Protocol adherence for continuously titrated interventions in randomized trials: an overview of the current...

Area of Science:

• Critical care medicine
• Clinical trial methodology

Background:

• Standard protocol adherence definitions are inadequate for interventions requiring continuous titration.
• Evaluating adherence in such trials presents unique challenges.

Purpose of the Study:

• To assess the impact of different protocol deviation definitions on adherence interpretation in a continuously titrated intervention trial.
• To propose improved methods for measuring protocol adherence in complex clinical trials.

Main Methods:

• Analysis of the OVATION pilot trial, an open-label randomized controlled trial comparing higher vs. lower mean arterial pressure (MAP) targets.
• Defining protocol deviations as MAP values outside targets for >4 hours without vasopressor dose adjustments.
• Utilizing an adjudication committee to determine if deviations were clinically justified.

Main Results:

• The definition of protocol deviations significantly influences the interpretation of protocol adherence.
• Adherence metrics vary based on deviation definitions and measurement frequency.
• Distinguishing clinically justified deviations acknowledges practical bedside decision-making.

Conclusions:

• Metrics for defining protocol deviations critically impact adherence interpretation in trials with continuous titration.
• Prespecified definitions for protocol deviations are essential and should correlate with between-arm separation where measurable.