Post on 03-Jan-2016
Jeffrey Jonas, MDVice President CNS - Forest Research
Institute
Citalopram and EscitalopramPediatric Safety Data
Outline
Overview of Studies
Escitalopram Pediatric Study
Analysis of SREs
Columbia classification
Lundbeck EU Study 94404
Activating Adverse Events
Responder Analyses
Overview
3 completed placebo-controlled studies in pediatric MDD
2 citalopram (Celexa®) studies
• US Study: CIT-MD-18 (7-17 years)
• EU Study: 94404 (13-18 years)
1 escitalopram (Lexapro®) study
• US Study: SCT-MD-15 (6-17 years)
– Submitted to FDA (May 19, 2004); SREs not classified by Columbia
SCT-MD-15: Escitalopram Ped Depression Study
8-week, double-blind, flexible dose
Placebo (N=133)
Escitalopram 10-20 mg/day (N=131)
DSM-IV defined major depressive disorder
Children and adolescents 6-17 years, outpatients only
CDRS-R 40 at baseline
Patients at high risk for suicide excluded
Mean Age: 12.3 yrs
Study Design
Efficacy Overview
Study Primary Measure Outcome
CIT-MD-18 CDRS-R Positive
SCT-MD-15 * CDRS-R Negative
94404 K-SADS-P Negative
* US escitalopram study showed clear trends in adolescent subpopulation (12-17 years)
RiskNumber Treated
Numberw/ SREStudy
SREs (Columbia Classification)
CIT-MD-18
Treatment
Placebo 2 85 0.024Citalopram 1 89 0.011
SCT-MD-15*Placebo 2 133 0.015Escitalopram 1 131 0.008
94404Placebo 5 112 0.045
121Citalopram 9 0.074
All StudiesPlacebo 9 330 0.027ESC/CIT 11 341 0.032
* not classified by Columbia
Relative Risk of SREs: Drug vs. Placebo
0.48
1.67
1.18
0.51
CIT-MD-18
94404
Overall
Relative Risk
SCT-MD-15
.01 0.1 1.0 10 100
Inclusion Criteria: US vs EU Studies
Inpatient
Recent psychiatric hospitalization
History of suicide attempt
US Studies EU Study
NO
NO
NO
YES
YES
YES
93
RiskNumber Treated
Number with SREStudy
SREs – Excluding Patients with History of Hospitalization or Inpatients
CIT-MD-18
Treatment
Pbo 2 85 0.024Cit 1 89 0.011
SCT-MD-15 * Pbo
Esc
21
133
1310.0150.008
94404 Pbo
Cit3
3
93 0.0320.032
All Studies
PboEsc/Cit
7
5
311313
0.023
0.016
* Not classified by Columbia
Relative Risk of SREs: Drug vs. PlaceboExc Patients with Hx of Hospitalization or Inpatients
0.48
0.51
0.71
1.00
CIT-MD-18
94404
Overall
Relative Risk
SCT-MD-15
.01 0.1 1.0 10 100
Activation Adverse Events (AAEs)
“Activating” AEs are Associated with initiation of treatment with
antidepressant drugs
Precursors to SREs
AAEs examined include Agitation, akathisia, anxiety, anxiety attack,
depression, depression aggravated, emotional lability, hyperkinesia, hypomania, impulsive behavior, insomnia, irritability, manic reaction, nervousness, personality disorder, suicidal tendency, suicide attempt
RiskNumber Treated
Numberw/ AAEStudy
Activation Adverse Events (AAEs)
CIT-MD-18
Treatment
Placebo 8 85 0.09Citalopram 11 89 0.12
SCT-MD-15*Placebo 9 133 0.07Escitalopram 13 131 0.10
94404Placebo 36 112 0.32
121Citalopram 37 0.31
All StudiesPlacebo 53 330 0.16ESC/CIT 61 341 0.18
* Not classified by Columbia
Relative Risk of AAEs: Drug vs. Placebo
1.31
1.11
0.95
1.47
CIT-MD-18
94404
Overall
Relative Risk
SCT-MD-15
.01 0.1 1.0 10 100
Responder Analyses
Hypothesis:
Suicide related events (SREs) are associated with course of depression rather than antidepressant treatment
Analyses:
Compared course of response in patients with and without SREs using change from baseline in primary efficacy measure (K-SADS or CDRS-R)
Study 94404: Response in Patients w/wo SRE
* similar effect seen with responder rates
20
25
30
35
40
2 5 9 12
Treatment Week
MeanScore
placebo w/SRE placebo w/out SRE
citalopram w/SRE citalopram w/out SRE
K-SADS (LOCF)*
Summary and Conclusions
Numerical rate of SREs in the 2 US studies lower in active drug groups vs. placebo
EU study enrolled patients with baseline imbalances in suicide-related risk factors. Removing this subset eliminates the SRE signal for this study
Summary and Conclusions
No evidence of overall increased rate of AAEs in the active drug group relative to placebo
Patients with SREs were typically poor responders whether receiving placebo or active drug