# Presentation: 685501

## EXPRESS Results

**Sibel Tekin, MD**
**Clinical Program Leader****Neuroscience Clinical Development and Medical Affairs****Novartis Pharmaceuticals Corporation**

## Overview

**Patient disposition and baseline characteristics**
**Efficacy results for the double-blind core study**
**Safety findings for the core and extension studies**

## Patient DispositionCore and Extension Studies

**177 (83.9%) completed**

** ****96 (78.0%) completed**

**211 to Exe-Exelon **

**123 to Plc-Exelon**

**Patient Disposition****Core and Extension Studies**

**Extension study**

**334 out of 410 entered O-L study **

- CSR Core T 7-1; Extension

**263 (72.7%) completed **

**147 (82.1%) completed **

**99 (27.3%)****discontinued**

**32 (17.9%)****discontinued**

**362 Exelon**

**179 placebo**

**Core study**

**541 randomized to core study **

**650 screened**

## Reasons for DiscontinuationCore Study

|  | ExelonN = 362n (%) | PlaceboN = 179n (%) |
| --- | --- | --- |
| Total discontinued | 99 (27.3) | 32 (17.9) |
| Adverse event | 62 (17.1) | 14 (7.8) |
| Withdrew consent | 21 (5.8) | 2 (1.1) |
| Protocol violations | 5 (1.4) | 2 (1.1) |
| Lost to follow-up | 4 (1.1) | 1 (0.6) |
| Death | 4 (1.1) | 7 (3.9) |
| Unsatisfactory therapeutic results | 2 (0.6) | 4 (2.2) |
| Abnormal test procedure result | 1 (0.3) | 0 |
| Administrative problems | 0 | 2 (1.1) |

- SCE T3-5.

## Baseline CharacteristicsCore Study

|  | ExelonN = 362 | PlaceboN = 179 |
| --- | --- | --- |
| Age, yr |  |  |
|    Mean ± SD | 72.8 ± 6.7  | 72.4 ± 6.4  |
| Gender, n (%) |  |  |
|    Male | 234 (64.6)  | 117 (65.4)  |
|    Female | 128 (35.4)  |   62 (34.6)  |
| Race, n (%) |  |  |
|    Caucasian | 360 (99.4)  | 179 (100)  |
|    Other |   2 (0.6)  | 0  |

- CSR Core Table 7-4, PTT7.4-1

## Timing of Imaging (MRI or CT Scans)Core Study—All Randomized Patients

|  | N = 541n (%) |
| --- | --- |
| Between screening and baseline visits | 179 (33.1) |
| ≤ 6 months prior to screening | 278 (51.4) |
| > 6 months to ≤ 1 year prior to screening | 15 (2.8) |
| > 1 year prior to screening |   6 (1.1) |
| After baseline visit | 18 (3.3) |
| Missing report, unable to retrieve, charts off site (Confirmed imaging was performed)
 | 20 (3.7) |
| Total response received to date (5/16/06) | 516 (95.4) |
| No response received to date | 25 (4.6) |

**Source data verification is ongoing.**

**40-6**

## Baseline CharacteristicsCore Study

|  | Mean ± SD |  |
| --- | --- | --- |
|  | ExelonN = 362 | PlaceboN = 179 |
| Time since idiopathic PD was first diagnosed by physician, years | 8.7 ± 5.7  | 9.4 ± 5.9  |
| Hoehn & Yahr staging, mean ± SD | 2.8 ± 0.9 | 2.8 ± 0.8 |
| UPDRS part III (‘on’ state), mean ± SD | 32.9 ± 14.2  | 32.5 ± 13.0  |
| MMSE score at baseline | 19.4 ± 3.8  | 19.2 ± 4.1  |
| Time between diagnosis of PD and first symptom of dementia, years | 6.6 ± 5.2 | 7.2 ± 5.2 |

- CSR Core T 7-5, PTT7.4-2

## Baseline Cognitive and Functional Assessment of EXPRESS Study PopulationCore Study—ITT-RDO Population

|  | Exelon |  | Placebo |  |
| --- | --- | --- | --- | --- |
|  | N | Mean ± SD  | N | Mean ± SD  |
| Cognition:
ADAS-cog—total | 329 | 23.8 ± 10.2 | 161 | 24.3 ± 10.5 |
| Executive function:
D-KEFS letter fluency† | 335 | 14.1 ± 9.5 | 166 | 15.1 ± 9.9 |
| Functional activity:
ADCS-ADL | 333 | 41.6 ± 18.6 | 165 | 41.2 ± 17.7 |

- 15-12 DV

**† ****Total correct responses/min.**

- CSR 2311 PTTs 9.1-1, 9.2-1, 9.2-7, 9.2-30, 9.2-34, 9.2-9, 9.2-13

## Baseline Neuropsychiatric Symptoms Core Study—ITT+RDO Population

| NPI-10 sub-item |  | ExelonN = 335% | PlaceboN = 166% |
| --- | --- | --- | --- |
|  | Apathy/Indifference | 53.9 | 54.2 |
|  | Depression/Dysphoria | 53.9 | 62.1 |
|  | Anxiety | 47.3 | 50.6 |
|  | Hallucinations | 41.0 | 47.0 |
|  | Agitation/Aggression | 32.3 | 31.3 |
|  | Irritability/Lability | 30.2 | 28.9 |
|  | Delusions | 24.3 | 24.7 |
|  | Aberrant motor behavior | 21.9 | 21.1 |
|  | Disinhibition | 10.2 | 15.7 |
|  | Euphoria/Elation | 3.3 | 4.2 |

- Post-text table 9.2-24

## Dopaminergic Agents Before Start of Study Drug Core Study

| Dopaminergic agents | ExelonN = 362  | PlaceboN = 179 |
| --- | --- | --- |
| Total, n (%)  | 362 (100)  | 178 (99.4)  |
| 	Adamantane derivatives  | 38 (10.5)  | 17 (9.5)  |
| 	Dopa and dopa derivatives†  | 347 (95.9)  | 169 (94.4)  |
| 	Dopamine agonists  | 165 (45.6)  | 83 (46.4)  |
| 	Monoamine oxidase B inhibitors  | 19 (5.2)  | 11 (6.1)  |
| 	Other dopaminergic agents  | 70 (19.3)  | 55 (30.7)  |
| Dopa and dopa derivatives dose (mg/day), mean ± SD | 663.4 ± 368.0 | 705.7 ± 349.9 |

- CSR Core T 8-3, PTT8.2-2, 8.2-4

**† ****Includes Levodopa, Levodopa with benserazide, and Carbidopa **

## Efficacy

**Double-Blind Core Study**

## Primary Outcomes

**Two primary outcome measures**
**Cognition: ADAS-cog**
**Global dementia assessment: ADCS-CGIC**
**Primary endpoint **
**Wk 24 **
**ITT+RDO population**

## ADAS-cog Least Squares (LS) Mean Change from Baseline Core Study—ITT+RDO Analysis

***P*****-value based on ANCOVA using treatment and country as factors and baseline ADAS-cog as a covariate.  **

**ADAS-cog Least Squares (LS) Mean ****Change from Baseline ****Core Study—ITT+RDO Analysis**

- 15-14 DV

**Improvement**

***p***** = 0.002**

***p *****< 0.001**

**16**

## ADCS-CGIC—Categorical Analysis at Wk 24Core Study—ITT+RDO Analysis

- CSR 2311 T 9-3, PTT9.1-8, 9.1-9, 9.1-10

***p *****= 0.007****†**

**† *****p*****-value based on van Elteren test blocking for country. **

## ADAS-cog—Change from Baseline at Wk 24Core Study

|  | Exelon |  | Placebo |  | LS meansdifference  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | n  | Mean ± SD  | n  | Mean ± SD  |  | 95% CI | p value |
| ITT+RDO |  |  |  |  |  |  |  |
| Baseline  | 329  | 23.8 ± 10.2  | 161  | 24.3 ± 10.5  |  |  |  |
| Change at Wk 24  | 329  | 2.1 ± 8.2  | 161  | –0.7 ± 7.5  | 2.88  | 1.44, 4.31  | < 0.001  |
| ITT-LOCF |  |  |  |  |  |  |  |
| Baseline  | 287  | 24.0 ± 10.3  | 154  | 24.5 ± 10.6  |  |  |  |
| Change at Wk 24  | 287  | 2.5 ± 8.4  | 154  | –0.8 ± 7.5  | 3.54  | 2.05, 5.04  | < 0.001  |
| OC |  |  |  |  |  |  |  |
| Baseline | 256  | 23.7 ± 10.4  | 139  | 23.4 ± 9.8  |  |  |  |
| Change at Wk 24  | 256  | 2.9 ± 8.3  | 139  | –1.0 ± 7.6  | 3.80  | 2.22, 5.37  | < 0.001  |

- CSR Core T 9-1

**Results were also statistically significant at Wk 16 in favor of Exelon**

## ADCS-CGIC—Categorical Analysis at Wk 24 Core Study

|  | ITT+RDO |  | ITT-LOCF |  | OC |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | ExelonN = 329 | PlaceboN = 165 | ExelonN = 289 | PlaceboN = 158 | ExelonN = 252 | PlaceboN = 145 |
| Mean±SD at Wk 24 | 3.8±1.4 | 4.3±1.5 | 3.7±1.4 | 4.3±1.5 | 3.7±1.4 | 4.2±1.5 |
| Treatment difference | 0.5 |  | 0.6 |  | 0.5 |  |
| Change, % |  |  |  |  |  |  |
| Markedly improved (1)   |   4 |   2 |   5 |   2 |   6 |   2 |
| Moderately improved (2) | 16 | 12 | 16 | 12 | 18 | 12 |
| Minimally improved (3)  | 21 | 15 | 23 | 16 | 23 | 15 |
| Unchanged (4)           | 26 | 28 | 25 | 28 | 25 | 29 |
| Minimally worse (5)     | 21 | 19 | 20 | 19 | 19 | 19 |
| Moderately worse (6)    | 11 | 16 |   9 | 17 |   8 | 17 |
| Markedly worse (7)      |   2 |   7 |   2 |   6 |   2 |   6 |
| p value | 0.007 |  | < 0.001 |  | < 0.001 |  |

- Source: [Report 2311-Table 9-3 ]

**Results were also statistically significant at Wk 16 in favor of Exelon.**

## Secondary Outcomes

**Functioning**
**Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)**
**Behavior**
**Neuropsychiatric Inventory (NPI-10 and NPI-D for caregiver distress)**
**Attention**
**Cognitive Drug Research (CDR) computerized attention battery**
**Executive function**
**Delis-Kaplan Executive Function System (D-KEFS), letter fluency test**

## ADCS-ADL—LS Mean Change from Baseline at Wk 24 Core Study—ITT+RDO Analysis

**ADCS-ADL—LS Mean Change from Baseline at Wk 24 ****Core Study—ITT+RDO Analysis**

***p *****= 0.023**

**Deterioration**

- 15-16 DV

- CSR 2311 T9-5 PTT 9.2-4

**16**

**24**

**Time, wk**

## NPI-10—LS Mean Change from Baseline at Wk 24Core Study—ITT+RDO Analysis

- 15-17 DV

- CSR 2311 T9-6PTT 9.2-22, STDERR_ANCOVA from Jay Hsu

***p *****= 0.015**

**Improvement**

**16**

**24**

**Time, wk**

## CDR Power of Attention—LS Mean Change from Baseline at Wk 24Core Study—ITT+RDO Analysis

**CDR Power of Attention—LS Mean Change from Baseline at Wk 24****Core Study—ITT+RDO Analysis**

**Power of attention score = Simple reaction time + digit vigilance + choice reaction time.**

***p *****= 0.009**

- 15-18 DV

- CSR 2311 T9-7 PTT9.2-10

**Improvement**

**16**

**24**

**Time, wk**

## D-KEFS Letter Fluency—Mean Change from Baseline at Wk 24Core Study—ITT+RDO Analysis

**Improvement**

**D-KEFS Letter Fluency—Mean Change from Baseline at Wk 24****Core Study—ITT+RDO Analysis**

***P-*****value based on van Elteren test blocking for country.**

***p *****< 0.001**

- 15-21 DV

- CSR 2311 T9-8 PTT 9.2-30

## Additional AnalysesCore Study

**Age, Gender, and Baseline Characteristics**

## ADAS-cog—Treatment Difference (95% CI) at Wk 24 by Baseline SubgroupsCore Study—ITT+RDO Population

|  |  | Patients, n |  |
| --- | --- | --- | --- |
|  |  | Exelon | Placebo |
| Age < 65 yr  |  | 46 | 17 |
| Age ≥ 65 yr |  | 283 | 144 |
| Male |  | 213 | 104 |
| Female |  | 116 | 57 |
| Moderate dementia* |  | 87 | 44 |
| Mild dementia**  |  | 237 | 115 |
| Visual hallucination |  | 107 | 60 |
| No visual hallucination |  | 220 | 101 |
| Tremor |  | 228 | 105 |
| No tremor |  | 101 | 56 |

**ADAS-cog—Treatment Difference (95% CI) at Wk 24 by Baseline Subgroups****Core Study—ITT+RDO Population**

**Favor Exelon**

**Favor placebo**

**–****5**

**0**

**5**

**10**

***Mild dementia: MMSE 18 - 24    ******Moderate dementia: MMSE 10 - 17**

## Patients With and Without Visual Hallucinations at Baseline—ADAS-cog at Wk 24Core Study—ITT+RDO Population

***p***** = 0.002**

***p***** = 0.015**

**4.3****†**

**2.1****†**

**With**

**Without**

**n = 107**

**60**

**220**

**101**

**Patients With and Without Visual Hallucinations at Baseline—ADAS-cog at Wk 24****Core Study—ITT+RDO Population**

- 4-11

**† ****Least squares means adjusted for baseline and country.**

**Visual hallucinations**

**Improvement**

- PTT 9.1-1c 2311 PTT 9.1-4c

## Patients With and Without Visual Hallucinations at Baseline—NPI-10 at Wk 24Core Study—ITT+RDO Population

- 4-11

**Visual hallucinations**

**Improvement**

- PTT 9.1-1c 2311 PTT 9.1-4c

**With**

**4.2****†**

**n = 110**

**64**

**223**

**102**

**0.4****†**

**Without**

***p***** = 0.013**

***p***** = 0.713**

**† ****Least squares means adjusted for baseline and country.**

## Antipsychotic Use Core Study 

|  | Core study |  | Patients with visual hallucinations at baseline |  |
| --- | --- | --- | --- | --- |
| 
Antipsychotic use | ExelonN = 362n (%) | PlaceboN = 179n (%) | ExelonN = 118n (%) | PlaceboN = 70n (%) |
| At baseline | 102 (28.2) | 48 (26.8) | 52 (44.1) | 26 (37.1) |
|    Increased dose |   9 (2.5) | 7 (3.9) | 4 (3.4) | 5 (7.1) |
|    Decreased dose |   5 (1.4) | 3 (1.7) | 1 (0.8) | 2 (2.9) |
| Newly introduced | 28 (7.7) | 20 (11.2) | 14 (11.9) | 14 (20.0) |

- 9-25 DV

- Final appeal dossier Nov 30 2005  Table 2-14

**Discontinuation of use of antipsychotic medication is included in decreased dose group.**

## Efficacy Summary

**Both primary outcome measures assessing cognition and overall dementia**
**Statistically significant results in favor ****of Exelon **
**Across analysis populations**
**At both Wk 16 and 24**
**Secondary outcome measures assessing activities of daily living, executive function, attention, and behavior**
**Statistically significant at Wk 24**

## Safety

**Double-Blind Core and Open-Label ****Extension Studies**

## Last Dose of Study Medication Core Study—Safety Population

| Dose at endpoint,mg/day | ExelonN = 362n (%) | PlaceboN = 179n (%) |
| --- | --- | --- |
| < 3 |   2 (0.6) | 0 |
| 3 - < 6 |   83 (22.9) |   16 (8.9) |
| 6 - < 9 |   76 (21.0) |     18 (10.1) |
| 9 - 12 | 201 (55.5) |   145 (81.0) |

- PHAT 2-105

## Percentage of Patients With Adverse Events (AEs) ≥ 5% in Any GroupCore and Extension Studies

|  | Core |  |
| --- | --- | --- |
|  | ExelonN = 362n (%)  | PlaceboN = 179  n (%)  |
| Total patients with AE(s)  | 303 (83.7)  | 127 (70.9)  |
| 	AE preferred term  |  |  |
| 	Nausea  | 105 (29.0)  | 20 (11.2)  |
| 	Vomiting  | 60 (16.6)  | 3 (1.7)  |
| 	Tremor  | 37 (10.2)  | 7 (3.9)  |
| 	Diarrhea  | 26 (7.2)  | 8 (4.5)  |
| 	Anorexia  | 22 (6.1)  | 5 (2.8)  |
| 	Fall  | 21 (5.8)  | 11 (6.1)  |
| 	Dizziness  | 21 (5.8)  | 2 (1.1)  |
| 	Hypotension  | 19 (5.2)  | 14 (7.8)  |
| 	Hallucination  | 17 (4.7)  | 17 (9.5)  |
| 	Constipation 	 | 17 (4.7)  | 12 (6.7)  |
| 	Confusional state  | 13 (3.6)  | 10 (5.6)  |
| 	Orthostatic hypotension  | 6 (1.7)  | 9 (5.0)  |

- CSC T 4-2, Core PTT10.1-4; Extension PTT 10.1-4

| Extension |  |
| --- | --- |
| Exe-ExelonN = 211  n (%)  | Plc-ExelonN = 123  n (%)  |
| 159 (75.4)  | 93 (75.6)  |
|  |  |
| 29 (13.7)  | 33 (26.8)  |
| 17 (8.1)  | 20 (16.3)  |
| 8 (3.8)  | 15 (12.2)  |
| 4 (1.9)  | 4 (3.3)  |
| 6 (2.8)  | 6 (4.9)  |
| 7 (3.3)  | 9 (7.3)  |
| 5 (2.4)  | 3 (2.4)  |
| 8 (3.8)  | 5 (4.1)  |
| 9 (4.3)  | 7 (5.7)  |
| 4 (1.9)  | 2 (1.6)  |
| 10 (4.7)  | 7 (5.7)  |
| 5 (2.4) | 4 (3.3) |

## Percentage of Patients With Serious Adverse Events (SAEs) ≥ 1% in Any Group Core and Extension Studies

- CSC T 4-10

|  | Core |  |
| --- | --- | --- |
| Preferred term | ExelonN = 362n (%) | PlaceboN = 179n (%) |
| Deaths | 4 (1.1) | 7 (3.9) |
| Total patients with SAE(s) | 47 (13.0) | 26 (14.5) |
| Vomiting | 1 (0.3) | 0 |
| Dehydration | 5 (1.4) | 2 (1.1) |
| Confusional state | 2 (0.6) | 2 (1.1) |
| Somnolence | 0 | 0 |
| Syncope | 0 | 2 (1.1) |
| Pneumonia | 3 (0.8) | 1 (0.6) |
| Urinary tract infection | 1 (0.3) | 1 (0.6) |
| Asthenia | 0 | 0 |

| Extension |  |
| --- | --- |
| Exe-ExelonN = 211n (%) | Plc-ExelonN = 123n (%) |
| 5 (2.4) | 2 (1.7) |
| 37 (17.5) | 20 (16.3) |
| 1 (0.5) | 2 (1.6) |
| 3 (1.4) | 0 |
| 3 (1.4) | 0 |
| 0 | 2 (1.6) |
| 1 (0.5) | 1 (0.8) |
| 2 (0.9) | 5 (4.1) |
| 2 (0.9) | 2 (1.6) |
| 0 | 2 (1.6) |

## Most Frequent Discontinuations Due to AEs (≥ 1% in Any Group)Core and Extension Studies

|  | Core |  |
| --- | --- | --- |
|  | ExelonN = 362 n (%) | PlaceboN = 179n (%)  |
| Total patients with AE(s)  | 303 (83.7)  | 127 (70.9)  |
| All AE discontinuations | 66 (18.2)  | 20 (11.2)  |
| 	Nausea  | 13 (3.6)  | 1 (0.6)  |
| 	Vomiting  | 7 (1.9)  | 1 (0.6)  |
| 	Tremor  | 6 (1.7)  | 0  |
| 	Diarrhea  | 4 (1.1)  | 2 (1.1)  |
| 	Hallucination  | 4 (1.1)  | 2 (1.1)  |
| 	Anorexia  | 1 (0.3)  | 2 (1.1)  |

- CSC T 4-11, PTT10-2-1 (Core), 10.2-1 (Extension)

| Extension |  |
| --- | --- |
| Exe-ExelonN = 211n (%) | Plc-ExelonN = 123
n (%)  |
| 159 (75.4)  | 93 (75.6)  |
| 21 (10.0)  | 17 (13.8)  |
| 1 (0.5)  | 5 (4.1)  |
| 0 | 3 (2.4)  |
| 1 (0.5)  | 2 (1.6)  |
| 0 | 0  |
| 1 (0.5)  | 2 (1.6)  |
| 0 | 1 (0.8)  |

**3 Exelon-treated and 2 placebo-treated patients in the core study and 2 patients in the****Plc-Exelon group had multiple above-mentioned AEs leading to discontinuation.**

## AEs Potentially Associated With Nonmotor Symptoms of PDCore and Extension Studies

|  | Core |  |
| --- | --- | --- |
|  | ExelonN = 362n (%)  | PlaceboN = 179n (%)  |
| Cardiac AEs | 16 (4.4) | 12 (6.7) |
| Bradycardia | 5 (1.4) | 1 (0.6) |
| Vascular AEs | 30 (8.3) | 31 (17.3) |
| Hypotension | 19 (5.2) | 14 (7.8) |
| Orthostatic hypotension | 6 (1.7) | 9 (5.0) |
| Psychiatric AEs | 86 (23.8) | 41 (22.9) |
| Hallucinations | 17 (4.7) | 17 (9.5) |
| Other |  |  |
| Constipation | 17 (4.7) | 12 (6.7) |
| Syncope | 2 (0.6) | 6 (3.4) |

- CSR 2311 T10-1, PTT10-1.1; 2311e1 T10-1, PTT 10.1-1

| Extension |  |
| --- | --- |
| Exe-ExelonN = 211n (%) | Plc-ExelonN = 123n (%) |
| 10 (4.7) | 2 (1.6) |
| 2 (0.9) | 0 |
| 19 (9.0) | 16 (13.0) |
| 8 (3.8) | 5 (4.1) |
| 5 (2.4) | 4 (3.3) |
| 51 (24.2) | 23 (18.7) |
| 9 (4.3) | 7 (5.7) |
|  |  |
| 4 (1.9) | 2 (1.6) |
| 4 (1.9) | 3 (2.4) |

## Predefined Group of Motor Symptom AEs— ‘Potentially Associated With PD’

**Akinesia **
**Balance disorder**
**Bradykinesia**
**Drooling **
**Dysarthria**
**Dyskinesia**
**Dsytonia**
**Fall**
**Freezing phenomenon**
**Gait abnormality **
**Hypertonia**
**Hypokinesia**

**Motor dysfunction**
**Movement disorder**
**Muscle rigidity**
**Musculoskeletal stiffness**
**On and off phenomenon**
**Parkinson’s disease worsening**
**Parkinsonism worsening**
**Rigors**
**Salivary hypersecretion**
**Tremor**

## Cardinal Extrapyramidal Motor Symptom AEs Core and Extension Studies

|  | Core |  |
| --- | --- | --- |
|  | ExelonN = 362
n (%) | PlaceboN = 179 n (%) |
| Any predefined AE(s) ‘potentially associated with PD’ | 99 (27.3) | 28 (15.6) |
| 		Tremor | 37 (10.2) | 7 (3.9) |
| 		Bradykinesia | 9 (2.5) | 3 (1.7) |
| 		Rigidity | 1 (0.3) | 0 |

**SCS T8-2, PTT10.2-3, 10.1-1 (Core), PTT10.2-3, (Extension) PTT10.2-3 (SCS); Post hoc 2-26 (Extension PTL App. 7.1  1-18)**

**3-23DV**

| Extension |  |
| --- | --- |
| Exe-ExelonN = 211 n (%) | Plc-ExelonN = 123 n (%) |
| 28 (13.3) | 32 (26.0)

 |
| 8 (3.8) | 15 (12.2) |
| 1 (0.5) | 0 |
| 0 | 1 (0.8) |

**Editor: keep apostrophe around ‘potentially . . .**

## Consequences of AEs of Tremor and ‘Potentially Associated With PD’ Core Study

|  | Tremor |  | All AEs ‘Potentially Associated with PD’ |  |
| --- | --- | --- | --- | --- |
|  | ExelonN = 362n (%) | PlaceboN = 179 n (%) | ExelonN = 362n (%) | PlaceboN = 179 n (%) |
| Total events, n | 40 | 7 | 132 | 42 |
| No. of patients with events | 37 (10.2) | 7 (3.9) | 99 (27.3) | 28 (15.6) |
| Severity† |  |  |  |  |
| 	Mild | 18 (5.0) | 5 (2.8) | 45 (12.4) | 17 (9.5) |
| 	Moderate | 18 (5.0) | 2 (1.1) | 46 (12.7) | 8 (4.5) |
| 	Severe | 1 (0.3) | 0 | 8 (2.2) | 3 (1.7) |
| Serious AEs | 0 | 0 | 3 (0.8) | 1 (0.6) |
| Resulted in DC | 6 (1.7) | 0 | 17 (4.7) | 2 (1.1) |
| Con. meds. added‡ | 4 (10.8) | 0 | 19 (19.2) | 4 (14.3) |
| Resolved‡ | 19 (51.4) | 3 (42.9) | 58 (58.6) | 17 (60.7) |

**† ****For patients with more than 1 event, the most severe event was used.**
**‡ ****Percentages based on number of patients with events.**

- 9

- 9-9 DV

- Final appeal dossier Nov 30 2005  T 2-7

## UPDRS Part III Change From Baseline at Wk 24 (Core) and Wk 48 (Extension) 

| UPDRS part III score | Mean ± SD |  |
| --- | --- | --- |
| Core study  | ExelonN = 263 | Placebo N = 146 |
| 	Change from baseline† | –0.3 ± 9.5 | –0.4 ± 8.5 |
|  |  |  |
|  |  |  |
| Extension study  | Exe-Exelon N = 171 | Plc-Exelon N = 96 |
| 	Change from baseline† | 1.1 ± 9.7 | 1.7 ± 12.1 |

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**†****	****Calculated only for patients who had Wk 24 and Wk 48 evaluations from baseline at Wk 0.**
**Negative change from baseline indicates improvement.**

## Safety ConclusionCore and Extension Studies

**Most frequent AEs in Exelon group were nausea, vomiting, and tremor**
**Majority were mild to moderate events with infrequent discontinuation **
**SAEs and deaths were consistent with events expected in the elderly population**
**Fewer events in the Exelon group**
**No increased cardiovascular or psychiatric events in the Exelon group**

## Safety ConclusionCore and Extension Studies

**Tremor was slightly higher in the Exelon group and was the main driver of AEs ‘potentially associated with PD’**
**Majority were mild to moderate events with infrequent discontinuation **
**Underlying PD did not worsen based on UPDRS part III total scores**
**Long-term (1 yr) treatment in PDD was not associated with any new safety concerns**