Longitudinal Analysis of Left-Censored Serum C-Terminal Telopeptide (sCTX) Levels in Treated Women with Postmenopausal Osteoporosis

• Activity Number: 428
• Type: Contributed
• Date/Time: Tuesday, August 6, 2013 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Matthew Austin*+ and Angela Tang and Nadia Daizadeh
• Companies: Amgen, Inc. and Amgen, Inc and Amgen, Inc
• Keywords: Left-censoring ; Weibull ; Mixed-effects ; Quantifiable limit ; Biomarker ; Longitudinal

Abstract

Postmenopausal osteoporosis is a disease caused by an imbalance between bone resorption and formation (resorption > formation). Antiresorptive treatments (ARTs) that markedly reduce biomarkers of bone resorption (e.g., sCTX) are likely to lead to censoring at the lower quantifiable limit (QL) of the assay.

Longitudinal sCTX levels were collected in a Phase 3 study of an ART, denosumab, for up to 7 years. Profiles of sCTX while on treatment showed a rapid reduction in sCTX (below QL) immediately after dosing, a period of sustained low sCTX and then an increase toward the end of the 6-month dosing interval.

In this analysis, a mixed-effect Weibull parametric survival model is proposed to characterize the mean sCTX profile during the dosing interval and its influencing factors. In the modeling, sCTX levels are held constant for the first two months after dosing and then assumed to follow a cubic polynomial through the end of the dosing interval. Covariates effects are introduced into the model by interactions with the linear component of time since last dose. A random slope explains individual level variability.