ABSTRACT
RATIONALE: Scleroderma Lung Study (SLS) II established mycophenolate mofetil (MMF) as an active therapy for scleroderma-related interstitial lung disease (SSc-ILD) and the need to consider background MMF in future study designs. SLS III envisioned combination therapy in which the rapid onset and anti-fibrotic effects of pirfenidone (PFD) would complement the delayed immunosuppressive/anti-inflammatory actions of MMF. However, the study design failed to adequately predict the impact from widespread use of MMF by community physicians or FDA approval of nintedanib (9/19) to slow pulmonary function decline in SSc-ILD. SLS III recruitment challenges and adaptive clinical trial modifications are presented. METHODS: SLS III is an investigator-initiated, multi-center, double-blind placebo-controlled Phase II clinical trial of PFD in SSc-ILD. 150 treatment-naive patients were to be randomized to PFD or placebo, along with initiating MMF, to determine the relative efficacy/safety of combination therapy to MMF alone. The primary endpoint is change from baseline in FVC-% predicted during the 18-month treatment. Three adaptations were implemented: relaxation of screening/entry criteria;expansion of participating clinical sites and enrollment period;and a shift in the target population to include those already receiving MMF. RESULTS: At study initiation (01/18), recruiting eligible treatment-naive patients was already identified as a challenge. The maximum allowed FVC-% at screening (80%) and minimum allowed DLCO-% at baseline (25%) were relaxed 5% to reduce screen failures. The definition of “treatmentnaive” was broadened to include <3 months of prior MMF without need for a washout. With the release of SENSCIS results (05/20), we increased the number of clinical sites and the recruitment period. However, the rapid adoption of MMF therapy as a community standard forced us to consider patients already on longer treatment with MMF. The time-dependent impact of prior MMF duration on treatment effect was explored using clinical trial simulations to assess study power (Fig 1) and prior MMF exposure stratified into groups (naïve;<3, >3-6 and >6-9 months). The data identified an acceptable power (0.80) if <50% of enrolled participants had prior MMF use and prior MMF exposure was capped at 6 months (i.e., 3 groups). Unfortunately, the impact from COVID-19 ultimately curtailed site expansion and led to a truncated recruiting period (10/1/2020). 51 participants were randomized (76% naive;14% <3 months MMF;10% >3-6 months MMF). CONCLUSIONS: The SLS III experience highlights challenges in designing treatment protocols for SSc-ILD and the application of background study data and clinical trial simulations to execute adaptive study changes. (Table Presented).