Predicting the Time to Clinically Worsening in Mild Cognitive Impairment Patients and its Utility in Clinical Trial Design by Modeling a Longitudinal Clinical Dementia Rating Sum of Boxes from the ADNI Database
Affiliations: [a] Pfizer Inc, Primary Care Business Unit, Groton, CT, USA | [b] Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA
Correspondence:
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Correspondence to: Kaori Ito, Pfizer Inc, Primary Care Business Unit, 445 Eastern Point Road, Groton, Connecticut 06340, USA. Tel.: +1 860 441 5743; E-mail: kaori.ito@pfizer.com.
Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
Abstract: Background:Growing interest in treating Alzheimer’s disease (AD) patients in the earliest stages requires new clinical endpoints. Currently, there is no established clinical endpoint or treatment duration for mild cognitive impairment (MCI) trials. Objective:This analysis attempts to answer “how long the MCI clinical trial would be necessary” using the Clinical Dementia Rating Sum of Boxes (CDR-SB) as a clinical endpoint, where CDR-SB is an example of a suitable tool to assess both cognition and function as a single primary efficacy outcome. Methods:A longitudinal model was developed to predict the CDR-SB time-profile. The CDR-SB is considered ideal to assess both cognition and function as a single primary endpoint in MCI trials. The median time for clinically “worsening”, defined using several thresholds for change from baseline, was calculated using individual CDR-SB predictions. Covariates predictive of worsening were also evaluated. Results:The median time to a 1-point change in CDR-SB was approximately 2 years in MCI patients. Higher baseline severity in disease, lower hippocampal volume, and ApoE4 carrier status were significant covariates predicting shorter times to worsening (faster progress). The results indicate that at least a 2-year trial would be necessary with 30% (or more) disease modifying drug with a sample size of n = 350 to detect the significant difference from placebo (80% power) and to achieve the target mean effect size of 0.5 point change in CDR-SB. Conclusion:Predictions of CDR-SB changes from a longitudinal model are able to inform study design and possible enrichment strategies, based on covariate analyses, for prospective planning of clinical trials in MCI patients.
Keywords: ADNI, biomarkers, bounded outcome, Clinical Dementia Rating Sum of Boxes (CDR-SB), clinical trial, enrichment strategy, longitudinal data, median time to worsening, mild cognitive impairment
