PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Zoloft / Sertraline THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See United States Package Insert (USPI) NATIONAL CLINICAL TRIAL NO.: NCT00677352 PROTOCOL NO.: A0501088 PROTOCOL TITLE: A Randomized, Double-Blind, Multicenter Study of Sertraline Compared With Paroxetine in the Treatment of Panic Disorder Study Center(s): Thirty-four (34) centers in Japan Study Initiation and Completion Dates: 16 May 2008 to 20 February 2010 Phase of Development: Phase 4 Study Objective(s): To evaluate the efficacy and safety of sertraline hydrochloride (hereinafter referred to as sertraline) in patients with panic disorder with paroxetine hydrochloride hydrate (hereinafter referred to as paroxetine) as the control, and to confirm the clinical positioning of sertraline as a drug for the treatment of panic disorder. The primary objective was to demonstrate the non-inferiority of sertraline in terms of the efficacy. METHODS Study Design: This study was conducted as a multicenter, randomized, double-blind, parallel-group, comparative study. The study consisted of a 2-week washout/observation period and a 16-week double-blind treatment period (12-week treatment phase and 4-week tapering phase) (Figure 1). Prescription A to Prescription D listed in Table 1 below were administered orally once daily after dinner. Page 1
PhRMA Web Synopsis Figure 1. Study Design -Week2 Week0 Week1 Week2 Week4 Week8 Week10 Week16 Week12 Double-blind treatment period Washout Observation Period Visit1 Week6 Tapering phase Treatment phase Visit2 Visit3 Visit4 Visit5 Visit6 Prescription Visit7 Visit8 D Visit9 Visit10 D C C B B mg/ A B A Table 1. Prescriptions Prescription A Prescription B Prescription C Prescription D Sertraline 25 mg/day 50 mg/day 75 mg/day 100 mg/day Paroxetine 10 mg/day 20 mg/day 30 mg/day 30 mg/day Number of Subjects (Planned and Analyzed): Planned: a total of 320 subjects (160 subjects/1 arm) Analyzed: a total of 321 subjects (157 subjects in the sertraline group and 164 subjects in the paroxetine group) Diagnosis and Main Criteria for Inclusion: <At the start of the washout/observation period> Subjects between 20 and 64 years of age with a diagnosis of panic disorder without agoraphobia or panic disorder with agoraphobia according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) diagnostic criteria who experienced at least 4 panic attacks that met the DSM-IV diagnostic criteria within 4 weeks before the start of the washout/observation period. <At the start of the double-blind treatment period> Subjects who experienced at least one panic attack that met the DSM-IV diagnostic criteria per week between the start of the washout/observation period and the start of the double- Page 2
blind treatment period and who had a total score of 18 or higher on the Panic and Agoraphobia Scale (PAS) at the start of the double-blind treatment period. Study Treatment: Sertraline or paroxetine was administered orally once daily after dinner. Once-daily morning administration was allowed if there was any tolerability concern for evening administration, or if treatment compliance could improve compared to evening administration. <Treatment phase: 12 weeks> At Visit 2, subjects were randomized to either sertraline or paroxetine. The study employed a mandatory dose titration regimen; as shown in Table 1, treatment was started from Prescription A, followed by increase to Prescription B at Week 1 (Visit 3), and treatment was continued for 3 weeks. If there was no tolerability concern at Week 4 (Visit 5) at the discretion of the investigator (or subinvestigator), the dose was increased to Prescription C and treatment was continued for 2 weeks. If there was no tolerability concern at Week 6 (Visit 6) at the discretion of the investigator (or subinvestigator), the dose was increased to Prescription D. Even if the efficacy had been achieved at a lower dose, the dose was increased to the maximum dose with an expectation of further effect as long as there was no tolerability concern. If there was any tolerability concern with dose increase, subjects were allowed to remain at the same dose at the discretion of the investigator (or subinvestigator). If there was any tolerability concern after dose increase, the dose could be reduced at the discretion of the investigator (or subinvestigator). If the dose could not be increased to Prescription B even at Week 4 (Visit 5), treatment had to be discontinued. <Tapering phase: 4 weeks> Prescription B was administered for 1 week after Week 12 (Visit 9), followed by Prescription A for 1 week, and no study medication during the last 2 weeks. The details of the study drugs are shown in Table 2. Table 2. Study Drug Drug Potency Formulation Sertraline 25 mg Tablet Sertraline Placebo Tablet Paroxetine 10 mg Capsule Paroxetine Placebo Capsule Efficacy Evaluations: Primary endpoint: Change from baseline in the PAS total score at the end of the treatment phase (Week 12)/discontinuation was evaluated. The change in the PAS total score was Page 3
chosen as the primary endpoint because the PAS is a measure that enables a more comprehensive evaluation of panic disorder than frequency of panic attacks. Secondary endpoints: Clinical Global Impression of Improvement (CGI-I), frequency of panic attacks, Hamilton Anxiety Scale (HAM-A) total score, and Hamilton depression rating scale (HAM-D) total score. Safety Evaluations: Adverse events, Antidepressant Discontinuation Scale (ADDS), physical examination, weight, blood pressure, pulse rate, 12-lead electrocardiograms, and clinical laboratory testing (hematology, serum chemistry, urinalysis) Statistical Methods: Efficacy analysis The Efficacy Evaluable Set (EES) was set as the primary analysis set, the Full Analysis Set (FAS) was set as the secondary analysis set, and the Completer Set (CS) was set as the efficacy analysis set for the tapering phase. As for the primary analysis of the primary endpoint, the two-sided 95% confidence interval (CI) of the intergroup difference (sertraline group paroxetine group) of the mean reduction in the PAS total score at each dose during the treatment phase was calculated using an analysis of covariance (ANCOVA) model with treatment group as a factor and baseline PAS total score as a covariate, and sertraline was concluded to be non-inferior to paroxetine when the upper limit of the CI fell below the non-inferiority margin of 4. As for the secondary analysis for the treatment phase, the adjusted mean of the intergroup difference of the mean reduction and the two-sided 95% CI were estimated based on the analysis using a repeatedmeasures model to evaluate changes in the PAS total score over time. In addition, summary statistics were calculated for the PAS total score at each week and change from baseline in the PAS total score. As for the secondary analysis for the tapering phase, change in the PAS total score from Week 12 to Week 16 was compared between treatment groups using t test. As for the secondary endpoints, the summary statistics (mean, standard deviation, median, minimum, and maximum) of each measured value and change from baseline were calculated for each treatment group. Subjects with remarkably or moderately improved CGI-I were regarded as improved subjects, and the proportion of improved subjects at each week was compared between the treatment groups using Fisher s exact test to evaluate changes over time during the treatment phase. The log-transformed frequency of panic attacks and HAM- A total score were analyzed using a repeated-measures model. In addition, change from baseline in the HAM-D total score was compared between the treatment groups using t test. For the tapering phase, the proportion of subjects with improved CGI-I at Week 16 was compared between the treatment groups using Fisher s exact test. Changes in the logtransformed frequency of panic attacks, HAM-A total score, and HAM-D total score from Week 12 to Week 16 were compared between the treatment groups using t test, as well as using an ANCOVA model. Page 4
Safety analysis The safety analysis was performed including subjects who had taken at least one dose of the study drug and who had visited the study center at least once after taking the study drug in the safety analysis set. Unless otherwise specified, the safety data were analyzed in accordance with the algorithm and format specified in Pfizer Data Standards which shows the Sponsor s standard data collection and reporting methods. Tabulation was performed separately for the treatment phase and tapering phase. RESULTS Subject Disposition and Demography: Among the subjects enrolled in the study, 321 subjects were randomized to either treatment group; sertraline was administered to 157 subjects and paroxetine was administered to 162 subjects. Among the randomized subjects, 2 subjects in the paroxetine group were withdrawn from the study without taking any dose of the study drug due to withdrawal of consent. Among the treated subjects, 126 subjects (80.3%) in the sertraline group and 112 subjects (68.3%) in the paroxetine group completed the study. During the treatment phase, 25 subjects in the sertraline group and 40 subjects in the paroxetine group were withdrawn from the study. The most common reason for withdrawal was adverse events related to the study drug, and these were noted in 11 subjects in the sertraline group and 12 subjects in the paroxetine group. In addition, 6 subjects in the sertraline group and 10 subjects in the paroxetine group were withdrawn from the study during the tapering phase. The most common reasons for withdrawal were withdrawal of consent (5 subjects) in the sertraline group and adverse events related to the study drug and withdrawal of consent (3 subjects each) in the paroxetine group (Table 3). Table 3. Subject Disposition [Number of subjects (%)] Sertraline Paroxetine Assigned to Study Treatment 157 164 Treated 157 162 Completed 126 (80.3) 112 (68.3) Discontinued 31 (19.7) 50 (30.5) <Treatment Phase> <Tapering Phase> <Treatment Phase> <Tapering Phase> Discontinued 25 6 40 10 Reason for Discontinuations Related to Study Drug 13 1 15 3 Adverse event 11 1 12 3 Lack of efficacy 2-3 - Not Related to Study Drug 12 5 25 7 Adverse event 3 0 10 2 Lost to follow-up 0-1 - Other 2 0 7 2 Subject no longer willing to participate in study 7 5 7 3 Page 5
Among the subjects enrolled, 2 subjects did not receive the study drug, while 157 subjects in the sertraline group and 162 subjects in the paroxetine group received at least one dose of the study drug (safety analysis set). Excluding 4 with inappropriate efficacy evaluation, 155 subjects in the sertraline group and 160 subjects in the paroxetine group evaluated for efficacy at least one assessment point after receiving the study drug were included in the FAS. Of them, 127 subjects in the sertraline group and 127 subjects in the paroxetine group met the criteria for the EES, and 124 subjects in the sertraline group and 118 subjects in the paroxetine group were included in the CS (Table 4). Table 4. Subject Evaluation Groups Sertraline Paroxetine Assigned to Study Treatment 157 164 Analyzed for Efficacy Full Analysis Set (FAS) 155 (98.7) 160 (97.6) Efficacy Evaluable Set (EES) 127 (80.9) 127 (77.4) Completer Set (CS) 124 (79.0) 118 (72.0) Analyzed for Safety Adverse events 157 (100) 162 (98.8) Laboratory data 156 (99.4) 159 (97.0) The numbers of male and female subjects in the analysis set were 44 and 113, respectively, in the sertraline group, and 53 and 109, respectively, in the paroxetine group; the proportion of female subjects was higher than that of male subjects in both treatment groups. The mean age was 37.9 years in the sertraline group and 36.9 years in the paroxetine group, and all subjects were between 20 and 64 years of age in both treatment groups. As for diagnosis, subjects with a diagnosis of panic disorder with agoraphobia outnumbered those with a diagnosis of panic disorder without agoraphobia in both treatment groups. There was little difference in the duration of disease between the treatment groups for both subjects with panic disorder with agoraphobia and those without agoraphobia. There was no imbalance in any of the subject background factors between the treatment groups. Efficacy Results: The intergroup difference of the mean reduction in the PAS total score in the EES during the treatment phase [sertraline paroxetine: adjusted mean (95% CI)], the primary endpoint, was -0.4 (-2.5, 1.6), and the upper limit of the 95% CI (1.6) fell below the non-inferiority margin of 4 (Table 5). Thus, the non-inferiority of sertraline to paroxetine was demonstrated. The adjusted mean (95% CI) of the intergroup difference of the mean reduction in the PAS total score in the FAS was -1.2 (-3.5, 1.1), and the upper limit of the 95% CI also fell below the non-inferiority margin of 4. Page 6
Table 5. PAS Total Score During the Treatment Phase (EES) Sertraline Paroxetine Number of subjects 127 127 Baseline Mean ± Standard Deviation 27.0±5.9 27.4±6.0 Week 12 (LOCF) a Mean ± Standard Deviation 9.7±8.3 10.3±8.8 Change from Baseline Mean ± Standard Deviation -17.3±9.3-17.1±9.0 Adjusted Mean b -17.4-17.0 95% confidence interval -18.9, -15.9-18.4, -15.5 Adjusted Mean Difference b -0.4 95% CI -2.5, 1.6 a: Last Observation Carried Forward b: Adjusted for baseline PAS total score As for changes from baseline in the PAS total score during the treatment phase, the reductions became greater over time for both sertraline and paroxetine, and the degree of improvement throughout the treatment phase was comparable between the treatment groups. As for the PAS subscores (panic attacks, agoraphobia/limited avoidance, anticipatory anxiety, disability due to the disease, and worries about health), the degree of improvement was also comparable between sertraline and paroxetine. As for the changes from baseline in the CGI-I, frequency of panic attacks, HAM-A total score, and HAM-D total score at Week 12/discontinuation during the treatment phase, the degree of improvement was comparable between sertraline and paroxetine for all these endpoints. As for the changes in the PAS total score, CGI-I, frequency of panic attacks, HAM-A total score, and HAM-D total score from Week 12 to Week 16 during the tapering phase, the degree of improvement was comparable between sertraline and paroxetine for all these endpoints. Safety Results: Table 6 summarizes adverse events during the treatment phase. All-causality adverse events observed in 3% of subjects from any group during the treatment phase are presented in Table 7. During the treatment phase, all-causality adverse events were noted in 127/157 subjects (80.9%) in the sertraline group and 134/162 subjects (82.7%) in the paroxetine group; the incidence was comparable between the treatment groups. Common all-causality adverse events that occurred during the treatment phase were somnolence, nausea, nasopharyngitis, diarrhoea, headache, and constipation in both the sertraline and paroxetine groups. During the treatment phase, treatment-related adverse events were noted in 108/157 subjects (68.8%) in the sertraline group and 120/162 subjects (74.1%) in the paroxetine group; the incidence was lower in the sertraline group than in the paroxetine group. Common treatment-related adverse events that occurred during the treatment phase were somnolence, nausea, diarrhoea, headache, and constipation in both the sertraline and paroxetine groups. The incidences of somnolence, nausea, headache, and constipation were Page 7
higher in the paroxetine group, whereas the incidence of diarrhoea was higher in the sertraline group. Table 6. Summary of Adverse Events During the Treatment Phase All-causality Treatment-related Sertraline Paroxetine Sertraline Paroxetine Subjects evaluable for adverse events 157 162 157 162 Subjects with adverse events (%) 127 (80.9) 134 (82.7) 108 (68.8) 120 (74.1) Number of adverse events 372 474 259 367 Subjects with serious adverse events a 1 2 1 0 Subjects with severe adverse events (%) 3 (1.9) 14 (8.6) 3 (1.9) 10 (6.2) Subjects discontinued due to adverse events (%) 14 (8.9) 23 (14.2) 11 (7.0) 12 (7.4) Subjects with dose reduced or temporary discontinuation due to adverse events (%) 13 (8.3) 14 (8.6) 13 (8.3) 12 (7.4) a: The number of subjects with serious adverse events is based on the information from the safety data base. Page 8
Table 7. All-causality Adverse Events During the Treatment Phase (Incidence 3% in Any Group) System Organ Class and Sertraline Paroxetine MedDRA (version 12.1) Preferred Term (%) Subjects evaluable for adverse events 157 162 Cardiac disorders 6 (3.8) 10 (6.2) Palpitations 6 (3.8) 7 (4.3) Ear and labyrinth disorders 3 (1.9) 9 (5.6) Tinnitus 1 (0.6) 5 (3.1) Gastrointestinal disorders 77 (49.0) 78 (48.1) Abdominal discomfort 7 (4.5) 6 (3.7) Abdominal pain upper 11 (7.0) 8 (4.9) Constipation 7 (4.5) 23 (14.2) Diarrhoea 28 (17.8) 18 (11.1) Dry mouth 15 (9.6) 10 (6.2) Nausea 34 (21.7) 46 (28.4) General disorders and administration site conditions 26 (16.6) 36 (22.2) Irritability 1 (0.6) 7 (4.3) Malaise 11 (7.0) 16 (9.9) Thirst 6 (3.8) 7 (4.3) Infections and infestations 40 (25.5) 35 (21.6) Nasopharyngitis 30 (19.1) 30 (18.5) Metabolism and nutrition disorders 6 (3.8) 8 (4.9) Decreased appetite 6 (3.8) 8 (4.9) Musculoskeletal and connective tissue disorders 14 (8.9) 12 (7.4) Musculoskeletal stiffness 7 (4.5) 1 (0.6) Myalgia 1 (0.6) 6 (3.7) Nervous system disorders 48 (30.6) 82 (50.6) Dizziness 9 (5.7) 8 (4.9) Headache 12 (7.6) 23 (14.2) Hypoaesthesia 3 (1.9) 5 (3.1) Somnolence 31 (19.7) 56 (34.6) Tremor 1 (0.6) 8 (4.9) Psychiatric disorders 22 (14.0) 35 (21.6) Insomnia 13 (8.3) 16 (9.9) Respiratory, thoracic and mediastinal disorders 6 (3.8) 10 (6.2) Yawning 1 (0.6) 5 (3.1) Skin and subcutaneous tissue disorders 20 (12.7) 18 (11.1) Hyperhidrosis 5 (3.2) 8 (4.9) Urticaria 5 (3.2) 2 (1.2) Table 8 summarizes adverse events during the tapering phase. All-causality adverse events observed in 3% of subjects from any group during the tapering phase are presented in Table 9. During the tapering phase, all-causality adverse events were noted in 73/132 subjects (55.3%) in the sertraline group and 87/122 subjects (71.3%) in the paroxetine group; the incidence was lower in the sertraline group than in the paroxetine group. Common allcausality adverse events that occurred during the tapering phase were dizziness, nausea, anxiety, headache, and diarrhoea in both the sertraline and paroxetine groups. The incidences of these events were lower in the sertraline group. During the tapering phase, treatment-related adverse events were noted in 60/132 subjects (45.5%) in the sertraline group and 85/122 subjects (69.7%) in the paroxetine group; the incidence was lower in the sertraline group than in the paroxetine group. Common treatment-related adverse events that occurred during the tapering phase were dizziness, nausea, anxiety, and headache in both the Page 9
sertraline and paroxetine groups. The incidences of these events were lower in the sertraline group. Table 8. Summary of Adverse Events During the Tapering Phase All-causality Treatment-related Sertraline Paroxetine Sertraline Paroxetine Subjects evaluable for adverse events 132 122 132 122 Subjects with adverse events (%) 73 (55.3) 87 (71.3) 60 (45.5) 85 (69.7) Number of adverse events 253 465 224 442 Subjects with serious adverse events a 1 2 1 0 Subjects with severe adverse events (%) 11 (8.3) 16 (13.1) 11 (8.3) 15 (12.3) Subjects discontinued due to adverse events (%) 1 (0.8) 4 (3.3) 1 (0.8) 3 (2.5) Subjects with dose reduced or temporary discontinuation due to adverse events (%) 0 0 0 0 a: The number of subjects with serious adverse events is based on the information from the safety data base. Page 10
Table 9. All-causality Adverse Events During the Tapering Phase (Incidence 3% in Any Group) System Organ Class and Sertraline Paroxetine MedDRA (version 12.1) Preferred Term (%) Subjects evaluable for adverse events 132 122 Cardiac disorders 6 (4.5) 14 (11.5) Palpitations 1 (0.8) 4 (3.3) Tachycardia 5 (3.8) 11 (9.0) Ear and labyrinth disorders 6 (4.5) 27 (22.1) Tinnitus 0 6 (4.9) Vertigo 6 (4.5) 20 (16.4) Gastrointestinal disorders 22 (16.7) 41 (33.6) Diarrhoea 13 (9.8) 16 (13.1) Nausea 12 (9.1) 31 (25.4) Vomiting 4 (3.0) 9 (7.4) General disorders and administration site conditions 25 (18.9) 47 (38.5) Asthenia 5 (3.8) 13 (10.7) Chills 7 (5.3) 16 (13.1) Fatigue 9 (6.8) 16 (13.1) Feeling jittery 6 (4.5) 15 (12.3) Irritability 7 (5.3) 17 (13.9) Infections and infestations 13 (9.8) 8 (6.6) Nasopharyngitis 10 (7.6) 5 (4.1) Musculoskeletal and connective tissue disorders 6 (4.5) 10 (8.2) Myalgia 6 (4.5) 10 (8.2) Nervous system disorders 48 (36.4) 70 (57.4) Crying 2 (1.5) 4 (3.3) Disturbance in attention 9 (6.8) 16 (13.1) Dizziness 36 (27.3) 58 (47.5) Headache 10 (7.6) 27 (22.1) Hypoaesthesia 2 (1.5) 4 (3.3) Myoclonus 4 (3.0) 6 (4.9) Paraesthesia 4 (3.0) 11 (9.0) Somnolence 5 (3.8) 12 (9.8) Tremor 5 (3.8) 12 (9.8) Psychiatric disorders 28 (21.2) 42 (34.4) Abnormal dreams 4 (3.0) 11 (9.0) Anxiety 16 (12.1) 21 (17.2) Depression 7 (5.3) 10 (8.2) Insomnia 7 (5.3) 16 (13.1) Mood altered 7 (5.3) 15 (12.3) Respiratory, thoracic and mediastinal disorders 3 (2.3) 6 (4.9) Yawning 2 (1.5) 5 (4.1) Skin and subcutaneous tissue disorders 11 (8.3) 10 (8.2) Hyperhidrosis 11 (8.3) 10 (8.2) As for the severity of adverse events noted during the treatment phase, the proportion of mild events was the highest in both treatment groups. The severity of most of the adverse events noted during the tapering phase was mild or moderate in both treatment groups. The incidence of severe adverse events during the treatment phase and tapering phase in the sertraline group was lower than that in the paroxetine group. Details of subjects who discontinued the double-blind phase due to treatment-related adverse events are presented in Table 10. During the treatment phase, the number of subjects withdrawn from the study due to treatment-related adverse events was 11 in the sertraline Page 11
group and 12 in the paroxetine group. During the tapering phase, the number of subjects withdrawn from the study due to treatment-related adverse events was 1 in the sertraline group and 3 in the paroxetine group. Table 10. Discontinued Subjects due to the Adverse Events Age/Sex MedDRA (version 12.1) Preferred Term Start day Stop day Causality Severity Outcome Treatment phase - Sertraline group 25/Female Ear discomfort 5 16 Yes Mild Recovered 40/Female Insomnia 1 8 Yes Mild Recovered 40/Male Suffocation feeling 3 4 No Severe Recovered 22/Female Depression 30 >30 No Moderate Still present 30/Female Dizziness 2 5 Yes Moderate Recovered 48/Male Headache 1 >8 Yes Moderate Still present 41/Female Nausea 2 4 Yes Moderate Recovered 53/Female Dizziness 3 >3 Yes Mild Still present 34/Female Vomiting 2 3 Yes Moderate Recovered 58/Female Erythema multiforme 26 >29 Yes Severe Recovered 29/Female Depression 18 99 No Moderate Recovered 42/Male Panic disorder 4 >4 Yes Moderate Still present 39/Female Drug eruption 15 >17 Yes Moderate Still present 40/Female Somnolence 9 25 Yes Mild Recovered Treatment phase - Paroxetine group 23/Female Enteritis infectious 17 >35 No Severe Still present 37/Female Panic attack 1 15 Yes Severe Recovered 31/Female Intentional overdose 70 70 No Mild Recovered 29/Female Depression 81 >84 No Mild Still present 30/Female Panic attack 4 >4 No Moderate Still present 57/Female Smear cervix abnormal 44 >99 No Moderate Still present 30/Female Depressed level of consciousness 2 10 Yes Mild Recovered 24/Female Nausea 9 37 Yes Moderate Recovered 31/Male Anxiety 23 >24 No Moderate Still present 58/Female Insomnia 3 >11 Yes Mild Still present 36/Female Panic disorder 10 >12 Yes Severe Still present 44/Female Palpitations 3 4 Yes Severe Recovered 33/Male Panic disorder 12 >15 No Moderate Still present 31/Male Panic disorder 10 >12 No Moderate Still present 34/Female Delirium 65 65 No Severe Recovered 20/Female Panic disorder 2 >5 No Moderate Still present 56/Male Insomnia 2 >3 Yes Severe Still present 31/Female Headache 7 >10 Yes Moderate Still present 58/Female Vomiting 76 76 No Mild Recovered 64/Female Palpitations 2 >8 Yes Mild Still present 43/Female Blood pressure increased 72 85 Yes Mild Recovered 23/Female Galactorrhoea 2 >27 Yes Moderate Still present 34/Male Malaise 2 >8 Yes Mild Still present Tapering phase - Sertraline group 39/Female Headache 98 102 Yes Moderate Recovered Tapering phase - Paroxetine group 26/Female Panic disorder 88 >99 No Moderate Still present 29/Female Anxiety 99 >111 Yes Severe Still present 39/Female Dizziness 97 >102 Yes Severe Still present 38/Female Dizziness 110 >113 Yes Moderate Still present No subject died in this study. Other serious adverse events are presented in Table 11. Allcausality serious adverse events were noted in 2 subjects in the sertraline group and 4 Page 12
subjects in the paroxetine group. Among these, treatment-related adverse events were erythema multiforme (1 subject), and depression and suicidal ideation (both in 1 subject) in the sertraline group. These events were confirmed to have resolved. Table 11. Serious Adverse Events Age/Sex MedDRA (version 12.1) Preferred Term Latest dose Start day Causality Outcome Sertraline group 58/Female Erythema multiforme 50 mg/day 13 Yes Recovered 41/Male Depression 25 mg/day 98 Yes Recovered Suicidal ideation 25 mg/day 102 Yes Recovered Paroxetine group 23/Female Enteritis infectious 20 mg/day 17 No Recovered 57/Female Cervix carcinoma 10 mg/day 131 No Still present 40/Female Ectopic pregnancy 20 mg/day 86 No Recovered 58/Female Inguinal hernia 30 mg/day 67 No Recovered The incidence of laboratory abnormalities, regardless of whether the baseline value was within or outside the reference range, was comparable between the sertraline and paroxetine groups. Laboratory abnormalities with an incidence of 10% or higher were urinary occult blood positive (qualitative), and no other specific items showed high incidences. No severe or serious adverse events concerning laboratory abnormalities were noted. As for the ADDS score at Week 16, the proportion of subjects who had experienced new symptoms, regardless of causal relationship with the study drug, or worsening of the severity compared with Week 12 was 59.7% in the sertraline group, and the incidence was significantly lower (P = 0.0062) than that in the paroxetine group (76.3%). As for physician s impression of discontinuation symptoms on the ADDS at Week 16, the incidence of discontinuation symptoms was significantly lower (P = 0.0003) in the sertraline group than in the paroxetine group. Changes from baseline in the blood pressure, pulse rate, and weight were comparable between the sertraline and paroxetine groups. CONCLUSION(S): In this study, the efficacy and safety of sertraline in Japanese patients with panic disorder were evaluated with paroxetine as the control. As for efficacy, the intergroup difference of the mean reduction in the PAS total score in the EES [sertraline paroxetine: adjusted mean (95% CI)], the primary endpoint, was -0.4 (-2.5, 1.6), and the upper limit of the 95% CI fell below the non-inferiority margin of 4. Thus, the non-inferiority of sertraline to paroxetine was demonstrated. In addition, the efficacy of sertraline was also demonstrated to be comparable to that of paroxetine in other efficacy endpoints in the FAS, as well as in the EES, and this supports the result for the primary endpoint. The incidence of adverse events during the treatment phase and tapering phase in the sertraline group was lower than that in the paroxetine group. The incidence of discontinuation symptoms during the tapering phase was lower in the sertraline group than in the paroxetine group, based on adverse events and the results of ADDS that enables a Page 13
comprehensive evaluation of discontinuation symptoms. The results of other safety evaluations were comparable between the sertraline and paroxetine groups. In the treatment of panic disorder in Japanese patients, sertraline showed comparable efficacy and better safety profiles when compared with paroxetine. Page 14