An Evaluation of Three Doses of NS 2330 in Patients With Mild to Moderate Dementia of the Alzheimer's Type

A Phase II Double-Blind, Randomized, Dose-Ranging, Placebo-Controlled, Multicenter, Safety and Efficacy Evaluation of Three Doses of NS 2330 in Patients With Mild to Moderate Dementia of the Alzheimer's Type

Objectives: The objective of this study will be to determine the safety, tolerability, drug blood levels, and efficacy of each of three doses of NS 2330 (Tesofensine) given once daily compared with placebo in patients with mild to moderate Dementia of the Alzheimer's Type.

INCLUSION CRITERIA

Patients may be included in this study if they meet all of the following criteria:

1. Male, and female without child bearing potential between 40 and 85 years of age, inclusive. Women who have been postmenopausal for less than 2 years must have a negative pregnancy test at screening.
2. Diagnosis of probable mild to moderate Dementia of the Alzheimer's Type as defined by National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS ADRDA) guidelines.9
3. Mini-Mental State Examination (MMSE) score of 10-24 and Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) score greater than 12 at screening.
4. Modified Hachinski Scale10 score no greater than 4.
5. Central nervous system imaging (CT or MRI scan of brain) compatible with Dementia of the Alzheimer's Type within the past year (also see exclusion criteria).
6. Exhibits reliability and physiologic capability sufficient to comply with all protocol procedures. Patient must be familiar with and fluent in English (i.e., sufficient to complete all study assessments from the language perspective).
7. Patients and/or a legal representative and their caregivers must have given informed consent. The legal representative and caregiver may be the same person.
8. Patient must have a reliable caregiver that is in frequent or daily contact with the patient, who will accompany the patient to the office and who will monitor the administration of prescribed medications. The caregiver will be able to communicate in English and be willing to comply with protocol requirements.

EXCLUSION CRITERIA

Patients must be excluded from this study if they meet any of the following criteria:

1. Secondary disorders inducing dementia such as neurosyphilis, craniocerebral trauma (CT/MRI), hyperthyroidism, or folic acid deficiency.

2. History of malignancy within 3 years, except for basal cell carcinoma.

3. History or diagnosis of symptomatic and/or unstable/uncontrolled:

   • Cardiovascular illnesses such as chronic congestive heart failure (with or without edema), arrhythmias, labile hypertension, ischemic heart disease, myocardial infarction (with residual angina), orthopnea, conduction defects (ECG), or other heart disease classified NYHA III or IV.
   • Liver disease such as cirrhosis, hepatitis B, hepatitis C, or primary or metastatic neoplasm.
   • Gastrointestinal disorder such as GI bleeding, malabsorption syndromes, post-gastrectomy, or active peptic ulcer disease.
   • Renal disease (primary or secondary) such as chronic renal failure (CLCR < 30 mL/min).
   • Endocrine disease such as diabetes mellitus or hypothyroidism.
   • Neurological disease (other than Dementia of the Alzheimer's Type such as Huntington's disease, Parkinson's disease, encephalitis, epilepsy, stroke, or multiple sclerosis) and psychiatric disorders such as schizophrenia, major depression, or mental retardation.
   • Significant pulmonary disease predisposing to hypoxia.
   • Immunological disorder such as clinically significant allergies, Lupus erythematosis, or scleroderma.
   • Hematological disease (regardless of cause) such as refractory anemia or refractory myelosuppression.
   • Organ system diseases which, in the opinion of the investigator, would impact on the primary and secondary endpoints of the trial such as dehydration (hematocrit >48%) or hypothyroidism.

4. Significant history of drug dependence or abuse (including alcohol, as defined in DSM IV or in the opinion of the investigator) within two years, or a positive urine drug screen for cocaine, heroin, or marijuana.

5. HIV positive.

6. Presence of Hepatitis C antibody.

7. Planned elective surgery requiring general anesthesia or hospitalization for more than 1 day during the study period.

8. Previous participation in any NS 2330 study.

9. Use of any investigational drug or procedure within 30 days before randomization.

10. Use of any drug within 14 days prior to randomization unless:

    • the dose of the drug and the condition being treated have been stable for at least 30 days and are expected to remain stable during the study
    • neither the drug nor the condition being treated is expected to interfere with the study endpoints.

11. Treatment with donepezil, galantamine, rivastigmine, or tacrine, is prohibited within 6 weeks before randomization.

12. Treatment with drugs that inhibit CYP 450 3A4 (see Appendix II for a list of relevant drugs.) If they are needed under emergency conditions, the patient should discontinue the trial.

13. Treatment with antipsychotics/neuroleptics is prohibited for 8 weeks prior to randomisation (see listing Appendix II).

14. Treatment with monoamine oxidase inhibitors is prohibited for 8 weeks prior to randomization.

15. Treatment with selective serotonin reuptake inhibitors is prohibited for 6 weeks prior to randomization.

16. Tricyclic antidepressants and antihistamines are prohibited for 4 weeks prior to randomization.