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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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A Phase II, Randomized, Multi-center, Placebo-controlled, Double-blind Study to Investigate the Safety of GS-248, and Efficacy on Raynaud's Phenomenon (RP) and Peripheral Vascular Blood Flow, in Subjects With Systemic Sclerosis (SSc)

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: GS-248
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GS-248<br>GS-248, capsule, 120 mg, once daily for 4 weeks | Drug: GS-248<br>* 120 mg, capsule, once daily for 4 weeks<br>|
| Placebo Comparator: Placebo<br>placebo, capsule, once daily for 4 weeks | Drug: Placebo<br>* capsule, once daily for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline to week 4 in the number of Raynaud attacks per week. | Patient reported number of Raynaud's attacks per day as registered in electronic diary. | Daily from Day -7 to Day 28 | 
| Mean change from baseline to week 4 in the Raynaud's Condition Score. | Patient reported Raynaud's Condition Score each day as registered in electronic diary. | Daily from Day -7 to Day 28 | 
| Mean change from baseline to week 4 in the cumulative duration of Raynaud attacks. | Patient reported duration of Raynaud's attacks per day as registered in electronic diary. | Daily from Day -7 to Day 28 | 
| Mean change from baseline to week 4 in pain experienced during Raynaud attacks. | Patient reported pain of each Raynaud attack using Numeric Rating Scale as registered in electronic diary. | Daily from Day -7 to Day 28 | 
| Number of treatment emergent adverse events | Frequency, severity and seriousness of treatment emergent adverse events | Daily from Day 1 to Day 42-49 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in peripheral blood flow in fingers | Peripheral blood flow will be measured with thermography assessments before and after cold challenge. | Day 1 at pre-dose and 2 hours post dose and Day 28 at pre dose |