Efficacy and Safety of Lornoxicam in Patients With Mild to Moderate Probable Alzheimer´s Disease.

A Multicentre Double-blind, Placebo-controlled, Randomised, Parallel-group Study to Evaluate the Efficacy and Safety of Lornoxicam in Patients With Mild to Moderate Probable Alzheimer´s Disease.

Study title: A multicentre double-blind, placebo-controlled, randomised, parallel-group study to evaluate the safety and efficacy of Lornoxicam in patients with mild to moderate probable Alzheimer's Disease.

Study phase: II

Indication: Alzheimer´s Disease

Investigational product, dose schedule and route of administration: Lornoxicam (8 mg) tablets to be taken orally two times daily (BID) for a period of 6 months.

Reference product, dose, schedule and route of administration: Placebo (8 mg) tablets to be taken orally two times daily (BID) for a period of 6 months.

Study title: A multicentre double-blind, placebo-controlled, randomised, parallel-group study to evaluate the safety and efficacy of Lornoxicam in patients with mild to moderate probable Alzheimer's Disease.

Study phase: II

Indication: Alzheimer´s Disease

Study objectives: Primary:

To evaluate the efficacy of Lornoxicam (8 mg, BID) administered for 6 months versus matched placebo based on the following end-point:

• Cognitive performance - ADAS-cog+

Secondary:

To evaluate the efficacy of Lornoxicam (8 mg, BID) administered for 6 months versus matched placebo based on the following end-point:

• Activities of daily living - ADCS-ADL
• Behavioral / psychiatric symptoms - NPI

To evaluate the safety of Lornoxicam (8 mg, BID) administered for 6 months versus matched placebo.

• Overall incidence of adverse events.

Exploratory:

In a subgroup of 50 patients MRI analyses will be performed. In a subgroup of 50 patients exploratory data on the production of amyloid biological markers - blood plasma concentration of Aß1-38, Aß1-40 and Aß1-42 will be collected.

An optional 6 month open-label phase will be available.

Subject population, diagnosis and main criteria for inclusion: Male and female patients with mild to moderate probable Alzheimer's Disease according to NINCDS-ADRDA criteria

• Age 50 - 85 years inclusive
• MMSE 18-26 inclusive
• No history of treatment with Acetylcholine-esterase inhibitors or 4 weeks wash out period before baseline visit.
• No history of treatment with Memantine or 4 weeks wash out period before baseline visit.

Duration of treatment: 6 month double-blind phase 6 month open-label phase (optional)

Total number of subjects: A total of 220 patients will be recruited to the study from approximately 20 centers in a treatment ratio of 1:1 (8 mg BID, 110 : placebo, 110). This reflects the minimum number of patients required and also allows for a drop out rate of approximately 20%. Additional subjects may be recruited based on interim analysis.

Number of study centres: Approximately 20; multinational Europe

Number of visits: Doubble-Blind Phase: 5 visits (including screening); Open-Label Phase: 3 visits

Investigational product, dose schedule and route of administration: Lornoxicam (8 mg) tablets to be taken orally two times daily (BID) for a period of 6 months.

Reference product, dose, schedule and route of administration: Placebo (8 mg) tablets to be taken orally two times daily (BID) for a period of 6 months.

Inclusion Criteria:

1. Men and women (non-childbearing potential) with a diagnosis of Alzheimer's Disease according to the NINCDS-ADRDA clinical criteria.
2. Mild to moderate stage of Alzheimer's disease according to MMSE 18-26 inclusive.
3. Modified Hachinski Ischemic Scale equal to or below 4.
4. Geriatric Depression Scale below or equal 7.
5. If anticholinesterasic treatment had been prescribed, the patient must undergo a 4 week wash out period before the baseline visit (visit 1).
6. If Memantine treatment had been prescribed, the patient must undergo a 4 week wash out period before the baseline visit (visit 1).

Exclusion criteria:

1. Clinical, laboratory or neuroimaging findings consistent with:

• other primary degenerative dementia, (dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, Jacob-Creutzfeld Disease, Down's syndrome, etc.)

• other neurodegenerative condition (Parkinson's Disease, amyotrophic lateral sclerosis, etc.)

• cerebrovascular Disease (major infarct, one strategic or multiple lacunar infarcts, extensive white matter lesions > one quarter of the total white matter)

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

• seizure disorder

• other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency confirmed by current analyses not older than 1 month, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc.) 2. A current DSM-IV diagnosis of active major depression, schizophrenia or bipolar disorder.

  3. Chronic daily drug intake for a time period of ≥ 14 days or expected for ≥ 14 days: "

• antidepressants, benzodiazepines, neuroleptics, major sedatives or other anti-inflammatory drugs including acetylic salicylic acid defined

• antiepileptics

• anticholinergics

• nootropics (including Ginkgo)

• centrally active anti-hypertensive drugs (clonidine, alpha-methyl dopa, guanidine, guanfacine,)

• opioid containing analgesics

• anti-inflammatory agents, cortico-steroids or immunosuppressants

• Cimetidin as gastroprotective drug 4. Severe thrombocytopenia defined as platelet counts <100.000 per mm3. 5. Coagulation disorders