Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data

Wharton, S., Astrup, A., Endahl, L., Lean, M. E.J. , Satylganova, A., Skovgaard, D., Wadden, T. A. and Wilding, J. P.H. (2021) Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data. International Journal of Obesity, 45(5), pp. 923-933. (doi: 10.1038/s41366-020-00733-x) (PMID:33462358) (PMCID:PMC8081661)

Abstract

In the approval process for new weight management therapies, regulators typically require estimates of effect size. Usually, as with other drug evaluations, the placebo-adjusted treatment effect (i.e., the difference between weight losses with pharmacotherapy and placebo, when given as an adjunct to lifestyle intervention) is provided from data in randomized clinical trials (RCTs). At first glance, this may seem appropriate and straightforward. However, weight loss is not a simple direct drug effect, but is also mediated by other factors such as changes in diet and physical activity. Interpreting observed differences between treatment arms in weight management RCTs can be challenging; intercurrent events that occur after treatment initiation may affect the interpretation of results at the end of treatment. Utilizing estimands helps to address these uncertainties and improve transparency in clinical trial reporting by better matching the treatment-effect estimates to the scientific and/or clinical questions of interest. Estimands aim to provide an indication of trial outcomes that might be expected in the same patients under different conditions. This article reviews how intercurrent events during weight management trials can influence placebo-adjusted treatment effects, depending on how they are accounted for and how missing data are handled. The most appropriate method for statistical analysis is also discussed, including assessment of the last observation carried forward approach, and more recent methods, such as multiple imputation and mixed models for repeated measures. The use of each of these approaches, and that of estimands, is discussed in the context of the SCALE phase 3a and 3b RCTs evaluating the effect of liraglutide 3.0 mg for the treatment of obesity.

• Item Type: Articles
• Additional Information: The SCALE trial program and the medical writing/editorial support for this paper were funded by Novo Nordisk A/S.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lean, Professor Michael
• Authors: Wharton, S., Astrup, A., Endahl, L., Lean, M. E.J., Satylganova, A., Skovgaard, D., Wadden, T. A., and Wilding, J. P.H.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: International Journal of Obesity
• Publisher: Nature Research
• ISSN: 0307-0565
• ISSN (Online): 1476-5497
• Published Online: 18 January 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in International Journal of Obesity 45(5): 923-933
• Publisher Policy: Reproduced under a Creative Commons License