A randomised, double-blind, placebo-controlled phase 3 study of lenabasum in diffuse cutaneous systemic sclerosis: RESOLVE-1 design and rationale

Abstract

Objective. The multi-systemic, heterogenous nature of diffuse cutaneous systemic sclerosis (dcSSc) presents challenges in designing clinical studies that can demonstrate a treatment effect on overall disease burden. We describe the design of the first Phase 3 study in dcSSc patients where the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score was chosen prospectively as the primary outcome. The CRISS measures key clinical disease parameters and patient-reported outcomes (PROs). Methods. RESOLVE-1 is a Phase 3, randomised, double-blind, placebocontrolled trial of dcSSc patients evaluating the efficacy and safety of lenabasum. Patients ≥18 years of age with dc-SSc and disease duration ≤6 years were eligible. Patients could continue stable background therapy for dcSSc, including stable immunosuppressive therapies. They were randomised to lenabasum 5 or 20 mg twice daily or placebo. The primary efficacy outcome was the mean change from baseline to 52 weeks in the ACR CRISS score.Results. The study enrolled 365 patients over 1.5 years at 77 sites in 13 countries in North America, Europe, Israel, and Asia-Pacific, with the last patient first visit on May 1, 2019. Conclusion. RESOLVE-1 is the firstPhase 3 interventional study to date in dcSSc to prospectively use the ACR CRISS as the primary efficacy outcome. Eligibility criteria allowed background therapy as might occur in clinical practice. This approach also facilitated timely patient enrolment. RESOLVE-1 provides a novel study design that may be used for future Phase 3 dcSSc studies to assess the holistic efficacy of therapy.

Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis

“…The study was designed to accurately represent current clinical practice in patients with dcSSc (26), allowing for enrollment of patients with dcSSc who were receiving stable doses of background IST, with few restrictions. The present study was specifically designed to assess whether lenabasum offered incremental benefit over standard therapy in dcSSc, which is currently inadequate.…”

“…Patients were required to have SSc disease duration ≤6 years from the time of the first non‐Raynaud's phenomenon symptom; if the disease duration was >3 years and ≤6 years, then MRSS had to be ≥15. Patients were excluded if they were medically unstable or had SSc with end‐stage organ involvement (26).…”

Cannabinoids for the treatment of autoimmune and inflammatory skin diseases: A systematic review

“…Recent studies have also demonstrated that cannabinoids are involved in skin homeostasis through different mechanisms, such as suppressing the proliferation of epidermal keratinocytes, modulating the production of pro‐inflammatory cytokines and regulating the generation of reactive oxygen species 16–18 . In line with these findings, cannabinoids are increasingly used for the treatment of various skin conditions, especially autoimmune and inflammatory ones that are often refractory to conventional therapy, including systemic sclerosis (SSc), dermatomyositis (DM), psoriasis (Pso) and atopic dermatitis (AD) 19–22 …”

“…[16][17][18] In line with these findings, cannabinoids are increasingly used for the treatment of various skin conditions, especially autoimmune and inflammatory ones that are often refractory to conventional therapy, including systemic sclerosis (SSc), dermatomyositis (DM), psoriasis (Pso) and atopic dermatitis (AD). [19][20][21][22] The aim of this review is to discuss the potential therapeutic effects of cannabinoids for autoimmune and inflammatory skin diseases. Initially, we provide an overview of the endocannabinoid system in the skin.…”