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Spiegel R, Berres M, Miserez AR, et al. For debate: substituting placebo controls in long-term Alzheimer's prevention trials. Alzheimers Res Ther. 2011;3(2):9doi: 10.1186/alzrt68.
Spiegel, R., Berres, M., Miserez, A. R., Monsch, A. U. (2011). For debate: substituting placebo controls in long-term Alzheimer's prevention trials. Alzheimer's research & therapy, 3(2), 9. https://doi.org/10.1186/alzrt68
Spiegel, René, et al. "For debate: substituting placebo controls in long-term Alzheimer's prevention trials." Alzheimer's research & therapy vol. 3,2 (2011): 9. doi: https://doi.org/10.1186/alzrt68
Spiegel R, Berres M, Miserez AR, Monsch AU. For debate: substituting placebo controls in long-term Alzheimer's prevention trials. Alzheimers Res Ther. 2011 Mar 21;3(2):9. doi: 10.1186/alzrt68. PMID: 21418632; PMCID: PMC3226271.
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Alzheimers Res Ther. 2011 Mar 21;3(2):9. doi: 10.1186/alzrt68.

For debate: substituting placebo controls in long-term Alzheimer's prevention trials.

Alzheimer's research & therapy

René Spiegel, Manfred Berres, André R Miserez, Andreas U Monsch,

Affiliations

  1. University Hospital Department of Geriatrics, Memory Clinic, Schanzenstrasse 55, CH 4031 Basel, Switzerland. [email protected].

PMID: 21418632 PMCID: PMC3226271 DOI: 10.1186/alzrt68

Abstract

INTRODUCTION: Novel compounds with potential to attenuate or stop the progression of Alzheimer's disease (AD) from its presymptomatic stage to dementia are being tested in man. The study design commonly used is the long-term randomized, placebo-controlled trial (RPCT), meaning that many patients will receive placebo for 18 months or longer. It is ethically problematic to expose presymptomatic AD patients, who by definition are at risk of developing dementia, to prolonged placebo treatment. As an alternative to long-term RPCTs we propose a novel clinical study design, termed the placebo group simulation approach (PGSA), using mathematical models to forecast outcomes of presymptomatic AD patients from their own baseline data. Forecasted outcomes are compared with outcomes observed on candidate drugs, thus replacing a concomitant placebo group.

METHODS: First models were constructed using mild cognitive impairment (MCI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. One outcome is the Alzheimer Disease Assessment Scale - cognitive subscale (ADAScog) score after 24 months, predicted in a linear regression model; the other is the trajectory over 36 months of a composite neuropsychological test score (Neuro-Psychological Battery (NP-Batt)), using a mixed model. Demographics and clinical, biological and neuropsychological baseline values were tested as potential predictors in both models.

RESULTS: ADAScog scores after 24 months are predicted from gender, obesity, Functional Assessment Questionnaire (FAQ) and baseline scores of Mini-Mental State Examination, ADAScog and NP-Batt with an R2 of 0.63 and a residual standard deviation of 0.67, allowing reasonably precise estimates of sample means. The model of the NP-Batt trajectory has random intercepts and slopes and fixed effects for body mass index, time, apolipoprotein E4, age, FAQ, baseline scores of ADAScog and NP-Batt, and four interaction terms. Estimates of the residual standard deviation range from 0.3 to 0.5 on a standard normal scale. If novel drug candidates are expected to diminish the negative slope of scores with time, a change of 0.04 per year could be detected in samples of 400 with a power of about 80%.

CONCLUSIONS: First PGSA models derived from ADNI MCI data allow prediction of cognitive endpoints and trajectories that correspond well with real observed values. Corroboration of these models with data from other observational studies is ongoing. It is suggested that the PGSA may complement RPCT designs in forthcoming long-term drug studies with presymptomatic AD individuals.

References

  1. J Am Geriatr Soc. 2008 Jan;56(1):111-6 - PubMed
  2. Arch Neurol. 2008 Nov;65(11):1467-71 - PubMed
  3. Arch Neurol. 2005 Oct;62(10):1556-60 - PubMed
  4. Alzheimers Res Ther. 2010 Feb 23;2(1):2 - PubMed
  5. Arch Gen Psychiatry. 2006 Aug;63(8):916-24 - PubMed
  6. Lancet Neurol. 2008 May;7(5):436-50 - PubMed
  7. JAMA. 2009 Jul 22;302(4):385-93 - PubMed
  8. J Am Geriatr Soc. 2008 Jan;56(1):37-44 - PubMed
  9. Am J Psychiatry. 1984 Nov;141(11):1356-64 - PubMed
  10. Arch Clin Neuropsychol. 2007 Jan;22(1):99-107 - PubMed
  11. Alzheimer Dis Assoc Disord. 2010 Apr-Jun;24(2):126-30 - PubMed
  12. Lancet Neurol. 2010 Jan;9(1):119-28 - PubMed
  13. Arch Neurol. 2001 Mar;58(3):449-54 - PubMed
  14. Alzheimers Res Ther. 2009 Jul 09;1(1):2 - PubMed
  15. Neurology. 2009 Nov 3;73(18):1436-42 - PubMed
  16. Lancet Neurol. 2006 Mar;5(3):228-34 - PubMed
  17. J Psychiatr Res. 1975 Nov;12(3):189-98 - PubMed
  18. Lancet Neurol. 2006 Jan;5(1):87-96 - PubMed
  19. Lancet Neurol. 2008 Sep;7(9):805-11 - PubMed
  20. Lancet Neurol. 2010 Jul;9(7):702-16 - PubMed
  21. J Gerontol. 1982 May;37(3):323-9 - PubMed
  22. Alzheimers Dement. 2010 Jul;6(4):359-62 - PubMed
  23. Int J Alzheimers Dis. 2009 Dec 22;2009: - PubMed
  24. Lancet Neurol. 2007 Jan;6(1):56-62 - PubMed
  25. Neurology. 2010 Jan 19;74(3):201-9 - PubMed
  26. Br J Psychiatry. 1982 Jun;140:566-72 - PubMed
  27. Biomark Med. 2010 Feb;4(1):3-14 - PubMed
  28. Neurology. 2007 Oct 16;69(16):1622-34 - PubMed
  29. Alzheimer Dis Assoc Disord. 2006 Jul-Sep;20(3 Suppl 2):S69-74 - PubMed
  30. Alzheimers Dement. 2010 Mar;6(2):158-94 - PubMed
  31. Arch Neurol. 2009 Mar;66(3):336-42 - PubMed
  32. Alzheimers Dement. 2009 Sep;5(5):388-97 - PubMed
  33. Arch Neurol. 2010 Jun;67(6):750-2 - PubMed
  34. Arch Gen Psychiatry. 2007 Dec;64(12):1443-50 - PubMed
  35. Arch Neurol. 2010 Jun;67(6):688-96 - PubMed
  36. Neurology. 2008 Sep 30;71(14):1057-64 - PubMed

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