A Phase 3 Study of Rotigotine in Combination with Rivastigmine in Mild to Moderate Alzheimer's Disease

Inclusion Criteria:

1. Men and women (non-childbearing potential, as defined in Appendix 2) with adiagnosis of AD according to IWG criteria

2. Age 50-85 years

3. MRI or computerized tomography (CT) assessment, corroborating the clinical diagnosisof AD and excluding other potential causes of dementia, especially cerebrovascularlesions (see exclusion criteria, number 3)

4. Patients who show CSF biomarker data supporting the diagnosis of AD (for CzechRepublic only: lumbar punctures can be performed for screening purposes), orpatients with a positive Amyloid Pet Scan will qualify for the study

5. Stable on a treatment with rivastigmine transdermal patch for at least 3 months, ofwhich at least the last month was at 9.5mg/day, or for one month, if the patient hadreceived donepezil before rivastigmine

6. Mild to moderate stage of AD according to MMSE ≥18 and ≤26

7. Clinical Dementia Rating (CDR) total score of 0.5 or 1 (mild)

8. Evidence of frontal lobe dysfunctions as assessed by FAB ≤14

9. Absence of major depressive disease according to GDS of < 5

10. Formal education for five or more years

11. Previous decline in cognition for more than six months as documented in patientmedical records

12. A caregiver available and living in the same household or interacting with thepatient and available if necessary to assure administration of drug

13. Patients living at home or nursing home setting without continuous nursing care

14. General health status acceptable for a participation in a 6-month clinical trial

15. Stable pharmacological treatment of any other chronic condition for at least onemonth prior to screening

16. No regular intake of prohibited medications

17. Signed informed consent by the patient. If there are any doubts that the patient ismentally capable of giving informed consent, the patient will be examined andverified to be mentally capable by an independent physician/ neurologist, prior tothe initiation of any study specific procedure. Signed consent of the caregiver

Exclusion Criteria:

1. Failure to perform screening or baseline examinations

2. Hospitalization or change of chronic concomitant medication one month prior toscreening or during screening period

3. Clinical, laboratory or neuro-imaging findings consistent with:

• other primary degenerative dementia (dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Creutzfeldt-Jakob Disease, Down'ssyndrome, etc.);

• other neurodegenerative condition (Parkinson's disease, amyotrophic lateralsclerosis, etc.);

• orthostatic hypotension and autonomic disorders

• cerebrovascular disease (major infarct, one strategic or multiple lacunarinfarcts, extensive white matter lesions > one quarter of the total whitematter);

• other central nervous system diseases (severe head trauma, tumors, subduralhematoma or other space occupying processes, etc.);

• seizure disorder;

• other infectious, metabolic, or systemic diseases affecting the central nervoussystem (syphilis, present hypothyroidism, present vitamin B12 or folatedeficiency, serum electrolytes out of normal range, juvenile onset diabetesmellitus, etc.).

4. A current DSM-V diagnosis of active major depression, schizophrenia, or bipolardisorder

5. Any suicidal ideation or suicidal behavior in the C-SSRS (C-SSRS score > 0)

6. Clinically significant, advanced, or unstable disease that may interfere withprimary or secondary variable evaluations, and which may bias the assessment of theclinical or mental status of the patient or put the patient at special risk, suchas:

• history of any kind of psychosis

• chronic liver disease, liver function test abnormalities or other signs ofhepatic insufficiency (ALT, AST, Gamma GT, alkaline phosphatase > 2.5 ULN);

• respiratory insufficiency;

• renal insufficiency (serum creatinine >2 mg/dl) or creatinine clearance ≤ 30mL/min according to Cockcroft-Gault formula). In case of creatinine clearance ≤30 mL/min, an alternative verification of the renal function must be completedusing Cystatin C analysis. In case of normal level of Cystatin C, the patientcan be included;

• heart disease (myocardial infarction, unstable angina, heart failure,cardiomyopathy within six months before screening);

• bradycardia (heart beat <50/min.) or tachycardia (heart beat >95/min);

• hypertension (>140/90 mm/Hg) or hypotension (<90/60 mm/Hg) requiring treatmentwith more than three drugs;

• AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinusnode dysfunction or prolonged QTcB-interval (males >450 and females >470 msec);

• uncontrolled diabetes defined by HbA1c >8.5;

• malignancies within the last five years except skin malignancies (other thanmelanoma) or indolent prostate cancer;

• metastases;

• disability that may prevent the patient from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc.);

• women who are fertile and of childbearing potential;

• chronic daily drug intake of ≥ 14 days or expected for ≥ 14 days:

• benzodiazepines, neuroleptics or major sedatives,

• antiepileptics,

• centrally active anti-hypertensive drugs (clonidine, l-methyl DOPA, guanidine,guanfacine, etc.),

• opioid containing analgesics,

• nootropic drugs (except Ginkgo Biloba);

• suspected or known drug or alcohol abuse, i.e., more than approximately 60 galcohol (approximately 1 liter of beer or 500 ml of wine) per day, indicated byelevated mean corpuscular volume (MCV) above normal value at screening; (Pleaseadvise all subjects that because of possible additive effects, patients shouldnot be taking alcohol in combination with rotigotine).

• suspected or known allergy to any components of the study treatments;

• hypersensitivity to the active substance rotigotine or to any of the excipientscontained in the patches (according to SmPC).

• enrollment in another investigational study or intake of investigational drugwithin the previous three months or five times the half-life of theIMP/metabolites (whichever is longer)

• any condition, which, in the opinion of the investigator, makes the patientunsuitable for inclusion;

• if the patient is in any way dependent on the sponsor or the principalinvestigator or if the patient is accommodated in an establishment on judicialor administrative order.