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

The purpose of this study is to to assess the safety and tolerability of pirfenidone 2403 mg/day for the treatment of RA-associated interstitial lung disease.

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 % predicted DLCO or TLCO ≥30 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.

Eligibility Criteria:
Patients must fulfill all of the following criteria to be eligible for enrollment in the study:

1. Age 18 through 85 years, inclusive, at Screening
2. Probable or definite diagnosis of RA according to revised 2010 ACR/EULAR criteria, without evidence or suspicion of an alternative diagnosis that may contribute to their interstitial lung disease.
3. Diagnosis of ILD

   1. supported by clinically indicated HRCT, and when available, surgical lung biopsy (SLB), prior to Screening, and
   2. presence of fibrotic abnormality affecting more than 10% of the lung parenchyma, with or without traction bronchiectasis or honeycombing, on screening and confirmed by adjudicated HRCT prior to Baseline
4. No features supporting an alternative diagnosis on transbronchial biopsy, or SLB, if performed prior to Screening
5. Attainment of the following centralized spirometry criteria (based on local spirometry on standardized equipment and centralized quality controlled):

   1. percent predicted FVC ≥ 40% at Screening
   2. change in pre-bronchodilator FVC (measured in liters) between Visit 1 (Screening) and Visit 2 (Randomization) must be a \<10% relative difference, calculated as: 100% \* \[absolute value (Visit 1 FVC - Visit 2 FVC) / Visit 1 FVC\]
   3. percent predicted DLCO or TLCO ≥25 % at Screening
   4. Screening (Visit 1) pre-bronchodilator(BD) and Post-BD spirometry meets ATS quality criteria as determined by a central reviewer
   5. Baseline (Visit 2) Pre-BD spirometry meets ATS quality criteria as determined by the site Investigator or the central reviewer
6. Able to understand and sign a written informed consent form.
7. 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.

   1. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
   2. Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
   3. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
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, as defined below:

   1. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 118 days after the last dose of study drug.
   2. Men must refrain from donating sperm during this same period.

PARTICIPANT EXCLUSION CRITERIA

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 or vaping 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, or 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 \<0.65 at Screening
7. Presence of pleural effusion occupying more than 20% of the hemithorax on Screening HRCT
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 principal investigator
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 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, and/or low grade prostate cancer.

    Criteria for low grade prostate cancer:
    * Patients with suspicion for prostate cancer based on PSA and/or DRE should have been evaluated by urology
    * Patients with NCCN very low risk prostate cancer (∙ T1c and Grade Group 1 (Gleason 6) and PSA \<10 ng/mL and Fewer than 3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/coreg and ∙ PSA density \<0.15 ng/mL/g) can be monitored without intervention and enrolled in study.
    * Patients with NCCN low risk prostate cancer can be monitored on a case by case basis (T1-T2a and Grade Group 1 (Gleason 6) and ∙ PSA \<10 ng/mL) and enrolled in study.
    * All other patients should be excluded.
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
18. Any of the following test criteria above specified limits:

    1. Estimated glomerular filtration rate \<30 mL/min/1.73m2
    2. ECG with a QTc interval \>500 msec at Screening
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. Potent inducers of CYP1A2.
    4. 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.
22. Any use of an approved anti-fibrotic medication within 28 days of screening.