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.: 29060/658 Title: A Placebo-Controlled Study to Investigate the Efficacy of Intermittent and Continuous Treatment With Paroxetine in Patients With Premenstrual Dysphoric Disorder (PMDD) Rationale: The purpose of this study was to evaluate the efficacy of paroxetine compared to placebo () for the treatment of PMDD, and to explore the possibility that intermittent administration (during luteal phases only) may be effective. Phase: Phase IIIA Study Period: 14 Sep 1998 to 12 May 2000 Study Design: This was a multi-centre, randomised, double-blind, -controlled, 3-arm parallel-group study. The study involved a total of 5 to 7 telephone contacts, and 4 to 5 clinic visits to screen subjects for the study and perform study-related procedures and assessments. Centres: 4 centers in Sweden Indication: PMDD Treatment: Eligible subjects were randomly assigned (1:1:1 ratio) and in a double-blind fashion to receive 1 of the following 3 treatments: Paroxetine-continuous () treatment (20mg/day orally (two 10mg capsules) for 3 treatment cycles) Paroxetine-intermittent () treatment (20mg/day orally (two 10mg capsules) only during the luteal phase for 3 treatment cycles) Objectives: The primary objective of the study was to compare the efficacy of paroxetine (20mg/day) administered either intermittently during the luteal phase only or continuously throughout the menstrual cycle, with that of for the treatment of PMDD. Primary Outcome/Efficacy Variable: The primary measures of efficacy were as follows: Percentage change from baseline in the luteal phase irritability visual analogue scale (VAS) score at study endpoint Overall proportion of responders (score of 1 or 2) on the Clinical Global Impression - Improvement (CGI-I) at study endpoint Secondary Outcome/Efficacy Variable(s): Secondary efficacy measures were as follows: Percentage change from baseline in the luteal phase score at study endpoint for all VAS items individually except irritability Raw change from baseline in the luteal phase score at study endpoint for all VAS items Overall proportion of responders for VAS items representing the core symptoms of PMDD at study endpoint (core symptoms were irritability, depressed mood, tension and affective lability, and responders achieved 50% reduction from baseline in individual VAS scores) Change from baseline to study endpoint in premenstrual tension score-observer rated (PMTS-O) CGI severity of illness and Sheehan disability scale (SDS) scores Overall proportion of responders on the patient global evaluation (PGE) (score of 1 or 2 ) at study endpoint Patient evaluation of study medication (PESM) at study endpoint Statistical Methods: The primary analyses of this study consisted of 2 variables, 1 subject-rated and 1 investigator-rated. Hence the overall sample size was based on the larger of the 2 requirements. The group was expected to show a response rate of 35% where response was defined as a score of 1 (very much improved) or 2 (much improved) on the CGI-I at study endpoint. Therefore, a total of 57 evaluable subjects per treatment group was sufficient to detect a difference of 30 percentage points between each paroxetine group and in the percentage of subjects classed as responders. This difference in percentages was detectable with a power of 90%, given a significance level of 5% and using a 2-sided significance test. Assuming an attrition rate of 20% through the first treatment cycle, 216 subjects (72 per group) were to be recruited into the active treatment phase of the study in order to ensure that at least 57 subjects/treatment group completed treatment cycle 1. Continuous efficacy variables (ie, percentage and raw change in VAS luteal phase score) and categorical efficacy variables with large numbers of categories (ie, change in PMTS-O total score and change in SDS scores) were analysed using analysis of variance (ANOVA) techniques (parametrically if assumptions were met or 1
non-parametrically if assumptions were not met). Categorical efficacy variables with small numbers of categories (ie, change in CGI severity of illness score) were analysed using non-parametric ANOVA techniques. Binary efficacy variables (ie, VAS and CGI responders) were analysed using parametric logistic regression techniques. All analyses adjusted for investigator effects. The effect of adjusting for baseline was investigated in the parametric analyses. Where deemed appropriate, baseline was included as a covariate in the parametric analyses. Results are presented in terms of mean or median differences and associated confidence intervals (CI) (continuous and categorical efficacy variables) or odds ratios and associated CIs (binary efficacy variables). All hypothesis tests were 2-sided. The effect of interactions (ie, treatment by investigator and treatment by baseline) were assessed at the 10% level of significance. All other hypothesis tests were assessed at the 5% level of significance. The primary interest was to determine the efficacy of the 2 paroxetine groups (ie, continuous and intermittent treatment). This was done by comparing each paroxetine group against the group. No statistical comparisons were made between and. Two populations were defined for the analysis of efficacy: the intent-to-treat (ITT) population and the per-protocol (PP) population. The ITT population consisted of all subjects who were randomised to study medication and who received at least 1 dose of randomised treatment. Subjects were included in the ITT efficacy analyses, if they additionally had at least 1 post-baseline efficacy evaluation. Subjects included in the ITT population were valid for inclusion in the PP efficacy analysis provided that all the following criteria were met: no major protocol violation existed with respect to the inclusion/exclusion criteria; the duration of active treatment was at least 1 complete menstrual cycle; no major protocol violation occurred between randomisation and completion of the treatment phase (ie, treatment cycles 1 to 3); and subject has not missed more than 3 consecutive days of study medication during the randomised treatment phase of the study. Study Population: Female (non-pregnant/non-lactating) outpatients aged 18 years who met DSM-IV criteria for PMDD (Criteria A-C to be fulfilled at screening interview and criterion D in the two reference cycles); had regular menstrual cycles (duration between 22-35 days); had experienced the condition for at least 10 menstrual cycles during the past year; and had a baseline (Visit 2: Reference Cycle 2) luteal phase CGI severity of illness score of 3 were eligible for participation in the study. In addition, at least 1 of the symptoms, irritability, depressed mood, tension or affective lability, had to be prominent and during 2 reference cycles, the subject had to rate 50% higher (VAS 0-100mm) on the symptoms irritability and/or depressed mood in the luteal phase as compared with the follicular phase; the mean luteal phase rating for this symptom had to be at least 25mm. Subjects who had fulfilled DSM-IV criteria for any Axis 1 disorder (other than PMDD) in the year prior to screening; had severe, clinically significant, co-existing conditions which, in the investigator's opinion, would have rendered the patient unsuitable for the study; had a baseline Montgomery Asberg depression rating scale (MADRS) score of >10 during the follicular phase of the menstrual cycle; was at significant risk for suicide; were receiving any ongoing medication which, in the opinion of the investigator, could affect their PMDD symptomatology (within 1 month prior to the screening visit and for the duration of the study period); had received any previous treatment with an SSRI for premenstrual symptoms; had a history of hypersensitivity or adverse reaction to paroxetine or other SSRIs; had any clinically significant abnormality in screening blood tests; or had used an investigational drug within 30 days or 5 half-lives (whichever was longer) preceding the first dose of study medication were excluded from participation in the study. Number of Subjects: Total Screened, N 274 Randomised, N 62 61 63 186 ITT Population a, N 59 59 60 178 PP Population, N 51 47 53 151 Number Subjects at Each Treatment Cycle, n (%) Treatment Cycle 1 59 (100.0) 59 (100.0) 60 (100.0) 178 (100.0) Treatment Cycle 2 56 (94.9) 54 (91.5) 56 (93.3) 166 (93.3) Treatment Cycle 3 53 (89.8) 51 (86.4) 52 (86.7) 156 (87.6) Completed the Study, n (%) 51 (86.4) 50 (84.7) 51 (85.0) 152 (85.4) Total Number Subjects Withdrawn b, n (%) 8 (13.6) 9 (15.3) 9 (15.0) 26 (14.6) Withdrawn Due to AEs, n (%) 1 (1.7) 3 (5.1) 5 (8.3) 9 (5.1) Withdrawn Due to Lack of Efficacy, n (%) 0 0 0 0 Withdrawn For Other Reasons, n (%) 7 (11.9) 6 (10.2) 4 (6.7) 17 (9.5) a. Subjects included were those who were randomised and received study medication only; 8 subjects were randomised but did not receive study medication. 2
b. Included subjects who had received study medication only. Demographics: N (ITT) 59 59 60 Females:Males, n:n 59:0 59:0 60:0 Mean Age in Years (Standard Error [SE]) 37.2 (0.93) 37.3 (0.76) 37.9 (0.77) Caucasian, n (%) 59 (100.0) 58 (98.3) 60 (100.0) Mean Age at Onset of PMDD Symptoms in Years 27.5 27.3 29.0 Onset of Initial PMDD Symptoms, n (%) Related to Menarche 1 (1.7) 6 (10.2) 1 (1.7) Related to Childbirth 20 (33.9) 17 (28.8) 16 (26.7) Related to Initiation of Oral Contraception 1 (1.7) 1 (1.7) 3 (5.0) Related to Stopping Oral Contraception 1 (1.7) 3 (5.1) 4 (6.7) Related to Sterilisation 0 0 0 Related to Other Reasons 3 (5.1) 0 0 Primary Efficacy Results (ITT & PP Populations): % Change From Baseline in Luteal Phase Irritability VAS Score at Endpoint ITT Population, N 56 55 56 Median Baseline Score 59.0 56.0 59.5 Median % Change From Baseline at Endpoint -45.35-90.00-91.30 Difference in Median % Changes vs. -39.35-43.00 95% CI -51.80, -26.10-53.70, -29.10 p-value <0.001 <0.001 Proportion of Responders (CGI Global Improvement) at Endpoint ITT Population, N 56 55 56 Proportion of Responders, n/n (%) 14/47 (29.8) 32/47 (68.1) 39/46 (84.8) Odds Ratio vs. 5.40 15.56 95% CI 2.25, 13.75 5.65, 48.76 p-value <0.001 <0.001 Secondary Efficacy Results (ITT Population): % Change From Baseline in Luteal Phase VAS Scores at Endpoint Depressed Mood, N 56 55 56 Median Baseline Score 47.50 45.00 46.50 Median % Change From Baseline at Endpoint -45.05-86.10-92.30 Difference in Median % Changes vs. -20.10-32.85 95% CI -40.70, -6.10-52.30, -16.70 Tension, N 56 55 56 Median Baseline Score 41.00 43.00 43.00 Median % Change From Baseline at Endpoint -43.50-82.40-90.10 Difference in Median % Changes vs. -24.60-31.40 95% CI -38.50, -8.00-46.90, -15.20 Affective Lability, N 56 55 56 Median Baseline Score 45.00 44.00 49.50 Median % Change From Baseline at Endpoint -47.60-93.10-92.80 Difference in Median % Changes vs. -30.85-32.20 95% CI -46.40, -14.40-48.40, -16.30 Mood Swings, N 56 55 56 Median Baseline Score 59.00 53.00 59.00 Median % Change From Baseline at Endpoint -42.65-92.20-92.25 Difference in Median % Changes vs. -37.50-39.75 95% CI -55.10, -25.40-56.80, -27.00 Bloatedness, N 56 55 56 Median Baseline Score 42.50 32.00 43.00 3
Median % Change From Baseline at Endpoint -22.40-60.00-74.70 Difference in Median % Changes vs. -32.10-44.05 95% CI -53.30, -10.60-64.40, -26.60 Breast Tenderness, N 56 55 55 Median Baseline Score 44.50 27.00 45.00 Median % Change From Baseline at Endpoint -60.00-78.30 Difference in Median % Changes vs. -26.15-34.10 95% CI -45.50, -7.10-54.80, -17.90 Lack of Energy, N 56 55 56 Median Baseline Score 35.00 36.00 35.00 Median % Change From Baseline at Endpoint -28.45-50.00-70.20 Difference in Median % Changes vs. -13.15-28.60 95% CI -35.90, 4.10-50.00, -7.80 Food Cravings, N 56 55 56 Median Baseline Score 36.00 37.00 38.50 Median % Change From Baseline at Endpoint -48.05-51.60-75.55 Difference in Median % Changes vs. -5.55-24.60 95% CI -25.20, 8.70-42.90, -7.90 Raw Change From Baseline in Luteal Phase VAS Scores at Endpoint Irritability, N 56 55 56 Mean Baseline Score 56.3 57.1 61.8 Mean Change From Baseline at Endpoint -21.8-44.9-50.6 Difference in Median % Changes vs. -23.3-26.1 95% CI -30.1, -16.6-32.9, -19.3 Depressed Mood, N 56 55 56 Mean Baseline Score 45.5 44.0 45.0 Mean Change From Baseline at Endpoint -19.9-32.5-38.0 Difference in Mean Changes vs. -14.3-19.1 95% CI -20.8, -7.8-25.6, 12.6 Tension, N 56 55 56 Mean Baseline Score 44.4 42.5 41.4 Mean Change From Baseline at Endpoint -17.7-32.4-33.6 Difference in Mean Changes vs. -16.8-18.5 95% CI -22.9, -10.7-24.6, -12.5 Affective Lability, N 56 55 56 Mean Baseline Score 47.7 45.5 48.8 Mean Change From Baseline at Endpoint -21.3-38.1-40.0 Difference in Mean Changes vs. -19.3-18.9 95% CI -25.4, -13.2-25.0, -12.8 Mood Swings, N 56 55 56 Mean Baseline Score 53.4 54.9 55.9 Mean Change From Baseline at Endpoint -20.5-43.1 45.9 Difference in Mean Changes vs. -22.1-24.3 95% CI -29.4, -14.8-31.5, -17.0 Bloatedness, N 56 55 56 Mean Baseline Score 41.4 40.2 44.5 Mean Change From Baseline at Endpoint -7.8-23.7-30.3 Difference in Mean Changes vs. -17.0-21.0 95% CI -24.5, -9.6-28.4, -13.6 Breast Tenderness, N 56 55 55 Mean Baseline Score 42.6 37.5 43.4 Mean Change From Baseline at Endpoint -9.1-21.3-29.9 Difference in Mean Changes vs. -15.5-20.6 95% CI -22.7, -8.3-27.8, -13.5 4
Lack of Energy, N 56 55 56 Mean Baseline Score 39.2 36.7 34.7 Mean Change From Baseline at Endpoint -10.2-16.9-20.8 Difference in Mean Changes vs. -8.6-13.6 95% CI -16.2, -1.0-21.2, -6.0 Food Cravings, N 56 55 56 Mean Baseline Score 40.3 38.5 42.1 Mean Change From Baseline at Endpoint -16.5-18.4-27.4 Difference in Mean Changes vs. -3.0-9.9 95% CI -10.2, 4.3-17.2, -2.7 Proportion of Responders for Individual Core PMDD VAS Items at Endpoint Irritability Proportion of Responders, n/n (%) 23/56 (41.1) 49/55 (89.1) 51/56 (91.1) Odds Ratio vs. 16.06 20.16 95% CI 5.81, 52.11 6.98, 70.60 Depressed Mood Proportion of Responders, n/n (%) 27/56 (48.2) 43/55 (78.2) 53/56 (94.6) Odds Ratio vs. 4.07 20.57 95% CI 1.79, 9.76 6.47, 92.45 Tension Proportion of Responders, n/n (%) 27/56 (48.2) 43/55 (78.2) 46/56 (82.1) Odds Ratio vs. 5.32 6.89 95% CI 2.21, 13.76 2.78, 18.58 Affective Lability Proportion of Responders, n/n (%) 27/56 (48.2) 46/55 (83.6) 47/56 (83.9) Odds Ratio vs. 7.23 7.48 95% CI 2.90, 19.77 3.00, 20.45 Change From Baseline in PMTS-O Total Score at Endpoint PMTS-O Total Score, N 43 41 44 Mean Baseline Score 21.3 19.5 21.0 Mean % Change From Baseline at Endpoint -7.0-10.7-12.4 Difference in Mean % Changes vs. -4.7-5.7 95% CI -7.6, -1.8-8.5, -2.9 Change From Baseline in CGI Severity of Illness Score at Endpoint CGI Severity of Illness Score, N 42 41 45 Median Baseline Score 5.0 5.0 5.0 Median Change From Baseline at Endpoint -1.0-3.0-3.0 Difference in Median % Changes vs. -1.0-2.0 95% CI -2.0, 0.0-3.0, -1.0 Change From Baseline in SDS Scores at Endpoint Work, N 49 50 45 Mean Baseline Score 5.7 4.6 5.9 Mean Change From Baseline at Endpoint -1.3-3.1-4.7 Difference in Mean Changes vs. -2.7-3.3 95% CI -3.7, -1.8-4.3, -2.3 Social Life/Leisure Activities, N 49 50 46 Mean Baseline Score 6.1 5.2 6.2 Mean Change From Baseline at Endpoint -1.8-3.5-5.0 Difference in Mean Changes vs. -2.4-3.1 95% CI -3.3, -1.4-4.1, -2.2 Family Life/Home Responsibilities, N 49 50 46 5
Mean Baseline Score 7.0 6.6 7.4 Mean Change From Baseline at Endpoint -2.3-4.4-6.0 Difference in Mean Changes vs. -2.3-3.4 95% CI -3.4, -1.3-4.4, -2.3 Proportion of Responders (PGE) at Endpoint PGE Proportion of Responders, n/n (%) 11/49 (22.4) 32/52 (61.5) 46/54 (85.2) Subject Evaluation of Study Medication n (%) n (%) n (%) Medication sufficiently beneficial to ask for again?, 58 53 60 N Yes 21 (36.2) 35 (66.0) 48 (80.0) No 33 (56.9) 13 (24.5) 9 (15.0) Not Sure 4 (6.9) 5 (9.4) 3 (5.0) Reason why subject would not ask for medication 33 13 9 again, N Lack of Efficacy 29 (87.9) 10 (76.9) 4 (44.4) Side Effects 2 (6.1) 3 (23.1) 5 (55.6) Anti-Medication 1 (3.0) 0 0 Other 1 (3.0) 0 0 Reason why subject is not sure whether she would 4 5 3 ask for medication again, N Lack of Efficacy 3 (75.0) 2 (40.0) 0 Side Effects 0 2 (40.0) 3 (100.0) Anti-Medication 1 (25.0) 0 0 Other 0 1 (20.0) 0 Safety Results (ITT Population): Adverse events were classed as occurring during the treatment phase if they started or worsened on or after the first day of randomised treatment and on or before the last day of randomised treatment. Adverse events were classed as occurring during the follow-up phase if they started or worsened within 14 days (inclusive) of the last day of randomised treatment, although for serious adverse events (SAEs) this was extended to 30 days (inclusive). Most Frequent AEs During Treatment Phase n (%) n (%) n (%) Subjects With Any AEs 43 (72.9) 53 (89.8) 57 (95.0) Headache 15 (25.4) 9 (15.3) 15 (25.0) Nausea 10 (16.9) 30 (50.8) 26 (43.3) Insomnia 9 (15.3) 5 (8.5) 6 (10.0) Infection Viral 7 (11.9) 3 (5.1) 2 (3.3) Anxiety 5 (8.5) 4 (6.8) 1 (1.7) Fatigue 5 (8.5) 10 (16.9) 11 (18.3) Nervousness 5 (8.5) 4 (6.8) 4 (6.7) Upper Respiratory Tract Infection 5 (8.5) 9 (15.3) 8 (13.3) Back Pain 4 (6.8) 4 (6.8) 5 (8.3) Abdominal Pain 3 (5.1) 3 (5.1) 5 (8.3) Dizziness 3 (5.1) 8 (13.6) 8 (13.3) Migraine 3 (5.1) 1 (1.7) 0 Pharyngitis 3 (5.1) 3 (5.1) 5 (8.3) Tachycardia 3 (5.1) 5 (8.5) 1 (1.7) Somnolence 2 (3.4) 9 (15.3) 14 (23.3) Sweating Increased 2 (3.4) 7 (11.9) 4 (6.7) Gastroenteritis 1 (1.7) 4 (6.8) 1 (1.7) Libido Decreased 1 (1.7) 2 (3.4) 10 (16.7) Mouth Dry 1 (1.7) 4 (6.8) 6 (10.0) 6
Vertigo 1 (1.7) 2 (3.4) 5 (8.3) Most Frequent AEs During Follow-Up Phase n (%) n (%) n (%) Subjects With Any AEs 4 (6.8) 11 (18.6) 20 (33.3) Dizziness 1 (1.7) 2 (3.4) 4 (6.7) Nervousness 1 (1.7) 3 (5.1) 2 (3.3) Sweating Increased 0 2 (3.4) 3 (5.0) Vertigo 0 2 (3.4) 11 (18.3) Nausea 0 0 3 (5.0) SAEs During Treatment Phase n (%) [n considered by the investigator to be related to study medication] Subjects With Non-Fatal SAEs 0 0 0 Subjects With Fatal SAEs 0 0 0 SAEs During Follow-Up Phase n (%) [n considered by the investigator to be related to study medication] Subjects With Non-Fatal SAEs 0 0 0 Subjects With Fatal SAEs 0 0 0 Conclusion: The results of the study clearly demonstrated the efficacy of and therapy compared with in the treatment of PMDD, with results for both primary efficacy variables and almost all the secondary efficacy variables showing statistically significant differences compared with. On therapy adverse events were reported in 43 (72.9%) of the placebo group, with headache and nausea being the most frequently reported; in the paroxetine intermittent group 53 (89.9%) of the subjects reported adverse events, with the most frequently reported being nausea and fatigue; in the paroxetine continuous group 57 (95%) subjects reported adverse events with the most frequently reported being nausea, headache and somnolence. No fatal or non-fatal serious adverse events were reported. Publications: Intermittent and continuous paroxetine treatment for pmdd. B. Hunter, M. Landen C. Ysander K. Sorvik H. Nissbrandt C. Allgulander 12th World Congress of Psychiatry 8/24/2002 Yokohama; Japan Date Updated: 01-Dec-2005 7