Sheehan-Suicidality Tracking Scale (Sheehan-STS) in Predementia Alzheimer’s Disease

Vlad Coric MD1, Robert M. Berman MD1, Jesse M. Cedarbaum MD PhD1 and David Sheehan MD2 1Research & Development, Bristol-Myers Squibb, Wallingford Connecticut

2University of South Florida, Tampa, Florida

February 21, 2013

Disclosure: Full-time, paid employee of Bristol-Myers Squibb Own stock in Bristol-Myers Squibb

1

Assessment of Suicidal Ideation/Behavior in Alzheimer’s Disease (AD) Populations

Limited published data regarding ideation/behavior in AD trials

No validated scale in Predementia AD – BMS Predementia AD study (CN156-018) initiated 2009

Challenges in AD clinical trial populations – patients with impaired MMSE and progressive decline over time – reliability of assessments over disease course unknown – high burden of psychometric testing (often several hours) – difficulty of obtaining reliable caregiver input (SI internal thoughts not

always expressed; preparatory behaviors often hidden from others)

Sheehan-STS incorporated in CN156-018 trial to assess its utility in a Predementia AD population

2

Sheehan-STS

Evolved from the Suicidality Module of the MINI Structured Diagnostic Interview for DSM-IV

Prospective, self-report or clinician-administered rating scale

Eight-item scale assesses – treatment-emergent suicidal ideations – treatment-emergent suicidal behaviors

Items scored on a 5-point Likert scale:

(0=not at all, 1=a little, 2=moderately, 3=very, and 4=extremely)

Efficient administration (completed in 1-2 minutes)

Maps to C-CASA 2010

3

Sheehan-STS

4

Sheehan-STS Data Analysis

Individual item scores

Suicidal ideation subscale score – sum of scores from items 2, 3, and 4, plus score from item 5 if ≤1

Suicidal behavior subscale score – sum of scores from items 6, 7a, and 8, plus score from item 5 if >1

Sheehan STS-total score – sum of ideation and behavior subscales

Change over time and assess for drug effects on treatment emergent ideation and behavior

5

Avagacestat Prodromal (Predementia) AD Study Design

Avagacestat

Placebo

aMCI

Observational cohort (not randomized) Nonpathologic

CSF n=100a

Pathologic CSF

n=270a

Treatment period (104 weeks minimum) 1:1 randomization

Screening to identify predementia patients

LP

aTarget

Sheehan-STS performed at ALL visits: -every 2 weeks for the first 3 months -then every 3 months thereafter

6

Key Entry Criteria

Clinical • Ages 45-90 • MMSE 24-30 • CDR-global 0.5

and CDR memory score ≥ 0.5

• MRI/other medical workup do not suggest non-AD causes of impairment

• Stable ChEIs or memantine allowed

• GDS < 6

Cognitive • Memory complaint by

subject or study partner

• Objective impairment on: • Logical Memory II

(WMS) test of Delayed Paragraph Recall or

• Free Cued Selective Reminding Test (total recall, free recall, or delayed free recall)

Biomarker • Cerebrospinal fluid

consistent with Alzheimer’s Disease pathology: • Aβ42 ≤ 200pg/ml

or • t-tau/Aβ42 ≥ 0.39 *CSF analyzed at a central

laboratory using LuminexxMAPtechnique

(INNO-BIA AlzBio3 kit; Innogenetics).

7

Sheehan-STS in Predementia AD Population (CN156-018)

3,348 administrations of Sheehan-STS in 263 subjects treated up to 152 weeks (interim analysis Nov-2012)

Randomization completed September 2011

24 month recruitment period

72 sites in North America and Europe

Study terminated November 2012 and subjects remain in follow-up phase

8

Demographics and Baseline Evaluation, randomized sample with baseline Sheehan-STS

Randomized (n=263)

Age, mean (range) 71.8 (49-90) Gender, % male 56 APOE4 Status, % carrier 68 MMSE (range) 27.0 (24-30) Baseline Sheehan-STS: Total Score = 0 94.7% (n=248) Total Score = 1 3.8% (n=10) Total Score > 1 1.5% (n=4) Suicidal Ideation Subscale 5% (n=14) Suicidal Behavior Subscale 0% (n=0)

9

Completion of Sheehan-STS in Predementia AD Visit Number records (%)

≥ 1 missing item Baseline 0/263

Week 2 1/258 (0.4%)

Week 4 0/248

Week 6 0/239

Week 8 0/248

Week 12 0/229

Week 16 0/223

Week 20 0/216

Week 24 1/219 (0.5%)

Week 32 0/203

Week 44 2/188 (1.1%)

Week 56 0/179

Week 68 0/163

Week 80 0/137

Week 92 0/119

Week 104 0/91

Week 116-152 0/125

TOTAL ACROSS WEEKS

4/3,348 (0.12%) (safety sample)

99.88% completion rate

without missing data

10

Observed Changes from baseline Sheehan-STS total score

Week < -1 -1 No Change 1 > 1 Week 2 3 9 240 2 1

Week 4 3 7 229 5 2

Week 6 3 6 221 7 1

Week 8 3 7 228 1 1

Week 12 3 6 213 3 1

Week 16 3 7 204 2 1

Week 20 3 8 198 4 1

Week 24 2 8 198 2 1

Week 32 1 7 189 4 1

Week 44 2 7 174 1 1

Week 56 1 7 166 1 2

Week 68 1 7 150 2 1

Week 80 1 6 127 1 2

Week 92 4 112 1 1

Week 104 3 88

(treatments pooled OC data set)

11

Agreement Between Sheehan-STS Suicidal Ideation Subscale and Treatment Emergent AEs

(cohort randomized to study treatment)

Agreement between

Sheehan-STS and TEAE reporting

STS

Idea

tion

Subs

cale

Sco

re

2,990 (98.3%)

52 (1.7%)

0

1 (0.03%)

No Yes

0

≥1

Treatment Emergent AE of SUICIDAL IDEATION

Sheehan-STS more sensitive than AE/SAE assessed SI

12

Agreement Between Sheehan-STS Suicidal Behavior Subscale and Treatment Emergent AEs

STS

Beh

avio

rs S

ubsc

ale

3,032 (99.6%)

11 (0.4%)

0

0

No

0

≥1

Treatment Emergent AE of SUICIDE ATTEMPT

Yes

(cohort randomized to study treatment)

Agreement between

Sheehan-STS and TEAE reporting

Sheehan-STS more sensitive than AE/SAE assessed SB

13

Sheehan-STS in Predementia AD Very low rates of missing data

Sensitive to change from baseline

High rates of agreement between Sheehan-STS and review of TEAE/SAEs

More sensitive than AE/SAE reporting of ideations/behaviors – Sheehan-STS ideation subscale identified 52 incidences of suicidal ideations

– Sheehan-STS behavior subscale identified 11 incidences of suicidal behaviors

Administrations did not fail to capture occurrences of SI/SB

14

Sheehan-STS in Predementia AD Sheehan-STS demonstrated significant utility during this

study and advantages include: – can be administered either via self report or clinicians

– more sensitive than AE/SAE reporting

– efficient (completed in only 1 to 2 minutes)

– assesses multiple domains of suicidal thoughts/behaviors (passive suicidal ideation, active suicidal ideation, suicidal behaviors, self-injurious behaviors, accidents)

– multiple analyses (individual item scores, total score, suicidal ideation subscale, suicidal behaviors subscale, treatment emergent changes)

– maps to the C-CASA (suicidality classification/coding system )

Future work needed: assess other AD populations, reliability over entire disease course, correlation with other scales, ↑ sample size, assess caregiver report

15

Acknowledgements

The authors acknowledge with deep appreciation all the patients and study partners who participated in the CN156-018 trial

We also recognize the efforts of the principal investigators and their clinical staff

16

Back-up Slides

17

Agreement Between Sheehan-STS and GDS-short form

(Administrations of cohort randomized to study treatment)

STS

Tota

l Sco

re 1,561

(93.9%)

51 (3.1%)

40 (2.4%)

11 (0.67%)

≤ 5 > 5 (mild depressive sx’s)

0

≥1

GDS-short form total score