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

No conflicts of interest to disclose

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)

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

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

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

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

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

Renewal Special Authority Form OPAR

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.

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

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

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

6-month CLIMAT change OPAR INDETERMINATE OPAR POSITIVE CH score

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

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

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

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

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

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

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