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

NCT ID: NCT02932566

Last Updated: 2020-07-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 129 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-02
• Study Completion Date: 2020-04-29

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.

Conditions

Cardiac Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Pirfenidone

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

Group Type: ACTIVE_COMPARATOR

Pirfenidone

Intervention Type: DRUG

Pirfenidone is an orally bioavailable, small molecule antifibrotic agent.

Placebo

Placebo capsule by mouth, three times a day (target dose) for 12 months

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo capsule, manufactured with the exact components of the Pirfenidone capsules, without the active ingredient / investigational medicinal product

Interventions

Pirfenidone

Pirfenidone is an orally bioavailable, small molecule antifibrotic agent.

Intervention Type: DRUG

Placebo

Placebo capsule, manufactured with the exact components of the Pirfenidone capsules, without the active ingredient / investigational medicinal product

Intervention Type: DRUG

Other Intervention Names

Esbriet

Eligibility Criteria

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.

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute for Health Research, United Kingdom

OTHER_GOV

Sponsor Role: collaborator

University of Manchester

OTHER

Sponsor Role: collaborator

University of Liverpool

OTHER

Sponsor Role: collaborator

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

Manchester University NHS Foundation Trust

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christopher A Miller, MBChB, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Manchester

Locations

Manchester University NHS Foundation Trust

Manchester, Greater Manchester, United Kingdom

Countries

United Kingdom

References

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Reference Type: BACKGROUND

PMID: 19996196 (View on PubMed)

King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18.

Reference Type: BACKGROUND

PMID: 24836312 (View on PubMed)

Van Erp C, Irwin NG, Hoey AJ. Long-term administration of pirfenidone improves cardiac function in mdx mice. Muscle Nerve. 2006 Sep;34(3):327-34. doi: 10.1002/mus.20590.

Reference Type: BACKGROUND

PMID: 16770778 (View on PubMed)

Yamazaki T, Yamashita N, Izumi Y, Nakamura Y, Shiota M, Hanatani A, Shimada K, Muro T, Iwao H, Yoshiyama M. The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice. Hypertens Res. 2012 Jan;35(1):34-40. doi: 10.1038/hr.2011.139. Epub 2011 Aug 25.

Reference Type: BACKGROUND

PMID: 21866107 (View on PubMed)

Wang Y, Wu Y, Chen J, Zhao S, Li H. Pirfenidone attenuates cardiac fibrosis in a mouse model of TAC-induced left ventricular remodeling by suppressing NLRP3 inflammasome formation. Cardiology. 2013;126(1):1-11. doi: 10.1159/000351179. Epub 2013 Jul 2.

Reference Type: BACKGROUND

PMID: 23839341 (View on PubMed)

Lewis GA, Rosala-Hallas A, Dodd S, Schelbert EB, Williams SG, Cunnington C, McDonagh T, Miller CA. Characteristics Associated With Growth Differentiation Factor 15 in Heart Failure With Preserved Ejection Fraction and the Impact of Pirfenidone. J Am Heart Assoc. 2022 Jul 19;11(14):e024668. doi: 10.1161/JAHA.121.024668. Epub 2022 Jul 13.

Reference Type: DERIVED

PMID: 35861823 (View on PubMed)

Lewis GA, Rosala-Hallas A, Dodd S, Schelbert EB, Williams SG, Cunnington C, McDonagh T, Miller CA. Impact of Myocardial Fibrosis on Cardiovascular Structure, Function and Functional Status in Heart Failure with Preserved Ejection Fraction. J Cardiovasc Transl Res. 2022 Dec;15(6):1436-1443. doi: 10.1007/s12265-022-10264-7. Epub 2022 Jul 5.

Reference Type: DERIVED

PMID: 35790651 (View on PubMed)

Lewis GA, Rosala-Hallas A, Dodd S, Schelbert EB, Williams SG, Cunnington C, McDonagh T, Miller CA. Predictors of myocardial fibrosis and response to anti-fibrotic therapy in heart failure with preserved ejection fraction. Int J Cardiovasc Imaging. 2022 Jul;38(7):1569-1578. doi: 10.1007/s10554-022-02544-9. Epub 2022 Feb 9.

Reference Type: DERIVED

PMID: 35138474 (View on PubMed)

Lewis GA, Dodd S, Clayton D, Bedson E, Eccleson H, Schelbert EB, Naish JH, Jimenez BD, Williams SG, Cunnington C, Ahmed FZ, Cooper A, Rajavarma Viswesvaraiah, Russell S, McDonagh T, Williamson PR, Miller CA. Pirfenidone in heart failure with preserved ejection fraction: a randomized phase 2 trial. Nat Med. 2021 Aug;27(8):1477-1482. doi: 10.1038/s41591-021-01452-0. Epub 2021 Aug 12.

Reference Type: DERIVED

PMID: 34385704 (View on PubMed)

Lewis GA, Schelbert EB, Naish JH, Bedson E, Dodd S, Eccleson H, Clayton D, Jimenez BD, McDonagh T, Williams SG, Cooper A, Cunnington C, Ahmed FZ, Viswesvaraiah R, Russell S, Neubauer S, Williamson PR, Miller CA. Pirfenidone in Heart Failure with Preserved Ejection Fraction-Rationale and Design of the PIROUETTE Trial. Cardiovasc Drugs Ther. 2019 Aug;33(4):461-470. doi: 10.1007/s10557-019-06876-y.

Reference Type: DERIVED

PMID: 31069575 (View on PubMed)

Other Identifiers

2016CD004

Identifier Type: -

Identifier Source: org_study_id