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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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).
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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.
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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.
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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
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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.
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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
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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%
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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.
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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.
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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.
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• 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).
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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.
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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
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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.
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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.
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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
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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
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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.
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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.”
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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).
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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
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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
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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
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• 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.
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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.
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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
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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
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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,
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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:
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• 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.
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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.
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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
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