Exercise treadmill testing for efficacy evaluation in randomized, controlled trials - 30/04/26

Doi : 10.1016/j.ahj.2026.107379

Andrew Morrow, PhD ^a, Robin Young, PhD ^b, George R. Abraham, BMBCh ^c, Stephen Hoole, DM ^c, Joana Maria Gomes Oliveira, MSc ^c, John P. Greenwood, MBChB, PhD ^d, Jayanth Ranjit Arnold, BMBCh, MA, DPhil ^e, Vanessa Ferreira, SB, MD, DPhil ^f, Roby Rakhit, BSc(Hons), MBBS MD ^g, Gavin Galasko, BA, BM, MA, DM ^h, Aish Sinha, BSc, MRCP ⁱ, Divaka Perera, MD, FRCP ⁱ, Rasha Al-Lamee, MBBS, PhD ^j, Ioakim Spyridopoulos, MD ^k, Ashish Kotecha, MBBS ^l, Gerald Clesham, MA, PhD ^m, Thomas J. Ford, MBChB(Hons), PhD ⁿ, Anthony Davenport, MA, PhD ^o, Sandosh Padmanabhan, MBBS, PhD ^a, Juan Carlos Kaski, MD, DSc ^p, Robin A. Weir, MBChB, MD ^q, Naveed Sattar, MBChB, PhD ^a, Philip Ambery, MBChB, PhD ^r, Paul Welsh, MSc, PhD ^a, Alex McConnachie, PhD ^b, Colin Berry, BSc, MBChB, PhD ^a,^⁎

The PRIZE Study Group

^a British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK

^b Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK

^c Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

^d Baker Heart and Diabetes Institute, Melbourne VIC, Australia

^e University of Leicester and The NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK

^f Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, NIHR Oxford Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, Oxford, UK

^g Royal Free Hospital, Royal Free London NHS Foundation Trust London, and Institute of Cardiovascular Science, UCL, UK

^h Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, and Lancaster University, Lancaster, UK

ⁱ Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, and Kings College London, UK

^j Hammersmith Hospital, Imperial College Healthcare NHS Trust and National Heart and Lung Institute, Imperial College London, UK

^k Translational and Clinical Research Institute, Newcastle University, UK

^l Royal Devon & Exeter Hospital, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK

^m Basildon University Hospital, Mid and South Essex NHS Foundation Trust, Basildon, UK

ⁿ Department of Cardiology, Gosford Hospital - Central Coast LHD, and The University of Newcastle, Australia

^o Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

^p Genomics and Cardiovascular Sciences Research Institute, City St. George's, University of London, London, UK

^q Department of Cardiology, University Hospital Hairmyres, East Kilbride, UK

^r Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden

^⁎ Reprint requests: Colin Berry, BSc, MBChB, PhD, British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, 126 University Place, University of Glasgow, Glasgow, Scotland G12 8TA, UK. British Heart Foundation Glasgow Cardiovascular Research Centre School of Cardiovascular and Metabolic Health 126 University Place, University of Glasgow Glasgow Scotland G12 8TA UK

ABSTRACT

Exercise treadmill testing measures functional capacity and inducible myocardial ischemia and has historically served as an endpoint in phase 2 trials. The Precision Medicine with Zibotentan in Microvascular Angina trial evaluated the selective endothelin-A receptor antagonist zibotentan as a potential disease-modifying therapy for microvascular angina. The trial had a randomized, double-blind, cross-over design and the primary outcome was exercise duration. Compared with placebo, zibotentan at a dose of 10-mg daily for 12-weeks did not improve exercise duration or angina symptoms. In this prespecified analysis, exercise duration was compared across four sequential study visits and the factors associated with within-trial changes were evaluated. Exercise test duration increased progressively in all participants during sequential trial phases, independent of treatment with either zibotentan or placebo. This improvement in exercise duration was associated with female sex (interaction p -value = .0213; effect estimate [95% confidence interval]) 34.95 [13.99, 55.78] seconds, P = .002). In conclusion, the exercise test has limitations as an objective endpoint of efficacy in randomized trials.

PRIZE; NCT04097314

Clinicaltrials.gov Registration: NCT04097314.

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Exercise treadmill testing for efficacy evaluation in randomized, controlled trials - 30/04/26

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