Pilot Study of Pirfenidone in Pulmonary Fibrosis With Anti-myeloperoxydase Antibodies (PIRFENIVAS)

A Pilot Study to Evaluate the Efficacy and Safety of Pirfenidone in Patients With Pulmonary Fibrosis With Anti-myeloperoxydase (MPO) Antibodies or With Anti-MPO Associated Vasculitis."

The purpose of this study is to determine wether pirfenidone is safe and effective in the treatment of pulmonary fibrosis with anti-myeloperoxydase (MPO) antibodies or pulmonary fibrosis with anti-MPO associated vasculitis.

Study Overview

• Status: Completed
• Conditions: Pulmonary Fibrosis
• Intervention / Treatment: Drug: Pirfenidone

Detailed Description

Pulmonary fibrosis can be associated with Anti-Neutrophil Cytoplasmic Antibody (ANCA) directed against MPO or with anti-MPO associated vasculitis, leading to increased disability and poor prognosis. The pathophysiology of this association remains unclear. Conventional therapies used for the treatment of vasculitis manifestations are often disappointing for the treatment of pulmonary fibrosis. The main cause of death in patients with anti-MPO ANCA associated vasculitis and associated pulmonary fibrosis is the progression of pulmonary fibrosis. No treatment has demonstrated efficacy to stabilize or improve pulmonary fibrosis associated with anti-MPO associated vasculitis.

Previous studies showed that Pirfenidone improves survival and pulmonary function in patients with idiopathic pulmonary fibrosis (IPF) and that Pirfenidone treatment is safe and well tolerated in IPF. Patients with anti-MPO associated vasculitis (or anti-MPO antibodies without vasculitis) and associated pulmonary fibrosis might benefit from the use of Pirfenidone. However, the efficacy and safety of pirfenidone in patients with anti-MPO associated vasculitis and associated pulmonary fibrosis has not been evaluated. This study was designed to assess the efficacy and safety of pirfenidone in patients with pulmonary fibrosis and anti-MPO ANCA associated vasculitis or anti-MPO antibodies without vasculitis.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75014
    • Cochin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18 years
• Presence of anti-MPO antibody (ELISA) at inclusion or during pulmonary fibrosis follow-up and/or diagnosis of anti-MPO associated vasculitis according to the 2012 Revised International Chapel Hill Consensus Conference definitions
• Definite or possible Usual Interstitial Pneumonia or Non Specific Interstitial Pneumonia based on high-resolution computed tomography
• Presence of pulmonary fibrosis, defined as a range of 50 to 90% of the %FVC and a range of 30 to 90% of the %DLCO
• Pulmonary fibrosis refractory (according to the investigator's judgment) to a conventional regimen used for anti-MPO associated vasculitis when a treatment against vasculitis has been used
• Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information) and comply with the study protocol procedures (including required study visits)
• Have affiliation with a mode of social security (profit our being entitled).

Exclusion Criteria:

• Other type of systemic vasculitis;
• Active vasculitis defined by Birmingham Vasculitis Activity Score >3 (BVAS) ;
• Contraindication to Pirfenidone;
• Unable to perform pulmonary function test (PFT);
• Pregnancy or lactation. Women of childbearing capacity are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using an effective method of birth control from the date of consent through the end of the study : implants of levonorgestrel; injectable progesterone; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progesterone only); double barrier method (condom, cervical cap or diaphragm with spermicidal agent); transdermal contraceptive patch; male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for the female subject;
• Any of the following liver function test criteria above specified limits: total bilirubin above 1,5 times the upper limit of normal (ULN), excluding patients with Gilbert's syndrome; aspartate (AST)/Glutamate Oxaloacétique Transaminase (SGOT) or alanine aminotransferase (ALT)/Glutamate Pyruvate Transaminase (SGPT), (AST/SGOT or ALT/SGPT) >3 × ULN; alkaline phosphatase >2.5 × ULN;
• Creatinine clearance (CrCl<30) mL/min, calculated using the Cockcroft-Gault formula at screening
• Current treatment with Nintedanib or past treatment with Nintedanib in the last 12 months;
• Current treatment with Fluvoxamine or past treatment with Fluvoxamine in the last 28 days before screening
• Prior use of Pirfenidone or known hypersensitivity to any of the components of study treatment;
• Expected to receive a lung transplant within 1 year from randomization or, on a lung transplant waiting list at randomization;
• Associated connective tissue disease (such as systemic sclerosis).;
• Electrocardiogram (ECG), with a heart-rate-corrected QT interval (corrected using Fridericia's formula, QTcF) ≥ 500 ms at Screening, or a family or personal history of long QT syndrome;
• Treatment with Cyclophosphamide in the last 3 months;
• Current smoking or past smoking in the last 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pirfenidone; All patients will receive Pirfenidone	Drug: Pirfenidone; Pirfenidone at a dose of 2403 mg/day for 50 weeks, after a 2 weeks period of titration (801 mg/day for one week then 1602 mg/day for one week).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment efficacy measured by the absolute change in percent predicted forced vital capacity (%FVC)	Treatment efficacy at Week 52 measured by the absolute change from baseline to Week 52 in percent predicted forced vital capacity (%FVC) : Patients with progressive disease will be defined as absolute decline of 10% or more in %FVC. Missing values or death will be also considered as progressive.; Patients with non-progressive disease will be defined as improvement or no decline in %FVC or a decline of %FVC<10%.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AE)	Safety parameters reported in the period from baseline to 28 days after the last dose of the study drug: Treatment-emergent AEs; Treatment-emergent Serious Adverse Events (SAE); Treatment emergent Adverse Event of Special Interest (AESI); Treatment-emergent treatment-related AEs; Treatment-emergent treatment-related SAEs; Treatment emergent related AESIs; AEs leading to early discontinuation of study treatment; Treatment-emergent deaths; Cause of death; Treatment-emergent changes in clinical laboratory findings; Vital signs	56 weeks corresponding to 28 days after the last dose of study drug
Treatment efficacy measured by the absolute change in percent predicted forced vital capacity (%FVC)	Treatment efficacy at Week 24 measured by the absolute change from baseline to Week 24 in percent predicted forced vital capacity (%FVC) : Patients with progressive disease will be defined as absolute decline of 10% or more in %FVC. Missing values or death will be also considered as progressive.; Patients with non-progressive disease will be defined as improvement or no decline in %FVC or a decline of %FVC<10%.	24 weeks
Relative change in in percent predicted forced vital capacity	Relative change from baseline to Week 52 in percent predicted forced vital capacity (%FVC)	52 weeks
Absolute change in in percent predicted forced vital capacity	Relative and absolute change from baseline to Week 52 in percent predicted forced vital capacity (%FVC)	52 weeks
Relative change in in percent predicted forced vital capacity	Relative and absolute change from baseline to Week 24 in percent predicted forced vital capacity (%FVC)	24 weeks
Absolute change in in percent predicted forced vital capacity	Relative and absolute change from baseline to Week 24 in percent predicted forced vital capacity (%FVC)	24 weeks
Six minute walk test (6MWT) distance	Change from Baseline to Week 52 in the six minute walk test (6MWT) distance	52 weeks
Six minute walk test (6MWT) distance	Change from Baseline to Week 24 in the six minute walk test (6MWT) distance	24 weeks
Carbon Monoxide Diffusing Capacity (%DLCO)	Change from Baseline to Week 52 in the percent predicted Carbon Monoxide Diffusing Capacity (%DLCO)	52 weeks
Carbon Monoxide Diffusing Capacity (%DLCO)	Change from Baseline to Week 24 in the percent predicted Carbon Monoxide Diffusing Capacity (%DLCO)	24 weeks
Progression-free survival	Progression-free survival defined as the time to the first occurrence of any one of the following: a confirmed decrease of 10 percentage points or more in %FVC, a confirmed decrease of 15 percentage points or more in %DLCO, or death.	52 weeks
Dyspnea	Change from Baseline to Week 52 in dyspnea as measured by the New York Heart Association classification, the modified Borg scale and by the Saint-George's Respiratory Questionnaire (SGRQ).	52 weeks
Chest CT-scan	Change in Chest-CT scan abnormalities at Week 52 (evaluated after a centralized blinded review of the chest CT-scans).	52 weeks
Quality of Life assessed by the Health Assessment Questionnaire (HAQ)		52 weeks
Quality of Life assessed by the Short Form-36 (SF-36)		52 weeks

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Roche Pharma AG
• Investigators: Principal Investigator: Jonathan London, MD, Cochin Hospital

Publications and helpful links

General Publications

• Lancaster L, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, Fishman RS, Glaspole I, Glassberg MK, King TE Jr, Lederer DJ, Lin Z, Nathan SD, Pereira CA, Swigris JJ, Valeyre D, Noble PW. Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials. BMJ Open Respir Res. 2016 Jan 12;3(1):e000105. doi: 10.1136/bmjresp-2015-000105. eCollection 2016.
• King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18. Erratum In: N Engl J Med. 2014 Sep 18;371(12):1172.
• Hervier B, Pagnoux C, Agard C, Haroche J, Amoura Z, Guillevin L, Hamidou MA; French Vasculitis Study Group. Pulmonary fibrosis associated with ANCA-positive vasculitides. Retrospective study of 12 cases and review of the literature. Ann Rheum Dis. 2009 Mar;68(3):404-7. doi: 10.1136/ard.2008.096131. Epub 2008 Oct 28.

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2018
• Primary Completion (Actual): July 24, 2020
• Study Completion (Actual): July 24, 2020

Study Registration Dates

• First Submitted: December 7, 2017
• First Submitted That Met QC Criteria: December 20, 2017
• First Posted (Actual): December 28, 2017

Study Record Updates

• Last Update Posted (Actual): May 3, 2021
• Last Update Submitted That Met QC Criteria: April 30, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Pirfenidone; Interstitial lung disease; Pulmonary fibrosis; Antibodies, Antineutrophil Cytoplasmic; Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis; Microscopic Polyangiitis
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Pirfenidone
• Other Study ID Numbers: P161001J; 2017-002782-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No