1. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 1 Issues Related to the Development of Drugs for the Treatment of Patients with Vascular Dementia (VaD) Andrew Satlin, M.D. Director, Clinical Research Novartis Pharmaceuticals Corporation March 14, 2001

2. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 2 Is VaD Clearly Definable Clinically? Maximize reliability and validity of diagnosis using –NINDS-AIREN criteria requiring focal signs on examination; neuroimaging evidence; and causal relationship

3. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 3 Is VaD Clearly Definable Clinically? Maximize reliability and validity of diagnosis using –NINDS-AIREN criteria requiring focal signs on examination; neuroimaging evidence; and causal relationship several studies (e.g., Chui et al. Arch Neurol 2000;57:191- 196) suggest that these criteria are conservative for diagnosis (i.e. less sensitive but likely to yield more homogeneous population than other criteria)

4. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 4 Is VaD Clearly Definable Clinically? Maximize reliability and validity of diagnosis using –NINDS-AIREN criteria requiring focal signs on examination; neuroimaging evidence; and causal relationship several studies (e.g., Chui et al. Arch Neurol 2000;57:191- 196) suggest that these criteria are conservative for diagnosis (i.e. less sensitive but likely to yield more homogeneous population than other criteria) misclassify only 9% of AD and 29% of mixed as VaD (Gold et al. Neurology 1997;49:690-694)

5. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 5 Is VaD Clearly Definable Clinically? Maximize reliability and validity of diagnosis using –NINDS-AIREN criteria requiring focal signs on examination; neuroimaging evidence; and causal relationship several studies (e.g., Chui et al. Arch Neurol 2000;57:191- 196) suggest that these criteria are conservative for diagnosis (i.e. less sensitive but likely to yield more homogeneous population than other criteria) misclassify only 9% of AD and 29% of mixed as VaD (Gold et al. Neurology 1997;49:690-694) have at least moderate inter-rater reliability (kappa = 0.42 - 0.72; Chui; Lopez et al. Neurology 1994;44:1240-1245)

6. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 6 Is VaD Clearly Definable Clinically? Maximize reliability and validity of diagnosis using –MRI scanning for all screened patients –eliminating requirement for temporal relationship in cases of pure subcortical VaD by MRI criteria –inter-rater training in applying NINDS-AIREN criteria

7. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 7 Is VaD distinguishable from AD? Patients who meet clinical criteria for VaD may also have AD pathology but –specificity of NINDS-AIREN criteria are high (91%) for exclusion of AD (Gold et al., Neurology 1997;49:690-694)

8. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 8 Is VaD distinguishable from AD? Patients who meet clinical criteria for VaD may also have AD pathology but –specificity of NINDS-AIREN criteria are high (91%) for exclusion of AD (Gold et al., Neurology 1997;49:690-694) –other evidence suggests that dementia in patients with VaD (even due to subcortical ischemic vascular disease) does not simply indicate the presence of AD (Fein et al., Neurology 2000;55:1626-1635)

9. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 9 Is VaD distinguishable from AD? Patients who meet clinical criteria for VaD may also have AD pathology but –specificity of NINDS-AIREN criteria are high (91%) for exclusion of AD (Gold et al., Neurology 1997;49:690-694) –other evidence suggests that dementia in patients with VaD (even due to subcortical ischemic vascular disease) does not simply indicate the presence of AD (Fein et al., Neurology 2000;55:1626-1635) –requirement for statistical and clinically relevant effect in VaD treatment study will preclude possibility that effect is entirely due to treatment of AD

10. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 10 Outcome Measures in the Design of VaD Clinical Drug Trials Two primary outcome measures, as in AD trials –VaDAS - cognitive includes ADAS-Cog, plus items targeting deficits found more commonly in VaD (attention/concentration; executive function; verbal fluency; working memory; psychomotor speed) additional items not validated in VaD, but each valid in assessing AD patients recommended by expert committee (Desmond, Ferris, Mohs; see Ferris, Alz Dis Assoc Disord 1999;13:S140-2) –ADCS-CGIC - global rating for clinical relevance

11. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 11 Other Features in the Design of VaD Clinical Drug Trials Trials need to be comparable in length to AD trials –Disease is characterized by a slow step-wise decline –Adequate duration needed to ensure decline in placebo group and to reduce variability –Longer duration also provides more safety data in a population that may be more medically ill Monitor for changes in vascular risk factors, e.g., hypertension; smoking; hyperlipidemia; diabetes

12. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 12 Conclusions A properly designed clinical trial in VaD should select as homogenous a population as possible to ensure that the overall effect is driven by the population of interest

13. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 13 Conclusions A properly designed clinical trial in VaD should select as homogenous a population as possible to ensure that the overall effect is driven by the population of interest Study must use outcome measures with demonstrated validity and reliability

14. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - March 14, 2001 14 Conclusions A properly designed clinical trial in VaD should select as homogenous a population as possible to ensure that the overall effect is driven by the population of interest Study must use outcome measures with demonstrated validity and reliability Study must be of adequate duration e.g., comparable to AD studies