A Thesis Submitted for the Degree of PhD at the University of Warwick Permanent WRAP URL: http://wrap.warwick.ac.uk/149337 Copyright and reuse: This thesis is made available online and is protected by original copyright. Please scroll down to view the document itself. Please refer to the repository record for this item for information to help you to cite it. Our policy information is available from the repository home page. For more information, please contact the WRAP Team at: [email protected] warwick.ac.uk/lib-publications A Randomized Trial of Neprilysin Inhibition with Sacubitril/valsartan vs Irbesartan in Chronic Kidney Disease by Dr Parminder Kaur Judge Thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy (PhD) in Medicine University of Warwick & Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford Submitted June 2020 1 Contents Section Page List of Tables 7 List of Figures 9 Acknowledgements 10 Declarations 12 Inclusion of Published Work 13 Abstract 14 Chapters 1 List of abbreviations 15 2 Introduction 19 3 Natriuretic peptide system and neprilysin 35 2 4 Angiotensin receptor-neprilysin inhibitor (ARNI) 46 Effects on renal function 50 Effects on albuminuria 53 5 Methods 65 Trial organisation 70 Staff training 70 Data management 70 Trial treatments 70 Consent 72 Biological samples 73 Randomized treatment and blinding 76 Blood and urine samples 76 3 Adverse events and compliance with trial treatment 77 Physical measurements 78 Blood and urine samples 78 Central laboratory methods 79 Issuing trial treatment 79 Final follow-up and mGFR 79 Analysis of Covariance (ANCOVA) 82 Repeated measures analyses of biomarkers 83 Imputation of missing data 83 Imputation of the primary outcome data 84 6 Trial Management 87 Trial protocol 88 Standard Operating Procedures and internal operating procedures 89 Participant-facing documents 90 Recruitment 97 Key data 98 Compliance 98 Data errors 99 4 CCO monitoring 100 Independent DMC monitoring 102 7 Results 103 Renal safety data 135 Liver safety data 135 8 Discussion 137 5 Effect of renin-angiotensin system inhibition on glomerular haemodynamics in heart failure 147 Effect of neprilysin inhibition on glomerular haemodynamics in heart failure 147 Effect of angiotensin receptor-neprilysin inhibition on glomerular haemodynamics in heart failure 148 Effects of renin angiotensin system inhibition on glomerular haemodynamics in CKD 148 Possible effect of neprilysin inhibition on glomerular haemodynamics in CKD149 Hyperkalaemia 159 Acute kidney injury 160 9 References 165 6 List of Tables Table 1: Prevalence estimates of chronic kidney disease in the United States by stage 19 Table 2: Examples of vasopeptidase inhibitors produced and studied in humans 41 Table 3: Angioedema rates in PARADIGM-HF patients treated with sacubitril/valsartan and enalapril 58 Table 4: Renal safety data from PARAMOUNT with sacubitril/valsartan and valsartan-alone 59 Table 5: Renal adverse events following treatment with sacubitril/valsartan in patients with heart failure 59 Table 6: UK HARP-III trial aims 66 Table 7: UK HARP-III trial inclusion and exclusion criteria 68 Table 8: Planned central laboratory blood and urine analyses 77 Table 9: Continuous and categorical data in UK HARP-III 82 Table 10: Reasons for ineligibility for UK HARP-III during the screening visit 106 Table 11: Reasons for withdrawal from pre-randomization run-in 107 Table 12: Any adverse event during pre-randomization run-in 108 Table 13: Reasons for ineligibility at randomization 109 Table 14A: Baseline characteristic of UK HARP-III participants randomized 110 Table 14B: Baseline characteristic of UK HARP-III participants randomized 111 Table 15: Compliance with trial follow-up visits following randomization in UK HARP-III 113 Table 16: Compliance with randomized treatment in UK HARP-III 115 Table 17: Reasons for stopping full dose randomized study treatment 116 Table 18: Reasons for completely stopping randomized study treatment 118 Table 19: Primary outcome: Effect of sacubitril/valsartan on rate of change in measured glomerular filtration rate at 12 months 119 Table 20: Pre-specified sensitivity analysis of the effect of randomization to sacubitril/valsartan on measured glomerular filtration rate as 12 months, excluding participants with missing measured glomerular filtration rate values at 12 months 120 Table 21: Effect of randomization to sacubitril/valsartan on urinary albumin:creatinine ratio at 3, 6 and 12 months 123 Table 22: Post-hoc exploratory analysis analysing the effect of allocation to sacubitril/valsartan on study average urinary albumin:creatinine ratio in a range of subgroups 124 Table 23: Effect of randomization to sacubitril/valsartan on rate of change in estimated glomerular filtration rate slopes 125 Table 24: Effect of randomization to sacubitril/valsartan on systolic and diastolic blood pressure 126 Table 25: Effect of randomization to sacubitril/valsartan on cardiac biomarkers 127 Table 26: Post-hoc assessment of the effect of sacubitril/valsartan on NT-proBNP 128 Table 27: Post-hoc assessment of the effect of sacubitril/valsartan on troponin I 129 7 Table 28: Associations between baseline characteristics and sacubitril/valsartan metabolite values at the 3 month visit 130 Table 29A: Effect of randomization to sacubitril/valsartan on serious adverse events 131 Table 29B: Effect of randomization to sacubitril/valsartan on serious adverse events 132 Table 30A: Effect of sacubitril/valsartan on non-serious adverse reactions 133 Table 30B: Effect of sacubitril/valsartan on non-serious adverse reactions 134 Table 31: Effect of sacubitril/valsartan on renal safety outcomes 135 Table 32: Effect of sacubitril/valsartan on liver safety outcomes 136 8 List of Figures Figure 1: Renin-angiotensin system 21 Figure 2: Renin-angiotensin system and sites of therapeutic blockade 23 Figure 3: Mechanism of action of natriuretic peptides and neprilysin 36 Figure 4: Production and metabolism of bradykinin 44 Figure 5: Mechanism of action of angiotensin receptor-neprilysin inhibitors 45 Figure 6: Difference in mean sitting systolic and diastolic blood pressure (BP) at 8 weeks with maximum sacubitril/valsartan (S/V; n=170) dose compared with full dose valsartan (n=163) 48 Figure 7: UK HARP-III trial design overview 69 Figure 8: Numbers of participants screened using the pre-screening and traditional methods of recruitment 104 Figure 9: Flow of participant through the UK HARP-III trial 105 Figure 10: Five-year risk of progression to End-stage kidney disease among UK HARP-III participants 113 Figure 11: Effect of sacubitril/valsartan on measured glomerular filtration rate at 12 months in a range of pre-specified sub-groups 121 Figure 12: Effect of randomization to sacubitril/valsartan on estimated glomerular filtration rate 122 9 Acknowledgements I would first like to thank the participants of the UK Heart and Renal Protection (HARP)- III trial without whom it would not have been possible to undertake this research. I am incredibly thankful to my supervisor, Professor Richard Haynes (Medical Research Council Population Health Research Unit [MRC PHRU], University of Oxford and Honorary Consultant Nephrologist, Oxford University Hospitals NHS Foundation Trust), for all his guidance, patience, kindness and friendship. He provided me with the opportunity and encouragement to undertake research in clinical trials at the MRC PHRU and through this mentorship, initiated my desire and motivation to pursue a career in clinical research and clinical trials. The opportunities and ongoing support he has always provided me over many years, has been instrumental to me gaining my current role as Senior Clinical Research Fellow within the Renal Studies Group, University of Oxford, and so I will be forever indebted to him. I am hugely grateful to Professor Colin Baigent (Professor of Epidemiology and Director of MRC PHRU, University of Oxford) for all his encouragement and guidance. His support has helped turn my ambition to become an academic researcher into a reality. I would also like to thank Professor Martin Landray (Professor of Medicine and Epidemiology, Big Data Institute, University of Oxford and fellow alumni of University of Birmingham) for all his support and guidance with undertaking clinical trials. I am extremely grateful for the kindness, encouragement and support of my clinical supervisor, Dr Edward Sharples (Consultant Nephrologist, Oxford University Hospitals NHS Foundation Trust). He has provided great mentorship, advice and friendship throughout my nephrology training and my time out of programme for research. Dr Daniel Mitchell, Co-Supervisor, (University of Warwick) has been extremely helpful, patient and generous with his time and provided invaluable support and assistance with completion of my thesis. I am also hugely thankful to Dr Natalie Staplin, Senior Statistician (MRC PHRU, University of Oxford), for all her guidance, assistance, time and friendship. Without her input and support the analyses presented within this thesis, and the many co-authored publications, would not have been possible. 10 I appreciate the support, teaching and mentorship I received from Dr William Herrington (Senior Clinical Research Fellow, Renal Studies Group, University of Oxford) on clinical trials and epidemiology and, for providing me with the opportunities to collaborate with him on a range of observational analyses. I would like to thank all of