Project description:Lockwood2006 - AlzheimersDisease PBPK model A mathematical model to predict the effectiveness of CI-1017 (muscarinic agonist) for Alzheimer's disease by evaluating changes in ADAS-cog score. This model is described in the article: Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer's disease. Lockwood P, Ewy W, Hermann D, Holford N. Pharm. Res. 2006 Sep; 23(9): 2050-2059 Abstract: OBJECTIVE: Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200-400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials. MATERIALS AND METHODS: A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A 'positive trial' reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025). RESULTS: A 4 x 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability. CONCLUSION: CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial. This model is hosted on BioModels Database and identified by: BIOMD0000000673. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:The objective of this study is to: 1) Characterize the immune responsiveness to administration of non-live vaccines in three cohorts of healthy adult subjects through the analysis of blood leukocytes transcriptional profiles. 2) Validate whole blood transcriptional profiles generated from standard 3mL blood draws versus 200uL blood draws obtained by finger stick. 3) Discover potential biomarkers for immune-responsiveness to non-live vaccines. A total of 621 blood samples were collected either by venipuncture (387) or finger prick (234) from four groups of healthy adults receiving either, 2009/10 seasonal influenza or 23-valent pneumococcal vaccine or placebo (saline) injections. Subjects were recruited in 3 cohorts with 4-7 individuals per group; cohort 3 was recruited for validation of the systemic day 1 immune signature in response to seasonal influenza and pneumococcal vaccination. From each subject, peripheral blood was drawn into Tempus tubes (Applied Biosystems) or obtained by finger prick into micro capillaries and then transferred into tempus reagent to lyse blood cells and stabilize RNA before storing at -80ºC until mRNA extraction. The training set for transcriptional profiling of blood obtained by venipuncture was performed in cohort 1 which included 6 healthy adult individuals receiving seasonal influenza vaccine, 6 healthy adult individuals receiving pneumococcal vaccine, and 6 healthy adult individuals receiving placebo (saline injections). The test set for transcriptional profiling of blood obtained by venipuncture was performed in cohort 2 which included 6 healthy adult individuals receiving seasonal influenza vaccine, 6 healthy adult individuals receiving pneumococcal vaccine, and 6 healthy adult individuals receiving placebo (saline injections). The validation set for confirming systemic day 1 transcriptome immune signature in response to seasonal influenza and pneumococcal vaccination was performed in cohort 3 which included 6 healthy adult individuals receiving seasonal influenza vaccine and 4 healthy adult individuals receiving pneumococcal vaccine. The training set for transcriptional profiling of blood obtained by finger prick was performed in cohort 2 and the test set in cohort 1.

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The gene expression profile of peripheral blood mononuclear cells (PBMCs) of infants (6 to 11 months) immunized with an inactivated EV71 vaccine or placebo

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