Therapy in Amyotrophic Lateral Sclerosis (TAME)
Condition: Amyotrophic Lateral Sclerosis; Frontal Temporal Dementia
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine if memantine at up to 20 mg twice a day when used
      in conjunction with riluzole, can slow down the disease progression of patients with ALS
      including potentially improving their neuropsychiatric changes, as well as determine if serum
      biomarkers can be used both as a diagnostic and a prognostic marker in patients with ALS.

      Funding Source: FDA - Orphan Products Development (OPD)
    

Detailed description: 
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 30,000
      Americans each year. Of these 30,000 Americans, it has been suggested that up to 50% will
      experience cognitive and behavioral changes in the form of frontotemporal dysfunction and up
      to 40% will meet criteria for frontotemporal dementia (FTD). Riluzole the only FDA approved
      agent for ALS extends a patient's lifespan by 2-3 months, and there are no proven therapies
      for the cognitive changes associated with ALS. More effective therapy for this universally
      fatal disease is desperately needed.

      Results from an open label pilot trial of 20 patients treated with memantine at 10 mg twice a
      day suggested that treatment with the combination of memantine and riluzole slowed ALS
      disease progression. This trial also showed that levels of specific protein biomarkers in the
      cerebrospinal fluid (CSF) at baseline correlated with the rate of disease progression. A
      concurrent phase II study performed by Dr. Carvalho, found no effect with similar dosing;
      however, the study was limited in terms of power. Comments on previous failed drug trials in
      ALS have raised the concern that many ALS trials study a potential therapeutic agent at only
      a single dose and thus may miss the potential efficacy of non FDA approved doses; therefore,
      this proposed study will test a higher dose of memantine, 20 mg twice a day, in a double
      blind, placebo controlled, randomized trial of 90 patients with ALS to determine if a therapy
      of memantine, especially in combination with riluzole, can slow disease progression compared
      to treatment with riluzole alone or no treatment. Participants who experience treatment
      related adverse events may undergo dose reduction or discontinuation. The primary outcome
      measure will be the rate of disease progression as measured by the ALS Functional Rating
      Scale- Revised (ALSFRS-R). In addition the investigators will examine the cognitive deficits
      seen in ALS patients measured by the ALS Cognitive Behavioral Screen (ALS-CBS) and the
      Neuropsychiatric Inventory Questionnaire (NPI-Q). Finally the investigators will examine
      specific validated protein serum biomarkers to determine if there is a correlation between
      the levels of these biomarkers and the rate of disease progression. In particular the
      investigators will measure the ratio of phosphorylated heavy neurofilament to Complement 3 to
      see if this ratio is predictive of disease progression and if the levels change during
      therapy with memantine.

      This project will offer unique insights into this untreatable disease. If this study confirms
      earlier results and suggests that memantine, when used in conjunction with riluzole,
      significantly slows down the progression of the disease, as well as ameliorates cognitive
      deficits in patients with fronto-temporal dysfunction, it will set the groundwork for
      conducting a larger phase III trial.
    

Intervention name(s): Memantine; Placebo (for Memantine)
Intervention type(s): Drug; Drug
Intervention description(s): All randomized patients will be instructed to take one tablet once a day for the first two weeks from a blinded bottle that contains 10 mg tablets or matching placebo. At week three, patients will be instructed to take one tablet twice a day from the 10 mg bottle or matching placebo. At week five, patients will be instructed to take one tablet in the morning and two tablets in the evening from the 10 mg bottle or matching placebo. At week seven patients will be instructed to take two tablets twice a day from the 10 mg bottle or matching placebo.; All randomized patients will be instructed to take one tablet once a day for the first two weeks from a blinded bottle that contains 10 mg tablets or matching placebo. At week three, patients will be instructed to take one tablet twice a day from the 10 mg bottle or matching placebo. At week five, patients will be instructed to take one tablet in the morning and two tablets in the evening from the 10 mg bottle or matching placebo. At week seven patients will be instructed to take two tablets twice a day from the 10 mg bottle or matching placebo.
Other intervention name(s): Namenda; Sugar pill manufactured to mimic memantine 10 mg
Intervention MeSH terms: Memantine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: ALS; FTD; Tau; pNF-H/C3