GAL-INT-6 The safety and efficacy of galantamine in patients with Vascular dementia or AD with cerebrovascular disease Sean Lilienfeld MD, FCP, MMed Janssen.

GAL-INT-6 The safety and efficacy of galantamine in

patients with Vascular dementia orAD with cerebrovascular disease

Sean Lilienfeld MD, FCP, MMedJanssen Research Foundation

VaDVaD ADADMixed

Erkinjuntti T

Interactions between vascular dementia and Alzheimer’s disease

Reminyl in vascular and mixed dementia: trial inclusion criteria

Patients with dementia secondary to cerebrovascular disease (CVD) with or without AD

– Probable Vascular dementia according to NINDS-AIREN criteria

– Mixed dementia according to NINCDS-ADRDA criteria of possible Alzheimer’s disease with CVD and NINDS-AIREN criteria of possible VaD

– MMSE at screening 10–25 and ADAS-Cog score at screening 12

– Positive radiology per NINDS-AIREN criteria

Inclusion Criteria Probable Vascular Dementia (NINDS-AIREN)

A. Dementia (decline from previous higher level of functioning):

– established by clinical examination and confirmed by neuropsychological test

– deficits in two or more areas of cognition

– no disturbance of consciousness, delirium, psychosis, severe aphasia, or major sensorimotor impairment precluding neuropsychological testing

– absence of systemic disorders or other brain diseases such as Alzheimer’s Disease (EXCEPT CEREBROVASCULAR DISEASE) that could account for the dementia

Inclusion Criteria Probable Vascular Dementia (NINDS-AIREN)

B. Cerebrovascular disease:

– focal neurologic signs consistent with previous stroke (even with negative stroke history)

– evidence of relevant cerebrovascular disease by CT or MRI scan

Inclusion Criteria Probable Vascular Dementia (NINDS-AIREN)

C. A relationship must exist between the dementia and the cerebrovascular disease:

– onset of dementia within 3 months of a recognised stroke

– abrupt deterioration in cognitive functions

– fluctuating, stepwise progression of cognitive deficits

Inclusion Criteria Mixed Dementia (Possible AD with CVD)

• NINCDS-ADRDA criteria for possible Alzheimer's disease and NINDS-AIREN criteria for possible Vascular Dementia

– Dementia established by clinical examination and confirmed by neuropsychological test

– Deficits in two or more areas of cognition

– Progressive worsening of memory and other cognitive functions no disturbance of consciousness

– Absence of systemic disorders or other brain diseases (EXCEPT AD and CEREBROVASCULAR DISEASE) that could account for the dementia

Inclusion Criteria Mixed Dementia (Possible AD with CVD)

• Radiologic evidence (satisfying the NINDS-AIREN radiologic criteria) as documented on a CT or MRI scan less than 12 months old of:

– Multiple (2 or more) basal ganglion/white matter infarcts or lacunes and/or

– Single strategically placed infarct in angular gyrus/thalamus/basal forebrain/Anterior Cerebral Artery or Posterior Cerebral Artery territory and/or

– Extensive periventricular white matter lesions.

Exclusion Criteria

• Other neurodegenerative disorders

• Other causes of cognitive impairment

• Relevant medical conditions eg. ulcers, bladder obstruction, severe hepatic, renal, pulmonary, cardiac diseases

NINDS-AIREN Radiology

• multiple large-vessel infarcts

• single strategically placed infarct [angular

gyrus, thalamus, basal forebrain, posterior or

anterior cerebral artery territory]

• multiple basal ganglia and white matter

lacunes• extensive periventricular white matter lesions• combinations of these

Patient characteristics

Placebo Reminyl 24 mg/day

(n = 196) (n = 396)

Female 46% 48%

Mean age (years) 75.2 75.0

Mean MMSE score 20.2 20.7

Diagnosis

Mixed dementia 50% 48%

Vascular dementia 41% 43%

Uncertain per MD 9% 9%

ADAS-cog Scores: Placebo patients Over 6 Months

-1

-2

Mean change +/- SE in

ADAS-cog/11

Baseline

2

1

0

-3

Time (months)

Combined Placebo (n = 162)

1 2 3 4 65

Deteriorated

Treatment group

Improved

Mixed D Placebo (n = 87)

Probable VaD Placebo (n = 67)

ADAS-cog Scores: Placebo patients Over 6 Months

1

-1

Baseline

3

2

0

-2

Time (months)

Mixed D Placebo (n = 87)

1 2 3 4 65

Deteriorated

Mean change +/- SE in

ADAS-cog/11

Treatment group

Improved

Probable VaD Placebo (n = 67)

= 2.2

p = 0.013

NPI Scores: Placebo patients Over 6 Months

-1

Mean change (+/- SE) in total NPI

Baseline

2

1

0

-2

Time (months)

Placebo

1 2 3 4 65

Deteriorated

Treatment group

Improved

Probable VaD PlaceboMixed D Placebo

NPI Scores: Placebo patients Over 6 Months

-1

Mean change (+/- SE) in total NPI

Baseline

2

1

0

-2

Time (months)

1 2 3 4 65

Deteriorated

Treatment group

Improved

Probable VaD PlaceboMixed D Placebo

= 0.4

p = 0.43

DAD Scores: Placebo patients Over 6 Months

-1

-4

Baseline

2

1

0

-6

Time (months)

Placebo

1 2 3 4 65

Improved

Mean change (+/- SE) in total DAD

Treatment group

-2

-3

-5 Deteriorated

Mixed D Placebo

Probable VaD Placebo

DAD Scores: Placebo patients Over 6 Months

-1

-4

Baseline

1

0

-8

Time (months)

Mixed D Placebo

1 2 3 4 65

Improved

Mean change (+/- SE) in total DAD

Treatment group

-2

-3

-7

-6

-5

Deteriorated

Probable VaD Placebo

= 4.7

p = 0.032

Efficacy results

• ADAS-cog positive

• CIBIC-plus positive

• NPI positive

• DAD positive

Conclusions

• Using NINDS-AIREN criteria physicians were able to differentiate patients with “probable” vascular dementia and “mixed” dementia

• Observed rates of deterioration in a cognitive scale, a neuropsychiatric scale and a functional scale, are different in the 2 placebo groups, thus these patients are indeed different clinical populations

Conclusions

• Patients with “mixed” dementia deteriorate at rates similar to those seen in clinical trials in patients with probable AD over 6 months whereas patients with probable VaD remain essentially at baseline over 6 months

Galantamine Significantly Improved Both Primary Endpoints and Both Secondary

Endpoints

• The current efficacy tools are able to detect differences between actively treated and placebo treated patients with a magnitude similar to that seen in trials in patients with AD