Management of Progressive Disease in Idiopathic Pulmonary Fibrosis

• ClinicalTrials.gov Identifier: NCT03939520
• Recruitment Status: Not yet recruiting
• First Posted: May 6, 2019
• Last Update Posted: May 6, 2019
• Sponsor: Hospices Civils de Lyon
• Information provided by (Responsible Party): Hospices Civils de Lyon

Study Description

Brief Summary:

Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease. It has been considered rare, with an incidence estimated to 11.5 cases per 100 000 individuals per year. Increasing rates of hospital admissions and deaths due to IPF suggest an increasing burden of disease. The median survival time from diagnosis is 2-4 years.

Recently two disease-modifying therapies, pirfenidone and nintedanib, have been approved worldwide. Both drugs reduce the disease progression as measured by progressive decline in forced vital capacity (FVC), with a reduction of overall mortality showed by meta-analysis of phase III pirfenidone trials.

However, progression of disease continues to occur despite the currently available drug therapy. Many patients die from progressive, chronic hypoxemic respiratory failure, or less frequently from acute exacerbation of pulmonary fibrosis. In these patients, no data are available to guide management between continuation of the prescribed antifibrotic drug, to switch to the other available antifibrotic drug, or to combine the available drugs.

The combination of nintedanib and pirfenidone is not recommended outside clinical trials. However, although both antifibrotic drugs were developed and approved as monotherapy, two recent trials have suggested the feasibility and safety of combining them over a 12-24 weeks period. These results encourage further studies of combination treatment with pirfenidone and nintedanib in patients with IPF. Such study is timely, as there is a risk that clinicians facing the continued worsening of disease in patients receiving one of the available drugs may prescribe both drugs combined outside clinical trials, potentially exposing patients to a currently unknown risk.

This study will evaluate the efficacy and tolerance of the combination pirfenidone and nintedanib as compared to a "switch monotherapy": i.e. switching from the current to the other of the two existing drugs prescribed as monotherapy, in patients who present chronic worsening IPF despite receiving either pirfenidone or nintedanib.

Condition or disease	Intervention/treatment	Phase
Progressive Idiopathic Pulmonary Fibrosis	Drug: pirfenidone and nintedanib; Drug: pirfenidone or nintedanib	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 210 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pragmatic Management of Progressive Disease in Idiopathic Pulmonary Fibrosis: a Randomized Trial
• Estimated Study Start Date: September 2019
• Estimated Primary Completion Date: April 2022
• Estimated Study Completion Date: April 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Combined therapy	Drug: pirfenidone and nintedanib; The experimental group will receive pirfenidone 2403 mg per day (at least 1602 mg) in combination with nintedanib 300 mg per day (at least 200 mg) during 24 weeks.
Active Comparator: Switch monotherapy	Drug: pirfenidone or nintedanib; The control group will switch from one monotherapy during 24 weeks: with pirfenidone 2403 mg per day (at least 1602 mg) or nintedanib 300 mg per day (at least 200 mg) to the other monotherapy (nintedanib in patients who received pirfenidone as first line therapy before inclusion and conversely).

Outcome Measures

Primary Outcome Measures :

1. Slope of the decline in the forced vital capacity (FVC) measured by spirometry [ Time Frame: 24 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patient aged between 50 and 80 years.
• Patient with Idiopathic Pulmonary Fibrosis satisfying the ATS/ERS/JRS/ALAT diagnostic criteria diagnosed since no more than 4 years.

In the absence of a surgical lung biopsy, high-resolution computed tomography (HRCT) must be "consistent with Usual Interstitial Pneumonia (UIP)" defined as meeting either criteria A, B, and C, or criteria A and C, or criteria B and C below:

A. Definite honeycomb lung destruction with basal and peripheral predominance. B. Presence of reticular abnormality and traction bronchiectasis consistent with fibrosis, with basal and peripheral predominance.

C. Atypical features are absent, specifically nodules and consolidation. Ground glass opacity, if present, is less extensive than reticular opacity pattern.

• Patients with diagnosis of IPF who fulfill one of the two following criteria for progressive disease within 12 months (+/- one month) of the screening visit as assessed by the investigator will be eligible:
• worsening of respiratory symptoms AND clinically significant decline in FVC % predicted (%pred) based on ≥10% relative decline;
• Worsening of respiratory symptoms AND marginal decline in FVC %predicted based on ≥5 - <10% relative decline in FVC, AND with increasing extent of fibrotic changes on chest imaging.
• Patient must have been on a stable dose of pirfenidone or nintedanib prescribed as first-line therapy for at least 6 months, with good tolerance of 1602 to 2403 mg per day of pirfenidone or 200 to 300 mg per day of nintedanib.
• Patient who has a FVC ≥ 50% and ≤ 90% of predicted.
• Patient who has an Hemoglobin (Hb) corrected and/or Hb uncorrected Diffusing capacity of the Lung for carbon monoxide (DLCO) ≥ 30% and ≤ 80% of predicted.
• Patient who has a forced expiratory volume in 1 second (FEV1)/FVC ratio > 0.70.
• Patient who has a life expectancy of at least 9 months.
• Patient who has provided his written informed consent to participate in the study.
• Patient affiliated to a social insurance regimen

Exclusion Criteria:

• Patients under judicial protection.
• Female patient who is pregnant or lactating, or is of child bearing potential (defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤ 55 years or 12 months if > 55 years) and who did not agree to use highly effective methods of birth control throughout the study.
• Patient who is currently on both pirfenidone and nintedanib.
• Patient who has already received pirfenidone and nintedanib either concomitantly or successively.
• Patient who has a contra-indication to pirfenidone or nintedanib.
• Patient who has emphysema > 15% on HRCT or the extent of emphysema is greater than the extent of fibrosis according to reported results from the most recent HRCT.
• Patient who had acute exacerbation of idiopathic pulmonary fibrosis within the previous 3 months.
• Patient who has a history of cigarette smoking within the previous 3 months.
• Patient who has received experimental therapy for IPF within 4 weeks before baseline.
• Patient who is receiving systemic corticosteroids equivalent to prednisone > 15 mg/day or equivalent within 2 weeks before baseline.
• Patient who received Immuno-suppressants (e.g. methotrexate, azathioprine, cyclophosphamide, cyclosporine, sirolimus, everolimus or other immunosuppressants) within 4 weeks before baseline.
• Patient who has a history of a malignancy within the previous 5 years, with the exception of basal cell skin neoplasms. In addition, a malignant diagnosis or condition first occurring prior to 5 years must be considered cured, inactive, and not under current treatment.
• Patient who, in the Investigator's opinion, is not able to perform home spirometry in accordance with the protocol.
• Patient who has any concurrent condition other than IPF that, in the Investigator's opinion, is unstable and/or would impact the likelihood of survival for the study duration or the subject's ability to complete the study as designed, or may influence any of the safety or efficacy assessments included in the study.
• Patient who has baseline resting oxygen saturation of < 88% on room air or supplemental oxygen.
• Patient who has a known post-bronchodilator (short-acting beta agonist [SABA] -albuterol or salbutamol) increase in FEV1 of >10% and in FVC of >7.5%.
• Patient who had lung transplantation or who is on a lung transplant list and the investigator anticipates the patient will not be able to complete the study prior to transplant.

Contacts and Locations

Contacts

Contact: Vincent COTTIN, Pr; 4 27 85 77 00 ext +33; vincent.cottin@chu-lyon.fr

Contact: Géraldine SAMSON; 4 27 85 53 26 ext +33; geraldine.samson@chu-lyon.fr

Locations

France

Hôpital Pneumologique et Cardiovasculaire Louis Pradel

Bron, France

Contact: Vincent Cottin, Pr vincent.cottin@chu-lyon.fr

Sponsors and Collaborators

Hospices Civils de Lyon

Investigators

• Principal Investigator: Vincent COTTIN, Pr; Hospices Civils de Lyon

More Information

• Responsible Party: Hospices Civils de Lyon
• ClinicalTrials.gov Identifier: NCT03939520
• Other Study ID Numbers: 69HCL19_029
• First Posted: May 6, 2019
• Last Update Posted: May 6, 2019
• Last Verified: May 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hospices Civils de Lyon:

Pneumology; idiopathic pulmonary fibrosis; progressive disease; combined therapy; pirfenidone; nintedanib

Additional relevant MeSH terms:

Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Disease Progression; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Idiopathic Interstitial Pneumonias; Lung Diseases, Interstitial; Disease Attributes; Pirfenidone; Nintedanib; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents