Phase ll Study of Pirfenidone in Patients With RAILD (TRAIL1)
Condition: Rheumatoid Arthritis Interstitial Lung Disease
MeSH terms: Arthritis; Arthritis, Rheumatoid; Lung Diseases; Lung Diseases, Interstitial
Intervention: Pirfenidone; Placebo
Intervention description: Pirfenidone three times daily (2403 mg) for 52 weeks; Placebo three times daily for 52 weeks
Intervention MeSH terms: Pirfenidone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 123.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: TRAIL1; TRAIL; Pirfenidone

Summary:

      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.
    

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.