The Efficacy and Safety of Pirfenidone in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction

Study Overview
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Brief Summary
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This randomised, double-blind, placebo-controlled, phase 2 study aims to evaluate the efficacy and safety of the anti-fibrotic drug pirfenidone in the treatment of patients with heart failure and preserved left ventricular ejection fraction (HFpEF). Participants will be randomised to receive either pirfenidone or placebo, for a period of 12 months.

Detailed Description
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Myocardial fibrosis is a key pathological mechanism in HFpEF. Pirfenidone is an anti-fibrotic medication licensed for the treatment of idiopathic lung fibrosis, for which it reduces lung function decline, improves progression free survival and reduces all cause mortality. In pre-clinical models, pirfenidone attenuates profibrotic pathways and is associated with regression of myocardial fibrosis. Previous studies in HFpEF populations using anti-fibrotic medications, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers and aldosterone antagonists have shown some benefit in reaching secondary end-points but do not reduce mortality. HFpEF is the final result of a number of specific underlying pathological mechanisms, and targeted treatment of these mechanisms has been cited as the future approach to further clinical trials. The investigators aim to select a population of HFpEF patients with high levels of interstitial myocardial fibrosis as measured on cardiac MRI (CMR), and randomise participants to receive pirfenidone or placebo. The primary outcome is to detect a significant reduction in myocardial fibrosis as measured on CMR after 12 months of intervention.

Official Title
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A Randomised, Double-blind, Placebo-controlled, Phase 2 Study of the Efficacy and Safety of Pirfenidone in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE)

Conditions
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Cardiac Failure

Intervention / Treatment
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* Drug: Pirfenidone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Male or female; aged 40 years or older. HF, defined as one symptom present at the time of screening, and one sign present at the time of screening or in the previous 12 months. Symptoms and signs are defined as: Symptoms: dyspnoea on exertion, orthopnoea or paroxysmal nocturnal dyspnoea Signs: peripheral oedema, crackles on chest auscultation post-cough, raised jugular venous pressure or chest x-ray demonstrating pleural effusion, pulmonary congestion, or cardiomegaly Left Ventricular Ejection Fraction (LVEF) > 45% at Visit 0, (any local LVEF measurement made using echocardiography or CMR). BNP ≥ 100 pg/ml or NTproBNP ≥ 300 pg/ml recorded at Visit 0. For patients in atrial fibrillation on Visit 0 ECG, BNP > 300pg/ml or NTproBNP > 900 pg/ml at Visit 0. Myocardial fibrosis, defined as Extracellular Matrix (ECM) volume > 27% by CMR at Visit 0. Exclusion Criteria: Myocardial infarction, coronary artery bypass graft surgery or percutaneous coronary intervention within the previous 6 months. Probable alternative cause of patient's HF symptoms that in the opinion of the investigator primarily accounts for patient's dyspnoea such as significant pulmonary disease, anaemia or obesity. Specifically, patients with the below are excluded: Severe chronic obstructive pulmonary disease (COPD) (i.e., requiring home oxygen, chronic nebuliser therapy, or chronic oral steroid therapy), or Haemoglobin < 9 g/dl, or Body mass index (BMI) > 55 kg/m2. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy. Clinically significant congenital heart disease. Presence of severe valvular heart disease. Atrial fibrillation or flutter with a resting ventricular rate > 100 bpm. Any medical condition, which in the opinion of the Investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study. Severe renal dysfunction at Visit 0, defined as estimated Glomerular Filtration Rate (eGFR) <30 mL/min (using Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI) calculation), or end-stage renal disease requiring dialysis. History of severe hepatic impairment or liver dysfunction at Visit 0, defined as total bilirubin above the upper limit of normal (ULN) (excluding patients with Gilbert's syndrome), aspartate aminotransferase (AST) or alanine transaminase (ALT) >3 times the ULN or alkaline phosphatase >2.5 times the ULN. Prolonged corrected QT interval, defined as a corrected QT interval >500 msec on ECG using Bazett formula. Known hypersensitivity to any of the components of the investigational medicinal product (IMP). Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer. Fluvoxamine use within 28 days of Visit 0. Contraindication to MRI scanning or gadolinium-based contrast agent Pregnancy, lactation or planning pregnancy. Women of childbearing capacity are required to have a negative serum pregnancy test before treatment, must agree to pregnancy tests at study visits as defined in the Section 7.2.5 and must agree to maintain highly effective contraception during the study and for 3 months thereafter. Similarly male participants with female partners of childbearing potential must agree to maintain highly effective contraception during the study and for 3 months thereafter.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pirfenidone<br>Pirfenidone 801mg capsule by mouth, three times a day (target dose) for 12 months | Drug: Pirfenidone<br>* Pirfenidone is an orally bioavailable, small molecule antifibrotic agent.<br>* Other names: Esbriet;|
| Placebo Comparator: Placebo<br>Placebo capsule by mouth, three times a day (target dose) for 12 months | Drug: Placebo<br>* Placebo capsule, manufactured with the exact components of the Pirfenidone capsules, without the active ingredient / investigational medicinal product<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extracellular volume fraction (ECV) | Absolute change in myocardial ECV, measured using CMR, from baseline to week 52 | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular (LV) mass | Absolute change in LV mass, measured using CMR, from baseline to week 52. | 12 months | 
| Left ventricular volume | Absolute change in LV volume, measured using CMR, from baseline to week 52. | 12 months | 
| Left ventricular ejection fraction | Absolute change in LV ejection fraction, measured using CMR, from baseline to week 52. | 12 months | 
| Left ventricular strain - CMR | Absolute change in LV strain, measured using CMR, from baseline to week 52. | 12 months | 
| Left ventricular strain - Echo | Absolute change in LV strain, measured using echocardiography, from baseline to week 52. | 12 months | 
| Left ventricular torsion | Absolute change in LV torsion, measured using echocardiography, from baseline to week 52. | 12 months | 
| Myocardial cell structure | Absolute change myocardial cell volume, measured using CMR, from baseline to week 52. | 12 months | 
| Diastolic function | Absolute change in LV diastolic function, measured using echocardiography, from baseline to week 52. | 12 months | 
| Left atrial volume | Absolute change in left atrial volume, measured using CMR, from baseline to week 52. | 12 months | 
| Myocardial energetic status | Absolute change in myocardial energetic status (Phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio), measured using Phosphorus-31 Magnetic Resonance Spectroscopy (31P MRS), from baseline to week 52. | 12 months | 
| Cardiac biomarkers - N-Terminal-Pro-Brain Natriuretic Peptide (NT-Pro BNP) | Absolute change in NT-Pro BNP from baseline to week 13, baseline to week 26 and baseline to week 52. | 12 months | 
| Cardiac biomarkers - high-sensitivity Troponin T (hsTnT) | Absolute change in hsTnT from baseline to week 13, baseline to week 26 and baseline to week 52. | 12 months | 
| Patient exercise capacity | Absolute change in exercise tolerance, measured using 6 minute walk distance, from baseline to week 52. | 12 months | 
| Patient morbidity | Absolute change in health status (quality of life), HF symptoms and physical limitations, measured using change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score, from baseline to week 52 | 12 months | 
| All cause mortality | All cause mortality will be recorded but the trial is not powered for this clinical outcome | 12 months | 
| Cardiovascular mortality | Cardiovascular mortality will be recorded but the trial is not powered for this clinical outcome | 12 months | 
| Hospitalisation for heart failure | Hospitalisation for heart failure will be recorded but the trial is not powered for this clinical outcome | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, Heart failure with preserved ejection fraction (HFpEF), Myocardial fibrosis, Extracellular volume fraction (ECV), Interstitial fibrosis