E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
We plan a large pragmatic trial to test the potential for spironolactone to to reduce overall cardiovascular events and death, to delay the decline in renal function, and to improve surrogate markers for vascular disease in people with stage 3b (eGFR 30-44 ml/min/1.73m2)Chronic Kidney Disease. |
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E.1.1.1 | Medical condition in easily understood language |
Chronic kidney disease (stage 3b) |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018355 |
E.1.2 | Term | Glomerular filtration rate |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007648 |
E.1.2 | Term | Cardiovascular disease, unspecified |
E.1.2 | System Organ Class | 100000004849 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the effect of aldosterone receptor antagonism on mortality and cardiovascular outcomes (onset or progression of cardiovascular disease) in patients with stage 3b CKD. |
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E.2.2 | Secondary objectives of the trial |
To determine the effect of aldosterone receptor antagonism in patients with stage 3b CKD on: 1. Measures of cardiovascular haemodynamics 2. Left ventricular function 3. Decline in renal function 4. Treatment costs and benefits 5. Incidence of TIA 6. To determine the safety of ARA in patients with stage 3b CKD
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Participant is willing and able to give informed consent for participation in the study. • Male or Female, aged 18 years or above. • Evidence of stage 3b CKD using the MDRD equation. This includes patients on the CKD register undergoing annual monitoring who have had 2 or more recent samples in the 3b range. as well as patients with at least two consecutive blood samples within the preceding 12 months (with a minimum of 6 weeks between tests) and no identifiable reason for a temporary reduction in eGFR. Where only one test has been performed and is in the 3b range, GPs will be reminded that standard care suggests a second confirmatory test. • Able (in the recruiting GP’s opinion) and willing to comply with all study requirements. • Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study. • Willing to provide contact details to the Research Team, for use at any time should the need arise, on trial related matters. • If the participant is a female of child-bearing potential, they are willing to ensure effective contraception during the trial period.
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E.4 | Principal exclusion criteria |
• Female participants who is pregnant, lactating or planning pregnancy during the course of the study. • Type 1 diabetes mellitus • Terminal disease or felt otherwise unsuitable by their GP. • Chronic heart failure clinical diagnosis or known LVSD with EF<40%. • Recent myocardial infarction (within 6 months). • Alcohol or drug abuse. • Suspected or known current hazardous or harmful drinking, as defined by an alcohol intake of greater than 42 units every week. • Suspected or known current substance misuse. • Documented previous hyperkalaemia not thought to be spurious, or intolerance of spironolactone. • Serum potassium at baseline over 5 mmol/L. • Documented Addisonian crisis and/or on fludrocortisone. • Documented symptomatic hypotension or baseline systolic blood pressure under 100mmHg. • Recent acute kidney injury or admission for renal failure. • ACR > 70 mg/mmol. • Prescription of medications with known harmful interactions with spironolactone as documented in the British National Formulary including tacrolimus, lithium and cyclosporine. • Any other significant disease or disorder which, in the opinion of the recruiting GP, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant’s ability to participate in the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Composite of death or first onset or hospitalisation for heart disease (coronary heart disease, arrhythmia, new onset/first recorded atrial fibrillation, sudden death, failed sudden death), stroke, or heart failure at 3 years. Primary end-points will be adjudicated by an independent end-points committee blinded to treatment arm. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
An evaluation of whether the primary outcome has been met will be performed at each trial visit by the member of the research team performing that visit. |
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E.5.2 | Secondary end point(s) |
• Change in carotid-femoral pulse wave velocity from baseline to final visit – intensively phenotyped group. • Change in blood pressure at final visit and annually • Rates of hypotension (<100mmHg systolic or >20 mmHg systolic drop on standing) • Mean change in ambulatory blood pressure from randomisation to final visit (measured in mmHg) – intensively phenotyped group. • Changes in BNP. • Change in ACR • Changes in eGFR • Change in health status on EQ-5D-5L • Cost effectiveness analysis • Transient Ischaemic Attack – as defined by the American Heart Association (2009) • Rates of adverse events o Rates of hyperkalaemia
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Due to the nature of the analysis of the secondary endpoints, which requires all results to have been collected, the evaluation will take place once all visits are complete. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
A prospective randomised open blinded endpoint (PROBE) trial |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 120 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of trial will be defined as the date of the last visit for the last patient for the initial 3 year follow-up period. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |