Cognitive Assessment in Schizophrenia Clinical Trials: MATRICS and Beyond

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Cognitive Assessment in Schizophrenia Clinical
Trials MATRICS and Beyond

• Michael F. Green, PhD
• Department of Psychiatry and Biobehavioral
  Sciences, Geffen School of Medicine at UCLA
• UCLA Semel Institute
• Department of Veterans Affairs, VISN 22 Mental
  Illness, Research, Education and Clinical Center
  (MIRECC)
• March 5th 2009
• ASENT / ISCTM Washington D.C.

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MATRICS Measurement and Treatment Research to
Improve Cognition in Schizophrenia

• Steve Marder, M.D., P.I.
• Michael Green, Ph.D., Co-P.I.
• NIMH Project Officer Wayne Fenton, M.D.
• NIMH Division Director, DMDBA Ellen Stover,
  Ph.D.
• www.matrics.ucla.edu

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Wayne Fenton 1953-2006 Science That Matters
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MATRICS Background and Rationale

• Increasing evidence that cognitive deficits are
  core features of schizophrenia
• Increasing support for relationships between
  cognition and functional outcome in schizophrenia
  
• Increasing research focus on the basic studies
  of neuropharmacology of cognition

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Targeting Cognition in Schizophrenia Why the
Bottleneck?

• Lack of consensus regarding cognitive targets.
• No widely accepted endpoint.
• Ambiguity regarding optimal clinical trial
  design.
• No path to FDA approval and labeling (not a DSM
  entity).

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FDA Processes Focus Industry Efforts

• FDA registration targets DSM disorders
• No fundamental objection to syndrome-based
  clinical targets (fever, pain, agitation)
• We will not accept a new clinical endpoint for
  the convenience of any drug company
• NIMH can use its convening authority as
  independent scientific entity to define new and
  valid clinical endpoints

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NIMH MATRICS Goals and Products

• Create Standardized Measure for use in Clinical
  Trials
• Define Optimal Experimental Designs
• Establish path to FDA Approval
• Attract large pharmaceutical companies to focus
  efforts on this important clinical target
• Success required involvement of NIMH, FDA,
  pharmaceutical industry, and academia

www.matrics.ucla.edu
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Alzheimers Dementia compared with Schizophrenia
Neuropsychological Deficit Scores
From Heaton et al. (1994)
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MATRICS Principles for Developing Consensus

• Consensus should be as broad as possible
• Transparency of process
• Inclusion of academia, NIMH, industry, FDA,
  consumer representatives
• A priori development of a path to consensus
  (e.g., RAND Panel, a modified Delphi process)
• Management of conflicts of interest

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Steps to MATRICS Consensus Cognitive Battery
1. Identify cognitive domains
2. Select key criteria for test selection
3. Solicit nominations for cognitive tests
4. Narrow tests to 6 or less per domain
Subgroup of NCC survey of experts
Survey of experts
NCC, based on survey of experts
NCC
6. Evaluate tests on criteria with RAND Method
5. Create data base on criteria for candidate
tests
7. Select 2-5 tests per domain for beta battery
RAND Panelists
MATRICS Team
NCC, based on ratings of Panelists
NCC MATRICS Neurocognition Committee PASS
MATRICS Psychometric and Standardization Study
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Essential Criteria for Consensus Cognitive
Battery for Clinical Trials in Schizophrenia

• Battery
• Inclusion of the seven cognitive domains
• Valid assessment of cognition at the level of all
  individual major cognitive domains
• Individual Tests
• High test-retest reliability
• High utility as a repeated measure
• Demonstrated relationship to functional outcome
• Demonstrated tolerability and practicality

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MATRICS Consensus Cognitive Battery Estimated
administration time 63.5 min

• Speed of Processing
• Category Fluency
• BACS Symbol Coding
• Trial Making A
• Attention / Vigilance
• Continuous Performance Test - Identical Pairs
  version
• Working Memory
• Maryland Letter Number Span
• WMS Spatial Span

• Verbal Learning
• Hopkins Verbal Learning Test
• Visual Learning
• Brief Visuospatial Memory Test
• Reasoning and Problem Solving
• NAB Mazes
• Social Cognition
• MSCEIT Managing Emotions

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MATRICS Consensus Cognitive Battery (MCCB)

• Distributed by
• Pearson - Harcourt Assessment, Inc
• Multi-Health Systems (MHS)
• Psychological Assessment Resources (PAR)

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Norms from MATRICS-Psychometric and
Standardization Study (PASS)
Kern et al. Am J. Psychiat. 2008
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Co-primary (Intermediate) Measure in Addition to
Cognitive Performance

• The current position of the FDA is that
  concurrent change on a co-primary measure of
  functional outcome will be required for approval
  of a neurocognitive drug for schizophrenia.
• Buchanan et al. Schizophrenia bulletin 2005
• Arguments for Community Status as Co-primary
• Increase face validity for consumers and
  clinicians
• Increase acceptance by consumers and clinicians
• The ultimate goal is better community functioning
• Arguments against Community Status Co-primary
• Measurement challenges
• Distance from biological systems (sensitivity to
  cognitive-enhancing drugs likely length of time
  to change)
• Intervening variables / level of psychosocial
  support
• Arguments by analogy (e.g., not needed for
  hallucinations, depression, Parkinsons tremor)

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Key Linkages for Cognition and Functional
Outcome
Community Outcome
Community
Assessment Environment
Clinic
Cognitive Performance Measures
Laboratory
Distal
Proximal
Intermediate
Within individual
Interpersonal
Sensitivity to cognitive drug effects
Less sensitive
More sensitive
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Follow up Activities to MATRICS

• 1) TURNS NIMH Sponsored Clinical trials network
  for cognition enhancing drugs
• TENETS Network (Treatment and Evaluation Network
  for Trials in Schizophrenia)
• 2) Negative Symptoms Initiative
• New negative symptom scale
• 3) CNTRICS NIMH Initiative for cognitive
  neuroscience measures in clinical trials
• 4) MATRICS-CT Translation and Co-primary
  Industry / Academic Consortium
• Translation and co-norming of MCCB into other
  languages for international trials
• Evaluation of co-primary measures

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TURNS Research Sites

• Sites
• Columbia University
• Duke University
• Harvard / Mass General
• Nathan Kline Institute
• University of Maryland
• UCLA
• Washington University

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NIMH-TURNS / TENETSOngoing Clinical Trials

• 1. Merck (MK-0777)
• 4-week trial
• GABAA (a2, a3) partial agonist
• 2. Allon (AL-108)
• 8-week trial
• 8 amino acid peptide fragment
• promotes assembly of microtubles
• potentially neuroprotective
• 3. Novartis (AQW051)
• single dose cross-over study
• 2-week parallel group study
• a7 nicotinic agonist

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• Identify set of cognitive systems and component
  processes as targets for treatment development in
  schizophrenia.
• Delineate psychometric and pragmatic issues
  relevant to the development of tasks that measure
  these cognitive systems.
• Develop specific measures of target cognitive
  processes that can be implemented as behavioral
  tasks, as well as non-invasive functional
  neuroimaging studies.

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MATRICS-CT Scientific Board

• Representation by
• NIMH
• NIH Foundation
• Academia
• Consumer Perspective
• Pharmaceutical Industry

AstraZeneca Bristol-Myers Squibb Eli
Lilly GlaxoSmithKline Lundbeck Johnson Johnson
Pfizer Merck Roche, Sanofi-Aventis Wyeth
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MATRICS CT Translation of the MCCB
Aug 09
Apr 09
Apr 08
Jun 08
Oct 08
Feb 09
Aug 07
Oct 07
Dec 07
Aug 08
Dec 08
Jun 09
Jun 07
Feb 08
Obtain Legal Permission, Licensing
Final Reconciliation, Cultural Adaptation
Establish Procedures for MCCB Academic
Translations
Page composition, Printing of MCCB Translated
Components
Forward / Backward Translations for MATRICS-CT
Languages
Collection of Norms
Test Owner Review and Approval
1st Tier Languages Chinese, German, Hindi,
Russian, Spanish (plus dialects for South and
Central America)
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Validation of Intermediate Measures (VIM) Study
Key Dependent Measures
Performance-based measures 1. Test of Adaptive
Behavior in Schizophrenia (TABS) 2. UCSD
Performance-based Skills Assessment (UPSA) 3.
Independent Living Scales (ILS) Each of these
performance-based assessments will be
administered so that short forms can be compared
with long forms. Interview-based measures 1.
Semi-structured Cognitive Assessment Interview
(CAI) 2. Global assessment (1-100 pt scale)
Global Assessment of Function from CAI 3.
Clinical impression (1-7 pt scale) CGI for
Cognitive Impairment
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MATRICS CT Validation of Intermediate
Measures (2007-2009)
VIM Committee Selects Invites Panelists
UCLA Staff Solicit Nominations Create Database

Meeting 3 Review of Recommendations
VIM Committee Selects Measures, Designs Trial, w/
input from Scientific Board
Meeting 1 Approval of Selection Criteria
Meeting 2 RAND Panel to Evaluate Instruments
VIM Committee Analyzes Data Makes
Recom-mendations
Selection Criteria Group Proposal
Valid. Study Start up / Training
Validation Study Data Collection
Aug 09
Apr 09
Apr 08
Jun 08
Oct 08
Feb 09
Aug 07
Oct 07
Dec 07
Aug 08
Dec 08
Jun 09
Jun 07
Feb 08
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What we did not anticipate in MATRICS

• Role of co-primary (intermediate) measures
• Importance of norms
• Intellectual property issues for tests selected
  for MCCB
• Challenges for inclusion of tests from cognitive
  neuroscience
• Limits of an English-only battery