Heart failure with preserved ejection fraction (HFpEF) MedDRA version: 19.0 Level: LLT Classification code 10069211 Term: Diastolic heart failure System Organ Class: 100000004849 MedDRA version: 19.0 Level: LLT Classification code 10019279 Term: Heart failure System Organ Class: 100000004849
Conditions
Interventions
Trade Name: Esbriet
Product Name: Esbriet
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Pirfenidone
CAS Number: 53179-13-8
Other descriptive name: 5-methyl-1-phenyl-2-[1H]pyridone
Concentra
Sponsors
University Hospital of South Manchester
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients eligible for inclusion in this study should fulfil all of the following 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. 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. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 100 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 100
Exclusion criteria
Exclusion criteria: Patients with the following characteristics will be excluded from the trial: 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: a. Severe chronic obstructive pulmonary disease (COPD) (i.e., requiring home oxygen, chronic nebuliser therapy, or chronic oral steroid therapy), or b. Haemoglobin 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 eGFR 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 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To test if pirfenidone compared to placebo leads to regression of myocardial fibrosis in patients with heart failure and preserved left ventricular ejection fraction and myocardial fibrosis at Visit 0.;Secondary Objective: To determine if pirfenidone is superior to placebo in leading to improvements in ventricular size, function and mechanics; left atrial volume and function; myocardial energetics; blood biomarkers of fluid status and myocardial injury; exercise tolerance and quality of life. Also to assess the safety of pirfenidone.;Primary end point(s): Absolute change in myocardial ECM volume, measured using CMR, from baseline to week 52. ;Timepoint(s) of evaluation of this end point: The primary endpoint of the study, change in myocardial ECM volume measured using CMR, represents a highly meaningful clinically outcome measure, demonstrated to be reliable, valid and strongly predictive of outcome in HF. Myocardial ECM volume is a physiological parameter. ECM expansion is a key component of HFpEF pathophysiology, and in keeping with this, ECM volume is strongly and independently associated with death and with hospitalisation for HF. CMR straightforwardly, accurately and highly reproducibly quantifies ECM volume and has therefore been used as an endpoint in multiple trials. ECM volume will measured by CMR at the start and end of the 52 week trial period, and study groups compared. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): a) Change in LV mass, volumes, ejection fraction and strain, measured using CMR, from baseline to week 52. b) Change in absolute myocardial ECM volume, measured using CMR, from baseline to week 52. c) Change in absolute myocardial cell volume, measured using CMR, from baseline to week 52. d) Change in LV diastolic function, strain and torsion, measured using echocardiography, from baseline to week 52. e) Change in left atrial volume and function, measured using CMR, from baseline to week 52. f) Change in myocardial energetic status (PCr/ATP ratio), measured using 31P MRS, from baseline to week 52. g) Change in NT-proBNP and hsTn from baseline to week 13, baseline to week 26 and baseline to week 52. h) Change in exercise tolerance, measured using 6 minute walk distance, from baseline to week 52. i) Change in health status (quality of life), HF symptoms and physical limitations, measured using change in KCCQ score, from baseline to week 52. j) All cause mortality, cardiovascular mortality and hospitalisation for heart failure will be recorded but the trial is not powered for these clinical outcomes ;Timepoint(s) of evaluation of this end point: All secondary end-points will be assessed at the start and end of week 52 of the trial, with cardiac biomarkers also being assessed at weeks 13 and 26. | — |
Countries
United Kingdom
Outcome results
None listed