title: Methods for Predicting Diabetes Phase III Efficacy Outcome From Early Data: Superior Performance Obtained Using Longitudinal Approaches.
abstract: The link between glucose and HbA1c at steady state has previously been described using steady-state or longitudinal relationships. We evaluated five published methods for prediction of HbA1c after 26/28 weeks using data from four clinical trials. Methods (1) and (2): steady-state regression of HbA1c on fasting plasma glucose and mean plasma glucose, respectively, (3) an indirect response model of fasting plasma glucose effects on HbA1c, (4) model of glycosylation of red blood cells, and (5) coupled indirect response model for mean plasma glucose and HbA1c. Absolute mean prediction errors were 0.61, 0.38, 0.55, 0.37, and 0.15% points, respectively, for Methods 1 through 5. This indicates that predictions improved by using mean plasma glucose instead of fasting plasma glucose, by inclusion of longitudinal glucose data and further by inclusion of longitudinal HbA1c data until 12 weeks. For prediction of trial outcome, the longitudinal models based on mean plasma glucose (Methods 4 and 5) had substantially better performance compared with the other methods.
authors.affiliation: Quantitative Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark.
authors.forename: J B
authors.initials: JB
authors.lastname: Møller
authors.affiliation: Quantitative Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark.
authors.forename: N R
authors.initials: NR
authors.lastname: Kristensen
authors.affiliation: Quantitative Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Klim
authors.affiliation: The Pharmacometrics Group, Uppsala University, Uppsala, Sweden.
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
authors.affiliation: Quantitative Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark.
authors.forename: S H
authors.initials: SH
authors.lastname: Ingwersen
authors.affiliation: The Pharmacometrics Group, Uppsala University, Uppsala, Sweden.
authors.forename: M C
authors.initials: MC
authors.lastname: Kjellsson