TRIAL SUMMARY:

This is an open-label, 24-week, investigator initiated study to evaluate the safety and efficacy of galantamine (16 8 to 24 mg/day; flexible dosing) in the treatment of Dementia with Lewy bodies. The primary efficacy variables will be the NPI -12, the COGDRAS tests of attention and visuospatial orientation, and the ADCS-CGIC. The secondary efficacy variables will be the MMSE, ADCS-ADL-Inventory, ADAS-Cog, PSQI, and the use of concomitant rescue antipsychotic medication. PET scanning will be obtained on 10 patients at one site. An interim analysis will also be performed. Safety outcome measures will be adverse event reports, vital signs, physical examinations, ECG, laboratory parameters and the UPDRS (motor subscale).

TRIAL DESIGN

1. Rationale

   In a previously published study of DLB treated with rivastigmine, efficacy was seen to be maximized at 20 weeks in multiple parameters compared to placebo. The efficacy was seen in the NPI - 4 as well as the NPI -10, MMSE and a Computerized Cognitive Assessment Systems Score5. There was no change in UPDRS score. The efficacy of rivastigmine for patients with DLB responding greater than 30 percent in behavioral measures was equal to or better than most studies of antipsychotic medications used for behavioral abnormalities in DLB and AD patients.

   Since the titration for galantamine involves less time than the titration for rivastigmine, an interim analysis may show efficacy at 12 weeks. However, for complete efficacy and safety evaluations, a 24-week treatment for galantamine is preferable. Since the cholinergic deficits in DLB patients is more profound than that for AD patients, the dose range of 16 8 to 24 mg/day for DLB patients should be sufficient to show efficacy. Since galantamine has previously been shown to be efficacious in the domains of behavior, cognition, ADL's and global assessment in AD patients, we expect efficacy to be shown similarly and perhaps to a greater extent in DLB patients.

   TREATMENT OF SUBJECTS

   There will be seven visits in this 24-week treatment trial with galantamine for DLB. For all visits a time window of +/- 3 days relative to baseline visit V2 is applicable.

   Screen: Visit 1 (-4 week - 0)

   At visit 1 (V1) subjects will be evaluated for their suitability for enrollment. It is acceptable for this visit to be conducted on more than one day, although it should not be done over longer than a week. Prior to the conduct of any trial related procedures a complete explanation (both verbally and written) of the nature and purpose of the trial will be given by the Investigator (or designee). The subject will be requested to sign and date the IRB/IEC approved Informed Consent. Subject's eligibility for the trial will be determined on the basis of the inclusion/exclusion criteria, and from the results of the following pre-treatment assessments:

   • Medical history

   • Complete neurological examination

   • Complete physical examination

   • CT Scan/MRI

   • Vital signs (blood pressure/heart rate)

   • Weight

   • Height

   • ECG

   • Complete chemistry panel, hematology, B12, folate, RPR, thyroid panels including TSH (if not done within the last 3 months)

   • Urine pregnancy test (if applicable)

   • Concomitant medications

   • Mini Mental State Exam (MMSE)

     • NPI-12

   • PSQI

   • Modified Hachinski Ischemic Scale (MHIS)

   Baseline: Visit 2 (Week 0)

   At the beginning of this visit the Investigator should review all test results from Visit 1, this will include the completion of eligibility criteria. If patient is eligible to continue in the trial, the following assessments will be carried out:

   • Brief physical examination

   • Vital signs (blood pressure/heart rate)
   • Weight
   • Concomitant medications
   • MMSE
   • NPI-12
   • ADAS-Cog
   • ADCS-CGIC
   • FDG-PET*
   • PSQI
   • ADCS-ADL inventory
   • Fluctuation scales
   • UPDRS
   • COGDRAS
   • Dispense medication (See table)
   • AE's

   Titration: Visits 3 (Week 4), Visit 4 (Week 8)

   During the titration visits (Visit 3 and Visit 4) the following assessments will be done:

   • Brief physical examination

   • Vital signs (blood pressure/heart rate) • Weight
   • Concomitant medications
   • NPI-12
   • PSQI
   • Fluctuation scales
   • Dispense medication (See table)
   • AE's
   • Drug accountability

   Maintenance: Visit 5 (Week 12), Visit 6 (Week 20)

   Subjects who have completed the titration phase will continue the 12 week maintenance phase. On clinic visit days subjects will have the following assessments:

   • Brief physical examination

   • Vital signs (blood pressure/heart rate)

   • Weight

   • Concomitant medications

   • MMSE (Visit 5 only)

   • NPI-12

   • ADAS-Cog (Visit 5 only)

   • PSQI

   • ADCS-ADL inventory (Visit 5 only)

   • Fluctuation scales

   • UPDRS (Visit 5 only)

   • COGDRAS (Visit 5 only)

   • Dispense medication (See table)

   • AE's

   • Drug Accountability

   • Efficacy measures (Visit 5 only)

   Final Visit: Visit 7 (Week 24)

   The subject will be scheduled for a clinic visit to perform the final assessments. The following assessments will be carried out:

   • Complete neurological examination

   • Complete physical examination

   • Vital signs (blood pressure/heart rate)
   • Weight
   • ECG
   • Complete chemistry panel and hematology
   • Urine pregnancy test (if applicable)
   • Concomitant medications
   • Mini Mental State Exam (MMSE)
   • NPI-12
   • ADAS-Cog
   • ADCS-CGIC
   • FDG-PET*
   • PSQI
   • ADCS-ADL inventory
   • Fluctuation scales
   • UPDRS
   • COGDRAS
   • Drug accountability

Inclusion Criteria:

• Male or female subjects (>50 years old) diagnosed with Dementia with Lewy bodies, in accordance with the consensus criteria for probable Dementia with Lewy bodies (McKeith et al., 1996) viii.
• NPI score ≥ 8 at screening
• MMSE ≥ 7 at screening
• Subjects living at home or in a residential or community care home. Subjects who live with or have regular daily visits from a responsible caregiver. Subjects must be able to read, write, and fully understand the language of the scales used in this trial.
• Subjects must exhibit sufficient visual, hearing, and communication capabilities
• The Informed Consent must be given by the subject and the subject's legally acceptable representative.
• The informed consent must also be signed by the caregiver.
• CT or MRI within last 12 months - to be performed if not done

Exclusion Criteria:

• Neurodegenerative disorders such as Alzheimer's disease, Frontotemporal dementia, including Pick's disease, Korsakoff's syndrome, Huntington's chorea, Down's syndrome, Creutzfeldt-Jacob disease and causes of Parkinsonism other than DLB.

• One of the following conditions possibly resulting in cognitive impairment:

  • Acute cerebral trauma, subdural hematoma and injuries secondary to chronic trauma (such as boxing).
  • Hypoxic cerebral damage whether or not due to acute or chronic cerebral hypoperfusion,
  • Vitamin deficiency state such as folate, vitamin B12 and other B complex deficiencies, e.g., thiamine deficiency in Korsakoff's syndrome. Note: subjects taking regular B12 and folate are not necessarily excluded (treatment must be stable, ongoing for at least 4 weeks prior to entry).
  • Infection such as cerebral abscess, neurosyphilis, meningitis or encephalitis.
  • Primary or metastatic cerebral neoplasia.
  • Significant endocrine or metabolic disease e
  • Mental retardation or oligophrenia. Multi-infarct dementia or clinically active cerebrovascular disease

• Subjects with the following co-existing medical condition:

  • Any history of epilepsy or convulsions except for febrile convulsions during childhood.
  • Current clinically significant psychiatric disease, as judged by DSM-IV criteria, in particular current major depression or schizophrenia.
  • Peptic ulcer: if the ulcer is to be considered still "active", i.e., treatment for this condition started <3 months ago or if treatment is not successful (still symptoms present), the subject is not eligible.
  • Clinically significant hepatic, renal, pulmonary, metabolic or endocrine disturbances.
  • Current, clinically significant cardiovascular disease that would be expected to limit the subject's ability to participate in and complete a 7-month trial.
  • Any agent being used for the treatment of dementia (approved, experimental or over the counter agents),

• History of drug or alcohol abuse within the last year or prior prolonged history.

• Female subject of childbearing potential without adequate contraception. Females who are breast-feeding are also excluded.

• Subjects who, in the opinion of the investigator, are otherwise unsuitable for a trial of this type.

• History of severe drug allergy or hypersensitivity; including recorded hypersensitivity to cholinesterase inhibitors, choline agonists or similar agents, bromide or the components of the drug under study.

• Subjects who have previously been enrolled in other galantamine HBr trials. Subjects who were screened for previous galantamine studies but not enrolled may be re-screened for this study.

• Subjects on antipsychotics other than Risperdal® (risperidone), Zyprexa® (olanzapine), Seroquel® (quetiapine), Geodon® (ziprasidone).

• Conditions that could interfere with the absorption of the compound or with the evaluation of the disease.