1. MCI Clinical Trial Design FDA Advisory Committee Meeting March 13, 2001 Gaithersburg, MD Michael Grundman, MD, MPH Alzheimer’s Disease Cooperative Study

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

3. Memory Testing Increases the Prediction Accuracy of Future AD Over Clinical Evaluation Alone Memory Tests: Normal Memory Tests: Impaired (  1 SD below normal) CDR Sum of Boxes =.00 CDR Sum of Boxes =.50 CDR Sum of Boxes  1.00 Time to AD (Years) Source: NIA Alzheimer’s Disease Centers’ Neuropsychological Database Initiative Clinically NormalSymptoms of Memory Loss Without Dementia

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

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

6. Advantages of MCI/AD 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

7. 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 Donepezil

8. Subject 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

9. MCI 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

10. MCI Trial Participants At Baseline Have Memory Deficits But Are Much Less Impaired than Patients in Standard AD Trials NormalMCIMild AD MMSE 292720 ADAS-COG 51126 Paragraph Delayed Recall 1231 Word List Delay 842 Clinical Dementia Rating – Global 00.51.0 Clinical Dementia Rating – Sum of Boxes 0.11.85.2 ADCS – ADL (MCI version) 504637

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

12. Hippocampal Volume Correlates with Baseline Memory Performance r = 0.36 p =.004

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

14. MCI Participants Progress at a Slower Annual Rate Than Patients in Standard AD Trials NormalsMCIAD MMSE change--------0.7-3.8 ADAS-COG change-------0.57.0 CGIC (mean change)-------0.40.9 CGIC (% worse)-------45%80% CDR SUM (mean change)-------0.32.2 CDR SUM (%worse)--------40%70%

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

16. Conclusions 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

17. Conclusions 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

18. Clinical 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