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 Research Foundation

1
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
2
Interactions between vascular dementia and
Alzheimers disease
VaD
AD
Mixed
Erkinjuntti T
3
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 Alzheimers disease with CVD and
  NINDS-AIREN criteria of possible VaD
• MMSE at screening 1025 and ADAS-Cog score at
  screening ? 12
• Positive radiology per NINDS-AIREN criteria

4
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 Alzheimers Disease (EXCEPT
  CEREBROVASCULAR DISEASE) that could account for
  the dementia

5
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

6
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

7
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

8
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.

9
Exclusion Criteria

• Other neurodegenerative disorders
• Other causes of cognitive impairment
• Relevant medical conditions eg. ulcers, bladder
  obstruction, severe hepatic, renal, pulmonary,
  cardiac diseases

10
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

11
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

12
ADAS-cog Scores Placebo patients Over 6 Months
Treatment group
Combined Placebo (n 162)
Mixed D Placebo (n 87)
Deteriorated
2
Probable VaD Placebo (n 67)
1
0
Mean change /- SE in ADAS-cog/11
-1
-2
Improved
-3
Baseline
1
2
3
4
6
5
Time (months)
13
ADAS-cog Scores Placebo patients Over 6 Months
Treatment group
Mixed D Placebo (n 87)
3
Deteriorated
Probable VaD Placebo (n 67)
2
1
Mean change /- SE in ADAS-cog/11
0
-1
Improved
-2
Baseline
2
3
4
5
1
6
Time (months)
D 2.2 p 0.013
14
NPI Scores Placebo patients Over 6 Months
Treatment group
Placebo
2
Mixed D Placebo
Deteriorated
Probable VaD Placebo
1
Mean change (/- SE) in total NPI
0
-1
Improved
-2
Baseline
1
2
3
4
6
5
Time (months)
15
NPI Scores Placebo patients Over 6 Months
Treatment group
2
Mixed D Placebo
Deteriorated
Probable VaD Placebo
1
Mean change (/- SE) in total NPI
0
-1
Improved
-2
Baseline
1
2
3
4
6
5
D 0.4 p 0.43
Time (months)
16
DAD Scores Placebo patients Over 6 Months
Treatment group
Placebo
Mixed D Placebo
2
Improved
Probable VaD Placebo
1
0
-1
Mean change (/- SE) in total DAD
-2
-3
-4
Deteriorated
-5
-6
Baseline
2
3
4
5
1
6
Time (months)
17
DAD Scores Placebo patients Over 6 Months
Treatment group
Mixed D Placebo
Probable VaD Placebo
1
Improved
0
-1
-2
-3
Mean change (/- SE) in total DAD
-4
-5
-6
Deteriorated
-7
-8
Baseline
2
3
4
5
1
6
D 4.7 p 0.032
Time (months)
18
Efficacy results

• ADAS-cog positive
• CIBIC-plus positive
• NPI positive
• DAD positive

19
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

20
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

21
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