FDA Recommended Outcomes in RCTs
Current summary of randomized clinical trials in FTD
Study | Sample size | Global endpoints | Cognitive endpoints | Behavioral endpoints |
---|---|---|---|---|
Moretti, R. et al. [20] | 16 | --- | MMSE, Ten Point Clock Test, Proverb Interpretation Tasks, Stroop Test | NPI, CIRS, CSDD, BEHAVE-AD |
Deakin, J.B. et al. [21] | 10 | --- | CANTAB*, Verbal fluency, Digit Span | NPI, CBI |
Lebert, F. [22] | 26 | CGI-I | MMSE | NPI |
Rahman, S. [23] | 8 | --- | NART, MMSE, CANTAB**, Cambridge Gamble Task | --- |
Huey, E.D. [24] | 8 | --- | RBANS | NPI |
Kertesz, A. [25] | 36 | CGI-S, CGI-I | WAB, MMSE, DRS | FBI, NPI, ADLS |
Vercelletto, M. [19] | 49 | CIBIC+ | MMSE, DRS | NPI, FBI, DAD, ZBI |
Boxer, A.L. [7] | 81 | CGI-C | CVLT, fluency, BNT, Trail Making test, Digit Backwards, Digit symbol | NPI |
Jesso, S. [26] | 20 | --- | Emotion recognition, emotion processing, Theory of Mind task | NPI, FBI |
Limitations of the existing literature
What makes a good endpoint?
Global measures
Individual measures
Composite measures
Behavioral measures
Conclusions
Domain | Test example | Strengths | Limitations |
---|---|---|---|
Global | Clinician Interview Based Impression of Change (with caregiver interview) | Evaluates behavior, cognition and functioning; previously used in clinical trials; demonstrated sensitivity to change | Relies on subjective data from caregivers |
Clinical Dementia Rating | FTD-Specific version available; sensitive to change; association with biomarkers | Reliance on subjective data; lengthy to administer; coarse metric | |
Clinical Global Impressions | Widely used in existing trials in FTD; sensitive to change; individual subscales available | Reliance on subjective data | |
Composite | Montreal Cognitive Assessment | Brief screen; sensitive to change; multicultural; alternate forms; freely available | Limited use in clinical trials; insufficient coverage of cognitive domains; potential for ceiling effects |
Repeatable Battery for the Assessment of Neuropsychological Status | Multi-domain assessment; alternate forms available | Inadequate coverage of executive functioning | |
Dementia Rating Scale, 2nd Ed. | Multi-domain assessment sensitive to presence of dementia; previously used in clinical trials | Limited assessment of executive functioning; no alternate form | |
EXAMINER | Developed with FTD in mind; intended for clinical trials; customizable; specific to executive functioning; measures social cognition and behavior | Actual trial performance is to be determined | |
Neuropsychological Test Battery | Proven trial performance; sensitive to change | Relies heavily on memory functioning; no alternate forms | |
Executive | Trail Making Test | Previously used in clinical trials; extensive normative data; widely used | Limited sensitivity to change in previous trials; prone to floor effects |
Stroop Test | Multiple variants available; extensive normative data; previously used in clinical trials; relatively immune to ceiling effects | Sensitive to practice effects; interference conditions may be prone to floor effects | |
EXIT-25 | Previously used in FTD trials | Longer and more complicated administration than comparable alternatives | |
Frontal Assessment Battery | Brief, simple administration; sensitive to change; multiple language versions | No alternate forms | |
Clock Drawing | Sensitive to executive dysfunction; simple and brief administration; many variants available | Sensitivity and specificity vary as a function of version used. | |
Language | Boston Diagnostic Aphasia Examination | Sensitive to expressive and receptive language impairments; | Limited use in clinical trials; limited sensitivity to speech abnormalities; no alternate forms; prone to ceiling effects |
Western Aphasia Battery | Sensitive to expressive language impairments; previous use in clinical trials | limited sensitivity to speech abnormalities; no alternate forms; prone to ceiling effects | |
Controlled Oral Word Association Test | Previously used in trials; sensitive to change | Only one well-validated alternate form; culturally limited | |
Boston Naming Test | Widely used; extensive normative data; some use in trials | Non-normal distribution of scores; no alternate forms; culturally limited | |
Memory | California Verbal Learning Test, 2nd Ed. | Provides multiple estimates of memory (including learning) and insight into executive functioning | Only one alternate form; lengthy to administer; Recognition trials vulnerable to ceiling effects |
Rey Auditory Verbal Learning Test | Previously used in clinical trials; provides estimates of learning, recall and recognition | Recognition trials vulnerable to ceiling effects; recall trials vulnerable to floor effects | |
Visuospatial Functioning | Judgment of Line Orientation | Relatively free from practice effects; minimal demand on motor and language | Vulnerable to ceiling effects; can be lengthy administration |
Figure Copy tests | Insights into perception, organization and executive functioning; multiple forms | Confounded by motor impairment; scoring can be complex | |
Behavior | Neuropsychiatric Inventory | Widely used in clinical trials; sensitive to change | Not specific to behavioral changes associated with FTD; large standard variations; Improvements may be related to increasing apathy |
Frontal Behavior Inventory | Sensitive to change; employed in existing trials | Improvements may be related to increasing apathy | |
Frontal Systems Behavior Examination | Allows for intra-individual comparison; quantification of apathy | Relies on reliable informant |