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

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)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04744207

Enrollment

Registered

2021-02-08

Start date

2020-12-29

Completion date

2022-06-15

Last updated

2024-08-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Systemic Sclerosis

Brief summary

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

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.

Interventions

DRUGGS-248

120 mg, capsule, once daily for 4 weeks

DRUGPlacebo

capsule, once daily for 4 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Mean Change From Baseline to Week 4 in the Number of Raynaud Attacks Per Week.	From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively	Patient reported number of Raynaud's attacks per day as registered in electronic diary.

Secondary

Measure	Time frame	Description
Mean Change From Baseline to Week 4 in the Raynaud's Condition Score.	From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively	Patients reported Raynaud's Condition Score (RCS) once a day in an electronic diary. RCS is a validated numeric rating scale (from 0 to 10) answering the question What difficulty did you have today with your Raynaud's condition? where a score of '0' = 'No difficulty', and a score of '10' = 'Extreme difficulty'.
Mean Change From Baseline to Week 4 in Pain Experienced During Raynaud Attacks.	From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively	The patient reported the experienced pain of each Raynaud attack using a Numeric Rating Scale (NRS) from 0 to 10 in an electronic diary where '0'='No pain' and '10'='Worst imaginable pain'.
Mean Change From Baseline to Week 4 in the Mean Duration of Raynaud's Attacks	From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively	The patient reported the start time (hh:mm) and stop time (hh:mm) of each Raynaud's attack in the electronic diary.
Mean Change From Baseline to Week 4 in the Cumulative Duration of Raynaud Attacks.	From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively	The patient reported the start time (hh:mm) and stop time (hh:mm) of each Raynaud's attack in the electronic diary.

Countries

Belgium, Netherlands, Poland, United Kingdom

Participant flow

Recruitment details

In addition to fulfilling all eligibility criteria, subjects must fulfil the following criteria to be randomised: •≥7 RP attacks during the last week of the run-in period as captured in the eDiary, with no more than 2 days without RP attacks. •Compliance with the eDiary during the 7 most recent days prior to baseline (Visit 2), excluding the visit day itself, defined as having submitted ≥5 days of eDiary records (out of a possible 7 days) for RCS and RP during that period.

Pre-assignment details

The run-in period was 14-21 days prior to Day 1, Baseline visit (the first dose of IMP). Of the 94 subjects enrolled into the study 69 subjects met the eligiblity criteria for randomization after the run-in period and were assigned to a treatment group.

Participants by arm

Arm	Count
GS-248 Participants received GS-248, (supplied as 40 mg capsules) Each single dose consisted of 3 capsules constituting a total of 120 mg, once daily for 4 weeks GS-248: 120 mg, capsule, once daily for 4 weeks	33
Placebo Participants received placebo, (supplied as 3 capsules), once daily for 4 weeks Placebo: capsule, once daily for 4 weeks	36
Total	69

Withdrawals & dropouts

Period	Reason	FG000	FG001
Treatment	Adverse Event	1	2
Treatment	Withdrawal by Subject	2	0

Baseline characteristics

Characteristic	GS-248	Total	Placebo
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	3 Participants	7 Participants	4 Participants
Age, Categorical Between 18 and 65 years	30 Participants	62 Participants	32 Participants
Age, Continuous	49.0 years STANDARD_DEVIATION 10.6	49.8 years STANDARD_DEVIATION 10.5	50.6 years STANDARD_DEVIATION 10.6
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	4 Participants	2 Participants
Race (NIH/OMB) White	30 Participants	64 Participants	34 Participants
Region of Enrollment Belgium	2 participants	3 participants	1 participants
Region of Enrollment Netherlands	2 participants	5 participants	3 participants
Region of Enrollment Poland	17 participants	37 participants	20 participants
Region of Enrollment United Kingdom	12 participants	24 participants	12 participants
Sex: Female, Male Female	27 Participants	60 Participants	33 Participants
Sex: Female, Male Male	6 Participants	9 Participants	3 Participants
Stratification factors FAS Ca-blockers	18 Participants	37 Participants	19 Participants
Stratification factors FAS No treatment	6 Participants	13 Participants	7 Participants
Stratification factors FAS PDE-5 inhibitors	9 Participants	19 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 33	1 / 36
other Total, other adverse events	10 / 33	9 / 36
serious Total, serious adverse events	0 / 33	1 / 36