Objective: While systemic sclerosis-related interstitial lung disease (SSc-ILD) trials predominantly use forced vital capacity (FVC) as the primary outcome, combining individual outcomes may lead to a more comprehensive measure of treatment response and minimize the risk of type 1 error. The present analysis aimed to develop a composite outcome measure to assess treatment response in SSc-ILD patients.
Methods: We used data from the Scleroderma Lung Study I (SLS-I) to create the composite outcome measure. SLS I was a multi-institutional, double-blind clinical trial, in which 158 patients with SSc-ILD were randomized to receive either oral cyclophosphamide (CYC) (titrated to 2.0 mg/kg once daily) or matching placebo for one year. To select the variables for inclusion in the composite outcome, we first performed a univariate analysis using all of the outcome variables measured in SLS I. We subsequently combined the variables with significant treatment effects (p<0.05) in a principal component analysis (PCA) to assess the difference between treatment groups. These variables included the FVC% predicted, computer-based score for quantitative lung fibrosis in the zone of maximum fibrosis (QLF-ZM) from thoracic high-resolution computer tomography (HRCT) scans, transitional dyspnea index (TDI), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at 12 months.
Results: Of the 158 patients, 82 had complete outcome data and were included in this analysis. There were no significant differences in baseline characteristics between the 82 patients included in this analysis and the remaining 76 patients. The regression model with the first principal component for FVC% predicted, QLF-ZM, TDI and HAQ-DI as the composite outcome demonstrated a significant treatment effect favoring cyclophosphamide (Estimate 0.7 [SE 0.2]; p=0.005). Eliminating FVC% predicted from the composite outcome model did not change the overall treatment effect (Estimate 0.8 [SE 0.2]; p=0.004).
Conclusion: The CYC treatment effect observed from using the composite outcome of FVC% predicted, QLF-ZM, TDI and HAQ-DI was stronger than the effect observed using FVC% predicted alone. These findings suggest that combining patient-reported outcomes with structural and physiologic outcomes into a single outcome may serve as a more robust measure of treatment response compared with FVC alone in SSc-ILD trials.
Keywords: Clinical trial; Cyclophosphamide; Interstitial lung disease; Mycophenolate; Outcome measures; Quantitative imaging analysis; Systemic sclerosis.