An investigator is conducting a randomized, double-blind, placebo-controlled clinical trial of a new drug for the treatment of peripheral neuropathy in adults with multiple myeloma (MM). One hundred fifty patients with MM are enrolled in the trial and randomized to receive either the new drug (n = 75) or placebo (n = 75). Trial protocol requires that patients in both groups take 1 pill per day and keep a pain diary. After 3 months of treatment, each patient is interviewed, and the pain diaries are reviewed; 9 patients taking the new drug and 3 patients taking placebo did not take the pills as instructed. The investigator decides to conduct an intention-to-treat analysis of the study data. Which of the following best describes how the data pertaining to all patients who did not adhere to protocol should be treated?

Question

An investigator is conducting a randomized, double-blind, placebo-controlled clinical trial of a new drug for the treatment of peripheral neuropathy in adults with multiple myeloma (MM).  One hundred fifty patients with MM are enrolled in the trial and randomized to receive either the new drug (n = 75) or placebo (n = 75).  Trial protocol requires that patients in both groups take 1 pill per day and keep a pain diary.  After 3 months of treatment, each patient is interviewed, and the pain diaries are reviewed; 9 patients taking the new drug and 3 patients taking placebo did not take the pills as instructed.  The investigator decides to conduct an intention-to-treat analysis of the study data.  Which of the following best describes how the data pertaining to all patients who did not adhere to protocol should be treated?

Quizplus · Accepted Answer

An intention-to-treat (ITT) analysis compares treatment groups in a randomized trial by including all subjects as initially allocated after randomization regardless of what happens during the study period. The rationale is that if subjects have such a poor treatment response (or are so inconvenienced by treatment administration or side effects) as to not follow protocol specifications or drop out of the study, then their outcomes should be attributed to that intervention (ie, nonadherence is related to the practical benefits of treatment). ITT analysis also helps avoid the effects of attrition (eg, loss to follow-up, dropout) and crossover (eg, switching to another assigned intervention), which may disrupt the benefit of randomization and introduce bias in the estimation of the effect of the intervention. ITT analysis may lead to a more conservative estimate of the effect of the intervention. If attrition or crossover is significant, ITT analysis may be less likely to identify a statistically significant difference between treatments (ie, shift toward the null hypothesis). However, results will reflect the expected effect of the intervention in a practical clinical setting. (Choices A, C, and D) In accordance with ITT analysis, the investigator in this case should keep the 12 nonadherent patients in their respective groups for analysis. (Choice B) An analysis that includes only those patients who strictly adhered to a research protocol (ie, excluding all nonadherent patients from analysis) follows a per-protocol (PP) principle. In PP analysis, the benefit of randomization can be lost with significant subject attrition (eg, sicker subjects selectively dropping out, introducing bias). PP analysis can also overestimate the effect of the intervention in a practical clinical setting, particularly when the treatment is somehow aversive to patients. Educational objective: Intention-to-treat analysis includes each subject in their initial randomization group even if subjects stop the intervention or shift to a different intervention. This approach tends to provide a conservative but more valid estimate of the intervention effect in real-world scenarios (ie, clinical settings).

An Investigator Is Conducting a Randomized, Double-Blind, Placebo-Controlled Clinical Trial