estimates and 95% CIs (nominal 95% CIs 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% CIs around the estimated odds ratios. Study Population: Female outpatients between 18 and 45 years of age (inclusive) with regular menstrual cycles of between 22 and 35 days and who met DSM-IV criteria for PMDD (criteria A to C to be fulfilled at visit 1 screening interview and criterion D in the two to three reference cycles). Subjects PMDD should have been present for at least the past year, during which symptoms were present in at least 9 out of 12 menstrual cycles. Number of Subjects: Randomized, N 119 131 123 ITT Population, N 116 130 120 PP Population, N 74 99 96 Completed, 87 (75.0) 104 (80.0) 101 (84.2) Total Number Subjects Withdrawn, N (%) 29 (25.0) 26 (20.0) 19 (15.8) Withdrawn Due to Adverse Events, 16 (13.8) 13 (10.0) 5 (4.2) Withdrawn Due to Lack of Efficacy, 2 (1.7) 2 (1.5) 6 (5.0) Withdrawn for Other Reasons, 11 (9.5) 11 (8.5) 8 (6.7) Demographics N (ITT) 116 130 120 Females 116 130 120 Mean Age, Years (SD) 37.2 (5.39) 35.9 (6.01) 36.9 (5.51) White, 116 (100.0) 125 (96.2) 118 (98.3) Primary Efficacy Results for ITT Population: Mean Luteal Phase VAS-Mood Score N for Baseline 116 130 119 Baseline, Mean (SD) 54.4 (24.46) 52.2 (21.35) 55.7 (21.52) N for Treatment Cycle 3 93 105 105 Treatment Cycle 3, Mean (SD) 16.2 (19.72) 21.4 (21.39) 29.6 (24.34) Adjusted Change from Baseline to Treatment Cycle 3 LOCF -34.73 (2.09) -31.61 (2.00) -23.94 (2.03) Endpoint, Least Square (LS) Mean (SE) -10.79-7.66 95% Confidence Interval (CI) for Treatment Difference -16.46, -5.12-13.25, -2.08 2
p-value for Treatment Difference <0.001 0.007 Secondary Efficacy Results for ITT Population: Mean Luteal Phase VAS Physical Symptoms Score Baseline, Mean (SD) 54.6 (28.05) 57.5 (29.13) 55.4 (29.02) -19.17 (2.56) -20.46 (2.46) -13.89 (2.49) -5.28-6.57 95% CI for Treatment Difference -12.26, 1.69-13.42, 0.29 Mean Luteal Phase VAS Total Score Baseline, Mean (SD) 545.2 (252.8) 522.0 (232.3) 539.3 (220.7) -283.54 (20.51) -278.85 (19.64) -205.72 (19.88) -77.82-73.13 95% CI for Treatment Difference -133.47, -22.16-127.91, -18.36 50% Reduction from Baseline Mean Luteal Phase VAS-Mood Score Responder Analysis N 112 122 119 Total Responders at Treatment Cycle 3 LOCF Endpoint, 81 (72.3) 81 (66.4) 59 (49.6) Odds Ratio 3.03 2.49 95% CI 1.66, 5.53 1.40, 4.45 Return to a Score of Less Than or Equal to Baseline Mean Follicular Phase VAS-Mood Score Responder Analysis N 112 122 120 Total Responders at Treatment Cycle 3 LOCF Endpoint, 35 (31.3) 21 (17.2) 8 (6.7) Odds Ratio 7.08 2.91 95% CI 3.03, 16.55 1.21, 7.01 AUC for Luteal Phase VAS-Mood Score, mm Baseline, Mean (SD) 43.7 (19.91) 41.8 (17.32) 44.8 (17.54) Adjusted Change from Baseline for Treatment Phase, LS Mean (SE) -26.32 (1.52) -25.00 (1.46) -18.19 (1.48) -8.13-6.81 square means) for Treatment Phase 95% CI -12.26, -3.99-10.88, -2.73 SDS Social/Leisure Item Score Baseline, Mean (SD) 5.9 (2.67) 5.7 (2.69) 6.0 (2.79) -2.97 (0.31) -3.07 (0.28) -2.34 (0.28) -0.63-0.72 95% CI -1.45, 0.18-1.49, 0.04 SDS Work Item Score Baseline, Mean (SD) 5.0 (2.60) 4.8 (2.74) 4.8 (2.41) -2.57 (0.28) -2.40 (0.25) -1.71 (0.24) -0.86-0.69 95% CI -1.59, -0.13-1.36, -0.01 SDS Family/Home Item Score 3
Baseline, Mean (SD) 7.0 (2.34) 6.1 (2.87) 6.4 (2.80) -3.65 (0.32) -3.43 (0.28) -2.73 (0.28) -0.91-0.70 95% CI -1.73, -0.09-1.47, 0.07 SDS Total Score Baseline, Mean (SD) 17.6 (6.38) 16.8 (7.46) 17.2 (6.88) -9.40 (0.86) -8.98 (0.75) -6.66 (0.74) -2.74-2.33 95% CI -4.97, -0.51-4.40, -0.26 PMTS-O Total Score Baseline, Mean (SD) 21.9 (6.39) 21.9 (6.38) 21.3 (5.55) -11.42 (0.84) -10.00 (0.74) -8.22 (0.76) -3.21-1.78 95% CI -5.42, -0.99-3.86, 0.30 CGI-Severity of Illness Score Baseline, Mean (SD) 4.7 (0.98) 4.7 (0.95) 4.6 (0.84) -2.36 (0.16) -2.02 (0.14) -1.75 (0.14) -0.61-0.27 95% CI -1.03, -0.20-0.67, 0.12 CGI-Global Improvement Item (Score of 1 or 2) Responder Analysis N 105 116 116 Total Responders at Treatment Cycle 3 LOCF Endpoint, 71 (67.6) 66 (56.9) 50 (43.1) Odds Ratio 3.47 1.97 95% CI 1.87, 6.43 1.11, 3.50 Patient Global Evaluation Item (Score of 1 or 2) Responder Analysis N 102 114 115 Total Responders at Treatment Cycle 3 LOCF Endpoint, 49 (48.0) 59 (51.8) 33 (28.7) Odds Ratio 2.67 3.07 95% CI 1.44, 4.94 1.69, 5.58 Safety Results for ITT Population: 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 - On-Therapy (Treatment Phase) N 116 130 120 Subjects with any AE(s), 89 (76.7) 88 (67.7) 68 (56.7) Nausea 27 (23.3) 16 (12.3) 2 (1.7) Asthenia 22 (19.0) 16 (12.3) 5 (4.2) Headache 18 (15.5) 16 (12.3) 17 (14.2) Libido Decreased 15 (12.9) 7 (5.4) 7 (5.8) Infection 10 (8.6) 5 (3.8) 8 (6.7) 4
Sweating 10 (8.6) 4 (3.1) 1 (0.8) Diarrhea 8 (6.9) 7 (5.4) 0 Dizziness 8 (6.9) 7 (5.4) 3 (2.5) Tremor 7 (6.0) 4 (3.1) 0 Respiratory Disorder 5 (4.3) 9 (6.9) 13 (10.8) Insomnia 4 (3.4) 13 (10.0) 3 (2.5) Sinusitis 3 (2.6) 7 (5.4) 2 (1.7) Serious Adverse Events On-Therapy (Treatment Phase) [n considered by the investigator to be related to study medication] CR 25 mg CR 12.5 mg Placebo N 116 130 120 Subjects with Non-Fatal SAEs, 1 (0.9) 2 (1.5) 2 (1.7) Anaphylactoid Reaction 1 (0.9) [1] 0 0 Trauma 0 0 2 (1.7) [0] Pulmonary Embolus 0 1 (0.8) [0] 0 Emotional Lability* 0 1 (0.8) [0] 0 Subjects with Fatal SAEs, 0 0 0 Serious Adverse Events - Follow-Up Phase [n considered by the investigator to be related to study medication] CR 25 mg Placebo CR 12.5 mg N 116 129 120 Subjects with Non-Fatal SAE, 1 (0.9) 1 (0.8) 0 Depression 0 1 (0.8) [0] 0 Emotional Lability* 0 1 (0.8) [0] 0 Abortion 1 (0.9) [0] 0 0 Subjects with Fatal SAEs, 0 0 0 * Term may include the following events: Completed suicides, self-harm, suicidal thoughts, attempted suicide, crying and mood fluctuations. Conclusion: The results of this study have demonstrated that intermittent paroxetine CR provides effective benefit in the treatment of females with PMDD. CR 25 mg and 12.5 mg were statistically superior to placebo for the primary efficacy variable (i.e., change from baseline in mean luteal phase VAS-Mood score at the treatment cycle 3 LOCF endpoint). 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. Date Updated: 24-Feb-2005 Publications: No Publication. 5