A ‘Call to Action’ in Determining and Estimating a Minimum Important Difference (MID) in 6-Minute Walking Distance (6MWD) in Ph-Ild

OBJECTIVES: This study aimed to estimate a MID threshold for the 6MWD of people with pulmonary hypertension associated with interstitial lung disease to inform the interpretation of patient outcomes in the INCREASE clinical trial (NCT0263036), using different analytical methods and structured expert elicitation (SEE).

METHODS: An anchor-based approach was infeasible due to the lack of a suitable anchor outcome collected in the trial. Thus, two distributional approaches were used to estimate the MID: effect size (ES) and standardised response mean (SRM). Both approaches computed the MID based on the sample variability. Using the ES approach, the MID was defined as the baseline SD multiplied by 0.2. Using the SRM approach, the SD of change was multiplied by 0.5. The outcomes reported in the intervention arm informed the calculations. A secondary analysis including patients whose 6MWD improved over 16 weeks (in both arms) was also conducted. The SEE-based estimate was generated using methods outlined in the Medical Research Council protocol.

RESULTS: The SEE-based estimate (mean=31.0m) was higher than the trial-based estimates: ES (19.8m) and SRM (25.8m). The SRM estimate corresponded with a 10% improvement in 6MWD from baseline. An ad hoc scenario analysis was conducted, excluding one expert response from the SEE analysis due to task comprehension concerns. The expected value for the pooled distribution in the scenario analysis was 28.6m. The secondary analyses estimating the MID based on patients displaying an improvement in 6MWD revealed lower values, ranging between 18.7m and 24.7m.

CONCLUSIONS: Multiple plausible PH-ILD-specific MID estimates were generated, ranging between 18.7m and 31.0m. These values fell below those demonstrated in PAH populations and were consistent with those for chronic respiratory diseases. The findings provide a foundation for interpreting clinical trials for PH-ILD-specific therapies. This study is a ‘call-to-action’ for further work, employing alternative anchor-based and distributional methods to supplement the current estimates.