ADCS-CGIC

Overview

ADCS-CGIC Overview!
!
!
General Information!
ADCS-CGIC Overview! !
!

ADCS-CGIC
Administration &
Testing Procedures!
!
NeuroCog Trials
Procedures!
2

A New Clinical Global Rating Scale for

Alzheimer's Clinical Trials
!

Lon S. Schneider, M.D. University of Southern California

Jason T. Olin, Ph.D. University of Southern California
Christopher M. Clark, M.D. University of Pennsylvania
Rachelle S. Doody, M.D., Ph.D. Baylor College of Medicine
Steven Ferris, Ph.D. New York University
John C. Morris, M.D. Washington University, St. Louis
Barry Reisberg, M.D. New York University
Frederick Schmitt, Ph.D. University of Kentucky

National Institute on Aging-Alzheimers Disease

Cooperative Study

Leon Thal, M.D., Principal Investigator

Instrumentation Committee
!

Steven Ferris, Ph.D., Chair Global Scales Committee

Lon S. Schneider, M.D., Chair
Christopher M. Clark, M.D.
Rachelle S. Doody, M.D., Ph.D.
Steven Ferris, Ph.D.
John C. Morris, M.D.
Jason T. Olin, Ph.D.
Barry Reisberg, M.D.
Frederick Schmitt, Ph.D.

Introduction

Clinical Global Impressions of Change

Historically important outcome in clinical trials!

14/17 controlled AD trials used global ratings (Lehmann, 1984)!
Traditionally used in depression, anxiety, schizophrenia trials!
Important indicator of clinical significance!
Efficacy observed without systematic measurement!
Change on a CGI is clinically significant -- by definition!
Global Rating in antidementia research!
Modest efficacy of current medications affects sensitivity!
Lack of structure limits reliability (Dahlke et al., 1992)!
Lack of consensus regarding clinically significant change!
Many sources of bias!

Historical Trends!

1970s--CGIC (Guy 1976)!

Minimal guidelines assume appropriate inferences by clinician!
Based on "total clinical experience" or "how much has he changed?"!

1986-90--NIA Mt. Sinai tacrine trial uses original CGIC (Davis et al., 1992)!
Improvement found on ADAS-Cog, none on CGIC!

1991--Tacrine 30-week trial introduces CIBIC ( CIBI, Knapp et al., 1994)!

Informant and subject interviewed at BL with 8 items, follow-up of subject
!only!
CIBI detects treatment effect!

1991--FDA draft guidelines!

CGIC should not include informant information, should remain holistic !

1992-93--NIA-ADCS, instrument protocol establishes goal to develop new

CGIC!
ADCS-CGIC instrument developed!

Current Issues: Global Ratings!

Structure vs. no structure!
Control of information sources (subject vs.
informant)!
!
Severity vs. change measures!
Need for consensus!

Rationale for use!

If a experienced and unbiased
clinician can detect a global change in
an AD patient solely on an interview
then that change is assumed to be
clinically relevant !
!
(FDA, 1991 and others)!

Global Change Rating!

CIBIC -- based solely on subject interview,
was originally recommended by FDA for
AD trials!
CIBIC+ -- includes a caregiver interview to
provide more complete information on
subject status!

ADCS-CGIC Rating!
Marked improvement (1)!
Moderate improvement (2)!
Minimal improvement (3)!
No change (4)!
Minimal worsening (5)!
Moderate worsening (6)!
Marked worsening (7)!

Development of ADCS-CGIC
Consensus identified among clinicians!
Survey sent to ADCS global raters!
Clinicians agreed that a CGIC should include:!
Interview of subject and informant!
Mental status examination!
Take approximately 20 minutes per interview!
Assess a common set of areas!
Format for ADCS-CGIC based on survey results:!
ADCS-CGIC requires separate interviews of subject and informant!
Worksheets created!
Include domains with specific areas and sample probes!
Content adapted from existing severity rating scales!
Space included for notes!
Not required to fill out forms or to assess every item!
!
Thus, consistency is permitted without forcing a structure on raters!

ADCS-CGIC Format
Instructions!
Note-taking as one would clinically!
Assess mental status!
Assessment of side effects prohibited!
20 minutes recommended per interview!
Ratings made with reference to baseline!
Baseline!
Separate interview of subject and informant!!
Follow-up/Subsequent Visit!
Separate interview of subject and informant!
Interview subject or informant first!
Global change rating made after 2nd interview (subsequent visit)!

ADCS-CGIC Validation Study!

N=242 AD subjects stratified by Mini Mental State Examination
(MMSE) and 64 controls!
Alzheimer's Disease Cooperative Study Clinical Global
Impression of Change (ADCS-CGIC) administered at BL, 1, 2, 6,
and 12 months!
MMSE, Clinical Dementia Rating (CDR), Geriatric Depression
Scale (GDS), Functional Assessment Staging of Alzheimers
Disease (FAST) administered at BL and 12 months!
ADCS-CGIC rating made after interview with subject and
informant!
Order of interviews randomly assigned for each subject!
Global rating is made after each interview; 2nd is the overall
rating!

ADCS-CGIC Results!

ADCS-CGIC distinguished AD subjects from controls (F(1,114)=55.86,

!P<0.0001)!
ADCS-CGIC significantly worsened over time (F(3,240)=68, p<0.0001)!
Time x level of cognitive impairment interaction (F(12,240)=1.93, p<0.03)!
Subjects with an MMSE > 10 showed linear worsening!
Subjects with MMSE < 10 showed the most rapid change at 6 months!

Frequency Distribution over Time

Percent

1 month
2 month
6 month
12 month

60
50
40
30
20
10
0

ADCS-CGIC Rating

ADCS-CGIC
Outcome Distributions Over Time!
ADCS-CGIC Outcome Distribution Over Time
60

Percent

50
40
30
20
10
0
1

ADCS-CGIC Rating
1 month

2 month

6 month

12 month

CGIC ADMINISTRATION &

TESTING PROCEDURES!
16
CONFIDENTIAL

General Issues!
Purpose: !
To detect clinically significant global
change from baseline!
!

Different versions:!
Differ with respect to the amount of
structure (ADCS-CGIC versus the
NYU Version in AD trials)!

CONFIDENTIAL

List of Domains Assessed!

Relevant History!
Observation/Evaluation!
Attention/Concentration!
Orientation!
Memory!
Language/Speech!
Praxis!
Judgment/Problem
solving/Insight!

Thought Content/
Hallucinations!
Behavior/Mood!
Sleep/Appetite!
Neurological/Psychomotor
Activity!
Basic and Complex
(Instrumental) Function!
Social Function!

CONFIDENTIAL

Issues to Consider ADCS-CGIC

Subjects may not be the primary (or best)
source of information for some items!
Observe behavior of subjects with and
without informant (dynamics/conflicts)!
The informant is not always correct!
Depression, frustration!
Small changes may be perceived as large
effects or rationalized!
At the beginning of the interview, remind the
interviewee not to mention any side effects
that the subject may be experiencing!
CONFIDENTIAL

Procedure!
Baseline interviews with subject and
informant !
Follow-up interview with subject and
informant at defined intervals!
Clinical Rating Review and recording of
the CIBIC rating using a 7-point Likert-type
scale!
Monitors must see evidence that it has
been!performed correctly!
CONFIDENTIAL

Basic Worksheet Structure!

Area

Probes

Individual domains within each

of four areas:
General, Mental/Cognitive
State, Behavior, Functioning

Assessment probes and

history probes are only
suggestionsUse your
skills!

CONFIDENTIAL

Caregivers or
Patients Notes

Administration Overview!
!
Three parts of the ADCS-CGIC administration:!
1. Part I Baseline evaluations!
a)
b)

Includes information from both subject and caregiver!

Used as a future reference for subsequent visits !

2. Part II Subsequent Visit evaluations!

a)
b)

Includes information from both subject and caregiver!

Used to gather information necessary to assess change from Baseline!

3. Part III Clinicians Impression of Change!

a)
b)

Completed at subsequent visits from Part II worksheets/notes!

Change Rating used to rate clinical impression of change from Baseline!
22
CONFIDENTIAL

Baseline Evaluation!
Interview the subject and informant separately!
Record any relevant information that was used
onto notes section of the CGIC!
Clinical information from any source can be
used for this interview !
Assessment of mental/cognitive state must be
done!
If psychometric scales are employed, these
must be recorded on the CGIC work sheets!
All domains must be assessed, however there
is no !prescribed order or recommended
technique!
CONFIDENTIAL

Follow-up Evaluations!
Domains for evaluation are same as at Baseline!
Record the use of any formal tests!
Rater may not consult any other member of the
team or use any information from the rest of the
clinic visit!
Rater should avoid asking opinions of the
subject or caregiver, and may not ask about side
effects!
Rater may only refer to the Baseline evaluation!
CONFIDENTIAL

Summary!
Stability over short intervals!
Sensitivity to change over time!
!

Effective method of generating a CGIC/

CIBIC!
!
Commonly used in clinical trials!
!
Rating of change from Baseline, not a
rating of !severity!
!
CONFIDENTIAL

Key Administration Points!

Baseline Evaluation!
Clinical information about the subject from the screening
visit, medical history, physical exam, and neurological
exam may be used !
Subsequent Visits!
Subjects should be reminded to avoid mentioning any
potential side effects !
Rater can refer to the information s/he collected at
baseline when determining the assessment of change!

!
!
!

26
CONFIDENTIAL

Key Administration Points!

Subject should not be present during the
caregiver interview!
!
Interview for baseline should occur with the
patient first and study partner second !
!
In order to ensure consistent data throughout the
study, the same trial partner/caregiver should be
interviewed at all visits!
27
CONFIDENTIAL