1. MRI as a Potential Surrogate Marker in the ADCS MCI Trial
Michael Grundman, M.D., M.P.H.
FDA PCNS Advisory Committee Meeting on Brain Imaging as an Outcome Measure in Phase III Trials for AD Gaithersberg, MD November 18, 2002

2. Decline in Mini-Mental State During Progression to AD
Normal
MCI AD

3. Mild Cognitive Impairment: Key Criteria
Memory Complaint Verified by Informant
Objective Memory Impairment
Generally Normal Cognition Other than Memory
Generally Normal Daily Function

4. Rate of Decline to AD among MCI Subjects and Normal Controls

5. MCI Trial with Vitamin E and Donepezil
Memory
Impairment
Alzheimer’s
Disease
Donepezil
Placebo 6 12 18 24 30 36
MONTHS

6. MCI Trial with Vitamin E and Donepezil
Recruit people with MCI
3 Treatments
Vitamin E – 2000 IU/day
Donepezil – 10mg/day
Placebo
Study objectives
Prevent development of Alzheimer’s disease
Slow decline on cognition and function
Reduce rate of atrophy on MRI
3 Year duration
769 Participants
69 Centers

7. Baseline Score on ADAS Cog Total in Normals, MCI and AD

8. MRI as Potential Surrogate Marker
Hippocampal atrophy on MRI has high face validity because it occurs early and appears to be substantially affected by the AD pathology and contribute to the memory impairment observed in AD.

9. Percent Annual Change in Hippocampal Volume by Clinical Group
Clinical Group Percent Change
Control -stable  0.9
MCI-stable  1.5
MCI-decliner  1.5
AD  1.8
Jack Jr. C.R., et al, Neurology 2000, Vol 55 p

10. Possible Stages of Decline in Hippocampal Volume Leading to AD
Normal
MCI AD

11. Mild Cognitive Impairment Trial: MRIs Performed to Date
Timing: MRIs Performed at Baseline, Time of Conversion or Study Completion
193 Baseline Scans
57 Second Scans

12. Neuroimaging Hypotheses
Hippocampal volume at baseline will correlate with cognitive and functional performance
MRI hippocampal volume at baseline will predict crossover to AD
Rate of volume loss will be greater in subjects who decline clinically
MRI volumetric analysis will be a useful surrogate for measuring therapeutic response

13. Hippocampal Volume is Correlated with Baseline Memory Function

14. NYU Delayed Paragraph Recall Scores (# Correct) were lower in Subjects with Smaller Hippocampal Volume

15. Baseline Hippocampal Volume Thus Far Appears to Predict Future Conversion to AD and Change on Clinical Measures

16. Conversion to AD by Hippocampal Volume at Baseline
1.0
0.9
0.8
Hippocampal Volume
Probability of Not Converting to AD
Top 50%
Bottom 50%
0.7
0.6
0.5
200
400
600
800
1000
Time on MCI Study (days)

17. CDR Sum of Boxes Change Scores by Hippocampal Volume at Baseline
56 %
44 %
Hippocampal Volume

18. Characteristics of an Optimal Surrogate Marker
Rapidly ascertainable
Correlated with the clinical outcome
Fully capture the treatment’s “net effect”
Able to be collected consistently
Precede clinical decline or failure

19. Observations that Would Support Brain Atrophy as a Surrogate Marker
for Disease Modification
Reduced rate of brain atrophy
Slower rate of clinical decline
Treatment

20. Determine Rate of Decline in Hippocampal Volume in Individual Subjects
Time in Study (Years)

21. Percent Change in Normalized Hippocampal Volume
Determine if the Mean Rate of Hippocampal Atrophy Accurately Predicts Clinical Outcome (AD)
Non-Converters
Percent Change in Normalized Hippocampal Volume
Converters
Time in Study (Years)

22. Percent Change in Normalized Hippocampal Volume
Determine if the Mean Rate of Hippocampal Atrophy is Slowed by Treatment
Treatment
Percent Change in Normalized Hippocampal Volume
Placebo
Time in Study (Years)

23. Possible Reasons Why Brain Atrophy May Not Always Be a Reliable Surrogate Marker
Brain atrophy may not always be in the direct causal pathway of the disease. Weight loss, diuretics or dehydration may also contribute to brain atrophy.
The intervention may reduce the rate of brain atrophy and not improve the clinical outcome. Agents that disrupt the BBB or induce an inflammatory response could lead to brain swelling but not improve clinical symptoms.
The intervention could interfere with causal pathways without slowing brain atrophy. Amyloid-lowering agents that are disease modifying might increase brain atrophy in the short run by ridding the brain of space occupying amyloid.

24. Body Mass Index and Mesial Temporal Cortex Volume in Alzheimer’s Disease Patients

25. Possible Reasons Why Brain Atrophy May Not Always Be a Reliable Surrogate Marker
The intervention could improve the clinical outcome without reducing the rate of brain atrophy. A clinical benefit might occur with agents that enhance synaptic transmission without altering the neurodegenerative process or resulting brain atrophy.
Unexpected adverse events could occur despite a beneficial effect on the surrogate. Clinical benefit and reduction in brain atrophy could occur with unacceptable side effects.

26. Conclusions
Erroneous decisions could be made based on rates of brain atrophy alone. It seems premature to accept differences in brain atrophy as a primary outcome measure in the absence of supportive clinical data.
In conjunction with slowing of decline on clinical measures and a good safety profile, slowing of brain atrophy could support a disease modification claim.
If brain imaging could be validated in AD or MCI trials for a particular agent it might be used to support an efficacy claim in subsequent trials while more clinical data was collected.