Evaluation of Pirfenidone and Nintedanib Combination Therapy Versus Monotherapy in Progressive Idiopathic Pulmonary Fibrosis: A Randomized Controlled Trial

Trial ID: 2024-511427-34-00
Protocol: 69HCL19_0029
Sponsor: Hospices Civils De Lyon

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Diseases & Conditions

Idiopathic pulmonary fibrosis

Objectives

The primary objective of this study is to evaluate the **efficacy** of combination therapy with pirfenidone and nintedanib compared to switch monotherapy (either pirfenidone or nintedanib) and no change monotherapy (either pirfenidone or nintedanib) in patients with **idiopathic pulmonary fibrosis**. This evaluation is based on the slope of the decline in forced vital capacity (FVC) over a 24-week period, as measured by hospital spirometry at baseline, week 4, week 12, and week 24. The clinical relevance of this objective lies in its potential to inform treatment strategies that may slow disease progression and improve respiratory function in affected patients.

Secondary objectives include:

Assessing the tolerance of combination therapy over 24 weeks compared to switch and no change monotherapy.
Evaluating the impact of combination therapy on the time to permanent discontinuation of the study drug.
Assessing the efficacy of combination therapy on the time to treatment failure.
Evaluating the impact on death and FVC decline during the 24-week follow-up.
Assessing hospitalization-free survival during the 24-week follow-up.
Evaluating the impact on the first non-elective hospitalization from a pulmonary cause during the 24-week follow-up.
Assessing the impact on all-cause mortality during the 24-week follow-up.
Evaluating the progression of fibrotic features via computed tomography at 24 weeks compared to baseline.
Assessing the impact on supplementary oxygen therapy during the 24-week follow-up.
Evaluating the impact on acute exacerbation of idiopathic pulmonary fibrosis during the 24-week follow-up.
Assessing changes in idiopathic pulmonary fibrosis questionnaires related to symptoms and quality of life between baseline and week 24.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic benefits and risks associated with combination therapy in this patient population.

Participants

The clinical trial involves participants diagnosed with **idiopathic pulmonary fibrosis**. The study population includes both male and female subjects aged 50 years and older. Participants are required to have a stable health status, specifically having been on a stable dose of pirfenidone or nintedanib for at least six months, with good tolerance. The trial does not include a vulnerable population. Participants must have a forced vital capacity (FVC) of at least 45% of the predicted value and a forced expiratory volume in one second (FEV1)/FVC ratio of at least 0.70. The trial population was selected based on specific inclusion criteria, including a life expectancy of at least nine months and a diagnosis of idiopathic pulmonary fibrosis according to established criteria. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of combination therapy with **pirfenidone** and **nintedanib** compared to switch monotherapy and no change monotherapy in patients with **idiopathic pulmonary fibrosis**. This is a randomized, double-blind, controlled trial with a duration of 24 weeks. Participants will be randomly assigned to one of the treatment groups and will receive either combination therapy or monotherapy. The primary endpoint is the slope of the decline in forced vital capacity (FVC) measured by hospital spirometry at baseline, week 4, week 12, and week 24. Secondary endpoints include tolerance of antifibrotic therapy, time to permanent study drug discontinuation, and time to treatment failure, among others.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis of idiopathic pulmonary fibrosis, and previous antifibrotic treatment. Participants must have a stable dose of pirfenidone or nintedanib for at least six months prior to enrollment. Following the screening, eligible participants will undergo randomization and begin the assigned treatment regimen. Study visits are scheduled at baseline, week 4, week 12, and week 24 to monitor treatment efficacy and safety, with spirometry assessments conducted at each visit.

The expected length of participant involvement is 24 weeks, with the possibility of early termination if certain conditions arise, such as permanent discontinuation of the study drug, transient discontinuation exceeding 28 consecutive days, or dose reduction below two-thirds of the full treatment dose. Participants will also be withdrawn if they experience significant adverse events or if the investigator deems it necessary for their safety. The trial is anticipated to start recruitment in April 2024 and conclude by April 2030, ensuring comprehensive data collection and analysis over the study period.

Treatment

The clinical trial involves the administration of **pirfenidone**, marketed under the name Esbriet, which is provided in the form of 267 mg **film-coated tablets**. The pharmaceutical form is designed for **oral use**. The maximum daily dose of pirfenidone is 2403 mg, and the treatment period extends up to 24 weeks. The active substance, pirfenidone, is of chemical origin and is authorized for use in the European Union under the marketing authorization number EU/1/11/667/005. The product is manufactured by Roche Registration GmbH.

Another experimental medication used in the trial is **nintedanib**, marketed as Ofev, available in 150 mg **soft capsules**. This medication is also administered orally. The maximum daily dose for nintedanib is 300 mg, with a treatment duration of up to 24 weeks. Nintedanib is a chemical substance, and its use is authorized in the European Union with the marketing authorization number EU/1/14/979/003. The manufacturer of this product is Boehringer Ingelheim International GmbH. Notably, nintedanib has been designated as an orphan drug under the designation number EU/3/13/1123.

The trial aims to evaluate the efficacy of combination therapy with pirfenidone and nintedanib compared to switch monotherapy or no change monotherapy in patients with idiopathic pulmonary fibrosis. The study monitors the decline in forced vital capacity (FVC) over a 24-week period, with spirometry assessments conducted at baseline, week 4, week 12, and week 24. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen.

Efficacy

The efficacy of the clinical trial titled "Pragmatic management of progressive disease in idiopathic pulmonary fibrosis: a randomized trial. PROGRESSION-IPF" will be assessed primarily through the **slope of the decline in the forced vital capacity (FVC)**. This parameter will be measured over a 24-week period using hospital spirometry. Measurements will be taken at baseline, week 4, week 12, and week 24, ensuring consistency by using the same spirometer throughout the trial.

Secondary endpoints include several parameters to evaluate the tolerance and effectiveness of the antifibrotic therapy. These include the proportion of patients continuing intent-to-treat therapy at week 24, time to permanent study drug discontinuation, and time to treatment failure. Additional secondary endpoints involve the proportion of patients with a ≥10% FVC relative decline or death at week 24, hospitalization-free survival, and time to first non-elective hospitalization from a pulmonary cause. The trial will also assess the progression of the disease through changes in the volume of fibrotic features at imaging by computed tomography at 24 weeks, and the time to initiation of supplementary oxygen therapy. Furthermore, the trial will evaluate the absolute change in idiopathic pulmonary fibrosis (IPF) questionnaires related to symptoms and quality of life between baseline and week 24, using tools such as the King’s Brief Interstitial Lung Disease Questionnaire (K-BILD), EQ-5D-5L Questionnaire, and Living with Pulmonary Fibrosis (L-PF) Symptoms and Impact questionnaires.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient aged ≥ 50 years
Diagnosis of Idiopathic Pulmonary Fibrosis according to ATS/ERS/JRS/ALAT criteria (Raghu G et al, AJRCCM 2018). High-resolution computed tomography (HRCT) and histopathology patters are classified according to the table in protocol
Patient who fulfill at least 1 of the 4 criteria for IPF progression in the 12 months (+/- six months) before screening, despite antifibrotic treatment in clinical practice (if yes check the option(s)). These criteria are: 0 Relative decline in FVC ≥10% predicted 0 Relative decline in FVC ≥5-<10% predicted and worsened respiratory symptoms 0 Relative decline in FVC ≥5-<10% predicted and increased extent of fibrotic changes on chest imaging 0 Worsened respiratory symptoms and increased 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 ≥ 45% of predicted (according to the GLI standard).
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 according to the investigator opinion.
Patient who has provided his written informed consent to participate in the study
Patient affiliated to a social insurance regimen

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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 a liver function with elevations in ALT and AST >3 × upper limit of normal (ULN)
Patient with moderate and severe hepatic impairment classified as Child Pugh B and C
Patient who has a severe renal impairment (Creatinine Clearance <30 ml/min) or end stage renal disease requiring dialysis
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 the previous 4 weeks
Patient who is receiving systemic corticosteroids equivalent to prednisone > 10 mg/day or equivalent within the previous 2 weeks
Patient who received Immuno-suppressants (e.g. methotrexate, azathioprine, cyclophosphamide, cyclosporine, sirolimus, everolimus or other immunosuppressants) within the previous 4 weeks.
Patient who has a history of a malignancy within the previous 2 years, with the exception of basal cell skin neoplasms. In addition, a malignant diagnosis or condition first occurring prior to 2 years must be considered cured, inactive, and not under current treatment
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.