Choice of estimand and analysis methods in diabetes trials with rescue medication

Abstract

The analysis of clinical trials aiming to show symptomatic benefits is often complicated by the ethical requirement for rescue medication when the disease state of patients worsens. In type 2 diabetes trials, patients receive glucose-lowering rescue medications continuously for the remaining trial duration, if one of several markers of glycemic control exceeds pre-specified thresholds. This may mask differences in glycemic values between treatment groups, because it will occur more frequently in less effective treatment groups. Traditionally, the last pre-rescue medication value was carried forward and analyzed as the end-of-trial value. The deficits of such simplistic single imputation approaches are increasingly recognized by regulatory authorities and trialists. We discuss alternative approaches and evaluate them through a simulation study. When the estimand of interest is the effect attributable to the treatments initially assigned at randomization, then our recommendation for estimation and hypothesis testing is to treat data after meeting rescue criteria as deterministically 'missing' at random, because initiation of rescue medication is determined by observed in-trial values. An appropriate imputation of values after meeting rescue criteria is then possible either directly through multiple imputation or implicitly with a repeated measures model. Crucially, one needs to jointly impute or model all markers of glycemic control that can lead to the initiation of rescue medication. An alternative for hypothesis testing only are rank tests with outcomes from patients 'requiring rescue medication' ranked worst, and non-rescued patients ranked according to final visit values. However, an appropriate ranking of not observed values may be controversial.

Missing data in clinical trials: control‐based mean imputation and sensitivity analysis

“…To clarify the concept of missing data, we quote from the 2010 National Research Council (NRC) report on The Prevention and Treatment of Missing Data in Clinical Trials : “by missing data we mean when an outcome value that is meaningful for analysis was not collected”. It is important to unambiguously link the expression “meaningful for analysis” with the clinical question of interest and the corresponding statistical estimand . For example, consider a clinical trial where diabetic patients are randomized to receive either an experimental drug (test treatment) or placebo (control treatment).…”

“…It is important to unambiguously link the expression "meaningful for analysis" with the clinical question of interest and the corresponding statistical estimand. [2][3][4][5][6][7][8][9] For example, consider a clinical trial where diabetic patients are randomized to receive either an experimental drug (test treatment) or placebo (control treatment). Suppose the primary efficacy endpoint is the glycated hemoglobin (HbA1c) change from baseline at 24 weeks after initiation of the assigned treatment.…”

Current approaches to handling rescue medication in asthma and eczema randomized controlled trials are inadequate: a systematic review

“…When participants experience an inadequate therapeutic effect or an exacerbation of symptoms, they may start nontrial treatment (which we throughout refer to as rescue medication) in addition to their randomized treatment in the trial [1]. Rescue medication presents a problem across the board; it is particularly present in chronic conditions, such as asthma and eczema, but also in areas such as mental health, cardiovascular health, and diabetes [2]. Access to rescue medication is often permitted for ethical reasons and to encourage recruitment and retention of participants.…”

Estimands in diabetes clinical trials

“…Intercurrent events may present in many forms, one of the most common in diabetes trials being the use of rescue medication [3]. For ethical reasons, patients can receive additional glucose lowering medication if they fail to achieve the glucose targets specified in the protocol.…”

“…The FDA's former position on the LOCF approach was illustrated in the 2011 public advisory committee meeting for dapagliflozin [3]. The trial sponsor excluded data accrued after the initiation of rescue medication, aiming to establish the true treatment effect of dapagliflozin.…”