Magnitude and Predictors of MATRICS Consensus Cognitive

Battery Change in Placebo Patients with Schizophrenia

Richard S.E. Keefe, Vicki Davis, Alexandra Atkins, Philip D. Harvey, Dana Hilt, Ilise Lombardo, Dragana Bugarski-Kirola,

Carol Reid

Duke University Medical Center, NeuroCog Trials, University of Miami, FORUM, Roche

Thank you to unnamed others who provided data for these analyses

Financial DisclosuresPast Three Years

CONSULTANT/AD BOARD/SERVICE PROVIDER Abbvie, Akebia, Amgen, Astellas, Asubio, Avanir, AviNeuro/ChemRar, Biogen Idec, BiolineRx, Biomarin, Boehringer-Ingelheim, Eli

Lilly, EnVivo/FORUM, GW Pharmaceuticals, Helicon, Janssen, Lundbeck, Merck, Minerva, Mitsubishi, Novartis, Otsuka, Pfizer,

Roche, Sanofi-Aventis, Shire, Sunovion, Takeda, Targacept

RESEARCH FUNDINGDepartment of Veteran’s Affairs, Feinstein Institute for Medical Research, GlaxoSmithKline, NIMH, Novartis, Psychogenics,

Research Foundation for Mental Hygiene, Singapore Medical Research Council

FOUNDER OF NEUROCOG TRIALS Providing rater training, data quality assurance and consultation to several pharmaceutical companies and other consortia

SHAREHOLDER Sengenix

ROYALTIES Brief Assessment of Cognition in Schizophrenia (BACS), MATRICS Consensus Cognitive Battery (MCCB), Virtual Reality Functional

Capacity Assessment Tool (VRFCAT)

Background

• The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Battery (MCCB) is described as the “gold standard” by members of the Psychiatry Division of the US FDA

• The psychometrics of the MCCB have been increasingly well established • High test-retest reliability (ICC = 0.90) over several large clinical trials

• Small (Cohen’s d ~ 0.2) practice effects at first testing interval

• Sensitivity to treatment with several different interventions (Green et al, AJP, 2014)

• However, the magnitude and predictors of improvement in sequential assessments with placebo treatment is unknown

Methods

• We combined data from 12 studies that assessed changes in MCCB performance in 813 patients with schizophrenia receiving placebo over 4 to 56 weeks

• Change from baseline was investigated with a mixed-effects model of repeated measures adjusting for baseline, study, baseline by study, and with visit nested within study

• Predictors included a variety of demographic, clinical and cognitive factors

• Practice effects were examined in a separate model using data from 7studies that measured cognition at screening

Demographic and Baseline Characteristics of the Samples

N (%)

Male 553 (68)

Race:

White

Black

Other

406 (50)

290 (36)

117 (14)

Geographical Region:

North America

Eastern Europe

Asia

Latin America

Western Europe

536 (66)

118 (15)

63 (8)

46 (6)

50 (6)

Post-Secondary Education 151 (27)

Current Smoker 258 (43)

Duration of Illness < 10 years 234 (37)

Baseline Antipsychotic:

Risperidone/Paliperidone

Olanzapine

Other

Quetiapine

Aripiprazole

159 (33)

118 (24)

89 (18)

66 (14)

56 (11)

Mean ± SD

(N)

Age41.2 ± 11.45

(813)

Age at Onset of

Illness

23.3 ± 8.34

(233)

Baseline MCCB

Composite T-Score

27.2 ± 12.78

(782)

Baseline UPSA-2

Total

87.8 ± 16.10

(225)

Baseline PANSS Total 59.7 ± 15.01

(669)

Baseline NSA-16

Total

56.5 ± 11.96

(489)

20

25

30

35

40

-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

CO

MP

OSI

TE T

-SC

OR

E

WEEK OF ASSESSMENT

Mean MCCB Composite T-Score by Study for Placebo Patients50

N = 0-19N = 20-39N = 40-59N = 60-79N = 80-99N = 100-119

Overall Placebo Change from Baseline by Study for MCCB Composite

Study

Number

1

(N=65)

2

(N=43)

3

(N=59)

4

(N=113)

5

(N=107)

6

(N=45)

7

(N=60)

8

(N=17)

9

(N=74)

10

(N=71)

11

(N=110)

12

(N=19)Placebo

Response

Mean

(SE)

1.8

(0.49)

0.7

(0.63)

0.8

(0.56)

3.4

(0.40)

2.9

(0.43)

1.7

(0.88)

2.1

(0.68)

2.7

(0.57)

1.4

(0.64)

1.3

(0.62)

2.8

(0.54)

1.4

(1.15)

Change from baseline was investigated with a mixed-effects model of repeated measures adjusting for baseline, study, baseline by study, and with visit nested within study

Overall Placebo Change from Baseline for MCCB Composite and Individual Subtests

Test

Overall

Composite

(N=778)

Trails A

(N=805)

BACS

Symbol

Coding

(N=807)

HVLT

(N=808)

Spatial

Span

(N=807)

Letter-

number

span

(N=752)

NAB

Mazes

(N=802)

BVMT

(N=808)

Fluency

(N=808)

MSCEIT

Managing

Emotions

(N=800)

CPT

(N=789)

Placebo

Response

Mean

(SE)

1.9

(0.22)

2.5

(0.39)

1.1

(0.27)

1.3

(0.28)

1.0

(0.29)

1.3

(0.28)

1.8

(0.27)

0.7

(0.36)

1.5

(0.28)

0.4

(0.35)

1.3

(0.30)

BACS, Brief Assessment of Cognition in Schizophrenia; HVLT, Hopkins Verbal Learning Test; NAB, Neuropsychological Assessment Battery; MSCEIT, Mayer-Salovey-Caruso Emotion Identification Test; CPT, Continuous Performance Test

Predictors Considered for MCCB Placebo Response*Demographics PANSS NSA-16 UPSA Practice Effect

Age

-0.03 ± 0.015PANSS Total NSA-16 Total UPSA-2

Change in Composite

from Screening to

Baseline

-0.33 ± 0.038

Gender PANSS Positive

SubscaleEmotion / Affect UPSA-2-ER

RacePANSS Negative

Subscale

Communication

-0.18 ± 0.085

Geographic Region PANSS General

Psychopathology

Motivation

-0.18 ± 0.080

EducationMarder Positive Factors Motor Retardation

Current Smoker Marder Negative Factors Social Involvement

Duration of Illness Marder Anxiety / Depression Global Negative Symptoms

Age at Onset of IllnessMarder Disorganized

Thoughts

Baseline Antipsychotic Marder Hostility / Excitement

Married

Employed

*Placebo response measured as change from baseline in the MCCB Composite T-Score using a linear mixed model repeated measures analysis with adjustment for baseline score, study, week nested within study, and the interaction between baseline and study. Noteworthy findings (p-value<0.05) are highlighted.

-4

-2

0

2

4

6

8

10

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

CH

AN

GE

IN C

OM

PO

SITE

T-S

CO

RE

WEEK OF ASSESSMENT

Placebo Change from Baseline in MCCB Composite T-scoreBy Level of Practice Effect between Screening and Baseline

<= -5 > -5 - <=5 > 5Practice Effect

-4

-3

-2

-1

0

1

2

3

4

5

6

7

0 4 8 12 16 20 24 28CH

AN

GE

IN C

OM

PO

SITE

T-S

CO

RE

WEEK OF ASSESSMENT

Change from 1st Followup Visit in Composite T-score By Level of PlaceboResponse between Baseline and Visit 1 in Studies without a Screening Assessment

<= -5 > -5 - <=5 > 5Placebo Response

CONCLUSIONS

• Improvement on the MCCB under placebo conditions was generally consistent with known practice effects

• The magnitude of placebo effect varied slightly across cognitive domains and individual studies

• The magnitude of placebo response was negatively correlated with age, negative symptoms, and especially, improvement during a screening to baseline assessment interval

• Placebo effects beyond known practice effects are not a major barrier for designing cognitive impairment treatment trials in patients with schizophrenia

• Studies with a higher number of assessments are susceptible to greater improvement in the placebo group