Clinical trial NCT02808871: Phase ll Study of Pirfenidone in Patients With RAILD (TRAIL1)
Official title: Phase 2 Study of Safety, Tolerability and Efficacy of Pirfenidone in Patients With Rheumatoid Arthritis Interstitial Lung Disease (TRAIL1)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis Interstitial Lung Disease
Keywords: TRAIL1
TRAIL
Pirfenidone
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2016-06-22
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: Number of Participants Who Developed Any Element of the Composite Endpoint
timeFrame: 52 weeks
Secondary outcomes:
measure: Number of Participants With FVC Decline From Baseline of 10% or Greater
timeFrame: 52 weeks
measure: Number of Participants With Progressive Disease
timeFrame: 52 weeks
measure: Change in Absolute Value FVC Over the 52 Week Study Period
timeFrame: 52 weeks
measure: Change in % Predicted FVC From Baseline to End of Study Over the 52 Week Study Period
timeFrame: 52 weeks
measure: Time to Composite of Decline in FVC or Death
timeFrame: 52 weeks
measure: Change in PRO of Dyspnea
timeFrame: 52 weeks
measure: All-cause Mortality
timeFrame: 52 weeks
measure: All Cause Hospitalization
timeFrame: 52 weeks
measure: Hospitalization for Respiratory Cause
timeFrame: 52 weeks
measure: Acute Exacerbations Requiring Hospitalization
timeFrame: 52 weeks
measure: Treatment-emergent Adverse Events (AEs)
timeFrame: 52 weeks
measure: Treatment-emergent Serious Adverse Events (SAEs)
timeFrame: 52 weeks
measure: Treatment-emergent/Treatment-related AEs
timeFrame: 52 weeks
measure: Treatment-emergent/Treatment-related SAEs
timeFrame: 52 weeks
measure: AEs Leading to Early Discontinuation of Study Treatment
timeFrame: 52 weeks
measure: Treatment-emergent Death or Transplant
timeFrame: 52 weeks
measure: Treatment-emergent RA-ILD-related Mortality
timeFrame: 52 weeks
Other outcomes:
measure: Disease Activity Score (DAS)
timeFrame: 52 weeks
measure: RAPID3 Score
timeFrame: 52 weeks
measure: Erythrocyte Sedimentation Rate (ESR)
timeFrame: 52 weeks
measure: CRP
timeFrame: 52 weeks
measure: Biomarker Expression
timeFrame: 52 weeks
measure: HRCT Parameters
timeFrame: 52 weeks
measure: SGRQ
timeFrame: 52 weeks
measure: Dyspnea 12
timeFrame: 52 weeks
measure: LCQ
timeFrame: 52 weeks
measure: Patient Global Assessment
timeFrame: 52 weeks
measure: Health Assessment Questionnaire
timeFrame: 52 weeks
Locations:
city: Birmingham
country: United States
facility: University of Alabama Site at Birmingham
state: Alabama
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Miami
country: United States
facility: University of Miami
state: Florida
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: John Hopkins Medicine
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah Health Care
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Brisbane
country: Australia
facility: Royal Brompton
state: Queensland
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: Sydney
city: Melbourne
country: Australia
facility: Melbourne Alfred Hospital
state: Victoria
city: Camperdown
country: Australia
facility: The Prince Charles Hospital
city: Calgary
country: Canada
facility: University of Calgary Cummings School of Medicine
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital - Providence Health Care
state: British Columbia
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Bristol
country: United Kingdom
facility: North Bristol NHS Trust Headquarters, Southmead Hospital
city: Cambridge
country: United Kingdom
facility: Papworth Hospital NHS Foundation Trust
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter NHS Foundation
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Foundation Trust
city: Liverpool
country: United Kingdom
facility: Aintree University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Brompton and Harefield NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust (South) Wythenshawe Hospita
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
city: Southhampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: Brigham and Women's Hospital
name: Ivan O. Rosas, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Solomon JJ, Danoff SK, Woodhead FA, Hurwitz S, Maurer R, Glaspole I, Dellaripa PF, Gooptu B, Vassallo R, Cox PG, Flaherty KR, Adamali HI, Gibbons MA, Troy L, Forrest IA, Lasky JA, Spencer LG, Golden J, Scholand MB, Chaudhuri N, Perrella MA, Lynch DA, Chambers DC, Kolb M, Spino C, Raghu G, Goldberg HJ, Rosas IO; TRAIL1 Network Investigators. Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet Respir Med. 2023 Jan;11(1):87-96. doi: 10.1016/S2213-2600(22)00260-0. Epub 2022 Sep 5.
citation: Solomon JJ, Danoff SK, Goldberg HJ, Woodhead F, Kolb M, Chambers DC, DiFranco D, Spino C, Haynes-Harp S, Hurwitz S, Peters EB, Dellaripa PF, Rosas IO; Trail Network. The Design and Rationale of the Trail1 Trial: A Randomized Double-Blind Phase 2 Clinical Trial of Pirfenidone in Rheumatoid Arthritis-Associated Interstitial Lung Disease. Adv Ther. 2019 Nov;36(11):3279-3287. doi: 10.1007/s12325-019-01086-2. Epub 2019 Sep 12.