Phase ll Study of Pirfenidone in Patients With RAILD (TRAIL1)

This is a phase 2, randomized, double blind, placebo controlled trial of pirfenidone for the
treatment of RA associated interstitial lung disease. Approximately 270 subjects will be
randomized to receive Pirfenidone 2403 mg per day or placebo in a 1:1 ratio. The primary
outcome of this study is to assess the efficacy of pirfenidone 2403 mg/day versus placebo in
patients with RA associated interstitial lung disease, as defined by progression free
survival over the 52 weeks of treatment. Patients will receive blinded study treatment from
the time of randomization until the Week 52 Visit.

Eligible patients aged 18 to 85 years must meet 2010 ACR/EULAR criteria for RA (Aletaha,
Neogi et al. 2010) as well as RA-associated ILD, as determined by imaging and, when
available, lung biopsy. Patients will be required to have a % predicted FVC ≥40 and ≤100 and
% predicted DLCO ≥30 and ≤100 at screening.

The dose of study treatment will be titrated over 14 days. Patients will receive a telephone
assessment at Weeks 1 and 2, and visit the clinic at Weeks 4, 8, 13, 19, 26, 39, and 52.
Subjects will have a follow up phone call 28 days after completion of the study drug.
Patients should complete a compliance diary between visits. If patients discontinue study
treatment for any reason before the end of the study, they should continue with all scheduled
study procedures through Week 52. If subjects are unable to complete the study visits as
scheduled, all efforts should be made to complete an early termination visit.

The primary outcome variable of this study will be progression free survival, defined as
progression free from decline in FVC of 10% or greater during the 52 week study period.

More information can be found at www.ralung.org.

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 RA-ILD

1. supported by HRCT and when available surgical lung biopsy (SLB).

2. Diagnosis of ILD, defined as the first instance in which a patient was informed
of having ILD, or having clinical symptoms consistent with ILD (i.e., cough,
dyspnea), at least 6 months before randomization

3. 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% and ≤ 100% 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. %DLCO ≥30% and ≤ 100% at Screening, confirmed by central review

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

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, polymyositis/dermatomyositis, systemic
lupus erythematosus)

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

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 or disease, myocardial infarction within
the previous year, heart failure within the last 3 years, or cardiac arrhythmia
requiring drug therapy

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.

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.