IntroductionNovel compounds with potential to attenuate or stop the progression of Alzheimer’s disease (AD) from its pre-symptomatic 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 pre-symptomatic 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 Placebo Group Simulation Approach (PGSA), using mathematical models to forecast outcomes of pre-symptomatic 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 MCI data from the ADNI database. One outcome is the ADAScog score after 24 months predicted in a linear regression model, the other the trajectory over 36 months of a composite neuropsychological test score (NP-Batt), using a mixed model. Demographics, 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, FAQ and baseline scores of MMSE, ADAScog and NP-Batt with an R-square of 0.63 and a residual SD 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 BMI, time, APO E4, age, FAQ, baseline scores of ADAScog and NP-Batt and four interaction terms. Estimates of the residual SD 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 pre-symptomatic AD individuals.