Nefiracetam in the Treatment of Alzheimer's Disease
Nefiracetam in the Treatment of Alzheimer's Disease
Some of the thinking difficulties of Alzheimer's patients may be due to a deficiency in a
 brain chemical called acetylcholine, which helps transmit messages between nerve cells.
 Nefiracetam is a new drug that stimulates acetylcholine. This study will test whether
 Nefiracetam can safely improve memory, thinking and activities of daily living in patients
 with mild to moderate intellectual impairment due to Alzheimer's disease.

 Patients in the study must have a caregiver and designated representative. Candidates will be
 given a medical history and physical examination that includes a complete neurologic and
 neuropsychologic evaluation, blood tests, and an electrocardiogram. A chest X ray and
 magnetic resonance imaging (MRI) test will be done on patients who have not had these tests
 within the previous two years. During the 20-week study, each patient will take three pills
 twice a day for twenty weeks of either Nefiracetame or placebo (sugar pill). Neither the
 patients nor the doctors will know which patients are getting the drug and which are getting
 the placebo. Blood and urine tests will be done frequently throughout the study. Patients
 will be asked to have a spinal tap (on a voluntary basis) to measure the levels of drug in
 the spinal fluid, and a PET scan (a brain imaging test).

 At the end of the study, patients who feel they are doing well with no side effects from the
 drug (or placebo) may be given the option of continuing treatment for another seven months.

 Animal studies showed that Nefiracetam improved learning impairment and memory in rats with
 dementia. In a small study of humans, about one-fourth of patients who were given a low dose
 of the drug had improved intellectual function, and about one-half who received a higher dose
 improved.
Diminished cholinergic function has long been implicated in the pathophysiology of Alzheimer
 type dementia. Studies in animal models of this disorder as well as in patients with
 Alzheimer's disease (AD) suggest that drugs capable of activating central cholinergic
 transmission can improve cognitive function. Nevertheless, no currently available drug of
 this or any other type consistently confers clinically significant benefit. To further
 evaluate the cholinergic hypothesis for symptom palliation with a mechanistically novel
 pharmacologic tool, the acute safety and antidementia efficacy of nefiracetam will be studied
 using a double-blind, placebo-controlled, parallel groups design. In contrast to the
 currently available cholinesterase inhibitors, nefiracetam enhances the activity of nicotinic
 acetylcholine receptors by interacting with a protein kinase C pathway and accelerates
 acetylcholine turnover and release. Efficacy in patients with mild to moderate dementia will
 be assessed through application of standardized neuropsychological test instruments in this
 first double-blind, randomized controlled trial of nefiracetam in AD. Safety will be
 monitored by means of frequent clinical evaluations and laboratory tests.
Study subjects will satisfy NINCDS-ADRDA criteria for probable AD. Dementia severity will
 be in the mild to moderate range, as evidenced by a Mini-Mental State Examination total
 score of 12-25 which is roughly equivalent to Alzheimer's Disease Assessment Scale
 Cognitive (ADAS-Cog) scores of 30 to 11, will include deficits in at least 2 areas of
 cognition, will have been present at least 1 year, and will have progressed gradually since
 onset. Patients must be between the ages of 50-90 with onset of dementia after age 40. The
 modified Hachinski Ischemia Score must be less than 4 and the brain MRI within 2 years of
 enrollment must be consistent with the diagnosis of AD.

 Patients must have had a brain MRI since the onset of dementia symptoms that is consistent
 with the diagnosis of AD.

 Patients must have an acceptable nutritional status (i.e., body weight within 20% of
 desirable weight for height).

 Patients must be surgically sterile.

 Patients must be post-menopausal or practicing adequate contraception.

 Physical and laboratory exams must be normal, or the abnormalities must be attributed to
 the dementing illness or judged clinically unimportant to the safe conduct of this trial.

 Chest X-ray within 1 year of enrollment must show no active disease.

 No history or clinical diagnosis of stroke within 1 year before or concurrent with onset of
 dementia; hydrocephalus, subdural hematoma, or mass lesion on screening MRI; current
 seizure disorder; head trauma with loss of consciousness and hospitalization within 1 year
 before or concurrent with onset of dementia; dementia onset within 1 year following cardiac
 arrest or surgery; Parkinson's disease (onset prior to or concurrent with dementia),
 Wilson's, Huntington's, Creutzfeldt-Jakob disease, Pick's disease, or Wernicke's
 encephalopathy; chronic CNS infection (positive RPR and/or FTA-ABS acceptable if luetic
 brain disease excluded by documented studies and/or treatment).

 No COPD or asthma requiring hospital treatment within 1 year before enrollment (treatment
 of acute respiratory infections is acceptable).

 No acute systemic infection.

 No hypothyroidism (TSH greater than 6.0 mclU/ml).

 No folic acid (less than 0.9 ng/ml) or B12 deficiency (less than 100 pg/ml) within 1 year
 before study enrollment.

 No recent or acute HAV or HBV infection, or chronic HBV infection by immuno-assays.

 No insulin dependent diabetes or poorly controlled non-insulin dependent diabetes.

 No history of leukopenia, neutropenia, or thrombocytopenia, cancer (except treated,
 non-recurrent skin cancer) within 2 years before enrollment.

 No severe renal insufficiency (Clcr less than 25 ml/min, BUN greater than 30 mg/dl, or
 creatinine greater than 2.0 mg/dl), hepatic insufficiency (as indicated by: ASAT (SGOT) 3 x
 ULN, ALAT (SGPT) 3 x ULN, or total bilirubin greater than 2.0 mg/dl).

 No homocysteinemia (greater than 14 micromol/L).

 No past history of schizophrenia.

 No substance use disorder within 1 year of dementia onset.

 No depression requiring medical treatment within the past 30 days.

 No administration of tacrine (Cognex) or donezepil (Aricept), investigational drugs, or
 nutritional supplements used as neurotransmitter precursors for cognitive enhancement
 within 30 days before enrollment.

 No use of anticonvulsants, psychostimulants, centrally acting anticholinergics and agents
 known to inhibit or be metabolized by CYP 3A4 (e.g., erythromycin, chlarythromycin,
 troleandomycin, fluconazole, miconazole, ketoconazole, itraconazole and grapefruit juice)
 within 2 weeks prior to enrollment.

 No hepatic, cardiovascular, gastrointestinal, or hematological illness which could
 interfere with drug absorption, distribution, metabolism, or excretion.

 No medical condition that contraindicates cholinergics.

 No known hypersensitivity to nefiracetam.

 Must be able to swallow/retain tablets.

 No history of medical noncompliance.

 Must have significant other person or caregiver to assure compliance.

 No uncorrectable loss of hearing or eyesight that precludes psychometric testing.

 Ability to comprehend instructions or respond to test items of the ADAS and Repeatable
 Battery for the Assessment of Neuropsychological Status (RBANS) during baseline
 administration.

 No male patients interested in conceiving children given the potential adverse effects on
 spermatogenesis.