A Study to Investigate Safety of GS-248 and Efficacy on Raynauds' Phenomenon in Systemic Sclerosis

The primary objective of this study is to determine the safety, and evaluate the efficacy of GS-248 versus placebo on Raynaud's Phenomenon (RP) in subjects with Systemic Sclerosis (SSc).

The primary objective of this study is to determine the safety, and evaluate the efficacy of GS-248 versus placebo on Raynaud's Phenomenon (RP) in subjects with Systemic Sclerosis (SSc).

This is a randomized, double-blind, placebo-controlled study conducted in multiple sites in 4 countries in Europe. Approximately 80 subjects will be randomized in a 1:1 allocation to receive either GS-248 (120 mg) or placebo once daily. The study will comprise an enrolment period, a treatment period, and a follow-up period, with a total of 5 study visits over approximately 10 weeks.

Eligibility Criteria:
Inclusion Criteria:

* Subjects must provide signed and dated written informed consent before the conduct of any study-specific procedures.
* Male and female subjects aged 18-75 years inclusive.
* Systemic Sclerosis diagnosed according to European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria (van den Hoogen F et al. 2013). Subjects with signs of other autoimmune diseases (e.g. Sjögren's syndrome, myositis, rheumatoid arthritis) could be included if SSc is the dominating phenotype.
* Raynaud attacks typically ≥7 times per week during the last 4 weeks prior to screening despite background medication (only allowed vasodilatory therapy is calcium channel blockers or PDE-5 inhibitors).
* Women of childbearing potential must be using a highly effective method of contraception to avoid pregnancy throughout the study and for 4 weeks after the last dose of Investigational Medicinal Product in such manner that the risk of pregnancy is minimised.
* Women must not be pregnant or breastfeeding.
* Male subjects to agree to use condom in combination with use of contraceptive methods with a failure rate of \<1% to prevent pregnancy and drug exposure of a partner, and refrain from donating sperm from the first date of dosing until 3 months after last dosing of the IMP.
* Ability of subjects to participate fully in all aspects of this clinical trial.

Exclusion Criteria:

* Systemic Sclerosis disease duration of greater than 120 months from first non-Raynaud manifestation
* Current smokers or stopped smoking \<3 months prior to Visit 1.
* Dose-change or initiation of vasodilating substances (calcium blockers or PDE-5 inhibitors) within 4 weeks prior to Visit 1.
* Use of iloprost or other intravenous (iv) or po prostacyclin receptor agonist within 4 weeks prior to Visit 1.
* Ongoing treatment with immunosuppressive therapies (other than mycophenolate) including, but not restricted to; cyclophosphamide, azathioprine, methotrexate, or cyclosporine, or use of those medications within 4 weeks of trial entry.
* Use of systemic corticosteroids during 4 weeks before screening and during the course of the study.
* Concurrent serious medical condition, with special attention to cardiovascular conditions, which in the opinion of the Investigator makes the subject not suitable for this study.
* Prolonged QTcF interval defined as a mean QTcF \>450 msec.
* Creatinine clearance \<50 mL/min (determined by Cockcroft-Gault equation) at Screening.
* Active digital ulcer (DU) within 4 weeks prior to Visit 1.
* Clinically meaningful laboratory abnormalities at Screening (Visit 1), as determined and documented by the Investigator.