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