Pirfenidone as Treatment of Skin Fibrosis in Systemic Sclerosis

Study Overview
=================
Brief Summary
-----------------
This study is to evaluate the efficacy and safety of an antifibrotic agent, pirfenidone as treatment of systemic sclerosis. The primary outcome of this study is improvement of skin fibrosis.

Detailed Description
-----------------
All patients enrolled should suffer from moderate to severe skin fibrosis at the screening stage. The study period is 52 week. The study contains two stages, a 24-week blind stage following with open stage for another 24-week period of time. Subjects will receive pirfenidone or placebo randomized in the first 24-week and will all receive pirfenidone treatment in the second 24-week, with of combination of low dose steroids. The secondary outcomes of this study include but not limit to safety, improvement of lung fibrosis and digital ulcer burden.

Official Title
-----------------
A Randomized, Double-blinded, Placebo Controlled Study to Evaluate Clinical Efficacy and Safety of Pirfenidone for Skin Fibrosis in Systemic Sclerosis

Conditions
-----------------
Systemic Sclerosis

Intervention / Treatment
-----------------
* Drug: Pirfenidone
* Drug: Placebo oral capsule
* Drug: Steroids


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Fulfill EULAR/ACR classification criteria (2013) for systemic sclerosis (SSc). Subjects must have mRSS≥10 at screening stage Subjects must have signs of fibrosis in their chest CT at screening stage If a subject has received treatments before, it should be stable at least 3 months until screening and with no significant efficacy (ΔmRSS≤-2) Exclusion Criteria: Subjects with other connective tissue diseases overlapping with SSc Subjects with skin atrophy as the main cutaneous manifestation Subjects with active digital ulcers or gangrene Active severe SSc-driven renal disease or heart dysfunction at screening Subjects with significant hematologic abnormalities Abnormal liver function test at screening (ALT, AST or total bilirubin over 2 fold of upper normal level Clinically significant active infection including ongoing and chronic infections History of human immunodeficiency virus (HIV) Confirmed Positive tests for hepatitis B or positive test for hepatitis C Active tuberculosis Live or attenuated vaccine within 4 weeks prior to screening Subjects with significant hematologic abnormalities

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pirfenidone group<br>The subjects will receive pirfenidone from 200mg three times a day, oral administrated, with low dose steroids. | Drug: Pirfenidone<br>* A chemical synthesized agent showing anti-fibrotic effects in idiopathic pulmonary fibrosis.<br>Drug: Steroids<br>* Low dose of glucocorticoids, a basic treatment for patients with systemic sclerosis<br>|
| Placebo Comparator: Control group<br>The subjects will receive placebo within first 24-week, and pirfenidone 200mg three times a day for the second 24-week, with low dose steroids. | Drug: Pirfenidone<br>* A chemical synthesized agent showing anti-fibrotic effects in idiopathic pulmonary fibrosis.<br>Drug: Placebo oral capsule<br>* Placebo for pirfenidone capsule<br>Drug: Steroids<br>* Low dose of glucocorticoids, a basic treatment for patients with systemic sclerosis<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rodnan Skin Score (mRSS） | A semi-quantitative score for skin fibrosis of every subjects | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rodnan Skin Score | A semi-quantitative score for skin fibrosis of every subjects | Week 24 | 
| Assessment of chest CT | Semi-quantitative scale for fibrotic changes in chest CT images from an individual patient | Week 52 | 
| Assessment of chest CT | Semi-quantitative scale for fibrotic changes in chest CT images from an individual patient | Week 24 | 
| Forced vital capacity | A marker for lung function that may decrease with pulmonary fibrosis | Week 52 | 
| Forced vital capacity | A marker for lung function that may decrease with pulmonary fibrosis | Week 24 | 
| Diffusing capacity | Another marker for lung function that may decrease with pulmonary fibrosis | Week 52 | 
| Diffusing capacity | Another marker for lung function that may decrease with pulmonary fibrosis | Week 24 | 
| 6 minute walk test | A simple, well-accepted and quantitative clinical exam to test heart and lung function | Week 52 | 
| 6 minute walk test | A simple, well-accepted and quantitative clinical exam to test heart and lung function | Week 24 | 
| Hand function assessment | Hand function will be measured by Cochin Hand Function Scale | Week 52 | 
| Hand function assessment | Hand function will be measured by Cochin Hand Function Scale | Week 24 | 
| Proportion of subjects with increased mRSS | Proportion of subjects with ∆mRSS≥5 | Week 52 | 
| Proportion of subjects with increased mRSS | Proportion of subjects with ∆mRSS≥5 | Week 24 | 
| Quality of life | Assessed by the health assessment questionnaire disability index | Week 52 | 
| Quality of life | Assessed by the health assessment questionnaire disability index | Week 24 | 
| Safety and Tolerability | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Week 52 | 
| Safety and Tolerability | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Week 24 |