Brain Imaging in Phase 3 Clinical Trials of Drugs for the Putative Treatment and Prevention of Alzheimer

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Brain Imaging in Phase 3 Clinical Trialsof Drugs
for the Putative Treatmentand Prevention of
Alzheimers Dementia

• Eric M. Reiman, MD
• University of Arizona
• Good Samaritan Medical Center
• Arizona Alzheimers Disease Core Center
• Arizona Alzheimers Research Center
• Current Financial Arrangements with Industry None

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Brain imaging techniques should provide
ancillarymeasures of efficacy in phase 3
clinical trials

• MRI and FDG PET are reasonably likely to
  predict a drugs clinical benefit.
• They are reasonably likely to determine the
  extent to which a drugs benefit is related to
  disease modification
• They offer greater statistical power than
  traditional outcome measures
• Their use in phase 3 trials is needed for the
  validation of these reasonably likely surrogate
  markers
• Their use is needed to provide a foundation for
  the efficient discovery of prevention therapies

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Volumetric MRI and FDG PET are currentlythe
imaging modalities of choice for phase 3 clinical
trials

• MRI measurements of hippocampal, entorhinal
  cortex, and whole brain volume
• PET measurements of posterior cingulate,
  parietal, temporal, and prefrontal glucose
  metabolism
• Reasonably likely to to predict a drugs clinical
  benefit and determine the extent to which it is
  related to disease modification
• Correlated with dementia severity, predict
  subsequent clinical decline, and predict the
  histopathological diagnosis of AD
• Longitudinal studies indicate that these declines
  are progressive and offer greater statistical
  power than traditional outcome measures
• Since these declines precede the onset of
  dementia, they offer extraordinary promise in AD
  prevention trials

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Two imaging modalities are better than one
Use BOTH volumetric MRI and FDG PET in phase 3
clinical trials

• Complementary measures, converging evidence in
  support of a drugs therapeutic effects
• Increases the certainty that the effects on both
  of the imaging outcome measures will predict
  clinical outcome and reflect disease modification
• (Increases the certainty of detecting a possible
  therapeutic effect, even in the unlikely event
  that a treatment masks this effect in one of the
  two imaging modalities)
• Provides the best foundation for the validation
  of these reasonably likely surrogate markers
• Provides the best foundation for establishing
  their relative roles in the efficient discovery
  of prevention therapies
• The additional costs are justified, both imaging
  techniques are widely available, and the
  logistical challenges can be readily addressed.

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Conclusions

• Volumetric MRI and FDG PET should provide
  ancillary measures of efficacy in phase 3
  clinical trials
• They are reasonably likely to predict a drugs
  clinical benefit and determine the extent to
  which it is related to disease modification
• They offer greater statistical power than
  traditional outcome measures
• Two imaging modalities are better than one use
  both MRI and PET in phase 3 clinical trials
• In addition to the discovery of drugs for the
  treatment of AD, their use in phase 3 clinical
  trials will have two extremely important
  long-term benefits
• The validation of these reasonably likely
  surrogate markers
• The development of a way to discover prevention
  therapies without losing a generation along the
  way.