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

NCT02932566 | Completed Phase 2 DMC

• 1 other identifier: 2016CD004
• Study Type: interventional
• Target: 129
• Locations: 1 country
• Sites: 1

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.

Conditions

Cardiac Failure

Keywords

Heart failure; Heart failure with preserved ejection fraction (HFpEF); Myocardial fibrosis; Extracellular volume fraction (ECV); Interstitial fibrosis

Outcome Measures

Primary Outcomes (1)

• Extracellular volume fraction (ECV)

  Absolute change in myocardial ECV, measured using CMR, from baseline to week 52

  12 months

Secondary Outcomes (17)

• Left ventricular (LV) mass

  12 months

• Left ventricular volume

  12 months

• Left ventricular ejection fraction

  12 months

• Left ventricular strain - CMR

  12 months

• Left ventricular strain - Echo

  12 months

Study Arms (2)

Pirfenidone

ACTIVE COMPARATOR

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

Drug: Pirfenidone

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Pirfenidone DRUG

Pirfenidone is an orally bioavailable, small molecule antifibrotic agent.

Also known as: Esbriet

Pirfenidone

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Manchester University NHS Foundation Trust: lead
• National Institute for Health Research, United Kingdom: collaborator
• University of Manchester: collaborator
• University of Liverpool: collaborator
• Hoffmann-La Roche: collaborator

Study Sites (1)

Manchester University NHS Foundation Trust

Manchester, Greater Manchester, M23 9LT, United Kingdom

Location

Related Publications (10)

• Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A, Takeuchi M, Raghu G, Kudoh S, Nukiwa T; Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010 Apr;35(4):821-9. doi: 10.1183/09031936.00005209. Epub 2009 Dec 8.

  PMID: 19996196 BACKGROUND

• 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.

  PMID: 24836312 BACKGROUND

• 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.

  PMID: 16770778 BACKGROUND

• 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.

  PMID: 21866107 BACKGROUND

• 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.

  PMID: 23839341 BACKGROUND

• 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.

  PMID: 35861823 DERIVED

• 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.

  PMID: 35790651 DERIVED

• 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.

  PMID: 35138474 DERIVED

• 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.

  PMID: 34385704 DERIVED

• 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.

  PMID: 31069575 DERIVED

MeSH Terms

Conditions

Heart Failure; Pulmonary Fibrosis

Interventions

pirfenidone

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Christopher A Miller, MBChB, PhD

  University of Manchester

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2016
• First Posted: October 13, 2016
• Study Start: March 2, 2017
• Primary Completion: November 29, 2019
• Study Completion: April 29, 2020
• Last Updated: July 2, 2020

Record last verified: 2020-07

Locations

GB (1)