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Confidential Paroxetine 29060 A Multi-center, Double-blind, Placebo Controlled Study of Paroxetine and Imipramine in Adolescents with Unipolar Major Depression- Acute Phase 29060/329 Final Clinical Report xxxxx x xxxxxx, B.S.*, xxxx xxxxx, Ph.D.* xxxxx x xxxxxxxxxx, B.S.*, xxxxxxxx xxxxx, M.S.** *Clinical Research, **Biometrics SB Document Number: BRL-029060/RSD-100TW9/1 Issue Date: 24 November 1998 BRL-029060/RSD-100TW9/1/CPMS-329 000001 www.cuwai.com BRL-029060/RSD-100TW9/1/CPMS-329 000002 www.cuwai.com Table of Contents List of Tables. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000006 List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000009 List of Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000010 List of Abbreviations and Definitions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 000011 Report Synopsis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000013 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000022 2 Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000024 2.1 Primary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000024 2.2 Secondary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000024 3 Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000025 3.1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000025 3.1.1 Protocol Amendments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000026 3.2 Investigators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000028 3.3 Ethics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000030 3.4 Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000030 3.4.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000030 3.4.2 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000030 3.5 Treatments and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . 000032 3.5.1 Study Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000032 3.5.2 Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . 000033 3.5.3 Methods of Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000035 3.5.4 Other Protocol-specified Therapy . . . . . . . . . . . . . . . . . . . . . . 000035 3.6 Compliance with Study Medication. . . . . . . . . . . . . . . . . . . . . . . . 000036 3.7 Prior and Concomitant Medication . . . . . . . . . . . . . . . . . . . . . . . . 000036 3.7.1 Prior Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000036 3.7.2 Concomitant Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000036 3.8 Study Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000036 3.8.1 Schedule of Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000036 3.8.2 Prestudy Screening and Enrollment . . . . . . . . . . . . . . . . . . . . 000037 3.8.3 Treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000039 3.8.4 Post-treatment Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000040 3.8.5 Reasons for Concluding Study . . . . . . . . . . . . . . . . . . . . . . . . 000040 3.9 Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000041 3.9.1 Primary Efficacy Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . 000043 3.9.2 Secondary Efficacy Parameters . . . . . . . . . . . . . . . . . . . . . . . . 000044 3.10 Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000044 3.10.1 Adverse Experiences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000044 BRL-029060/RSD-100TW9/1/CPMS-329 000003 www.cuwai.com 3.10.2 Laboratory Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000045 3.10.3 Vital Signs and Body Weight . . . . . . . . . . . . . . . . . . . . . . . . 000046 3.10.4 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000046 3.10.5 Pregnancy Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000046 3.11 Plasma/Serum Concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . 000046 3.12 Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000047 3.13 Statistical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000048 3.13.1 Comparison of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000049 3.13.2 Target Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000049 3.13.3 Method of Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . 000049 3.13.4 Planned Efficacy Evaluations . . . . . . . . . . . . . . . . . . . . . . . . 000049 3.13.5 Methods of Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000050 3.13.6 Populations/Data Sets to be Evaluated . . . . . . . . . . . . . . . . . 000051 3.13.7 Safety Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000054 4 Study Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000056 4.1 Study Dates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000056 4.2 Patient Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000056 4.2.1 Number and Distribution of Patients . . . . . . . . . . . . . . . . . . . . 000056 4.2.2 Number of Patients Present at Each Visit . . . . . . . . . . . . . . . . 000057 4.2.3 Withdrawal Reasons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000058 4.3 Protocol Violations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000060 4.3.1 Protocol Violations Excluded from the Per-Protocol Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000060 4.3.2 Protocol Deviations Included in the Per-Protocol Population. 000061 4.4 Demographic and Baseline Characteristics . . . . . . . . . . . . . . . . . . 000063 4.4.1 Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . 000063 4.4.2 Baseline Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000064 4.5 Presenting Conditions and Medical History. . . . . . . . . . . . . . . . . . 000065 4.6 Prior and Concomitant Medications. . . . . . . . . . . . . . . . . . . . . . . . 000067 4.7 Treatment Compliance and Titration . . . . . . . . . . . . . . . . . . . . . . . 000068 4.7.1 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000068 4.7.2 Titration of Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000069 5 Efficacy Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000071 5.1 Efficacy Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000071 5.1.1 Data Sets Analyzed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000071 5.2 Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000071 5.2.1 Change from Baseline in Total HAM-D Score . . . . . . . . . . . . 000071 5.2.2 Change from Baseline in HAM-D Subscales . . . . . . . . . . . . . 000073 5.2.3 Responders and Remission Analysis . . . . . . . . . . . . . . . . . . . . 000074 BRL-029060/RSD-100TW9/1/CPMS-329 000004 www.cuwai.com 5.2.4 Sustained Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000078 5.2.5 CGI Improvement Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000079 5.2.6 K-SADS-L - Depression 9-Item Scale - Change from Baseline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000083 5.2.7 Change from Baseline in K-SADS-L Depressed Mood Item . 000085 5.3 Functional, Self Perceptive and Behavioral Scales . . . . . . . . . . . . 000086 5.3.1 Autonomous Functioning Checklist . . . . . . . . . . . . . . . . . . . . 000086 5.3.2 Self Perception Profile. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000087 5.3.3 Sickness Impact Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000088 5.4 Efficacy Subgroup Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000089 6 Safety Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000092 6.1 Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000092 6.2 Adverse Experiences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000094 6.2.1 Adverse Experiences by Severity . . . . . . . . . . . . . . . . . . . . . . 000101 6.2.2 Adverse Experiences by Time of First Occurrence. . . . . . . . . 000102 6.3 Dose Reductions for Adverse Experiences . . . . . . . . . . . . . . . . . . 000104 6.4 Adverse Experiences Requiring Corrective Treatment . . . . . . . . . 000105 6.5 Deaths. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000106 6.6 Serious Non-fatal Adverse Experiences. . . . . . . . . . . . . . . . . . . . . 000106 6.7 Withdrawals for Adverse Experiences . . . . . . . . . . . . . . . . . . . . . . 000110 6.8 Vital Signs and Body Weight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000114 6.9 Other Safety Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000117 6.10 Laboratory Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000118 7 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000121 8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000124 9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000125 10 Data Source Tables: Study Population . . . . . . . . . . . . . . . . . . . . . . . . 000128 11 Data Source Tables: Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . 000186 12 Data Source Tables: Safety Results . . . . . . . . . . . . . . . . . . . . . . . . . . 000222 13 Data Source Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000527 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000529 BRL-029060/RSD-100TW9/1/CPMS-329 000005 www.cuwai.com List of Tables Table 1 Principal Investigators, the SB Assigned Center Number and Affiliations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000029 Table 2 Appearance, Formulation, Dosage Strengths, and Batch Numbers of Study Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000032 Table 3 Dosing Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000034 Table 4 Schedule of Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000037 Table 5 Comparison of HAM-D 17-Item Scale and K-SADS-L 9-Item Depression Subscale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000042 Table 6 Criteria for Assessment of Vital Signs . . . . . . . . . . . . . . . . . . . . 000054 Table 7 Number of Patients Who Were Randomized (R) to Each Treatment Group and Who Completed* (C) Acute Phase of Treatment at Each Center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000057 Table 8 Number of Patients Remaining in the Study by Visit and Treatment Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000058 Table 9 Number (%) of Randomized Patients Who Completed or Were Withdrawn from the Study, by Reason for Withdrawal . . . . . . . . . . . . . 000059 Table 10 Number and Cumulative Percentage of Patients Withdrawn from the Study by Reason and by Week. . . . . . . . . . . . . . . . . . . . . . . . . 000060 Table 11 Numbers of Patients With Protocol Violations Leading to Exclusion From the Per-Protocol Analysis. . . . . . . . . . . . . . . . . . . . . . . 000061 Table 12 Numbers of Patients With Protocol Deviations Included in the Per-Protocol Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000062 Table 13 Demographic Characteristics of Randomized Patients . . . . . . . 000063 Table 14 Baseline Characteristics Regarding Major Depressive Disorder of All Randomized Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . 000065 Table 15 Medical or Surgical Conditions Occurring in 3 or More of Patients in Any Treatment Group at Baseline (number (%) of patients) 000066 Table 16 Presenting Conditions Occurring in 3 or More of Patients in Any Treatment Group at Baseline (number (%) of patients) . . . . . . . . . 000067 Table 17 Concomitant Medications Received by 5% or More of Patients in Any Treatment Group (number (%) of patients). . . . . . . . . . 000068 Table 18 Summary of Patient Compliance with Study Medication over the 8 Week Treatment Period (number (%) of patients) . . . . . . . . . . . . 000069 Table 19 Number of Patients at Dose Level by Treatment Group and Study Week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000070 Table 20 Baseline Mean (+/- SE) and Mean Change from Baseline (+/- SE) in Total HAM-D Score for OC Dataset at Each Treatment Week and the LOCF Dataset at Week 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000072 Table 21 Week 8 (OC and LOCF) Mean Treatment Differences (95% C.I.) in Total HAM-D Score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000072 BRL-029060/RSD-100TW9/1/CPMS-329 000006 www.cuwai.com Table 22 Baseline Mean (+/- SE) and Mean Change from Baseline (+/- SE) in Mood Item and Factors* of the HAMD for the Week 8 LOCF and OC Week 8 Datasets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000074 Table 23 Number (%) of Patients Who Responded* to Treatment for OC Dataset at Each Treatment Week and the LOCF Dataset at Week 8 000076 Table 24 Week 8 (OC and LOCF) Mean Treatment Difference (95% C.I.) of Patients who Responded*. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000076 Table 25 Number (%) of Patients in Remission* for OC Dataset at Each Treatment Week and the LOCF Dataset at Week 8 . . . . . . . . . . . . . . . . 000076 Table 26 Week 8 (OC and LOCF) Mean Treatment Difference (95% C.I.) of Patients in Remission* . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000077 Table 27 Survival Analysis of Sustained Response During the Acute Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000079 Table 28 Mean Improvement Score (+/- SE) on the CGI Scale for OC Dataset at Each Treatment Week and the LOCF Dataset at Week 8 . . . 000080 Table 29 Week 8 (OC and LOCF) Mean Treatment Differences (95% C.I.) on the CGI Scale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000080 Table 30 Number and Percent of Patients Having a CGI Score of "Very Much Improved" or "Much Improved" for OC Dataset at Each Treatment Week and the LOCF Dataset at Week 8 . . . . . . . . . . . . . . . . 000082 Table 31 Week 8 (OC and LOCF) Mean Treatment Differences (95% C.I.) of Patients Having a CGI Score of "Very Much Improved" or "Much Improved" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000082 Table 32 Baseline Mean (+/- SE) and Change from Baseline (+/- SE) in K-SADS-L - Depression 9-Item Scale for OC Dataset at Each Treatment Week and the LOCF Dataset at Week 8 . . . . . . . . . . . . . . . . 000084 Table 33 Week 8 (OC and LOCF) Mean Treatment Differences (95% C.I.) in K-SADS-L Depression 9-Item Scale . . . . . . . . . . . . . . . . . . . . . 000084 Table 34 Baseline Mean (+/- SE) and Mean Change from Baseline (+/- SE) in Depressed Mood Item of the K-SADS-L Depression Scale for the Week 8 OC and Week 8 LOCF Datasets . . . . . . . . . . . . . . . . . . . . . 000086 Table 35 Week 8 (OC and LOCF) Mean Treatment Differences (95% C.I.) in Depressed Mood Item. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000086 Table 36 Baseline Mean (+/- SE) and Mean Change from Baseline (+/- SE) in Total Score and Subscores on the Autonomous Functioning Checklist at Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000087 Table 37 Baseline Mean (+/- SE) and Mean Change from Baseline (+/- SE) in Total Score on the Self Perception Profile for the Week 8 OC and Week 8 LOCF Datasets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000088 Table 38 Baseline Mean (+/- SE) and Mean Change from Baseline (+/- SE) in Total Score and Subscores on the Sickness Impact Profile for the Week 8 OC and Week 8 LOCF Datasets . . . . . . . . . . . . . . . . . . . . . 000089 Table 39 Summary of Responders by Subgroup at Endpoint . . . . . . . . . 000090 Table 40 Summary of Covariate Analysis for Responders at Endpoint . 000091 BRL-029060/RSD-100TW9/1/CPMS-329 000007 www.cuwai.com Table 41 Exposure of Patients to Each Daily Dose of Study Drug (in mg) and Duration of Exposure, by Treatment Group (number (%) of patients). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000093 Table 42 Treatment-emergent Adverse Experiences Most Frequently Reported (by = or > 5% in Any Treatment Regimen), by Body System and Preferred Term (number (%) of patients). . . . . . . . . . . . . . . . . . . . . 000096 Table 43 Number and Percent of Patients with Adverse Experiences by Age (by = or >5% in Any Group), by Body System, and Preferred Term (number (%) patients) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000098 Table 44 Severe Treatment-emergent Adverse Experience and those Occurring in More Than One Patient in any Group (number ( %) of patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000101 Table 45 Number (%) of Patients of the Four Most Frequently Reported Treatment-emergent Adverse Experiences by the Time of First Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000103 Table 46 Treatment-emergent Adverse Experiences That Led to Dose Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000105 Table 47 Adverse Experiences That Required Corrective Treatment (>= 5%), Regardless of Attribution to Study Medication . . . . . . . . . . . . . . . 000106 Table 48 Serious Non-fatal Adverse Experiences . . . . . . . . . . . . . . . . . . 000109 Table 49 Treatment-emergent Adverse Experiences, Regardless of Attribution, Leading to Withdrawal (number (%) of patients) . . . . . . . . 000111 Table 50 Adverse Experiences Leading to Withdrawal. . . . . . . . . . . . . . 000113 Table 51 Vital Signs and Body Weight at Screening, Baseline and at Endpoint (mean +/- SD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000116 Table 52 Number (%) of Patients with Vital Sign or Body Weight Values of Potential Clinical Concern at Any Time During Treatment. . 000117 Table 53 Criteria for Flagging of Selected Laboratory Parameters . . . . . 000119 Table 54 Number of Patients with Laboratory Values Considered to Be of Clinical Concern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000120 BRL-029060/RSD-100TW9/1/CPMS-329 000008 www.cuwai.com List of Figures Figure 1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000026 Figure 2 Titration Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000033 Figure 3 Mean Change from Baseline (SE) in Total HAM-D Score for the Week 8 LOCF and Week 8 OC Datasets . . . . . . . . . . . . . . . . . . . . . 000073 Figure 4 Percent of Patients in LOCF and OC Datasets Achieving Responder and Remission Status* . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000078 Figure 5 Kaplan Meier Survival Curves for Time to Sustained Response During Acute Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000079 Figure 6 Mean CGI Score (SE) for Week 8 LOCF and Week 8 OC Datasets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000081 Figure 7 Percent of Patients Very Much Improved and Much Improved in CGI Global Improvement at Endpoint . . . . . . . . . . . . . . . . . . . . . . . . 000083 Figure 8 Mean Change From Baseline (SE) in K-SADS-L - Depression 9-Item Scale For Week 8 LOCF and Week 8 OC Datasets . . . . . . . . . . 000085 BRL-029060/RSD-100TW9/1/CPMS-329 000009 www.cuwai.com List of Appendices Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000530 Appendix B Patient Data Listings of Demographic and Baseline Characteristics, Including Exposure to Medication . . . . . . . . . . . . . . . . 001483 Appendix C Patient Data Listings of Efficacy . . . . . . . . . . . . . . . . . . . . . 001485 Appendix D Patient Data Listings of Adverse Experiences . . . . . . . . . . . 001486 Appendix E Patient Data Listings of Vital Signs . . . . . . . . . . . . . . . . . . . 001487 Appendix F Patient Data Listings of Laboratory Tests. . . . . . . . . . . . . . . 001488 Appendix G CRT Tabulations by Patient . . . . . . . . . . . . . . . . . . . . . . . . . 001489 Appendix H CRFs for All Patients with Adverse Experiences Leading to Withdrawal, Serious Adverse Experiences and Deaths . . . . . . . . . . . 001490 BRL-029060/RSD-100TW9/1/CPMS-329 000010 www.cuwai.com List of Abbreviations and Definitions ADECS Adverse Drug Experience Coding System (based on COSTART system) AE Adverse experience AFC Autonomous Functioning Checklist ANOVA Analysis of variance BID Twice a day (bis in die) BP Blood pressure CATMOD Categorical Modeling C-GAS Child Global Assessment Scale CGI Clinical Global Impression CRF Case Record Form CNS Central nervous system DMI Desipramine DSM-III-R Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (1987) EKG Electrocardiogram FH-RDC Family History - Research Diagnostic Criteria GLM General Linear Model HAM-D Hamilton Depression Scale hpf High power field HPLC High-pressure liquid chromatography IMI Imipramine IPL Placebo match to imipramine BRL-029060/RSD-100TW9/1/CPMS-329 000011 www.cuwai.com IRB Institutional Review Board ITT Intent to treat K-SADS-L Schedule for Affective Disorders and Schizophrenia for School-age Children -- Lifetime Version K-SADS-P Schedule for Affective Disorders and Schizophrenia for School-Age Children -- Present Episode Version LSMEANS Least square means LOCF Last observation carried forward PPL Placebo matched to paroxetine SADS-L Schedule for Affective Disorders and Schizophrenia – Lifetime SAS Statistical Analysis System SB SmithKline Beecham SD Standard deviation SE Standard error of the mean SGOT (AST) Serum glutamic oxaloacetate transferase (aspartate transaminase) SGPT (ALT) Serum glutamic pyruvic transferase (alanine transaminase) SIP Sickness Impact Profile SPP Self Perception Profile SSRI Selective serotonin reuptake inhibitor TCA Tricyclic antidepressant TSH Thyroid-stimulating hormone WBC White blood cell WHO ATC World Health Organization Anatomical Therapeutic Chemical BRL-029060/RSD-100TW9/1/CPMS-329 000012 www.cuwai.com Report Synopsis Title A Multi-center, Double-blind, Placebo Controlled Study of Paroxetine and Imipramine in Adolescents with Unipolar Major Depression - Acute Phase (29060/329) Investigators and Centers Investigators from 10 centers in the United States and 2 in Canada participated in the study. All were affiliated with either a university or a hospital psychiatry department and had extensive experience in treating adolescent patients. Publications Keller MB, Ryan ND, Birmaher B, Klein RG, Strober M, Wagner KD, Weller EB, Paroxetine and Imipramine in the Treatment of Adolescent Depression. Abstract NR206, Annual Meeting of the American Psychiatric Association (APA), Toronto Ontario, Canada, 2 June 1998. Wagner KD, Birmaher B, Carlson G, Clarke G, Emslie G, Geller B, Keller M, Klein R, Kutcher, S, Papatheodorou G, Ryan N, Strober M, Weller E, Safety of Paroxetine and Imipramine in the Treatment of Adolescent Depression. Abstract 69, Annual Meeting of New Clinical Drug Evaluation Program (NCDEU), Boca Raton, Florida, USA, 11 June, 1998, Study Dates The first patient received study medication on 20 April 94, the final patient was enrolled on 15 March 1997. The final study visit for the acute phase occurred on 07 May 1997, the final study visit for the continuation phase occurred on 15 February 1998. BRL-029060/RSD-100TW9/1/CPMS-329 000013 www.cuwai.com Objectives The primary objective was to compare the efficacy and safety of imipramine and paroxetine to placebo in the treatment of adolescents with unipolar major depression. The secondary objectives were as follows: to identify predictors of treatment outcomes across clinical subtypes of major depressive disorder; to provide information on the safety profile of paroxetine and imipramine when these agents were given for an extended period of time; to estimate the rate of relapse among imipramine, paroxetine and placebo responders who were maintained on treatment. This report presents the results from the 8 week acute phase. Findings from the continuation phase, which include long term safety and the analysis of relapse, will be reported separately. Study Design This was a multi-center, double-blind, placebo controlled, parallel group trial of the efficacy and safety of treatment with paroxetine or imipramine compared with placebo in adolescents with major depressive disorder. The study plan included two phases, an acute phase in which patients were treated for 8 weeks and a continuation phase in which responders had the option to continue to receive blinded study medication for an additional 6 months. Eligible patients were randomized to treatment with paroxetine, imipramine or placebo for 8 weeks; clinic visits for efficacy and safety assessments were made weekly. At the completion of the 8 week study, patients who met specific criteria for a clinical response could be continued on the same medication in a double-blind manner for a 6 month continuation treatment phase; clinical visits were made monthly. Study Population Eligible patients were adolescents (12 years 0 months through 18 years 11 months inclusive), were currently in an episode of major depression (DSM-III-R criteria) for at least 8 weeks, and had a total score ≥ 12 on the 17-item Hamilton Depression Scale (HAM-D). BRL-029060/RSD-100TW9/1/CPMS-329 000014 www.cuwai.com Treatment and Administration Test product: Paroxetine was supplied as film coated, capsule shaped tablets, yellow containing 10 mg (batch no U95085) and pink containing 20 mg (batch no. U95086). Reference therapies: Imipramine (50 mg) was bought commercially and supplied as green film coated round tablets (batch nos. U95121, U-93135, and U- 93139). "Paroxetine placebos" (batch no. U95084) matched the paroxetine 20 mg tablets, and "imipramine placebos" (batch no. U95087) matched the imipramine tablets. All tablets were over-encapsulated in bluish-green capsules to preserve blinding. Patients took their study medication twice daily, once in the morning and once at night. Total daily doses of imipramine were 50, 100, 150, 200, 250, and 300 mg for dosing levels 1 to 6, respectively. Daily doses of paroxetine were 20 mg for levels 1 to 4, 30 mg for level 5, and 40 mg for level 6. At the beginning of the study, all patients were started at level 1 and titrated up to level 4 at weekly intervals, regardless of response. Non-responders could be titrated up to level 5 or 6 during the next 4 weeks. Evaluation Criteria Efficacy Parameters: The efficacy assessments in the trial included the Hamilton Rating Scale for Depression (HAM-D), the 9-item depression subscale of the Schedule for Affective Disorders and Schizophrenia for School-age Children - Lifetime Version (K-SADS-L), the Clinical Global Improvement (CGI), and the following functional and quality of life assessments: the Self Perception Profile (SPP), the Autonomous Functioning Checklist (AFC), and the Sickness Impact Profile (SIP). The protocol defined the primary efficacy parameters as the change from baseline in the HAM-D total score, and the proportion of responders defined as patients with a 50% reduction in the total HAM-D or a score of 8 or less. Secondary parameters included the change in baseline in the K-SADS-L depression subscale, the mean CGI score, and the functional/quality of life instruments. An analytical plan developed prior to opening of the blind also described additional outcome measures including patients in "remission" (a score of 8 or less on the HAM-D total), and the mean change in the depressed mood items from the HAM-D and the K-SADS-L instruments. BRL-029060/RSD-100TW9/1/CPMS-329 000015 www.cuwai.com Safety Parameters: Adverse experiences, vital signs and body weight; clinical laboratory evaluations, and electrocardiograms (EKGs). Other Parameters: Plasma paroxetine and serum IMI and DMI concentrations were determined at the completion of 4 and 8 weeks of treatment. Statistical Methods All patients who received at least one dose of study medication and had at least one post-baseline efficacy assessment were included in the ITT efficacy population. Statistical conclusions concerning the efficacy of paroxetine and imipramine were made using data obtained from the last observation carried forward (LOCF) and observed cases (OC) datasets. The last observation carried forward consisted of each patient’s last on-therapy assessment during the acute phase. All hypotheses were two sided. The comparisons of interest were paroxetine vs. placebo and imipramine vs. placebo at week 8 LOCF. Hypotheses concerning these comparisons were tested at the alpha level of 0.05. No comparisons were made between paroxetine and imipramine. Interactions were considered significant at the 10% level of significance. Continuous efficacy variables were analyzed by analysis of variance using the general linear model (GLM) procedure of SAS with effects for treatment and investigator. Categorical data were analyzed by logistic analysis using the categorical modeling procedures (CATMOD) of SAS with effects for treatment and investigator. Covariate analyses were also carried out using the general linear model procedures. For the covariate analyses, each analysis used a model including effects for treatment, covariate, and treatment by covariate interaction. Patient Disposition and Key Demographic Data Two hundred and seventy five patients were enrolled in the acute phase and randomized to the three treatment regimens: 93 paroxetine, 95 imipramine, 87 placebo. The baseline demographic features and the clinical features of depression of the three treatment groups were comparable at entry. Over 70% of the paroxetine and the placebo patients completed the 8-week acute phase. In contrast, 60% of imipramine patients completed the acute phase. The most common reason for early withdrawal for the imipramine group was adverse events. BRL-029060/RSD-100TW9/1/CPMS-329 000016 www.cuwai.com Demographic and Clinical Characteristics at Entry Paroxetine Imipramine Placebo N = 93 N = 95 N = 87 Age (yrs.) mean (S.D.) 14.8 (1.6) 14.9 (1.7) 15.1 (1.6) Weight (lbs) mean (S.D.) 146.3 (38.9) 139.4 (36.7) 145.3 (40.8) Race Caucasian 83% 87% 81% Black 5% 3% 7% Other 12% 9% 13% Female 62% 59% 66% Duration of current depressive episode (mos.) mean (S.D.) 14.4 (17.5) 14.2 (17.9) 12.5 (16.6) Age at first episode (yrs.) mean (S.D.) 13.2 (2.8) 13.2 (2.7) 13.5 (2.3) % patients with > 1 prior episode 18% 19% 22% Baseline Mean HAM-D at entry (S.D.) 19.0 (4.1) 18.3 (4.3) 19.2 (4.3) Patient Disposition Paroxetine Imipramine Placebo Entered 93 95 87 Completed 8 weeks 72% 60% 76% Reason for Withdrawal Adverse Event 10% 32% 7% Lack of efficacy 4% 1% 7% Other reason+ 14% 7% 10% Mean dose (mg) (S.D.) 28.0 (8.5) 206 (64.0) 0 + Other includes patients withdrawn for protocol violations and lost to follow-up Efficacy Results The protocol described two primary efficacy endpoints: the change in the total HAM-D score, and the percentage of responders, defined as patients with at least 50% reduction in the baseline HAM-D score or a score of 8 or less. There were six secondary measures. These included the change from baseline in the 9-item K-SADS-L depression subscore, the change in the depression item scores of both the HAM-D and the K-SADS-L, the mean global improvement scores, percent of patients rated "very much" or "much improved," and the percent of patients in remission defined as patients with a final HAM-D score of 8 or less. The analyses of these measures support that paroxetine is beneficial in treating adolescents with major depression, but the support is derived mainly from the secondary measures. In the protocol defined primary endpoints, the placebo response was large and the magnitude of the benefit of paroxetine response over BRL-029060/RSD-100TW9/1/CPMS-329 000017 www.cuwai.com placebo was modest and did not achieve statistical significance. For the LOCF dataset, the mean change in the HAM-D scores for the paroxetine group was approximately 2 points greater than placebo (-10.7 units vs -8.9; p=0.113). In the responder analyses, 67% of paroxetine patients and 55% of placebo patients were classified as responders (p=0.112). In the secondary measures, however, paroxetine treatment was numerically superior to placebo in all six endpoints and achieved statistical significance in four: the depression item of the HAM-D (p=0.003), the depression item from the K-SADS-L (p=0.049), the percent of patients rated "very much" or "much improved" (p=0.020), and the percent of patients in remission (p=0.019). There was little evidence to support the benefit of imipramine at the doses tested in treating adolescents with depression. BRL-029060/RSD-100TW9/1/CPMS-329 000018 www.cuwai.com Mean Change from Baseline in HAM-D Total Score, Depression Item, K-SADS-L Depression Subgroup, K-SADS-L Depression Item, Mean CGI Score, and Percent of Patients Meeting Definition of Responder or Remission Week 8 ITT Population Paroxetine Imipramine Placebo Paroxetine Imipramine vs Placebo vs Placebo *Mean Change in HAM-D Total (SEM) Wk 8 OC -12.2 ± 0.88 -10.6 ± 0.97 -10.5 ± 0.88 p = 0.153 p = 0.945 Wk 8 LOCF -10.7 ± 0.81 -8.9 ± 0.81 -9.1 ± 0.83 p = 0.133 p = 0.873 Mean Change HAM-D Depressed Mood (SEM) Wk 8 OC -2.21 ± 0.17 -1.76 ± 0.18 -1.56 ± 0.17 p = 0.003 p = 0.358 Wk 8 LOCF -2.0 ± 0.14 -1.62 ± 0.14 -1.33 ± 0.14 p = 0.001 p= 0.135 Mean Change in K-SADS-L 9-Item Depression Subscore (SEM) Wk 8 OC -12.0 ± 0.93 -10.7 ± 1.02 -10.8 ± 0.93 p = 0.348 p = 0.883 Wk 8 LOCF -11.7 ± 0.84 -9.6 ± 0.83 -9.6 ± 0.83 p = 0.065 p = 0.984 Mean Change in K-SADS-L Depression Item (SEM) Wk 8 OC -2.35 ± 0.20 -2.05 ± 0.22 -1.93 ± 0.20 P = 0.113 P = 0.661 Wk 8 LOCF -2.20 ± 0.18 -1.77 ± 0.18 -1.73 ± 0.19 P = 0.049 P = 0.868 Mean Clinical Global Improvement Score (SEM) Wk 8 OC 1.9 ± 0.15 2.2 ± 0.17 2.4 ± 0.16 p = 0.030 p = 0.371 Wk 8 LOCF 2.4 ± 0.16 2.7 ± 0.15 2.7 ± 0.16 p = 0.094 p = 0.896 *% Responders (50% ↓ HAM-D Total or a Score ≤ 8) Wk 8 OC 81% (54/67) 73% (41/56) 65% (43/66) p = 0.051 p = 0.363 Wk 8 LOCF 67% (60/90) 59% (55/94) 55% (48/87) p = 0.112 p = 0.612 % Responders (CGI Rating of "Very Much Improved" or "Much Improved") Wk 8 OC 79% (53/67) 68% (38/56) 61% (40/66) p = 0.020 p = 0.506 Wk 8 LOCF 66% (59/90) 52% (49/94) 48% (42/87) p = 0.020 p = 0.642 % Remission (HAM-D Score ≤ 8) Wk 8 OC 76% (51/67) 64% (36/56) 58% (38/66) p = 0.019 p = 0.440 Wk 8 LOCF 63% (57/90) 50% (47/94) 46% (40/87) p = 0.019 p = 0.574 * Protocol defined primary measures of efficacy. Safety Results Adverse Experiences: The nature and incidence of adverse events reported for the paroxetine group were similar to that reported for adult depressed patients receiving paroxetine in controlled trials of comparable duration[1] and as described in the Paxil U.S. prescribing information. Two exceptions to the profile seen in adults include tooth disorder and hostility. The latter term includes aggressiveness and conduct disorders. These exceptions may be related to the age of the study population. As in the adult, adverse events were more likely to occur during the initial weeks of treatment. Analysis by age suggests that events associated with the nervous BRL-029060/RSD-100TW9/1/CPMS-329 000019 www.cuwai.com system (dizziness, sleep problems, and conduct disorders) were more likely to occur in the younger subset (<15 yrs.). There were no deaths during the trial. Serious adverse events occurred in 18 patients, 11 in the paroxetine group, 5 in the imipramine group, and 2 in the placebo group. One of the paroxetine patients experienced migraine headache during down titration after completing 8 weeks of treatment. For the remaining patients the events were psychiatric in nature and included worsening depression, suicidal ideation/gestures, and conduct disturbances (hostility). In the imipramine group, one patient developed a maculopapular rash, one had dyspnea associated with chest pain, one reported auditory hallucinations, and two were reported to have serious conduct disturbances (hostility). In the placebo group, the two serious events were worsening depression. Adverse Events Occurring in ≥ 5% of Any Group and at Least 2X Placebo Paroxetine Imipramine Placebo N = 93 N = 95 N = 87 Cardiovascular Tachycardia 2 (2%) 18 (19%) 1 (1%) Postural Hypotension 1 (1%) 13 (14%) 1 (1%) Vasodilatation 0 (0) 6 (6%) 2 (2%) Chest Pain 2 (2%) 5 (5%) 2 (2%) Gastrointestinal Dry Mouth 19 (20%) 43 (45%) 12 (14%) Dyspepsia 6 (7%) 9 (9%) 4 (5%) Constipation 5 (5%) 9 (10%) 4 (5%) Tooth Disorder 5 (5%) 2 (2%) 2 (2%) Central Nervous System Somnolence 16 (17%) 13 (14%) 3 (3%) Insomnia 14 (15%) 13 (14%) 4 (5%) Hostility 7 (8%) 3 (3%) 0 (0) Emotional Lability 6 (7%) 3 (3%) 1 (1%) Dizziness 22 (24%) 45 (47%) 16 (18%) Tremor 10 (11%) 14 (15%) 2 (2%) Other Abnormal Vision 1 (1%) 7 (7%) 2 (2%) Sweating 1 (1%) 6 (6%) 1 (1%) Vital Signs: Changes in vital signs (blood pressure and pulse rate) as well as body weights were small in the paroxetine and placebo treatment groups. In the imipramine treatment group, however, marked increases were seen in the mean pulse rate. BRL-029060/RSD-100TW9/1/CPMS-329 000020 www.cuwai.com Laboratory Tests: The number of patients identified with laboratory values of clinical concern was low in all treatment groups. None were considered to be of clinical significance. Conclusions This study supports that paroxetine is beneficial in treating adolescents with major depression although the support is derived mainly from secondary measures. The superiority of the paroxetine response over placebo appears less than seen in adults; this may be a result of the weekly supportive psychotherapy sessions allowed by the protocol producing a large "placebo" response. The safety profile of paroxetine in the adolescent appears similar to that reported in adults. The study provided little support for the benefit of imipramine in treating adolescent depression. BRL-029060/RSD-100TW9/1/CPMS-329 000021 www.cuwai.com 1 Introduction Similarities between adolescent and adult depression in symptomatology, family history, and prospective course provide compelling rationale for investigating the efficacy of antidepressant drug therapy in young patients with depression. But unlike adults, the evidence from trials in adolescents has not supported drug efficacy, although the existing studies reported at the start of this trial had collectively evaluated fewer than 200 patients, a number hardly adequate for reliable clinical or statistical inferences. [2] A placebo controlled trial reported during the conduct of the present study, however, supports the benefit of fluoxetine in children and adolescents with major depression [3], but remission of symptoms was rare. This apparent difference in response between adults and younger patients has been the subject of much debate. Recent reviews have focused on three major areas of concern.[2][4][5] These include: deficiencies in study design, methodology and conduct; the adequacy of diagnostic criteria and various nosological problems and developmental issues, in that children and adolescents who suffer from adult-like depression may respond in a pharmacologically different manner due to quantitative and/or qualitative developmental differences in neurotransmitter/receptor systems. The study that is summarized in this report was performed to examine the efficacy and safety of two active antidepressant therapies in adolescents with unipolar major depression. The study plan included several features designed to avoid the perceived flaws of previous studies. The study design was placebo-controlled and double-blind. The study was conducted at multiple sites to achieve a target enrollment that would provide sufficient statistical power to detect clinical differences among treatment groups, should those differences exist. The inclusion and exclusion criteria for patient participation were rigorous, so that the study population was more homogenous than reported from previous trials. Diagnostic interviews were reviewed among the various sites to confirm the criteria for symptoms of depression and to promote uniformity in diagnosis. One of the treatment arms was paroxetine (Paxil), an orally administered antidepressant with a chemical structure unrelated to other members of its class, the selective serotonin reuptake inhibitors (SSRI). Paroxetine had not been systematically studied in adolescent depression. The other active treatment arm was imipramine, a tricylic antidepressant (TCA) that had been previously studied in two small open-labeled clinical trials in adolescents, one of which BRL-029060/RSD-100TW9/1/CPMS-329 000022 www.cuwai.com demonstrated a modest therapeutic response in patients with nondelusional depression.[6] Patients eligible for inclusion in the study were adolescents who were currently in an episode of major depression, according to the Diagnostic and Statistical Manual of Mental Disorders III-R, [7] with a minimum duration of 8 weeks. Each patient had a 17-item Hamilton Depression Scale total [8] score of 12 or greater upon entry. During the treatment period, interpersonal, cognitive or behavioral psychotherapy focusing on psychological themes was not permitted. Investigators and their staff were instructed to provide psychosocial interaction between the investigator and the patient that would maximize the chance of observing a pharmacotherapeutic effect and assure careful and safe monitoring of patients. To this end, the Clinical Management for Adolescent Depression Manual was used to define the boundaries of the supportive therapy and to assure consistency of approach among the investigators. Non-responders at the end of the 8-week period were withdrawn from study medication and additional treatment was at the discretion of the investigator. The blind was not to be broken. Patients who responded to treatment were eligible to continue on the same blinded medication at the same dosage level for an additional 6 months in a continuation phase of the study. It should be noted that the continuation phase of this trial was not designed to determine whether paroxetine or imipramine are superior to placebo in preventing relapse. The prevention of relapse is more adequately addressed using designs in which responders are re-randomized to remain on therapy or to receive placebo. Rather, the purpose of the continuation phase was to provide an estimate of the long-term safety profile of paroxetine and imipramine and to provide information on the relapse rates of responders over an extended period. The results of the continuation phase are reported as an addendum to this report. BRL-029060/RSD-100TW9/1/CPMS-329 000023 www.cuwai.com 2 Objectives 2.1 Primary • To compare the efficacy and safety of imipramine and paroxetine to placebo in the treatment of adolescents with major depression. 2.2 Secondary • To identify predictors of treatment outcomes across clinical subtypes (e.g. endogenous subtype, age at onset, number of prior episodes, duration and severity of current episode, comorbidity with separation anxiety disorder, attention deficit disorder, and conduct disorder). • To estimate the rate of relapse among imipramine, paroxetine and placebo responders who were maintained on treatment. Analysis of relapse will be reported separately. • To provide information on the safety profile of paroxetine and imipramine when these agents are given for an extended period of time. Results of this evaluation will be reported separately as an addendum to this report. BRL-029060/RSD-100TW9/1/CPMS-329 000024 www.cuwai.com 3 Methodology 3.1 Study Design1 This was a multi-center, double-blind, placebo-controlled, parallel group trial. Patients were eligible for inclusion if they were adolescents from ages 12 years 0 months through 18 years 11 months inclusive. The patients were diagnosed as being currently in an episode of major depression according to DSM-IIIR criteria [7] with a minimum duration of 8 weeks, using the Schedule for Affective Disorders and Schizophrenia for Adolescents - Lifetime Version (K-SADS-L). They were required to have a Hamilton Depression Scale (HAM-D) [8] total score of 12 or greater. Eligible patients were randomized to treatment with paroxetine, imipramine or placebo for 8 weeks. During this time, the patients made weekly visits to the clinic. The effects of treatment on depression were evaluated using standardized instruments and global assessments. Safety assessments were also performed at each visit. At the completion of the 8 week acute study, patients who met specific criteria for a clinical response could be continued on the same medication in a double blind manner for a 6 month continuation treatment phase. Patients who were non- responders at the end of the 8-week treatment period were withdrawn from the study and were to be treated as clinically indicated. The blind was not to be broken. The study design is illustrated on the next page. 1 Appendix A contains the protocol and sample case report forms. BRL-029060/RSD-100TW9/1/CPMS-329 000025 www.cuwai.com Figure 1 Study Design SCREENING/ ACUTE CONTINUATION BASELINE TREATMENT TREATMENT PHASE PHASE PHASE Inclusion criteria: Forced titration to Responders continue Adolescent (12 yr., level 4 (paroxetine 20 same treatment at 0 mo. to 18 yr., 11 mo.) mg/day or imipramine dose level achieved at Male/female 200 mg/day) endpoint of acute Current episode of → → phase major depression for Optional titration to 8 weeks or longer level 5 or 6 HAM-D score of (paroxetine 30 or 40 12 or higher mg/day or imipramine Goals: 250 or 300 mg/day) Prevention of relapse Long-term safety Responder: HAM-D Baseline evaluations score of 8 or lower, or Stability of depressive decrease from baseline symptoms in HAM-D score of 50% or more at endpoint 7 to 10 days 8 x weekly visits 6 x monthly visits No treatment ←Double-blind treatment→ ↑ ↑ RANDOMIZATION ENTRY INTO (paroxetine, imipramine CONTINUATION PHASE or placebo) (responders only) 3.1.1 Protocol Amendments2 Amendment 1 (approved 17 April, 1994) This amendment was instituted prior to enrollment of the first patient. The diagnosis of major depression was made using the Schedule for Affective Disorders and Schizophrenia for Adolescents - Lifetime Version (K-SADS-L) in place of an earlier version, the K-SADS-P. The K-SADS-L includes the elements of the K-SADS-P but also assesses additional disorders (e.g., attention deficit/hyperactivity disorder, antisocial personality disorder, social phobia) omitted from the K-SADS-P, and it provides for lifetime inquiry in addition to the current disorder. 2 Appendix A contains the protocol amendments. BRL-029060/RSD-100TW9/1/CPMS-329 000026 www.cuwai.com If the diagnosis of major depressive disorder was uncertain, the investigator was to contact one of the senior investigators at a separate site to discuss the case. The external reviewer was to review the audiotape of the screening interview, if available, and to return a decision within 2 days. The external reviewer’s opinion was to take precedence in the event that the external reviewer and the investigator disagreed on the patient’s eligibility for the study. The amendment also included additional safety measures. In addition to the 12- lead EKGs performed at weeks 4 and 8, rhythm strip EKGs were to be obtained during the other weekly visits. Sampling for plasma concentrations of imipramine and desipramine and for plasma concentrations of paroxetine was to be performed at the week 4 and 8 visits. The plasma was to be analyzed for imipramine and desipramine in real time, and the results blinded on the laboratory report sent to the investigator. However, if a patient had a combined serum concentration of imipramine and desipramine exceeding 500 mcg/L (500 ng/mL), the investigator was to be notified by telephone to withdraw the patient from the trial. The criterion for heart rate elevation requiring a dose adjustment was changed to agree with FDA guidelines for studies in adolescents. Patients whose heart rate exceeded 110 bpm on two consecutive visits or 130 bpm at any time had their dosage decreased by one level if they were at dose level 5 or 6 or were removed from the study if they were at dose level 4 or below. These dose adjustments were to be made without breaking the blind. Amendment 2 (approved 28 October 1996) Clinical supplies for the trial were prepared in two batches, the first in 1991 and the second in 1993. Due to a slower-than-expected rate of enrollment, part of the initial batch of study medication expired before use. The remaining supplies were insufficient to provide for both acute and continuation phase treatment of 300 patients. Without opening the blind, the variability in HAM-D scores was assessed using the initial 189 patients who completed the acute phase. Based on this assessment, the target for total enrollment into the acute phase was reduced from 300 to approximately 275 patients (see Section 3.13.1). It was anticipated that this reduction in sample size would have no adverse effects on the estimated 80% BRL-029060/RSD-100TW9/1/CPMS-329 000027 www.cuwai.com power of this study to detect a four point difference between placebo and active groups. The number of individual study medication packets for the continuation study presented additional problems. This is because the number of patients entering the continuation phase from each treatment regimen could not be estimated exactly. With the reduced study supplies, it was anticipated that there may not be study supplies for a small number of patients who qualified for the continuation phase. Accordingly, the following two options were provided for patients who qualified for continuation treatment but for whom blinded medication may not be available. With both options, the patient was withdrawn from the trial, and his medication assignment was not revealed to any personnel (investigator, investigator staff or sponsor personnel) associated with the trial. The first option was that treatment could be continued by a third party not associated with the trial, who was provided with the identity of the study medication by the SB safety group. The second option was that the patient be treated with open-label paroxetine for up to 6 months following down titration over a 1-week washout period. In this case, the patient could elect to remain under the care of the present study physician. 3.2 Investigators3 The study was performed at ten centers in the United States and two in Canada, as shown in Table 1. The investigators were chosen for their interest in the study and their ability to enter eligible patients. The initial study plan called for six investigative sites to enroll a minimum of one patient per center per month beginning in April 1994. Using this rate it was anticipated that approximately four years would be needed to randomize the 300 patients required by the protocol. However, after completion of the first year of enrollment, both the sponsor and the investigators concluded that the projected initial enrollment rate could not be met with only six sites. Accordingly, six additional sites were recruited for participation in the trial. The study enrollment was completed in March 1997. To ensure that study procedures were standardized across all investigator sites, representatives of SmithKline Beecham reviewed the protocol, CRF and safety reporting procedures with each investigator and his/her personnel responsible for the conduct of the study. Two investigator meetings were held in Philadelphia. 3 Appendix A contains the curriculum vitae of each principal investigator. BRL-029060/RSD-100TW9/1/CPMS-329 000028 www.cuwai.com The first of these meetings occurred in September 1993 before initiation of the study. The second meeting was held in June 1995, and included the original investigators (sites 1-6) as well as the six additional investigators (sites 7-12). In addition, scheduled teleconferences between representatives of SB and the investigators were held twice monthly to resolve any issues that had arisen at any of the study centers, and resolutions to major issues were documented in the form of written monitoring guidelines.4 Adherence to the protocol requirements and verification of data generation accuracy was achieved through monitoring visits to each investigator site. Table 1 Principal Investigators, the SB Assigned Center Number and Affiliations Center Investigator Affiliated Institution City/State/Provence 001 xxxxxxx xxxxx, MD xxxxxxxxxx xxxxxxxxxx xx.xxxxxx, xx xxxxxxx xx xxxxxxx 002 xxxxx x.xxxxx, MD xxxxxx xxxxxxxxxx xx xxxxxxxxx, xx xxxxxxxx 003, Site 1 xxxxxx xxxxx, PhD xxx xxxx xxx xxxxxxxxxxx xxx xxxx, xx xxxxx xxxxxxxxx, MD xxxxxxxxx 003, Site 2 xxxxx xxxxxx MD xxxx xxxx xxxxx xxxxx xx xxx xxxx xxxxx xx 004 xxxx xxxxx, MD* xxxxxxxxxxxxxxxxxxxxxx xxxxxx, xxxxxx, x. xxxxxxxxxxx, MD xxxxx xxxxx 005 xxxx xxxx, MD xxxxxxxx xxxxxxxxxx xxxxxxxx, xx xxxx xxxxxxx, MD xxxxxx xx xxxxxxx 006 xxxxxx xxxxxx, PhD xxxxxxxxxx xxxxxxxxxxx xxx xxx xxxxxxx xx xxxx xxxxxx, MD xxxxxx xxxxxxx xxxxx 007 xxxxx xxxxx, MD, PhD xxxxxxxxx xxxxxx xxxxxxxx, xx xxxxx xxxxx 008 xxxx xxxx, PhD xxxxx xxxxx xxxxxx xxxxxx, xx xxxxxx xxx, MD xxxxxxxxx 009 xxxxx xxxxxx, MD xxxxxxxx xx xxxxx xxxxx, xx xxxxxxxx xxxxxxx 010 xxxxxxx xxxxxx, MD xxxx xxxx xxxxxxxxx xxxxxxxx, xx xxxxxxx xxxxxx 011 xxxxxx xxxxx, MD xxxxx xxxxxxxxxxx xx xxxxx xxxxx, xx xxxx xx xxxx xxxxx 012 xxxx xxxxxx, MD xxxxx xxxxx xxxxx xxxxx, xxxx xxxx xxxxxx, MD* xxxxxx’x xxxxxxx xxxx, xxxx Source: Appendix A contains the curriculum vitae (or biographical sketch) of each principal investigator * Dr. xxxxxxx participated at site 004 from March 1994 through April 1995, and at site 012 from May 1995 through study completion. 4 Appendix A contains the monitoring guidelines for the study. BRL-029060/RSD-100TW9/1/CPMS-329 000029 www.cuwai.com 3.3 Ethics The study was conducted in accordance with good Clinical Practices and the Declaration of Helsinki as amended in Hong Kong (1989). The protocol and statement of informed consent5 were approved by an Institutional Review Board (IRB) prior to each center’s initiation, in compliance with 21 United States Code of Federal Regulations (CFR) Part 56. Written informed consent was obtained from each patient prior to entry into the study, in compliance with 21 CFR Part 50. Case report forms were provided for each patient’s data to be recorded. 3.4 Eligibility Criteria 3.4.1 Inclusion Criteria Before entry into the study, each patient was to satisfy all of the following criteria: • Adolescent between the ages of 12 years 0 month and 18 years 11 months inclusive. • Currently in an episode of major depression for at least 8 weeks. A diagnosis of major depression was to be made on summary data aggregating parent and child reports using the K-SADS-L as a diagnostic tool. In addition, both adolescent and parent(s) were to agree that the adolescent had a disorder meriting treatment. • A severity score less than 60 on the Child Global Assessment Scale (C-GAS). • A score of 12 or greater on the 17-item Hamilton Depression Scale (HAM-D). • Medically healthy as determined by physical examination, medical history and laboratory screening. • IQ ≥ 80 by Peabody Picture Vocabulary Test. 3.4.2 Exclusion Criteria A patient was to be excluded from the study if any of the following criteria applied to that patient: 5 Appendix A contains the protocol. The sample informed consent is an appendix to the protocol. BRL-029060/RSD-100TW9/1/CPMS-329 000030 www.cuwai.com • Current or lifetime DSM-III-R diagnosis of bipolar disorder, schizo-affective disorder, anorexia nervosa, bulimia, alcohol or drug abuse/dependence, obsessive/compulsive disorder, autism/pervasive mental disorder, or organic psychiatric disorder. • Current diagnosis (within 12 months) of post traumatic stress disorder per DSM-III-R criteria. • Adequate trial of antidepressants within 6 months prior to beginning this study. An adequate trial was defined as a treatment of at least 4 weeks or more with imipramine, desipramine, or amitriptyline at a dosage of 150 mg per day or greater, with nortriptyline at a dosage of 50 mg per day or greater, or with fluoxetine at a dosage of 20 mg per day or greater. • Presence of suicidal ideation with a definite plan or of a suicide attempt within the current episode, or any past history of attempting suicide by medication overdose. • Medical illness contraindicating the use of heterocyclic antidepressants (e.g. cardiovascular disease). • Use of : • any psychotropic medication including anticonvulsants, anxiolytics, neuroleptics or lithium carbonate • any illicit drug, as documented by a drug screen within two weeks of starting the study. • Presence of organic brain disease, epilepsy, or mental retardation. • Pregnancy or lactation. • If female, sexual activity without using a reliable methods of contraception (oral contraception, surgical sterilization, IUD, or diaphragm in conjunction with spermicidal foam and condom on partners). • Use of an investigational drug within 30 days of entry into the study or within five half lives of the investigational drug (the longer period was to apply). BRL-029060/RSD-100TW9/1/CPMS-329 000031 www.cuwai.com 3.5 Treatments and Administration 3.5.1 Study Medication Table 2 shows the presentation, formulation and clinical trial supply numbers of the study medications, which were provided as over-encapsulated tablets to preserve the blind. Paroxetine was formulated as 10 mg and 20 mg bisected tablets. Imipramine (50 mg tablets; debossed with B1 on one side and 21 on the other side) was obtained commercially. “Paroxetine placebos” matched to 20-mg paroxetine tablets and “imipramine placebos” matched to imipramine tablets were prepared at SB. Table 2 Appearance, Formulation, Dosage Strengths, and Batch Numbers of Study Medication Study drug Appearance Formulation Dosage strength Batch numbers Paroxetine Yellow, film coated, Over encapsulated 10 mg U95085 capsule-shaped tablet tablet U93127 Paroxetine Pink, film coated, Over encapsulated 20 mg U95086 capsule-shaped tablet tablet U93128 Placebo matched to Pink, film coated, Over encapsulated - U95084 paroxetine capsule-shaped tablet tablet U93126 Imipramine* Green, film-coated, Over encapsulated 50 mg U95121 round tablet tablet U93135 U93139 Placebo matched to Green, film-coated, Over encapsulated - U95087 imipramine round tablet tablet U93178 Data source: Appendix A contains the batch numbers for SB manufactured products, lot numbers for purchased comparators, and Certificates of Analysis for SB batches of formulated products. * Imipramine tablets (lot numbers 18857, 20154, and 27763) were purchased from Biocraft Laboratories, Fairlawn, NJ USA. Study medication was issued to the patients as foil-backed blister cards containing sufficient supplies for a 1-week treatment period (10 days). The tear-off portion of the double-blind label was affixed to the CRF at the time that study medication was dispensed to the patient. Study medication was kept in a locked area at each study site. BRL-029060/RSD-100TW9/1/CPMS-329 000032 www.cuwai.com 3.5.2 Dosage and Administration The patients were instructed to take study medication twice daily, one dose in the morning and one at night. There were 6 dosing levels. During the first 4 weeks, all patients were titrated to level 4 (corresponding to paroxetine 20 mg or imipramine 200 mg bid) regardless of response. Non-responders could be titrated up to level 5 or 6 during the next 4 weeks. The number of capsules per dose depended on the dosing level, so that the number of capsules to be taken daily ranged from two to six. The titration design is shown in Figure 2 and the dosing schedule for each treatment group and dose level is shown in Table 3. Figure 2 Titration Design 40 m g 30 m g Paroxetine 20 mg 300 m g 250 m g Random ization Imipram ine 50 mg 100 mg 150 m g 200 m g Placebo Day 0 W eek W eek W eek W eek W eek W eek W eek W eek 1 2 3 4 5 6 7 8 PRN up-titration Source: Appendix A contains the study protocol BRL-029060/RSD-100TW9/1/CPMS-329 000033 www.cuwai.com Table 3 Dosing Schedule Dose level Paroxetine Imipramine Placebo Daily a.m. p.m. Daily a.m. p.m. a.m. p.m. dose dose 1 (Days 1-7) 20 mg 1 x P20 1 x PPL 50 mg 1 x I50 1 x IPL 1 x PPL 1 x PPL 2 (Days 8-14) 20 mg 1 x P20 1 x PPL 100 mg 1 x I50 1 x I50 1 x PPL 1 x PPL 3 (Days 15-21) 20 mg 1 x P20 1 x PPL 150 mg 1 x I50 2 x I50 1 x PPL 2 x PPL 1 x PPL 4 (Days 22-28) 20 mg 1 x P20 2 x PPL 200 mg 2 x I50 2 x I50 2 x PPL 2 x PPL 1 x PPL 5* 30 mg 1 x P20 1 x P10 250 mg 2 x I50 3 x I50 2 x PPL 3 x PPL 1 x PPL 2 x PPL 6* 40 mg 1 x P20 1 x P20 300 mg 3 x I50 3 x I50 3 x PPL 3 x PPL 2 x PPL 2 x PPL Source: Appendix A contains the study protocol *Optional Key: P20, paroxetine 20 mg; P10, paroxetine 10 mg; PPL, placebo matched to paroxetine 20mg; I50, imipramine 50 mg; IPL, placebo matched to imipramine 50 mg Dosage Adjustment Based on Cardiovascular Parameters The following cardiovascular criteria were established as limits which warrant reduction in dosage: • Sitting heart rate ≥ 130 bpm • Sitting systolic BP ≥ 140 mmHg with sitting diastolic BP < 85 mmHg • PR interval ≥ 0.21 sec • QRS interval ≥ 0.12 sec and ≥ 150% of baseline value • QTC interval ≥ 0.48 sec Cardiovascular parameters outside these limits resulted in reduction of dose level by one step for patients who were at a dose level of 5 or 6 and withdrawal from the study for patients who were at a dose level of 4 or lower. In addition, patients who had a sitting heart rate exceeding 110 bpm on two successive visits were to have their dosage reduced or to be withdrawn from the study. BRL-029060/RSD-100TW9/1/CPMS-329 000034 www.cuwai.com At weeks 4 and 8, blood samples were obtained to assess serum levels of study medication. If the combined serum concentration of imipramine and desipramine exceeded 500 mcg/L (500 ng/mL) the patient was to be withdrawn from study medication, using down-titration if necessary. 3.5.3 Methods of Blinding “Paroxetine placebo” tablets were identical in size, color and shape to the paroxetine 20 mg tablets. “Imipramine placebo" tablets were identical in appearance to the imipramine tablets. All tablets were placed inside identically appearing bluish-green Supro B locking capsules to preserve the blinded nature of the study. Copies of the randomization codes were stored at SB's Clinical Safety Department. The blind was to be broken only in the event of a serious adverse experience that the investigator felt could not be adequately treated without knowing the identity of the study medication. Amendment #2 to the protocol, which addressed the expiration of the study supplies, allowed the identity of the study medication to be provided to a third party. The condition for such unblinding was that a patient had completed 8 weeks of the acute phase, qualified as a "responder" but no continuation study medication was available. Under this circumstance, the blind was provided by a member of the SB Worldwide Safety staff to the third party. Neither the investigator nor SB personnel associated with the trial were told the identity of the study medication. 3.5.4 Other Protocol-specified Therapy Supportive psychotherapy for the depressive episode was provided in a manner similar to that described by Fawcett and coworkers in the Adolescent Depression Collaborative Research Group.[10] Psychotherapy was intended to provide the psychosocial interaction between the patient and the therapist that would permit observation of any pharmacotherapeutic effect of the study medication. Therefore, the sessions were to focus on providing supportive therapy rather than implementing interpersonal or cognitive/behavioral strategies. At each weekly visit, the patient had a 45-minute visit with the therapist. However, emergency contact of greater duration was permitted under unusual circumstances. BRL-029060/RSD-100TW9/1/CPMS-329 000035 www.cuwai.com 3.6 Compliance with Study Medication Compliance with taking study medication was assessed by recording the amount of drug dispensed, taken, and returned in the CRF for each patient. The patient was instructed to return the previous interval’s drug container, including any unused medication, at each visit. Non-compliance with study medication was defined as a return capsule count of less than 80% or more than 120% of the predicted capsule return count at two consecutive visits, and resulted in withdrawal of the patient from the study. Any patient who missed two consecutive visits was also to be withdrawn. 3.7 Prior and Concomitant Medication 3.7.1 Prior Medication Antidepressants in adequate dosage (see Section 3.4.2) had to be discontinued for a minimum of 6 months, and all other psychotropic drugs had to be stopped at least 2 weeks before entry into the study. Investigational drugs were to be discontinued at least 30 days or 5 half-lives. Use of illicit drugs was forbidden and was screened out using the results from a urine sample obtained within 2 weeks before the start of the study. 3.7.2 Concomitant Medication The patients were not allowed to take any concomitant psychotropic medications during the study. Medications that are not psychotropic, but may have CNS side effects (e.g. prednisone or antihistamines) were to be avoided or to be used for the minimum length of time consistent with good medical care. The use of medications without any CNS effects was permitted as necessary for the treatment of medical illnesses or conditions. All concomitant medication taken during the study was recorded in the case report form with indication, daily dose, and dates of administration. 3.8 Study Procedures 3.8.1 Schedule of Assessments The study consisted of the following: 1) a screening period of 7-10 days to assess the suitability of a patient for inclusion into the trial; 2) a treatment period of 8 BRL-029060/RSD-100TW9/1/CPMS-329 000036 www.cuwai.com weeks in which patients were randomly assigned to receive either imipramine, paroxetine, or placebo; and 3) a continuation phase of 6 months’ duration during which clinical responders were blindly continued on their randomization medication. Non responders at the end of the 8-week study were withdrawn from the study and treated in an open-label manner. The timing of study visits and the procedures to be carried out at each visit are shown in Table 4. Table 4 Schedule of Assessments Assessments Baseline Acute Phase Continuation Phase Time (Weeks) -1 0 1 2 3 4 5 6 7 8 12 16 20 24 28 32 Informed Consent X Medical History, Physical Exam X Clinical Laboratory Studies X X X X Serum Pregnancy Test X X* X* EKG-12 Lead X X X X X EKG Rhythm Strip X X X X X X X X X X Hamilton Depression Scale X X X X X X X X X X X X X X X X Full K-SADS-L X X Affect Section of K-SADS-L X X X X X X X X X X X C-GAS X CGI-I X X X X X X X X X X X X X X SADS-L X FH-RDC X Autonomous Functioning Checklist X X Self Perception Profile X X Sickness Impact Scale X X Randomization X Adverse Events X X X X X X X X X X X X X X X Supportive Psychotherapy X X X X X X X X X X X X X X X Serum/Plasma Samples for Drug X X X X X Analyses Study Medication Record X X X X X X X X X X X X X X Concomitant Medication Record X X X X X X X X X X X X X X X X * On suspicion of pregnancy Data source: Appendix A, Protocol and Sample CRF 3.8.2 Prestudy Screening and Enrollment Prospective patients were initially screened by telephone, and those who appeared likely to meet the study criteria were evaluated promptly thereafter at the study BRL-029060/RSD-100TW9/1/CPMS-329 000037 www.cuwai.com site. Diagnostic assessment was done using the K-SADS-L with both the adolescent and parent(s). The K-SADS-L was developed using the adult Schedule for Affective Disorders and Schizophrenia (SADS) [11] as a point of departure and is in the form of a semi-structured clinical interview.[12] The Lifetime version includes both present and past psychiatric disorders. The parent(s) and the adolescent were interviewed separately. The clinician formed a summary rating based on the best overall information combining all sources. For those symptoms where there was significant discrepancy between information provided by the adolescent and information provided by the parent(s), the clinician, adolescent and parent(s) were to sit together, discuss the information provided by each source and reach a best conclusion. The diagnostic interviews were audiotaped at most of the study sites. However, refusal of a prospective subject to be audiotaped was not a reason to deny entry. The K-SADS-L interview data were to be reviewed at the study site by a senior clinician (psychiatrist or psychologist), who interviewed both the adolescent and parent(s) at the first medication visit (before dispensing medication cards) and confirmed each of the positive criteria for depression. The senior clinician also reviewed each of the items for the Hamilton Depression Rating Scale. If the diagnosis of major depressive disorder was uncertain, the investigator was to contact one of the senior investigators at a separate site to discuss the case. The external reviewer was to review the audiotape and return a decision within 2 days. The external reviewer’s opinion was to take precedence in the event that the external reviewer and the investigator disagreed on the patient’s eligibility for the study. Following the initial assessment of the patient's eligibility and signing of the informed consent form by both the patient and parent, the 7 to 10 day screening period was used to obtain medical or psychiatric records of prior treatment and to document that the depressive symptomatology was stable. Safety evaluations, including a physical examination, clinical laboratory studies, and a cardiovascular evaluation (12-lead EKG and heart rate and blood pressure measurements) were performed during this time. Also during the screening period, the adolescent's overall global functioning was assessed using the Child Global Assessment Scale (C-GAS). A family history was obtained on all first degree family members using the Family History- Research Diagnostic Criteria (FH-RDC). The mother was the preferred informant but the other parent or a parent surrogate could be used, if necessary. BRL-029060/RSD-100TW9/1/CPMS-329 000038 www.cuwai.com At the end of the screening period, the patient returned to the clinic for re- evaluation. Only patients continuing to meet the inclusion criteria (DSM-III-R major depression and the Hamilton Rating Scale total score of 12 or greater) were randomized to study medication. The Autonomous Functioning Checklist [13], Harter’s Self Perception Profile for Adolescents [14], and the Sickness Impact Scale [15] modified for an adolescent, medically healthy population were administered at the end of the screening period. 3.8.3 Treatment Period During the 8-week treatment period of the study, each patient made weekly visits to the clinic. The following assessments were performed: • HAM-D (every visit) • Depression section from the K-SADS-L (every other visit) • Clinical Global Impressions (CGI) Improvement Item (every visit after baseline) • Adverse events (every visit) • Cardiovascular functioning • Electrocardiogram (12-lead EKG at Weeks 4 and 8 and rhythm strip EKG at all other visits) • Sitting and standing blood pressure and heart rate (every visit) • Clinical laboratory studies (Week 8) • Serum/plasma drug concentration (Weeks 4 and 8) • Self Perception Profile, Autonomous Functioning Checklist and Sickness Impact Profile (Week 8) At the end of treatment, each patient was classified as a "responder" or a "non- responder.” A "responder" was defined as a patient who had either a HAM-D score ≤8 or a decrease from baseline in HAM-D total score ≥50% at this time. In addition, a patient whose HAM-D score was ≤8 at the end of the acute phase was defined as being “in remission.” BRL-029060/RSD-100TW9/1/CPMS-329 000039 www.cuwai.com Evaluation for responders who entered into the continuation phase are discussed in an addendum to this report. 3.8.4 Post-treatment Period The following evaluations were carried out at the patient’s final visit: • HAM-D • Full K-SADS-L • CGI Improvement Scale • Adverse events • Cardiovascular functioning (12-lead EKG; sitting and standing blood pressure and heart rate) • Clinical laboratory studies • Serum/plasma drug concentration If a patient was withdrawn before the end of the study, the safety evaluations (adverse events, cardiovascular functioning, and clinical laboratory studies) specified for the final visit were obtained, if possible. For early terminations a discontinuation taper over a 7-17 day period was recommended in a blinded manner. Study medication was unblinded for safety reasons only. 3.8.5 Reasons for Concluding Study A patient could withdraw or be withdrawn from the study prior to completion for one of the following six reasons: • Adverse experiences, including intercurrent illness • Lack of efficacy • Protocol deviation, including non-compliance • Loss to follow-up • Termination of the study by SB • Other (reason was to be specified). BRL-029060/RSD-100TW9/1/CPMS-329 000040 www.cuwai.com The investigator determined the primary reason for withdrawal and recorded it in the CRF. A patient who withdrew for a drug-related adverse experience was followed up for a minimum of 30 days. 3.9 Efficacy Assessments Efficacy in the treatment of depressive symptomatology was assessed by the investigator using the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions (CGI) Improvement Scale, and the 9-item depression subscale of the K-SADS-L scale. Effects on psychological functioning were assessed using the Self Perception Profile (SPP), the Autonomous Functioning Checklist (AFC), and the Sickness Impact Profile (SIP). Hamilton Rating Scale for Depression (HAM-D) [8] The HAM-D assessed the following 17 items: depressed mood; feelings of guilt; suicide; early insomnia; middle insomnia; late insomnia; work and activities; retardation; agitation; psychic anxiety; somatic anxiety; gastrointestinal somatic symptoms; general somatic symptoms; genital symptoms; hypochondriasis; loss of weight; and insight. Eight items (three insomnia items, two somatic symptom items, genital symptoms, loss of weight, and insight were graded on an ordinal scale of 0 to 2. The remaining items were graded on an ordinal scale of 0 to 4. A higher number indicates a greater severity of illness for each item. Clinical Global Impressions (CGI) Improvement Scale [16] The change in the severity of depression relative to baseline was rated using the CGI Improvement Scale, an ordinal scale that ranges from 1 (very much improved) to 7 (very much worse). K-SADS-L Depression Subscale The K-SADS is a validated schedule in assessing depression in children and adolescents. It is essentially a modification of the Schedule for Affective BRL-029060/RSD-100TW9/1/CPMS-329 000041 www.cuwai.com Disorders and Schizophrenia (SADS, Spitzer, 1978). The version employed in this trial was an additional modification by one of the investigators, Dr. x. x. xxxxx, Ph.D., to provide for lifetime inquiry (thus the "K-SADS-L" designation). It also provided for the diagnosis of ADHD, oppositional disorder, antisocial personality disorder, social phobia, PTSD, tic schedules, and to expand the anxiety complexes. The depression subscale of the K-SADS-L consisted of the following nine items of the full K-SADS-L affect schedule: depressed mood; excessive or inappropriate guilt; anhedonia, lack of interest, apathy, low motivation, or boredom; difficulty concentrating, inattention, or slowed thinking; psychomotor agitation; psychomotor retardation; hypersomnia; insomnia; and suicidal ideation. Depressed mood and suicidal ideation were rated on an ordinal scale from 1 to 7, and the remaining items were rated on an ordinal scale from 1 to 6. A higher number indicates a greater severity of illness for each item. The total score for the 9-item depression subscale of the K-SADS-L is 56. A comparison with the 17 item HAM-D, which has a total score of 55, is presented below in Table 5: Table 5 Comparison of HAM-D 17-Item Scale and K-SADS-L 9-Item Depression Subscale Symptom HAM-D 17-Item Scale K-SADS-L 9-Item Depression Subscale # Items Total Score # Items Total Score Depressed Mood 1 4 1 7 Guilt 1 4 1 6 Suicidality 1 4 1 7 Sleep Disturbances 3 6 2 12 Work/Activity 1 5 1 6 Psychomotor Retardation 1 4 2 12 Agitation 1 4 1 6 Anxiety 2 8 Somatic Symptoms 3 8 Hypochondriasis 1 4 Weight Loss 1 2 Insight 1 4 Total 17 55 9 56 Self Perception Profile (SPP) [14] The Self Perception Profile for adolescents consisted of 45 pairs of “opposite” statements pertaining to issues of self-esteem. For each pair of statements, the patient was to choose the statement that reflected his/her self-perception and rate BRL-029060/RSD-100TW9/1/CPMS-329 000042 www.cuwai.com it as being either “really true for me” or “sort of true for me”. The results of each pair of statements were coded on an ordinal scale ranging from 0 (response of “really true for me” for the statement that indicated negative self-esteem) to 3 (response of “really true for me” for the statement that indicated positive self- esteem). A total score was calculated, with a high score indicating a more positive overall perception of self-esteem. Autonomous Functioning Checklist (AFC) [13] The Autonomous Functioning Checklist was completed by the patient’s parent. It consisted of 78 questions grouped into 4 categories to assess the patient’s level of autonomy in performing daily activities. Twenty-two questions on self and family care, 20 questions on management, and 16 questions on recreational activities were rated on an ordinal scale ranging from 0 (“does not do”) to 4 (“does every time there is an opportunity”). Twenty questions on social and vocational activities were answered as “yes” (coded 1) or “no” (coded 0). A total score and a subscore for each of the 4 categories were calculated, with higher values indicating a greater degree of autonomy. Sickness Impact Profile (SIP) [15] The Sickness Impact Profile was used in a modified version appropriate for adolescent patients in good medical health. The patients rated their present health and their present quality of life on an ordinal scale ranging from 1 (very good) to 5 (very poor). Then they answered 53 questions pertaining to negative effects of illness on 6 aspects of daily living as “yes” (coded as 1) or “no” (coded as 0). The 6 aspects were sleep/rest, home management, social interaction, alertness behavior, communication, and recreation/pastimes. A total score and a subscore for each of the 6 categories were calculated, with higher values indicating a greater impact of illness on the patient’s life. 3.9.1 Primary Efficacy Parameters The primary efficacy parameters as defined by protocol were as follows: • The change from baseline in the total score on the HAM-D from beginning of treatment to end of the 8 week acute phase BRL-029060/RSD-100TW9/1/CPMS-329 000043 www.cuwai.com • The percentage of responders (≥50% reduction in HAM-D and/or a HAM-D score ≤8) at the end of the acute phase 3.9.2 Secondary Efficacy Parameters The secondary efficacy parameters for the acute phase defined by protocol were change from baseline in the following parameters: • Depression subscale of K-SADS-L • The CGI Improvement score • Autonomic Function Checklist • Self Perception Profile • Sickness Impact Scale Prior to opening the blind, the sponsor and investigators developed a plan to analyze the efficacy data. The plan described a definition of responders and called for additional measures of effectiveness. These included the depression items from the HAM-D and K-SADS-L instruments, and the plan provided for a status of remission. Further description of the analysis plan is provided in Section 3.13.4 and in the statistical report in Appendix A. 3.10 Safety Assessments 3.10.1 Adverse Experiences Adverse experiences (AEs) were elicited by the investigator asking the patient a non-leading question such as “Do you feel differently in any way since starting the new treatment?” If the patient responded “Yes”, details of the treatment emergent AE and its severity including any change in study drug administration, investigator attribution to study drug, any corrective therapy given, and outcome status were documented on the case report form. Attribution or relationship to study drug was judged by the investigator to be unrelated, probably unrelated, possibly related, probably related, or related. All adverse experiences were coded from the verbatim term by body system and preferred term according to the Adverse Drug Experience Coding System (ADECS), which is based on the COSTART system. BRL-029060/RSD-100TW9/1/CPMS-329 000044 www.cuwai.com Serious Adverse Experiences Serious adverse experiences were defined as those that were fatal, life-threatening, disabling or incapacitating, or resulted in hospitalization, prolonged a hospital stay, or was associated with congenital abnormality, cancer or overdose (whether accidental or intentional). In addition, any experience that the investigator regarded as serious or that suggested any significant hazard, contraindication, side effect or precaution that may be associated with the use of the drug was reported as a serious adverse event. All serious adverse experiences that occurred during the study or within 30 days of receiving the last dose of study medication were reported by the investigator to the study monitor within 24 hours. 3.10.2 Laboratory Monitoring Clinical laboratory tests were performed at the screening visit and at the end of the study week 8. These tests included hematology, clinical chemistry, and urinalysis. All laboratory tests were performed at the Clinical Trials Center of SmithKline Beecham Clinical Laboratories (SBCL) in Van Nuys, California. The following hematology variables were measured in blood: hemoglobin; hematocrit; red blood cell (RBC) count; mean corpuscle hemoglobin; mean corpuscle volume; white blood cell (WBC) count, including total and differential; and platelet count. The following clinical chemistry variables were measured in serum: liver function tests (consisting of total bilirubin, alkaline phosphatase, SGOT, and SGPT); renal function tests (consisting of blood urea nitrogen and creatinine), at screening only; human chorionic gonadotrophin (HCG), only in females of child-bearing potential; and other tests (consisting of albumin, globulin, total protein, uric acid, and random glucose). Urine specimens were tested using dipstick for the presence of protein and glucose. If protein was noted, microscopy was performed. In addition, a urine test for drugs of abuse was performed at the screening visit. Any laboratory abnormalities considered clinically significant were to be recorded in the adverse experience pages of the CRF. In addition, laboratory values of clinical concern were defined by the sponsor and tabulated. BRL-029060/RSD-100TW9/1/CPMS-329 000045 www.cuwai.com 3.10.3 Vital Signs and Body Weight Sitting and standing blood pressures and heart rates were measured at every clinic visit, as was body weight. Values of clinical concern were defined by the sponsor and tabulated. 3.10.4 Electrocardiogram Twelve-lead EKGs were obtained at the screening evaluation and after 4 and 8 weeks of treatment. Rhythm strip EKGs were obtained at all other clinic visits. All clinically significant abnormalities were to be recorded in the adverse experience pages of the CRF. 3.10.5 Pregnancy Tests Serum for assay of human chorionogonadotrophin (HCG) was obtained from all female patients of childbearing potential at the screening visit. Serum was also to be obtained at the week 5 and 24 visits or at any other time during the study if pregnancy was suspected. The samples were assayed for serum HCG at SBCL, and the results were reported promptly to the investigator. Any patient who became pregnant during the study was withdrawn from the study immediately. In addition, any patient who discovered that she had become pregnant during the study or within 30 days (or 5 half-lives, whichever was longer) after the treatment period was to notify the investigator of this fact. Whenever possible, the pregnancy was to be followed to term, any premature termination reported, and the status of mother and child after delivery reported to SB. 3.11 Plasma/Serum Concentrations Serum samples to be assayed for imipramine and desipramine concentrations and plasma samples to be assayed for paroxetine concentrations were obtained at baseline and after 4 and 8 weeks of treatment. Patients scheduled for a morning clinic visit were to delay taking their morning dose of study drug until after completion of the blood draws, while patients scheduled for a visit later in the day were to take their morning dose as usual. Blood (10 mL) for imipramine/desipramine assay was drawn into red-topped tubes and allowed to clot. Following centrifugation, the serum sample (≥3 mL) was transferred to a plastic screw-cap vial and shipped to the Clinical Trials BRL-029060/RSD-100TW9/1/CPMS-329 000046 www.cuwai.com Center at SBCL. The serum samples were assayed immediately using a standard high-pressure liquid chromatography (HPLC) method for detection of tricyclic antidepressants. Following addition of protriptyline as an internal standard, each sample was extracted with hexane and isoamyl alcohol at basic pH. The organic layer was separated, evaporated to dryness, and reconstituted with mobile phase before injection onto the HPLC. Imipramine and desipramine were chromatographed using a cyano column (Supelco) and detected using ultraviolet absorbance at 215 nm. For both analytes, the standard curve was linear from 25 to 750 ng/mL (mcg/L), the coefficient of variation for replicate low and high control samples was ≤10%, and the detection limit was determined to be 25 ng/mL (mcg/L). The imipramine and desipramine results were blinded on the lab report sent to the investigator. However, if the sum of the imipramine and desipramine concentrations exceeded 500 mcg/L (500 ng/mL), the investigator was notified by telephone, and the patient was withdrawn from imipramine treatment (see Section 3.5.2). Blood (5 mL) for paroxetine assay was drawn into lavender-topped tubes, mixed, and centrifuged. The plasma sample (≥ 2 mL) was transferred to the inner vial of a “vial within a vial” and frozen. The frozen samples were shipped to SBCL and stored there in a frozen state until assayed in batch mode using a previously validated HPLC method. Following addition of protriptyline as an internal standard, interfering substances were removed from the samples by applying them to C-2 solid-phase columns. Paroxetine was eluted with 0.3 N HCl in methanol. The eluates were dried and reconstituted in mobile phase prior to injection onto the HPLC. Paroxetine was chromatographed using a cyano-propyl column (Supelco) and detected using ultraviolet absorbance at 215 nm. Any sample with a paroxetine concentration above 200 ng/mL was re-assayed following dilution with water. The standard curve was linear from 20 to 200 ng/mL. Coefficients of variation for replicates were 13.2% for low controls (25 ng/mL) and 9.7% for high controls (125 ng/mL). The detection limit was determined to be 10 ng/mL. Blood levels for paroxetine, imipramine, and desimipramine will be reported separately with the continuation phase data as an addendem to this report. 3.12 Data Quality Assurance To the best of our knowledge, this study was conducted according to Good Clinical Practices. Pharmaco LSR, Inc. (Austin, TX), a Contract Research BRL-029060/RSD-100TW9/1/CPMS-329 000047 www.cuwai.com Organization (CRO), was employed to perform data management according to an agreed contract. The responsibilities of Pharmaco were conducted according to its standard operating procedures (SOPs), consistent with guidelines provided by SB. Upon receipt at SB, the case report forms (CRFs) were photocopied and forwarded to Pharmaco, where they were manually reviewed for completeness and accuracy according to pre-determined monitoring guidelines. Any issues or inconsistencies arising from this review were resolved according to SB standard data management practices, in conjunction with the SB medical monitor, clinical investigation staff, and the external investigators. The data were then entered by Pharmaco and transferred and loaded onto the SB database. Subsequent data handling and reporting processes were subject to in-process Quality Control at SB. Programmed computer validations were run against the database to test the reasonableness of the data. A final audit of the frozen database against the CRF was performed, in which approximately five percent of the patient population was randomly selected. This audit showed an error rate less than 0.5 percent for the database as a whole. Except for the data entry and management functions performed by Pharmaco, all of the above procedures were performed according to methodologies detailed in SmithKline Beecham’s SOPs. This study was subject to audit by SmithKline Beecham’s department of Worldwide Regulatory - GCP (WRC-GCP). A list of audited sites can be found in Appendix A. 3.13 Statistical Evaluation A description of the statistical analyses can be found in the Statistical Appendix. The data are presented in the form of data listings and tables of counts, means and standard deviations/standard error. These listings and tables were obtained using the Statistical Analysis System (SAS) statistical package, Version 6.08. Summary tables of demographic and baseline characteristics, safety variables, and secondary efficacy variables are presented for the intent-to-treat population only. Summary tables of the primary efficacy variables are presented for both the intent-to-treat and the per-protocol efficacy populations. Data listings are presented for all patients and support the summary tables. Although the tables for this report describe data from the acute phase, the listings, BRL-029060/RSD-100TW9/1/CPMS-329 000048 www.cuwai.com which present individual patient information, provide the data from both the acute and continuation phase. This allows a reviewer to follow an individual patient’s participation through the entire study. 3.13.1 Comparison of Interest The comparisons of interest were paroxetine vs. placebo and imipramine vs. placebo. Hypotheses concerning these comparisons were tested at the alpha level of 0.05 using the acute phase (8 week) data of the study. No comparisons were made between paroxetine and imipramine. 3.13.2 Target Sample Size The sample size of the study was chosen to ensure adequate power for detection of a difference between both of the active treatments and placebo with a two tailed alpha level of 0.05 and a power of 0.80. A difference was defined as a between- treatment difference in the change from baseline of total HAM-D score that was 4.0 at the endpoint of the acute phase. A standard deviation of 10 was initially chosen to reflect the greater variability in response expected in an adolescent population. Subsequently, the standard deviation of the HAM-D scores was found to be 8 in a blinded evaluation of approximately 100 patients. Therefore, a total population of 275 patients was expected to provide adequate power to detect a difference according to the criteria outlined above. 3.13.3 Method of Randomization A computer-generated randomization list of 360 numbers for the acute phase was generated in which the treatments were balanced in blocks of 6 consecutive patients. Each investigator was allocated a block of consecutively numbered treatment packs, and patients were assigned treatment numbers in strict sequential order. Patients were randomized in a 1:1:1 ratio to treatment with paroxetine, imipramine, or placebo. 3.13.4 Planned Efficacy Evaluations No interim analyses were planned for the study. Primary Efficacy Variables The protocol defined the primary efficacy parameters for comparing the efficacy of each active treatment with that of placebo to be: BRL-029060/RSD-100TW9/1/CPMS-329 000049 www.cuwai.com • The change from baseline in total HAM-D score at endpoint of the acute phase. • The percentage of responders at the endpoint of the acute phase. Initially the protocol defined a "responder" as a patient whose HAM-D at endpoint was at least 50% lower than the baseline score. This definition was to be used as "operational" criteria for entry into the continuation phase. Prior to opening the blind, the sponsor and the investigators developed an analytical plan. Among other issues, this agreed plan included a definition of a "responder" and a "remission" status. The intent was to provide a robust definition of "response" and to describe a status of "remission" in order to provide a rigorous anchor point in analyzing relapses in the continuation phase. The agreed analytical plan described a "responder" as a patient whose HAM-D score was 8 or less or was reduced from baseline by at least 50%. The remission status was defined as a HAM-D score of 8 or less. The agreed analytical plan also called for the following measure of effectiveness to be included in the analysis: the 9-item depression subscale of the K-SADS-L, the depression item from both the HAM-D and the K-SADS-L, and two methodologies for analyzing the clinical global improvement score: 1) the mean scores and 2) the proportion of patients with rating of "1" or "2" ("very much" or "much improved" respectively). The initial protocol described the K-SADS-L and CGI instruments as secondary measures. The protocol defined as secondary measures the behavior and functional instruments. These included the Autonomic Function Checklist (AFC), the Self- Perception Profile (SPP), and the Sickness Impact Scale (SIP). The agreed analytical plan included a time to sustained response and various subsidiary covariate analysis of response as secondary analyses. 3.13.5 Methods of Analysis The demographic characteristics, description of the baseline depressive episode, additional psychiatric diagnoses, and personal history variables of the patients were summarized descriptively by treatment group. Tests of hypotheses regarding model assumptions, such as the significance of treatment-by-investigator interactions, were made at the 10% level. All other statistical tests were two-tailed and performed at the 5% significance level. BRL-029060/RSD-100TW9/1/CPMS-329 000050 www.cuwai.com Endpoint was defined as the patient’s last observed assessment (i.e., last observation carried forward [LOCF] dataset) during the acute phase of the study. Changes from baseline to endpoint in the total HAM-D score were analyzed by using an analysis of variance (ANOVA) via the General Linear Models (GLM) procedure of SAS. The model included terms for treatment group (paroxetine, imipramine, and placebo) and investigator. Since interaction was not significant (p>0.10), it was dropped from the model. Pair-wise comparisons between paroxetine and placebo and between imipramine and placebo were made at the 0.05 level of significance using the CONTRAST statement. In addition to the endpoint analyses, analyses of the efficacy variables were done at each weekly visit using the model determined from the endpoint analyses. Analysis of covariance was used to evaluate the effect of possibly important prognostic variables using the endpoint of responders (defined by 50% reduction or score of 8 or less in the total HAM-D). These included endogenous subtype, age at onset, number of prior episodes, comorbidity with separate anxiety disorder. CGI Improvement Scale scores and changes from baseline in the 9-item depression subscale of the K-SADS-L were analyzed using analysis of variance as described above for the change from baseline in HAM-D scores. Categorical variables (e.g., the percent of patients who responded to treatment) were analyzed using logistic analysis via the Categorical Modeling (CATMOD) procedure of SAS. The model included terms for treatment group and investigator. The nonsignificant (p>0.10) interaction effect was removed from the model. Pair-wise comparisons between treatments were made at the 0.05 level of significance using the CONTRAST statement. 3.13.6 Populations/Data Sets to be Evaluated Intent-to-Treat Efficacy Population The intent-to-treat efficacy population consisted of all patients who were randomized to study medication and had at least one post-treatment efficacy evaluation. The intent-to-treat population was the primary population in the efficacy analyses. BRL-029060/RSD-100TW9/1/CPMS-329 000051 www.cuwai.com Per-Protocol Efficacy Population A per-protocol patient population was identified from the intent-to-treat population and excluded those patients for whom any of the following applied: 1 Compliance < 80% or >120% on two consecutive visits 2 C-GAS score ≥ 60 at screening 3 Younger than 12 years or older than 18 years 4 Not in an episode of major depression for at least 8 weeks 5 HAM-D score < 12 on the first 17 items at screen or baseline visit 6 An adequate trial of antidepressants within 6 months prior to beginning the study. An adequate trial was defined as treatment for 4 or more weeks with imipramine, desipramine, or amitriptyline at a dosage of 150 mg/day or higher, with nortriptyline at a dosage of 50 mg/day or higher, or with fluoxetine at a dosage of 20 mg/day or higher. 7 Use of an investigational drug within 30 days of entry into the study or within five half lives of the investigational drug (the longer period applied) 8 Current use of (1) psychotropic medication including anticonvulsants, anxiolytics, neuroleptics, lithium carbonate, (2) any illicit drug, as documented by a drug screen within 2 weeks of starting the study 9 Suicidal ideation with a definite plan, or made a suicide attempt within the current episode, or made a suicide attempt by medication overdose 10 Did not give written informed consent 11 Evidence of organic brain disease, epilepsy, or mental retardation 12 A medical illness which contraindicated the use of heterocyclic antidepressants (e.g., cardiovascular disease) 13 Did not have an IQ ≥ 80 14 Not medically healthy at screening 15 A current diagnosis (within 12 months) or post-traumatic stress disorder BRL-029060/RSD-100TW9/1/CPMS-329 000052 www.cuwai.com
