MRI as a Potential Surrogate Marker MRI as a Potential Surrogate Marker in the ADCS MCI Trialin the ADCS MCI Trial

Michael Grundman, M.D., M.P.H.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, MDNovember 18, 2002

Decline in Mini-Mental State During Decline in Mini-Mental State During Progression to ADProgression to AD

20.00

21.00

22.00

23.00

24.00

25.00

26.00

27.00

28.00

29.00

30.00

Time

MM

SE

Sco

re

Normal

MCI

AD

Mild Cognitive Impairment: Key CriteriaMild Cognitive Impairment: Key Criteria

Memory Complaint Verified by Informant

Objective Memory Impairment

Generally Normal Cognition Other than Memory

Generally Normal Daily Function

Rate of Decline to AD among MCI Rate of Decline to AD among MCI Subjects and Normal ControlsSubjects and Normal Controls

YEARS OF FOLLOW UP

543210

PR

OP

OR

TIO

N D

EM

EN

TIA

FR

EE 1.00

.95

.90

.85

.80

.75

.70

.65

.60

.55

.50

.45

.40

.35

.30

.25

.20

.15

.10

.050.00

NORMAL CONTROLS

MCI SUBJECTS

MCI Trial with Vitamin E and DonepezilMCI Trial with Vitamin E and Donepezil

Vitamin E

Donepezil

Placebo

0 18126 3024 36MONTHS

Memory

Impairment

Alzheimer’s

Disease

Recruit people with MCI3 Treatments

Vitamin E – 2000 IU/dayDonepezil – 10mg/dayPlacebo

Study objectivesPrevent development of Alzheimer’s diseaseSlow decline on cognition and functionReduce rate of atrophy on MRI

3 Year duration769 Participants 69 Centers

MCI Trial with Vitamin E and DonepezilMCI Trial with Vitamin E and Donepezil

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

Normals

MCI

AD

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

20.00

22.00

24.00

26.00

28.00

ADAS Cog Total

AD

AS

To

tal S

co

res

MRI as Potential Surrogate MarkerMRI 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.

Percent Annual Change in Hippocampal Percent Annual Change in Hippocampal Volume by Clinical GroupVolume by Clinical Group

Clinical Group Percent Change

Control -stable -1.7 0.9 MCI-stable -2.5 1.5MCI-decliner -3.7 1.5AD -3.5 1.8

Jack Jr. C.R., et al, Neurology 2000, Vol 55 p.484-489

Possible Stages of Decline in Hippocampal Possible Stages of Decline in Hippocampal Volume Leading to ADVolume Leading to AD

Time

Hip

po

cam

pal

Vo

lum

e

Normal

MCI

AD

Mild Cognitive Impairment Trial: Mild Cognitive Impairment Trial: MRIs Performed to DateMRIs Performed to Date

Timing: MRIs Performed at Baseline, Time of

Conversion or Study Completion

193 Baseline Scans

57 Second Scans

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

Neuroimaging HypothesesNeuroimaging Hypotheses

Hippocampal Volume is Correlated Hippocampal Volume is Correlated with Baseline Memory Functionwith Baseline Memory Function

NYU Delayed Paragraph Recall Scores NYU Delayed Paragraph Recall Scores (# Correct) were lower in Subjects with (# Correct) were lower in Subjects with

Smaller Hippocampal VolumeSmaller Hippocampal Volume

3.1

3.7

4.7

2.0

2.5

3.0

3.5

4.0

4.5

5.0

NY

U D

elay

ed P

arag

rap

h R

ecal

l Sco

res

at

Bas

elin

e

Lowest Middle Highest

Normalized Hippocampal Tertiles

Baseline Hippocampal Volume Thus Far Baseline Hippocampal Volume Thus Far Appears to Predict Future Conversion Appears to Predict Future Conversion

to AD and Change on Clinical Measuresto AD and Change on Clinical Measures

10008006004002000

1.0

.9

.8

.7

.6

.5

Conversion to AD by Conversion to AD by Hippocampal Volume at BaselineHippocampal Volume at Baseline

Time on MCI Study (days)

Pro

bab

ility

of N

ot C

onve

rtin

g to

AD

0.5

0.8

0.7

0.6

0.9

1.0

4002000 800600

Top 50%

Bottom 50%

Hippocampal Volume

1000

CDR Sum of Boxes Change ScoresCDR Sum of Boxes Change Scores by Hippocampal Volume at Baseline by Hippocampal Volume at Baseline

56 %

44 %

Hippocampal Volume

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

0 6 M onths 12 M onths 18 M onths 24 M onths

Ch

an

ge

Sc

ore

Bottom 50% Top 50%

Characteristics of an Optimal Characteristics of an Optimal Surrogate MarkerSurrogate 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

Observations that Would Support Observations that Would Support Brain Atrophy as a Surrogate Marker Brain Atrophy as a Surrogate Marker

for Disease Modificationfor Disease Modification

Reduced rate of brain atrophy

Slower rate of clinical declineTreatment

Determine Rate of Decline in Hippocampal Determine Rate of Decline in Hippocampal Volume in Individual SubjectsVolume in Individual Subjects

TIME

3.53.02.52.01.51.0.50.0-.5

RA

W7000

6000

5000

4000

3000

Time in Study (Years)

Hip

po

cam

pal

Vo

lum

e

SCAN_2TM

3.53.02.52.01.51.0.50.0

NO

RM

_CP

.05

0.00

-.05

-.10

-.15

-.20

-.25

Determine if the Mean Rate of Hippocampal Atrophy Determine if the Mean Rate of Hippocampal Atrophy Accurately Predicts Clinical Outcome (AD)Accurately Predicts Clinical Outcome (AD)

Time in Study (Years)

Per

cen

t C

han

ge

in N

orm

aliz

ed H

ipp

oca

mp

al V

olu

me

Non-Converters

Converters

SCAN_2TM

3.53.02.52.01.51.0.50.0

NO

RM

_CP

.05

0.00

-.05

-.10

-.15

-.20

-.25

Determine if the Mean Rate of Hippocampal Determine if the Mean Rate of Hippocampal Atrophy is Slowed by TreatmentAtrophy is Slowed by Treatment

Time in Study (Years)

Per

cen

t C

han

ge

in N

orm

aliz

ed H

ipp

oca

mp

al V

olu

me

Treatment

Placebo

Possible Reasons Why Brain Atrophy May Possible Reasons Why Brain Atrophy May Not Always Be a Reliable Surrogate MarkerNot 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.

0

20

40

60

80

100

1st

Qtr

2nd

Qtr

3rd

Qtr

4th

Qtr

East

West

North

MEN

WOMEN

MESIAL TEMPORAL VOLUME/CRANIAL VOLUME X 100

3.53.02.52.01.51.0

BO

DY

MA

SS

IN

DE

X

32

30

28

26

24

22

20

18

16

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

Possible Reasons Why Brain Atrophy May Possible Reasons Why Brain Atrophy May Not Always Be a Reliable Surrogate MarkerNot 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.

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.

ConclusionsConclusions