MCI Clinical Trial DesignMCI Clinical Trial DesignFDA Advisory Committee MeetingFDA Advisory Committee Meeting

March 13, 2001March 13, 2001Gaithersburg, MDGaithersburg, MD

Michael Grundman, MD, MPHMichael Grundman, MD, MPHAlzheimer’s Disease Cooperative StudyAlzheimer’s Disease Cooperative Study

Individuals With MCI Develop Clinical AD At A Individuals With MCI Develop Clinical AD At A Much Higher Rate Than Normal ElderlyMuch Higher Rate Than Normal Elderly

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

Memory Testing Increases the Prediction Accuracy of Memory Testing Increases the Prediction Accuracy of Future AD Over Clinical Evaluation AloneFuture AD Over Clinical Evaluation Alone

Memory Tests: Normal

Memory Tests: Impaired (1 SD below normal)

Sum of Boxes = .00

Time to AD (Years)

876543210

Cum

ulat

ive S

urviv

al

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Sum of Boxes = .50

Time to AD (Years)

876543210

Cum

ulat

ive

Surv

ival

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Sum of Boxes = 1.00

Time to AD (Years)

876543210

Cum

ulat

ive S

urviv

al

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

CDR Sum of Boxes = .00 CDR Sum of Boxes = .50 CDR Sum of Boxes 1.00

Time to AD (Years) Time to AD (Years) Time to AD (Years)

Source: NIA Alzheimer’s Disease Centers’ Neuropsychological Database Initiative

Clinically Normal Symptoms of Memory Loss Without Dementia

Prevention of AD is Highly Desirable but Prevention of AD is Highly Desirable but Prevention Trials with Clinically Normal Individuals Prevention Trials with Clinically Normal Individuals

are Necessarily Large and Expensiveare Necessarily Large and Expensive

• Require thousands of subjects• Few conversions to AD/dementia• Long follow-up (5 -7 years) required• Selection on the basis of advanced age (e.g. age > 80 )

• Limits study generalizability to patients with very advanced age• Excludes participation by individuals at younger ages• High mortality in people over 80

• Normals developing AD within several years often have non-recognized memory impairment at baseline

Far Fewer MCI Subjects Than Normals Are Needed to Far Fewer MCI Subjects Than Normals Are Needed to Demonstrate a 33% Reduction in Conversion Rate to ADDemonstrate a 33% Reduction in Conversion Rate to AD

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

10,000

11,000

12,000

0% 3% 6% 9% 12% 15% 18% 21% 24% 27% 30% 33% 36% 39% 42% 45%

Percent of Control Group Reaching Endpoint at the End of Study

Nu

mb

er o

f S

ub

ject

s R

equ

ired

Advantages of MCI/AD Prevention Trials Advantages of MCI/AD Prevention Trials Over Primary Prevention Trials Over Primary Prevention Trials

• Higher proportion of individuals are likely to develop clinical AD over the course of the trial

• Fewer subjects necessary• Younger subjects can participate• Less costly• Shorter duration• More treatments/preventive agents can be tested• More efficient

• Recruit individuals with MCI• 3 treatments

• vitamin E – 2000 IU/day• Donepezil – 10mg/day• placebo

• Study objectives• prevent development of Alzheimer’s disease• slow decline on measures of cognition• reduce rate of atrophy on MRI

• 3 year duration• Approximately 760 participants • 75 centers

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

Subject SelectionSubject Selection• Diagnostic Criteria:

• Memory complaints or problems that can be verified by others• Memory impairment documented with a cognitive instrument• General cognition and function sufficiently preserved such that a

clinical diagnosis of AD cannot be made• Mini-mental Exam > 24• Global Clinical Dementia Rating = 0.5• Modified Hachinski score <= 4• Spouse or companion available to spend several hours a week with the

patient• No evidence of underlying neurological disease on baseline imaging• No clinically important laboratory abnormalities• No concomitant use of medication that may impair cognition

MCI Trial EndpointsMCI Trial Endpoints• Primary

• Conversion to AD

• Cognitive• General – ADAS-COG, MMSE• Neuropsychological battery

• Word List Recall, Delayed Paragraph Recall, Digits Backwards, Number Cancellation Test, Maze, Symbol Digit, Category Fluency, Boston Naming Test, Clock Drawing Test

• Clinical/Functional• CDR, CDR-SOB, ADCS-CGIC, ADCS-ADL, GDS,

QOL• Biological

• Neuroimaging, Oxidative markers

MCI Trial Participants At Baseline Have MCI Trial Participants At Baseline Have Memory Deficits But Are Much Less Impaired Memory Deficits But Are Much Less Impaired

than Patients in Standard AD Trialsthan Patients in Standard AD Trials

Normal MCI Mild AD

MMSE 29 27 20

ADAS-COG 5 11 26

Paragraph Delayed Recall 12 3 1

Word List Delay 8 4 2

Clinical Dementia Rating – Global 0 0.5 1.0

Clinical Dementia Rating – Sum of Boxes 0.1 1.8 5.2

ADCS – ADL (MCI version) 50 46 37

0.00

0.50

1.00

1.50

Cinical Dementia Rating Domain

CD

R B

ox

Sco

re

Normal

MCI

Mild AD

MCI Study Participants Have Only Subtle Impairment MCI Study Participants Have Only Subtle Impairment in Function Compared to Mild AD Patientsin Function Compared to Mild AD Patients

Hippocampal Volume Correlates with Baseline Hippocampal Volume Correlates with Baseline Memory PerformanceMemory Performance

r = 0.36 p = .004

Lowest Middle Highest

Hippocampal Volume (tertiles)

1

2

3

4

5

AD

AS

Wo

rd L

ist

Del

ayed

Rec

all C

orr

ect

Rate of Conversion to AD in MCI Trial at Rate of Conversion to AD in MCI Trial at 1 Year Approximates Predicted Rate1 Year Approximates Predicted Rate

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Per

cen

t C

on

vert

ing

to

AD

6 months 12 months

Time

MCI Participants Progress at a Slower Annual MCI Participants Progress at a Slower Annual Rate Than Patients in Standard AD TrialsRate Than Patients in Standard AD Trials

Normals MCI AD

MMSE change ------- -0.7 -3.8

ADAS-COG change ------- 0.5 7.0

CGIC (mean change) ------- 0.4 0.9

CGIC (% worse) ------- 45% 80%

CDR SUM (mean change) ------- 0.3 2.2

CDR SUM (%worse) -------- 40% 70%

MCI Trial Participants Generally Decline Slowly While MCI Trial Participants Generally Decline Slowly While Converters to AD Show More Rapid Decline over 1 YearConverters to AD Show More Rapid Decline over 1 Year

ADAS-COG

-2

-1

0

1

2

3

0 5 10 15

All MCI

Non-converters

Converters to AD

ADCS-ADL

-5

-4

-3

-2

-1

0

1

0 5 10 15

All MCI

Non-converters

Converters to AD

CDRSUM

-1

0

1

2

0 5 10 15

All MCI

Non-converters

Converters to AD

ADCS-CGIC

-1

-0.5

0

0.5

1

1.5

2

0 6 12 18

All MCI

Non-converters

Converters to AD

ConclusionsConclusions• Individuals with MCI can be reliably identified for clinical trials

• have a clinically significant decline in memory beyond that expected with normal aging

• lack the severity of cognitive deficits and functional impairment typical of patients diagnosed with AD

• decline more slowly than clinically diagnosed AD patients• at increased risk of developing clinical AD within several years

• Results or recommendations based on conventional AD trials cannot be extrapolated to people with MCI

• MCI trials require different trial design assumptions than those for mild to moderate AD patients

• MCI provides an opportunity to intervene both to improve memory loss and prevent further cognitive decline to clinical AD

ConclusionsConclusions• MCI trials lasting several years are likely to meet their

objective of demonstrating whether an agent can reduce the risk of developing clinical AD

• Short term MCI trials lasting approximately 1 year may be capable of demonstrating treatment effects particularly if they can reverse the pathology and improve symptoms or cognitive impairment

• Biological markers (MRI brain volume, CSF or plasma measures) that could be validated would be a useful adjunct to the clinical measures in demonstrating effects on the disease process

Clinical Value of MCI DiagnosisClinical Value of MCI Diagnosis• Fills a clinical niche between a diagnosis of normal and

dementia (widely understood to refer to a generalized loss of intellectual abilities with disturbed behavior)

• More accurate description of a person’s clinical status than dementia, and a more acceptable diagnosis to patients at this stage than AD

• Although MCI indicates an increased risk of clinical AD in future years, it properly reflects the uncertainty about when this transition will occur for individual patients

• Because MCI is less stigmatizing than AD, it is likely that patients and physicians will seek earlier diagnosis and treatment if effective therapies were available