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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
129
Pirfenidone is an orally bioavailable, small molecule antifibrotic agent.
Placebo capsule, manufactured with the exact components of the Pirfenidone capsules, without the active ingredient / investigational medicinal product
Manchester University NHS Foundation Trust
Manchester, Greater Manchester, United Kingdom
Extracellular volume fraction (ECV)
Absolute change in myocardial ECV, measured using CMR, from baseline to week 52
Time frame: 12 months
Left ventricular (LV) mass
Absolute change in LV mass, measured using CMR, from baseline to week 52.
Time frame: 12 months
Left ventricular volume
Absolute change in LV volume, measured using CMR, from baseline to week 52.
Time frame: 12 months
Left ventricular ejection fraction
Absolute change in LV ejection fraction, measured using CMR, from baseline to week 52.
Time frame: 12 months
Left ventricular strain - CMR
Absolute change in LV strain, measured using CMR, from baseline to week 52.
Time frame: 12 months
Left ventricular strain - Echo
Absolute change in LV strain, measured using echocardiography, from baseline to week 52.
Time frame: 12 months
Left ventricular torsion
Absolute change in LV torsion, measured using echocardiography, from baseline to week 52.
Time frame: 12 months
Myocardial cell structure
Absolute change myocardial cell volume, measured using CMR, from baseline to week 52.
Time frame: 12 months
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Diastolic function
Absolute change in LV diastolic function, measured using echocardiography, from baseline to week 52.
Time frame: 12 months
Left atrial volume
Absolute change in left atrial volume, measured using CMR, from baseline to week 52.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 12 months
Patient exercise capacity
Absolute change in exercise tolerance, measured using 6 minute walk distance, from baseline to week 52.
Time frame: 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
Time frame: 12 months
All cause mortality
All cause mortality will be recorded but the trial is not powered for this clinical outcome
Time frame: 12 months
Cardiovascular mortality
Cardiovascular mortality will be recorded but the trial is not powered for this clinical outcome
Time frame: 12 months
Hospitalisation for heart failure
Hospitalisation for heart failure will be recorded but the trial is not powered for this clinical outcome
Time frame: 12 months