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

Phase 2

Completed

• Conditions: Cardiac Failure
• Interventions: Drug: Placebo; Drug: Pirfenidone

• Registration Number: NCT02932566
• Lead Sponsor: Manchester University NHS Foundation Trust

Brief Summary

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

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 Timeline

• Study First Submitted: 2016-09-27
• Study First Submitted QC: 2016-10-12
• Study First Posted: 2016-10-13
• Study Start: 2017-03-02
• Primary Completion: 2019-11-29
• Study Completion: 2020-04-29
• Status Verified: 2020-07
• Last Update Submitted: 2020-07-01
• Last Update Posted: 2020-07-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 129

Inclusion Criteria

1. Written informed consent.

2. Male or female; aged 40 years or older.

3. 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

4. Left Ventricular Ejection Fraction (LVEF) > 45% at Visit 0, (any local LVEF measurement made using echocardiography or CMR).

5. 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.

6. Myocardial fibrosis, defined as Extracellular Matrix (ECM) volume > 27% by CMR at Visit 0.

Exclusion Criteria

1. Myocardial infarction, coronary artery bypass graft surgery or percutaneous coronary intervention within the previous 6 months.

2. 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:

   1. Severe chronic obstructive pulmonary disease (COPD) (i.e., requiring home oxygen, chronic nebuliser therapy, or chronic oral steroid therapy), or
   2. Haemoglobin < 9 g/dl, or
   3. Body mass index (BMI) > 55 kg/m2.

3. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy.

4. Clinically significant congenital heart disease.

5. Presence of severe valvular heart disease.

6. Atrial fibrillation or flutter with a resting ventricular rate > 100 bpm.

7. 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.

8. 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.

9. 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.

10. Prolonged corrected QT interval, defined as a corrected QT interval >500 msec on ECG using Bazett formula.

11. Known hypersensitivity to any of the components of the investigational medicinal product (IMP).

12. Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer.

13. Fluvoxamine use within 28 days of Visit 0.

14. Contraindication to MRI scanning or gadolinium-based contrast agent

15. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo capsule by mouth, three times a day (target dose) for 12 months
Pirfenidone	Pirfenidone	Pirfenidone 801mg capsule by mouth, three times a day (target dose) for 12 months

Primary Outcome Measures

Name	Time	Method
Extracellular volume fraction (ECV)	12 months	Absolute change in myocardial ECV, measured using CMR, from baseline to week 52

Secondary Outcome Measures

Name	Time	Method
Left ventricular strain - Echo	12 months	Absolute change in LV strain, measured using echocardiography, from baseline to week 52.
Left atrial volume	12 months	Absolute change in left atrial volume, measured using CMR, from baseline to week 52.
Myocardial energetic status	12 months	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.
Left ventricular volume	12 months	Absolute change in LV volume, measured using CMR, from baseline to week 52.
Left ventricular strain - CMR	12 months	Absolute change in LV strain, measured using CMR, from baseline to week 52.
Diastolic function	12 months	Absolute change in LV diastolic function, measured using echocardiography, from baseline to week 52.
Myocardial cell structure	12 months	Absolute change myocardial cell volume, measured using CMR, from baseline to week 52.
Patient morbidity	12 months	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
Cardiovascular mortality	12 months	Cardiovascular mortality will be recorded but the trial is not powered for this clinical outcome
Left ventricular (LV) mass	12 months	Absolute change in LV mass, measured using CMR, from baseline to week 52.
Left ventricular ejection fraction	12 months	Absolute change in LV ejection fraction, measured using CMR, from baseline to week 52.
Left ventricular torsion	12 months	Absolute change in LV torsion, measured using echocardiography, from baseline to week 52.
Cardiac biomarkers - high-sensitivity Troponin T (hsTnT)	12 months	Absolute change in hsTnT from baseline to week 13, baseline to week 26 and baseline to week 52.
All cause mortality	12 months	All cause mortality will be recorded but the trial is not powered for this clinical outcome
Hospitalisation for heart failure	12 months	Hospitalisation for heart failure will be recorded but the trial is not powered for this clinical outcome
Cardiac biomarkers - N-Terminal-Pro-Brain Natriuretic Peptide (NT-Pro BNP)	12 months	Absolute change in NT-Pro BNP from baseline to week 13, baseline to week 26 and baseline to week 52.
Patient exercise capacity	12 months	Absolute change in exercise tolerance, measured using 6 minute walk distance, from baseline to week 52.

Trial Locations

Locations (1)

Manchester University NHS Foundation Trust; 🇬🇧 Manchester, Greater Manchester, United Kingdom