Post on 17-Jul-2020
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