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Adults with dc<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c of \u22646 years\u2019 duration who were receiving stable standard\u2010of\u2010care treatment were randomized to receive lenabasum (n = 27) or placebo (n = 15). Lenabasum doses were 5 mg once daily, 20 mg once daily, or 20 mg twice daily for 4 weeks, followed by 20 mg twice daily for 8 weeks. Safety and efficacy were assessed at weeks 4, 8, 12, and 16.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Adverse events (<jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>s) occurred in 63% of the lenabasum group and 60% of the placebo group, with no serious <jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>s related to lenabasum. Compared to placebo, lenabasum treatment was associated with greater improvement in the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis (<jats:styled-content style=\"fixed-case\">CRISS<\/jats:styled-content>) score and other efficacy outcome measures that assessed overall disease, skin involvement, and patient\u2010reported function. The median <jats:styled-content style=\"fixed-case\">CRISS<\/jats:styled-content> score increased in the lenabasum group during the study, reaching 0.33, versus 0.00 in the placebo group, at week 16 (<jats:italic>P<\/jats:italic> = 0.07 by 2\u2010sided mixed\u2010effects model repeated\u2010measures analysis). Gene expression in inflammation and fibrosis pathways was reduced, and inflammation and fibrosis were improved on histologic evaluation of skin biopsy specimens, in the lenabasum group compared to the placebo group (all <jats:italic>P<\/jats:italic> \u2264 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Despite a short trial duration in a small number of patients in this phase <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> study in dc<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c, our findings indicate that lenabasum improves efficacy outcomes and underlying disease pathology with a favorable safety 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