Inclusion Criteria:
Diagnosis of Interstitial Lung Disease:
1. Age 18 through 85 years, inclusive, at screening. 2. Diagnosis of RA according to revised 2010 ACR/EULAR criteria. 3. Diagnosis of ILD. 1. Supported by clinically indicated HRCT, and when available surgical lung biopsy
(SLB).
2. Presence of reticular abnormality affecting more than 10% of the lung parenchyma,
with or without traction bronchiectasis or honeycombing, on HRCT. 4. No features supporting an alternative diagnosis on transbronchial biopsy,
bronchoalveolar lavage (BAL), or SLB, if performed. 5. Attainment of the following centralized spirometry criteria (based on local spirometry
on standardized equipment and centralized quality controlled):
1. % predicted FVC ≥ 40% at Screening. 2. Change in pre- and post-bronchodilator FVC (measured in liters) between Screening
(Visit 1) and Visit 2 must be a <10% relative difference, calculated as shown
below:
Screen FVC (L)
- - Day 1 FVC (L) × 100% Screen FVC (L)
3.
%predicted DLCO ≥ 30% at Screening. Informed Consent and Protocol Adherence:
6. Able to understand and sign a written informed consent form. 7. Pregnancy or lactation. For women of childbearing potential: agreement to remain
abstinent (refrain from heterosexual intercourse) or use two adequate methods of
contraception, including at least one method with a failure rate of <1% per year,
during the 52 week treatment period and for at least 118 days after the last dose of
study drug.
8. For men who are not surgically sterile: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from
donating sperm.
Exclusion Criteria:
Disease-Related Exclusions:
1. Not a suitable candidate for enrollment or unlikely to comply with the requirements of
this study, in the opinion of the investigator. 2. Cigarette smoking within 3 months of Screening or unwilling to avoid tobacco products
throughout the study. 3. History of clinically significant environmental exposure known to cause pulmonary
fibrosis (PF), including but not limited to drugs (such as amiodarone), asbestos,
beryllium, radiation, and domestic birds. 4. Concurrent presence of the following conditions:
1. other interstitial lung disease, related to but not limited to radiation, drug
toxicity, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans
organizing pneumonia,
2. Medical history including Human Immunodeficiency Virus (HIV),
3. Medical history of viral hepatitis (positive Hep A antibody in the absence of
elevated liver enzymes is not an exclusion)
5. Concurrent presence of other pleuropulmonary manifestations of RA, including but not
limited to rheumatoid nodular disease of the lung, pleuritis/pleural thickening, and
obliterative bronchiolitis. 6. Post-bronchodilator FEV1/FVC < 0.7. 7. Presence of pleural effusion occupying more than 20% of the hemithorax. 8. Clinical diagnosis of a second connective tissue disease or overlap syndrome
(including but not limited to scleroderma, sjogren's,polymyositis/dermatomyositis,
systemic lupus erythematosus, but excluding Raynaud's phenomena)
9. Coexistent clinically significant COPD/emphysema or asthma in the opinion of the site
principle investigator. Medical Exclusions:
10. Clinical evidence of active infection, including but not limited to bronchitis,
pneumonia, sinusitis, urinary tract infection, or cellulitis. The infection should be
resolved per PI assessment prior to enrollment. Any use of antibiotics must be
completed 4 2weeks prior to the screening visit. Note that prophylactic antibiotics
are not contraindicated or exclusionary.
11. Any history of malignancy diagnosed within 5 years of screening, other than basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, or low grade cervical
carcinoma in situ.
12. History of LFT abnormalities as outlined below, or imaging, laboratory or other
clinical information suggesting liver dysfunction, advanced liver disease or
cirrhosis. Evidence of hepatic impairment that in the opinion of the investigator
could interfere with drug metabolism or increase the risk of the known hepatotoxicity
of study drug.
Any of the following liver function abnormalities:
1. Total bilirubin above the upper limit of normal (ULN), excluding patients with
Gilbert's syndrome;
2. Aspartate or alanine aminotransferase (AST/SGOT or AST/SGPT) > 3 X ULN;
3. Alkaline phosphatase > 2.5 X ULN.
13. History of end-stage renal disease requiring dialysis. 14. History of unstable or deteriorating cardiac disease, or unstable cardiac arrhythmia
or arrhythmia requiring modification of drug therapy, myocardial infarction within the
previous year, heart failure requiring hospitalization.
15. Any condition that, in the opinion of the investigator, might be significantly
exacerbated by the known side effects associated with the administration of
pirfenidone. 16. History of alcohol or substance abuse in the past 2 years, at the time of screening. 17. Family or personal history of long QT syndrome.
Laboratory Exclusions:
18. Any of the following test criteria above specified limits:
1. Estimated glomerular filtration rate < 57. 2. Electrocardiogram (ECG) with a QTc interval >500 msec at Screening. Medication Exclusions:
19. Prior use of pirfenidone or known hypersensitivity to any of the components of study
treatment. 20. Use of any of the following therapies within 28 days before Screening and during
participation in the study:
1. Investigational therapy, defined as any drug that has not been approved for
marketing for any indication in the country of the participating site. 2. Potent inhibitors of CYP1A2 (e.g. fluvoxamine, enoxacin)
3. Sildenafil (daily use). Note: intermittent use for erectile dysfunction is
allowed. 21. Introduction and/or modification of dose of corticosteroids or any cytotoxic,
immunosuppressive, or cytokine modulating or receptor antagonist agent for the
management of pulmonary manifestations of RA, within 3 months of screening, is an
exclusion criterion, for enrollment, with the exception of dose modification of
systemic corticosteroids that are maintained at or below 20 mg prednisone daily or the
equivalent.
22. Any use of an approved anti-fibrotic medication.
However, introduction and/or modification of dose of corticosteroids or any cytotoxic,
immunosuppressive, or cytokine modulating or receptor antagonist agent for the management
of extrapulmonary manifestations of RA is not an exclusion criterion for enrollment.
