Effects of an Anti-Inflammatory Drug in Alzheimer's Disease
Condition: Alzheimer's Disease
MeSH terms: Alzheimer Disease
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to evaluate the effects of the drug cyclophosphamide (CY) on
      inflammation and immune responses in individuals with Alzheimer's Disease (AD).

      Inflammation and immunologic response appear to contribute to neurodegeneration in people
      with AD. In a process called gliosis, the brain immune cells microglia and astroglia undergo
      activation and possible proliferation, which promotes neuronal injury and death. Activated
      microglia and astroglia produce compounds that are cytotoxic to neurons, and they express
      molecules that greatly amplify immune and inflammatory processes in the brain. Excessive
      glial activation and proliferation are thought to be pivotal events that hasten the demise of
      synapses and neurons in AD. Fortunately, increased understanding of immune and inflammatory
      pathology in AD has provided new opportunities for designing disease-altering treatments for
      AD. Studies suggest that medications such as nonsteroidal anti-inflammatory drugs (NSAIDs)
      and immunomodulatory agents may have an important role in altering the course of AD. CY is a
      potent anti-inflammatory and immunomodulatory drug that inhibits proliferation of immune
      cells. This study will evaluate the effects of CY on individuals with mild to moderate AD.

      Participants in this study will be randomly assigned to receive either two different doses of
      CY or placebo (an inactive pill) for 6 months. Participants who receive placebo during the 6
      months will have the option of receiving CY for an additional 6 months. Participants will
      undergo magnetic resonance imaging (MRI) scans of the brain. Measures of cerebral spinal
      fluid biomarkers or neurodegeneration, neuroinflammation, and neuroimmune activation will be
      taken. In addition, peripheral lymphocyte subsets and peripheral markers of inflammation will
      be assessed.
    

Detailed description: 
      Objectives. The protocol is focused on the immune and inflammatory reactions in Alzheimer's
      disease (AD) and the possibility that blocking the inflammatory response may alter the course
      of the illness. The specific plan is to evaluate the biologic and clinical effects of two
      doses of cyclophosphamide (CY) immunotherapy in AD patients compared to the clinically
      available cyclooxygenase-2 inhibitor (COX-2), rofecoxib. The study will test the hypotheses
      that CY: 1) Is safe and tolerable in AD patients in meaningful clinical doses, 2) Can modify
      central nervous system inflammation and immune responses in AD, 3) Inhibits neurodegeneration
      in AD brains as indicated by peripheral biomarkers of AD pathology, and 4) Is different
      quantitatively or qualitatively in its effect on immune markers than placebo or other
      clinically-available anti-inflammatory drugs such as the COX-2 inhibitor, rofecoxib.

      Rationale. Inflammation and immunologic responses appear to contribute significantly to
      neurodegeneration in (AD). In a pathological process termed gliosis, the brain's resident
      immune cells (microglia and astroglia) undergo chronic activation and possible proliferation,
      promoting neuronal injury and death by several means. Activated microglia and astroglia
      produce compounds that are directly cytotoxic to neurons, and they express molecules that
      greatly amplify immune and inflammatory processes in the brain. Excessive glial activation
      and proliferation are thought to be pivotal events hastening the demise of synapses and
      neurons in AD. Conversely, the growing understanding of immune and inflammatory pathology in
      AD has provided new opportunities for designing disease-altering treatments for AD.
      Preliminary clinical trials of anti-inflammatory drugs in AD patients, epidemiologic studies
      of anti-inflammatory drug use, and experimental models linking neurodegeneration with
      neuroimmune/neuroinflammatory processes suggest strongly that medications such as
      nonsteroidal-anti-inflammatory drugs (NSAIDs) and immunomodulatory agents may have an
      important role in altering the course of AD. CY is a potent anti-inflammatory and
      immunomodulatory drug that acts primarily by inhibiting proliferation of immune cells.
      Moreover, as immune cell proliferation appears to be an important aspect of AD
      pathophysiology and disease progression, an exploratory, dose-finding trial of a
      cytotoxic/cytostatic drug such as CY is appropriate, especially since CY is already widely
      used for the treatment of other immune-mediated illnesses. Furthermore, a preliminary
      European trial of CY in AD patients has already demonstrated an improvement in cognitive
      function that correlated highly with the degree of immunomodulation achieved.

      Design. Study subjects will include 60 male and female patients with mild-moderate AD. In a
      randomized, placebo-controlled trial, two doses of CY or rofecoxib will be compared over a
      6-month period. While the primary outcome measures will be safety and immunologic data,
      cognitive and other behavioral measures will also be collected. The biological outcome
      measures will include measures of brain volume (assessed by magnetic resonance imaging) and
      cerebrospinal fluid biomarkers of neurodegeneration, neuroinflammation, and neuroimmune
      activation. In addition, peripheral lymphocyte subsets and peripheral markers of inflammation
      will be assessed. This design is meant to provide dose-finding data to help design a more
      definitive efficacy trial with CY if the safety/tolerability parameters are acceptable in
      this pilot study.
    

Intervention name(s): Cyclophosphamate
Intervention type(s): Drug
Primary purpose: Treatment
Keywords: Alzheimer's Disease; Immunomodulatory; Antiinflammatory; Cyclophosphamide; Non-steroidal; Complement; Immune Function; Immunotherapy