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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02808871
Recruitment Status : Recruiting
First Posted : June 22, 2016
Last Update Posted : September 23, 2019
Information provided by (Responsible Party):
Ivan O. Rosas, Brigham and Women's Hospital

Brief 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.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Interstitial Lung Disease Drug: Pirfenidone Drug: Placebo Phase 2

Detailed Description:

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 ≥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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 270 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Safety, Tolerability and Efficacy of Pirfenidone in Patients With Rheumatoid Arthritis Interstitial Lung Disease (TRAIL1)
Actual Study Start Date : April 7, 2017
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021

Arm Intervention/treatment
Experimental: Pirfenidone
Pirfenidone 2403 mg/d for 52 weeks
Drug: Pirfenidone
Pirfenidone three times daily (2403 mg) for 52 weeks
Other Name: Esbriet

Placebo Comparator: Placebo
Placebo for 52 weeks
Drug: Placebo
Placebo three times daily for 52 weeks

Primary Outcome Measures :
  1. Incidence of the composite endpoint [ Time Frame: 52 weeks ]
    Incidence of the composite endpoint of decline in percent predicted FVC of 10% or greater or death.

Secondary Outcome Measures :
  1. Incidence of the composite endpoint [ Time Frame: 52 weeks ]
    Incidence of the composite endpoint of decline in percent predicted forced vital capacity (FVC) of 10% or greater

  2. Frequency of progressive disease [ Time Frame: 52 weeks ]
    Frequency of progressive disease as defined by OMERACT: FVC% relative decline of >=10% or FVC% change in >=5< 10% and >=15% diffusing capacity (DLCO)

  3. % FVC change stratified by background therapy [ Time Frame: 52 weeks ]
  4. % FVC change stratified by Usual Interstitial Pneumonitis (UIP) vs. non-UIP pattern on HRCT [ Time Frame: 52 weeks ]
  5. Change in mean slope of FVC [ Time Frame: 52 weeks ]
  6. Time to decline of 10% or greater in percent predicted FVC or death [ Time Frame: 52 weeks ]
  7. All-cause mortality [ Time Frame: 52 weeks ]
  8. Rate of acute exacerbation of interstitial lung disease (ILD) [ Time Frame: 52 weeks ]
  9. All-cause hospitalization [ Time Frame: 52 weeks ]
  10. Hospitalization for respiratory cause [ Time Frame: 52 weeks ]
  11. Incidence of acute exacerbation of ILD [ Time Frame: 52 weeks ]
  12. Number of respiratory exacerbations requiring hospitalizations [ Time Frame: 52 weeks ]
  13. Treatment-emergent Adverse Events (AEs) [ Time Frame: 52 weeks ]
  14. Treatment-emergent serious adverse events (SAEs) [ Time Frame: 52 weeks ]
  15. Treatment-emergent/treatment-related AEs [ Time Frame: 52 weeks ]
  16. Treatment-emergent/treatment-related SAEs [ Time Frame: 52 weeks ]
  17. AEs leading to early discontinuation of study treatment [ Time Frame: 52 weeks ]
  18. Treatment-emergent death or transplant [ Time Frame: 52 weeks ]
  19. Treatment-emergent RA-ILD-related mortality [ Time Frame: 52 weeks ]
  20. Change from Baseline to Week 52 in dyspnea, as measured by the University of California at San Diego Shortness-of-Breath Questionnaire (UCSD SOBQ) score [ Time Frame: 52 weeks ]
  21. Change from Baseline to Week 52 on St. George's Respiratory Questionnaire [ Time Frame: 52 weeks ]

Other Outcome Measures:
  1. Disease Activity Score (DAS)/Routine assessment of patient index data (RAPID)3 score (RA disease activity scores) [ Time Frame: 52 weeks ]
  2. Joint counts [ Time Frame: 52 weeks ]
  3. erythrocyte sedimentation rate (ESR)/c-reactive protein (CRP) [ Time Frame: 52 weeks ]
  4. Candidate biomarker expression in the peripheral blood of patients with RA-ILD over the 52 weeks of treatment and the study follow-up period [ Time Frame: 52 weeks ]
  5. Extent and severity of fibrotic lung involvement, as measured by changes in Chest CT scans evaluated by quantitative functional imaging [ Time Frame: 52 weeks ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02808871

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Contact: Ivan Rosas, M.D. 617-510-9910

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Sponsors and Collaborators
Ivan O. Rosas
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Principal Investigator: Ivan O. Rosas, M.D. Brigham and Women's Hospital
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Ivan O. Rosas, Associate Professor, Brigham and Women's Hospital Identifier: NCT02808871    
Other Study ID Numbers: TRAIL1
First Posted: June 22, 2016    Key Record Dates
Last Update Posted: September 23, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Ivan O. Rosas, Brigham and Women's Hospital:
Additional relevant MeSH terms:
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Arthritis, Rheumatoid
Lung Diseases
Lung Diseases, Interstitial
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Respiratory Tract Diseases
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Antirheumatic Agents
Antineoplastic Agents