A Pilot Study to Explore the Safety and Tolerability of Galantamine HBr in the Treatment of Pick Complex/Frontotemporal Dementia
Condition: Frontotemporal Dementia; Pick Complex
MeSH terms: Dementia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Frontotemporal Lobar Degeneration
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to explore the safety and tolerability and the efficacy of
      galantamine treatment in subjects with Pick Complex/ Frontotemporal Dementia (PC/FTD). The
      safety and tolerability of galantamine therapy will be assessed over the entire treatment
      period (26 weeks). The 8 week withdrawal period will be used to confirm the safety of
      galantamine withdrawal in this subject group and it impact on any symptom improvement
      achieved during the first 18 weeks of galantamine treatment ( symptom improvement would be
      expected to stabilize or decline on withdrawal of an effective therapy).

      The primary efficacy objective is to explore the effect of galantamine on behavior as
      measured by the Frontal Behavioral Inventory during the randomized withdrawal period. In
      addition, for subjects with primary progressive aphasia (limited ability for languages), the
      effects of galantamine on language will be explored using the Aphasia Quotient of the Western
      Aphasia Battery, and for all subjects the Clinical Global Impressions will be used to explore
      global change.
    

Detailed description: 
      Pick Complex (PC) and Frontotemporal Dementia (FTD) are a group of neurodegenerative
      dementias, initially characterized by frontotemporal lobar atrophy, that have overlapping
      clinical presentations and pathologic findings. Although the pathogenesis of Pick
      Complex/Frontotemporal Dementia remains unknown, and the neurotransmitter changes in Pick
      Complex/Frontotemporal Dementia are not well characterized, there is evidence for decreased
      cholinergic receptor binding in several cortical regions and decreased serotonin binding in
      the hypothalamus, frontal cortex, and temporal cortex. Galantamine is a reversible
      cholinesterase inhibitor. Recent studies indicate that galantamine is also an allosteric
      modulator at nicotinic cholinergic receptor sites. This nicotinic modulation appears to not
      only potentiate the response to acetylcholine binding, but also to modulate release of
      several other neurotransmitters, including serotonin. This pilot study will explore the
      safety and tolerability and efficacy of galantamine 8 mg and 12 mg twice a day treatment in
      subjects with Pick Complex/Frontotemporal Dementia. The study comprises an 18 week, open
      label, galantamine treatment phase followed by an 8 week, randomized, double blind, placebo
      controlled withdrawal phase. The safety and tolerability of galantamine therapy will be
      explored during both the open label and randomized withdrawal periods. The 8 week randomized
      withdrawal period will be used to confirm the safety of galantamine withdrawal in this
      subject group and its impact on possible symptom improvement achieved during the open label
      period as a marker for efficacy.

      The expectation is that subjects who remain on galantamine for the additional 8 weeks will
      continue to improve or will remain stable with regard to their behavior, language, cognition,
      and global function, whereas subjects who are assigned to placebo will show a decline in some
      of these functions. This approach will allow an assessment of the effects of galantamine
      treatment (challenge) and galantamine withdrawal (de-challenge).

      This study will involve a maximum of 40 subjects with Pick Complex/Frontotemporal Dementia.
      Subjects who meet the inclusion and exclusion criteria will receive galantamine 4 mg twice a
      day for 4 weeks followed by 8 mg twice a day for 4 weeks. At 8 weeks, the dose of galantamine
      will be maintained at 8 mg or increased to 12 mg twice a day based on tolerability. At the
      end of 12 weeks the dose of galantamine will be maintained at 8 or 12 mg twice a day or
      reduced to 8 mg twice a day, based on tolerability. The dose will be fixed for the remainder
      of the open label treatment period. Following 18 weeks of galantamine treatment, subjects
      will be randomly assigned (1:1) to continued treatment with galantamine (at the same dose) or
      placebo for an additional 8 weeks. Subjects and caregivers will be contacted by phone during
      the study and encouraged to contact the site at any time if they have concerns. If the
      subject's symptoms appear to be substantially worsening, and the investigator determines that
      the subject has deteriorated, he will advise the subject and caregiver about possible early
      completion of the study (early escape). Subjects electing early escape will complete final
      efficacy and safety assessments, then discontinue study medication. Once they have completed
      the study, they will begin the treatment of their choice in consultation with their
      physician. Subjects will be seen for assessment at Visit 1 (screening), Visit 2 (baseline),
      Visits 3 and 4 (12 and 18 weeks after the start of open label galantamine treatment), and
      Visit 5 (8 weeks after the start of the double blind withdrawal period or at early escape) or
      upon premature discontinuation. The subject and caregiver will return for an unscheduled
      visit if, in the judgment of the investigator, the subject requires clinical assessment
      between visits.

      Subject selection criteria will ensure inclusion of subjects who have a clinical diagnosis of
      Pick Complex/Frontotemporal Dementia established by published consensus criteria and
      supported by neuroradiologic confirmation. The subjects selected for the study will have a
      diagnosis of primary progressive aphasia or frontotemporal dementia.

      Safety and tolerability will be monitored by assessment of adverse events,
      electrocardiograms, physical examinations, blood pressure, heart rate, weight, and laboratory
      tests. Efficacy on symptoms will be explored by measuring changes in the Frontal Behavioral
      Inventory (FBI), the Aphasia Quotient (AQ) of the Western Aphasia Battery (WAB), the Mini
      Mental State Examination (MMSE), the Mattis Dementia Rating Scale (MDRS), the Frontal
      Assessment Battery (FAB), the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease
      Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale, the Clinical Global
      Impressions (CGI) Scales of Severity or Change, and subscales of the WAB and FBI. Changes in
      the results of neurologic examinations will also be documented.

      The descriptive analyses will be performed, no hypotheses are specified for statistical
      testing. Safety and efficacy assessments will be summarized. Safety and Efficacy changes will
      be calculated from the screening/baseline of the galantamine treatment period to Week 18
      (open label galantamine treatment period) and Week 26 (entire study for subjects randomized
      to galantamine for the 8 week withdrawal period). Comparisons between the placebo and
      galantamine treatment groups will use the changes in safety and efficacy parameters from
      Weeks 18 to 26 (the double blind, placebo controlled, randomized withdrawal period). Using a
      flexible dosing regimen, subjects will receive galantamine as oral tablets up to 8 or 12 mg
      twice per day for 18 weeks. Subjects will then be randomly assigned (1:1) in a double blind
      fashion to galantamine at the same dose or to placebo for an additional 8 weeks of treatment.
    

Intervention name(s): galantamine hydrobromide
Intervention type(s): Drug
Intervention MeSH terms: Galantamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Frontotemporal Dementia; Pick Complex; galantamine hydrobromide