1. The ADTI CLIMAT (Clinical Meaningfulness in Alzheimer Disease) Study
Claudia Jacova
Assistant Professor
Division of Neurology
Presented at the 26th International Conference of Alzheimer’s Disease International, Toronto, March 27, 2011

2. No conflicts of interest to disclose

3. ADTI CLIMAT study team PI: Claudia Jacova (UBC)
Co-PI: Philip Lee (UBC & St. Paul’s)
Co-Is: G-Y Robin Hsiung (UBC), Marilyn Bater (Royal Jubilee), Pamela Thornton (Peace Arch)
Project Manager: Penny Slack (UBC)

4. CLIMAT Scale
Novel instrument for the measurement of clinically meaningful change
The guiding hypotheses:
Two distinct dimensions matter in AD symptom assessment: Severity of impairment, and severity of impact
Impact is a basis for weighting change.
© Jacova, Feldman, Schulzer, Money, UBC Invention Disclosure 2007

5. CLIMAT Example of change: + 2 units Impact/Impairment ratio
Gain
Loss 25 20 15 10
Impact/Impairment ratio 5
Weighted change -5
0.1
0.5 1 2 10
-10
Less impactful
More
impactful
-15
-20
-25

6. Description Clinician-rated scale
Separate subject and caregiver interviews
17 items assessed within:
social function, everyday function, cognition, behaviour
Impairment and impact assessed at baseline; impairment tracked over time
Interview notes entered here
© Jacova, Feldman, Schulzer, Money, UBC Invention Disclosure 2007

7. CLIMAT Ratings Comparators
CDR Boxes
CLIMAT
IMPAIRMENT
QOL-AD
[Sub / CG]
CLIMAT
IMPACT
Evidence supports validity for subject-reported impairment and impact, and for caregiver-reported impairment

8. ADTI CLIMAT study
Aim: Refine our understanding of clinically meaningful treatment response to cholinesterase inhibitors
Key research questions:
Characterize positive treatment response
Resolve indeterminate treatment response
Track longer-term response trajectories
Derive clinical probes that can guide treatment decisions

9. Renewal Special Authority Form
OPAR

10. Recruitment Goal: Challenges: Current: 250 subject /caregiver dyads
Subjects naive or non-naive to ChEI
Newly enrolled in ADTI
Challenges:
Slow start: small number of referrals, ethics approval from different health authorities, no research infrastructure at non-UBC sites
Current:
Revised inclusion criteria with recruitment of any ADTI enrolee
70 subject / caregiver dyads with subject newly enrolled in ADTI at start of study (Cohort 1)
20 subject / caregiver dyads with subject already enrolled in ADTI (Cohort 2)
CGIC Clinicians Global Impression of Change. This version may or may not use collateral source,may or may not reference to mental status testing and may or may not reference to cognitive assessment results. The CIBIC is the FDA’s Clinician’s Interview Based Impression of Change with rating of patient only and referenced to 7 point scale 1 very much improved, 2 much improved 3 minimal improved and 4 no changes. The CIBIC plus uses both patient and caregiver input. The ADCS-CGIC is the most commonly used presently with 15 areas probed under cognition, behavior, social and daily functioning. Change rating is made on the 7 point scale. Interviewing carer first works best. The order of interview may influence the outcome by almost a magnitude of order similar to a positive drug effect size. The CIBI used in the tacrine trials specified 8 domaines at baseline with mental status testing. At followup interview only with patient.

11. Study flow March 2011 Recruitment: 90 SB/CG dyads 82 SB/CG dyads
BL CLIMAT &
ADTI assessment
29 SB/CG dyads
6-M CLIMAT &
ADTI assessment
15 SB/CG dyads
12-M CLIMAT &
ADTI assessment
3 SB/CG dyads
18-M CLIMAT &
ADTI assessment
Loss to f/u:
3 SB/CG dyads: 2 unwilling, 1 unable to attend interview
Loss to f/u:
1 SB/CG dyad: no longer SA eligible
Loss to f/u:
2 SB/CG dyads: stopped ChEI treatment despite SA eligibility

12. Baseline characteristics
Cohort 1 naive
n=47
Cohort 1 continuing
n=10
Cohort 2 all continuing
n=14
Total
n=71
Age
77.7 (7.6)
74.2 (10.4)
71.7 (20.6)*
76.5 (8.7)
Sex:
% Females
% Males
63.8
36.2
50.0
42.9
57.1 57 43
Education
% Secondary
% College/Univ.
% Post-graduate
55.3
32.0
12.7
40.0
10.0
30.0
59.5
9.5
51.0
38.5
10.5
SMMSE
23.8 (2.2)
22.8 (4.2)
20.6 (5.3)*
23.7 (7.1)
Diagnosis
% AD
% AD w/LBD
% AD w/vascular
59.6
2.1
27.7
100.0**
71.3
7.1
21.4
66.3
2.7
23.0
* p<.05 between naive and continuing in Cohort 1; ** p<.05 between Cohort 1 and Cohort 2

13. Baseline CLIMAT scores
BL score
Continuing use of ChEI (Cohort 2, cohort 1 continuing) is associated with higher CG but not SB ratings

14. 6-month CLIMAT change
OPAR INDETERMINATE
OPAR POSITIVE
CH score

15. Boxplots of impact/impairment ratios for individual items
Social
Functional
Cognitive
Behavioural

16. Subject-reported cognitive change
CH score
Naive
Naive
Continuing
Naive
Naive
Continuing
Continuing
Continuing

17. Caregiver-reported cognitive change
CH score
Naive
Naive
Continuing
Naive
Naive
Continuing
Continuing
Continuing

18. Conclusions
Subjects and caregivers’ perceptions of symptoms inform clinically meaningful change
Subjects may have a more positive perception of their symptoms and symptom changes than caregivers
The assessment of the subjective dimension of impact may help resolve clinically indeterminate response

19. UBC Alzheimer Research Unit
Non-UBC Sites
B. Lynn Beattie
GY Robin Hsiung
Philip Lee
Dean Foti
Howard Feldman
Ian R. Mackenzie
Sunsern
Limsoontarakul
Penny Slack
William Wang
Michele Assaly
Phoenix Bouchard
Alice Fok
Bonnie Leung
Jonathan Money
Benita Mudge
Joanne Ng
Pheth Sengdy
Peace Arch Hospital, White Rock, BC
Pamela Thornton
David Gayton
Mary-Grace Parr
Heather Esau
Heidi Cumberworth
Donna Horahan
Royal Jubilee Hospital, Victoria, BC
Marilyn Bater
Marilyn Malone
Michael Cooper
Laurie Robson
Ralph Fisher & Alzheimer Society of BC Professorship in Alzheimer’s Research Endowment Fund

20. CAREGIVER SUBJECT .57* .37* .09 -.01 -.22 -.24 -.23 -.37* CDR BOXES
CLIMAT
IMPAIRMENT
IMPACT
CDR BOXES
QOL-AD
[CG]
CLIMAT
IMPAIRMENT
IMPACT
CDR BOXES
QOL-AD
[SUB]
.57*
.37*
.09
-.01
-.22
-.24
-.23
-.37*
Convergent & discriminant validity for impairment and impact
Convergent & discriminant validity for impairment
Jacova et al. Alzheimer’s & Dementia 2009

21. Treatment response in AD
Only ~half of AD trials to date have addressed the clinical meaningfulness of their results
Yet, clinical meaningfulness and its measurement are pivotal in dementia where treatments have no normative outcomes
Molnar et al. JAGS 2009