# Presentation: 008348

## 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

**Notes:**
TEXT (speaker notes)

## 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

## 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)

## 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)

## 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)

## 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

## 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)

## 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)

## 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

## 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

## 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

## 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

## 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

## 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