E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with chronic kidney disease who do not have pre-existing cardiovascular disease |
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E.1.1.1 | Medical condition in easily understood language |
Patients with reduced kidney function or protein in the urine who have no previous history of heart attack or stroke |
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E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 |
The primary objective of the research is to test the hypothesis that low-dose (75mg non-enteric coated) aspirin reduces the risk of major vascular events (excluding confirmed intracranial haemorrhage) (primary endpoint) in people with CKD who do not have pre-existing CVD. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the research are:
1. To assess the impact of the addition of low-dose aspirin to usual care in people with CKD and no CVD on the incidence of major intracranial and extracranial bleeds
2. To assess the impact of the addition of low-dose aspirin to usual care in people with CKD and no CVD on the incidence of clinically relevant non-major bleeds
3. To assess the impact of the addition of low-dose aspirin to usual care on other key secondary endpoints including: all-cause mortality; combined endpoint of major vascular events and revascularisation (coronary and non-coronary); individual components of the primary endpoint; TIA; unplanned hospitalisation; new diagnosis of cancer (colorectal/other); CKD progression; health-related quality of life (HRQoL)
4. To examine a priori the effect of low-dose aspirin on primary and secondary endpoints in various subgroups of people with CKD: high risk and very high risk CKD as defined by KDIGO (KDIGO 2012); diabetes; age |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females aged 18 years and over at the date of screening
2. Subjects with diagnosed CKD, defined by: a) estimated GFR <60mL/min/1.73m2 using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR (at least two test results with eGFR <60mL/min/1.73m2 at least 90 days apart with no values ≥60mL/min/1.73m2 in the intervening period) and/or: b) ACR ≥3mg/mmol (at least two test results in this range at least 90 days apart with no values <3mg/mmol in the intervening period). Where no historical (within the last four years) results of ACR are available, patients with a screening ACR >3mg/mmol who have a PCR ≥15mg/mmol at least 90 days before with no values of PCR <15mg/mmol in the intervening period will be eligible. Where there are no historical (within the last four years) ACR or PCR results, patients with a screening ACR >3mg/mmol who have +protein or greater on a reagent strip at least 90 days before with no reagent strip results showing negative or trace protein in the intervening period will be eligible
3. Subjects willing to give permission for their paper and electronic medical records to be accessed and abstracted by trial investigators for the duration of the trial
4. Subjects willing to be contacted and interviewed by trial investigators should the need arise for adverse event assessment
5. Subjects able to communicate well with the investigator or designee, to understand and comply with the requirements of the study and to understand and sign the written informed consent |
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E.4 | Principal exclusion criteria |
1. Subjects with CKD GFR category 5
2. Subjects with pre-existing CVD: angina, MI, stroke (ischaemic and haemorrhagic [intracerebral/subarachnoid]), TIA, significant peripheral vascular disease, coronary or peripheral revascularisation for atherosclerotic disease; aortic aneurysm is not an exclusion criterion
3. Subjects with a pre-existing condition associated with increased risk of bleeding other than CKD: upper GI bleed or peptic ulcer in the previous five years, lower GI bleed in previous twelve months, active chronic liver disease (such as cirrhosis), bleeding diathesis (investigator opinion)
4. Subjects taking over the counter aspirin continuously
5. Subjects currently prescribed anticoagulant or antiplatelet agent, including: • acenocoumarol, phenindione, warfarin • apixaban, edoxaban, rivaroxaban • argatroban, bivalirudin, dabigatran • aspirin, cangrelor, selexipag, cilostazol, clopidogrel, dipyridamole, prasugrel, ticagrelor, abciximab, eptifibatide, tirofiban, epoprostenol, iloprost • unfractionated heparin, dalteparin, enoxaparin, tinzaparin • danaparoid, fondaparinux
6. Subjects who are currently and regularly taking other drugs with a potentially serious interaction with low-dose aspirin, including: • non-steroidal anti-inflammatories (except topical preparations), including: aceclofenac, acemetacin, brcelecoxib, dexibuprofen, dexketoprofen, diclofenac (and combination diclofenac-misoprostol preparation), etodolac, etoricoxib, felbinac, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac trometamol, mefenamic acid, meloxicam, nabumetone, naproxen (and naproxen-esomeprazole), parecoxib, phenylbutazone, piroxicam, sulindac, tenoxicam, tiaprofenic acid, tolfenamic acid • selective serotonin re-uptake inhibitors: citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline • serotonin and noradrenaline re-uptake inhibitors: duloxetine, venlafaxine • nicorandil
7. Subjects with a known allergy to aspirin or definite previous clinically important adverse reaction to aspirin
8. Subjects with poorly controlled hypertension, defined as average of three readings at screening visit of systolic BP ≥180mm Hg and/or diastolic BP ≥105mm Hg
9. Subjects with anaemia: Hb <90g/L; or Hb <100g/L with MCV ≤75 fL
10. Subjects who are pregnant or likely to become pregnant during the study period
11. Subjects with malignancy that is life-threatening or likely to limit prognosis, other life-threatening co-morbidity, or terminal illness
12. Subjects whose behaviour or lifestyle would render them less likely to comply with study medication (e.g. alcoholism, substance abuse, debilitating psychiatric conditions or inability to provide informed consent)
13. Subjects in prison
14. Subjects currently participating in another interventional clinical trial, or who have taken part in a trial in the last three months |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is the time to first major vascular event from the date of randomisation. A major vascular event is defined as a primary composite outcome of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death (excluding confirmed intracranial haemorrhage). Deaths from other causes (including fatal bleeding) will be treated as competing events. Patients who do not experience a major vascular event will be censored at the date of last follow-up. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time to first major vascular event from the date of randomisation. |
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E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS The secondary endpoints are listed below. These will be time to event except health-related quality of life:
Efficacy 1. Death from any cause 2. Composite outcome of major vascular event or revascularisation (coronary and non-coronary) 3. Individual components of the primary composite endpoint 4. Health-related quality of life
Safety 1. Composite outcome of intracranial haemorrhage (fatal and non-fatal), fatal extracranial haemorrhage and non-fatal major extracranial haemorrhage (adjudicated) 2. Fatal and non-fatal (reported individually and as a composite) intracranial haemorrhage comprising: i) primary haemorrhagic stroke (to distinguish from haemorrhagic transformation of ischaemic stroke): a) intracerebral and b) subarachnoid haemorrhage (reported individually and a composite) (adjudicated) ii) other intracranial haemorrhage: a) subdural and b) extradural haemorrhage (reported as a composite) (adjudicated) 3. Fatal and non-fatal (reported individually and as a composite) major extracranial haemorrhage: i) vascular-procedural; ii) vascular-non-procedural; iii) gastrointestinal; iv) genitourinary; v) respiratory; vi) pericardial; vii) ocular; viii) other; ix) undetermined (adjudicated) 4. Clinically relevant non-major bleeding (adjudicated if hospitalised)
TERTIARY ENDPOINTS The following exploratory endpoints will also be studied. These will be time to event except hospitalisation: 1. Transient ischaemic attack 2. Unplanned hospitalisation 3. New diagnosis of cancer (colorectal/other) 4. CKD progression 5. New diagnosis of dementia |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From randomisation onwards (to time of event, except for health-related quality of life / hospitalisation |
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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 | 500 |
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 | No |
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 the trial is defined as reaching the required number of endpoints (1827) - this is an endpoint-driven trial |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |