<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03796156</url>
  </required_header>
  <id_info>
    <org_study_id>31844</org_study_id>
    <nct_id>NCT03796156</nct_id>
  </id_info>
  <brief_title>Aspirin to Target Arterial Events in Chronic Kidney Disease</brief_title>
  <acronym>ATTACK</acronym>
  <official_title>Aspirin to Target Arterial Events in Chronic Kidney Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Southampton</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Nottingham</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Warwick</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Nottingham University Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>East Kent Hospitals University NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Durham</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Epsom and St Helier University Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Southampton</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study aims to find out whether people with chronic kidney disease [CKD] should take low&#xD;
      dose aspirin to reduce the risk of first heart attack or stroke (cardiovascular disease&#xD;
      [CVD]). CKD is common and is associated with an increased risk of CVD.&#xD;
&#xD;
      CVD is caused by small blood clots and aspirin thins the blood to reduce the risk of such&#xD;
      clots developing but it also increases the risk of bleeding.&#xD;
&#xD;
      Aspirin is recommended to prevent further CVD in people who have already had a first CVD&#xD;
      event (so called secondary prevention). Here the investigators want to study the use of&#xD;
      aspirin as primary prevention in people with CKD who have not had a CVD to prevent the first&#xD;
      event, to assess whether the potential benefits exceed the risks.&#xD;
&#xD;
      Eligible patients will be recruited from their United Kingdom (UK) general practices and&#xD;
      allocated by chance to be prescribed once daily low dose aspirin or usual care only.&#xD;
      Follow-up will be for several years both electronically (for general practice, hospital and&#xD;
      mortality data) and by annual questionnaires to ascertain CVD and bleeding events.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aim To test the hypothesis that the addition of 75mg aspirin once daily to usual care reduces&#xD;
      the risk of major vascular events in patients with chronic kidney disease (CKD) who do not&#xD;
      have pre-existing cardiovascular disease (CVD)&#xD;
&#xD;
      Design Open label, multi-centre randomised controlled trial&#xD;
&#xD;
      Setting UK general practices&#xD;
&#xD;
      Sample size 25,210 patients (12,605 per arm). A total of 1,827 major vascular events overall&#xD;
      are required.&#xD;
&#xD;
      Eligibility Inclusion Criteria&#xD;
&#xD;
        1. Males and females aged 18 years and over at the date of screening&#xD;
&#xD;
        2. Subjects with CKD (reduced eGFR and/or albuminuria) defined as: • estimated glomerular&#xD;
           filtration rate [eGFR] &lt;60mL/min/1.73m2 for at least 90 days, and/or • kidney disease&#xD;
           code on the GP electronic patient AND most recent eGFR in CKD-defining range&#xD;
           (&lt;60mL/min/1.73m2), and/or • albuminuria or proteinuria (defined as urine&#xD;
           albumin:creatinine ratio [ACR] ≥3mg/mmol, and/or urine protein:creatinine ratio [PCR]&#xD;
           ≥15mg/mmol, and/or +protein or greater on reagent strip)&#xD;
&#xD;
        3. Subjects who are willing to give permission for their paper and electronic medical&#xD;
           records to be accessed by trial investigators&#xD;
&#xD;
        4. Subjects who are willing to be contacted and interviewed by trial investigators&#xD;
&#xD;
        5. Subjects who can communicate well with the investigator or designee, understand the&#xD;
           requirements of the study and understand and sign the written informed consent&#xD;
&#xD;
      Exclusion Criteria&#xD;
&#xD;
        1. Subjects with CKD eGFR category 5&#xD;
&#xD;
        2. Subjects with pre-existing cardiovascular disease (angina, myocardial infarction,&#xD;
           stroke, transient ischaemic attack (TIA), significant peripheral vascular disease,&#xD;
           coronary or peripheral revascularisation for atherosclerotic disease)&#xD;
&#xD;
        3. Subjects with a current pre-existing condition associated with increased risk of&#xD;
           bleeding other than CKD&#xD;
&#xD;
        4. Subjects currently prescribed anticoagulants or antiplatelet agent, or taking over the&#xD;
           counter (OTC) aspirin continuously&#xD;
&#xD;
        5. Subjects who are currently and regularly taking other drugs with a potentially serious&#xD;
           interaction with aspirin&#xD;
&#xD;
        6. Subjects with a known allergy to aspirin or definite previous clinically important&#xD;
           adverse reaction&#xD;
&#xD;
        7. Subjects with poorly controlled hypertension (systolic blood pressure [BP] ≥180 mmHg&#xD;
           and/or diastolic BP ≥105 mmHg)&#xD;
&#xD;
        8. Subjects with other conditions which in the opinion of their General Practitioner (GP)&#xD;
           would preclude prescription of aspirin in routine clinical practice, for example&#xD;
           significant anaemia or thrombocytopenia.&#xD;
&#xD;
        9. Subjects who are pregnant or likely to become pregnant during the study period&#xD;
&#xD;
       10. Subjects with malignancy that is life-threatening or likely to limit prognosis, other&#xD;
           life-threatening co-morbidity, or terminal illness&#xD;
&#xD;
       11. Subjects whose behaviour or lifestyle would render them less likely to comply with study&#xD;
           medication&#xD;
&#xD;
       12. Subjects in prison&#xD;
&#xD;
       13. Subjects currently participating in another clinical trial of an investigational&#xD;
           medicinal product or who have taken part in such a trial in the last three months&#xD;
           (Covid-19 vaccine studies are acceptable)&#xD;
&#xD;
      Interventions Suitable participants will be randomised to receive: 75mg non-enteric coated or&#xD;
      dispersible aspirin once daily in addition to their usual medication; or no additional&#xD;
      treatment and avoidance of aspirin.&#xD;
&#xD;
      Duration The trial will continue until at least 1,827 adjudicated primary endpoint events&#xD;
      (major vascular events) have occurred, or before if the trial is discontinued after the&#xD;
      internal pilot or for any other reason. It is anticipated that at least 6 years of&#xD;
      recruitment (taking account a recruitment pause for the Covid-19 pandemic) and 2.5 years of&#xD;
      follow-up will be required to complete the trial.&#xD;
&#xD;
      Randomisation and blinding Eligible participants, based on results of routine blood and urine&#xD;
      tests at screening, will be randomised (open label randomisation) 1:1 to general practitioner&#xD;
      (GP) prescription of aspirin vs. no prescription, stratified by age, diabetes and CKD&#xD;
      severity.&#xD;
&#xD;
      Follow-up Data on potential CVD and bleeding outcomes will be collected electronically from&#xD;
      GP records and national hospitalisation and mortality records. Adjudication panels (for CVD&#xD;
      and for bleeding) will asses the information blind to allocation.&#xD;
&#xD;
      Patients will complete an annual quality of life questionnaire (EQ5D).&#xD;
&#xD;
      Outcomes. Primary outcome measure&#xD;
&#xD;
      Time to first major vascular event from the date of randomisation. A major vascular event is&#xD;
      defined as a primary composite outcome of non-fatal myocardial infarction (MI), non-fatal&#xD;
      stroke and cardiovascular death (excluding confirmed intracranial haemorrhage and other fatal&#xD;
      cardiovascular haemorrhage).&#xD;
&#xD;
      Secondary outcome measures (all time to event except quality of life)&#xD;
&#xD;
      Efficacy&#xD;
&#xD;
        1. Death from any cause&#xD;
&#xD;
        2. Composite outcome of major vascular event or revascularisation (coronary and&#xD;
           non-coronary)&#xD;
&#xD;
        3. Individual components of the primary composite endpoint&#xD;
&#xD;
        4. Health-related quality of life&#xD;
&#xD;
      Safety&#xD;
&#xD;
        1. Composite outcome of intracranial haemorrhage (fatal and non-fatal), fatal extracranial&#xD;
           haemorrhage and non-fatal major extracranial haemorrhage (adjudicated)&#xD;
&#xD;
        2. Fatal and non-fatal (reported individually and as a composite) intracranial haemorrhage&#xD;
           comprising: i) primary haemorrhagic stroke (to distinguish from haemorrhagic&#xD;
           transformation of ischaemic stroke); ii) other intracranial haemorrhage (adjudicated).&#xD;
           Intra-cranial haemorrhage will be sub-categorised as traumatic or non-traumatic.&#xD;
&#xD;
        3. Fatal and non-fatal (reported individually and as a composite) major extracranial&#xD;
           haemorrhage: i) upper gastrointestinal; ii) lower gastrointestinal; iii)&#xD;
           sight-threatening ocular; iv) multiple trauma; v) other (adjudicated).&#xD;
&#xD;
        4. Clinically relevant non-major bleeding if hospitalised (adjudicated).&#xD;
&#xD;
        5. Composite outcome of fatal and non-fatal major extracranial haemorrhage and clinically&#xD;
           relevant non-major bleeding (if hospitalised).&#xD;
&#xD;
      Tertiary (exploratory) outcome measures (all time to event except hospitalisation)&#xD;
&#xD;
        1. Transient ischaemic attack&#xD;
&#xD;
        2. Unplanned hospitalisation&#xD;
&#xD;
        3. Hospitalisation with heart failure&#xD;
&#xD;
        4. New diagnosis of cancer (colorectal/other)&#xD;
&#xD;
        5. Death due to cancer (where cancer is the underlying cause of death)&#xD;
&#xD;
        6. CKD progression&#xD;
&#xD;
        7. New diagnosis of dementia&#xD;
&#xD;
        8. Major non-traumatic lower limb amputation&#xD;
&#xD;
      Statistical methods The primary outcome measure of time to first major vascular event will be&#xD;
      analysed for the intention-to-treat (ITT) population. Deaths from other causes (including&#xD;
      fatal bleeding) will be treated as competing events. Patients who do not experience a major&#xD;
      vascular event will be censored at the date of last follow-up.&#xD;
&#xD;
      All primary, secondary and tertiary time to event outcomes will be described using&#xD;
      Kaplan-Meier curves or Cumulative Hazard plots for time to event outcomes involving competing&#xD;
      risks for the ITT population. Analyses of time to event outcomes will be performed using Cox&#xD;
      proportional hazards models or Competing Risk regression models, both unadjusted and adjusted&#xD;
      for stratification factors: age, diabetes and CKD severity.&#xD;
&#xD;
      The adjusted Competing Risk regression model for time to first major vascular event, with&#xD;
      deaths from other causes (including fatal bleeding) treated as competing events, and patients&#xD;
      who do not experience a major vascular event censored, will form the primary endpoint&#xD;
      analysis model.&#xD;
&#xD;
      Other secondary and tertiary endpoints will be assessed by arm using summary statistics (e.g.&#xD;
      Pearson's χ² tests) in the ITT population.&#xD;
&#xD;
      The amount of missing data and reasons for the incompleteness will be explored and presented&#xD;
      overall i.e. not by group. If the amount of missing data is deemed too high and if&#xD;
      appropriate (i.e. assuming the missing data is either missing at random [MAR] or missing&#xD;
      completely at random [MCAR] and censoring assumed to be non-informative), multiple imputation&#xD;
      will be performed accordingly, for which all covariates included in the multivariable model,&#xD;
      together with the censoring/event indicator and the cumulative baseline hazard will be&#xD;
      included in the multiple imputation model.&#xD;
&#xD;
      Health economic analysis will also be undertaken.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 25, 2019</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2025</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Adjudication of outcomes blinded</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with a Major vascular event: Composite outcome of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death (excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage)</measure>
    <time_frame>Over average 4 years follow-up</time_frame>
    <description>Acute MI defined according to the Third Universal Definition of myocardial infarction (MI).&#xD;
Acute stroke defined in accordance with the World Health Organization (WHO) definition as &quot;rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer, with no apparent cause other than of vascular origin&quot;. This excludes cases of primary cerebral tumour, cerebral metastasis, subdural haematoma, post-seizure palsy, brain trauma and TIA. Haemorrhagic stroke (fatal and non-fatal) including intracerebral haemorrhage and SAH which has been confirmed on appropriate imaging is excluded from the primary composite endpoint and included within the secondary endpoints.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants dying from any cause</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with major vascular events plus revascularisation</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Primary outcome plus coronary and non coronary arterial revascularisation. It will include open and percutaneous coronary and non-coronary (including carotid, aortic and limb) procedures (as defined in Office of Population Censuses and Surveys OPCS-4 procedure codes) and will be ascertained from Hospital Episode Statistics (HES) data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Non-fatal myocardial infarction</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Non-fatal myocardial infarction. Acute MI defined according to the Third Universal Definition of myocardial infarction (MI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related quality of life, mean utility score</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Euroqol EQ-5D utility score derived from 5 states (scoring 1-5) converted to utility values using UK general population set</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with intra-cranial haemorrhage, fatal and non fatal major extra cranial haemorrhage</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Intra-cranial haemorrhage includes intracerebral haemorrhage, subarachnoid haemorrhage, subdural haemorrhage, and extradural haemorrhage.&#xD;
Extra-cranial haemorrhage is:&#xD;
Fatal bleeding, or&#xD;
Symptomatic bleeding in a critical area or organ, such as intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, or&#xD;
Bleeding that leads to the transfusion of two or more units of whole blood or red cells&#xD;
In particular, to be classified as major, bleeds in a critical area or organ should:&#xD;
Be associated with a symptomatic clinical presentation (not following an incidental finding)&#xD;
Be the cause of the symptoms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Fatal and non-fatal intra-cranial haemorrhage</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Fatal and non-fatal intra-cranial haemorrhage as above It comprises primary haemorrhagic stroke(to distinguish from haemorrhagic transformation of ischaemic stroke) ii)other intra-cranial haemorrhage (adjudicated). Intra-cranial haemorrhage will be sub categorised as traumatic and non-traumatic.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Fatal and non-fatal major extra-cranial haemorrhage</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Fatal and non-fatal major extra-cranial haemorrhage as above. Categorised as i) upper-gastro-intestinal ii) lower gastro-intestinal iii) sight threatening ocular iv)multiple trauma v) other</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Clinically relevant non major bleeding (hospitalised)</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Defined in accordance with the International Society on Thrombosis and Haemostasis (ISTH) as any sign or symptom of haemorrhage (e.g. more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria:&#xD;
• Leading to hospitalisation&#xD;
This definition excludes all minor bleeding episodes that lead to medical evaluation involving direct patient contact.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Non-fatal stroke</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Non-fatal stroke excluding confirmed intracranial haemorrhage. Acute stroke defined in accordance with the World Health Organization (WHO) definition as &quot;rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer, with no apparent cause other than of vascular origin&quot;. This excludes cases of primary cerebral tumour, cerebral metastasis, subdural haematoma, post-seizure palsy, brain trauma and TIA. Haemorrhagic stroke ( including intracerebral haemorrhage and sub-arachnoid haemorrhage) which has been confirmed on appropriate imaging is excluded.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Cardiovascular death</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Cardiovascular death (excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with fatal and non fatal major extra-cranial haemorrhage and clinically relevant non major bleed (if hospitalised)</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Definitions above</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of participants with transient ischaemic attack</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>A transient episode of neurological dysfunction caused by focal brain spinal cord or retinal ischemia without acute infarction</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Unplanned hospitalisations per participant</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Defined as an official admission that is for a duration greater than 24 hours or a minimum of 2 calendar days where exact time of stay is unavailable.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of participants with new diagnosis of cancer</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Any new cancer diagnosis excluding non melanotic skin cancer</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of participants with CKD progression</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Defined as at least one of:&#xD;
&gt;30% fall in eGFR over two years, or&#xD;
need for renal replacement therapy or 50% decline in eGFR, or&#xD;
new eGFR&lt;15mL/min/1.73m2, or&#xD;
25% decline in GFR together with a drop in GFR category</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of participants with new diagnosis of dementia</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Coded dementia (ICD, Read) from linked GP and hospital data</description>
  </other_outcome>
  <other_outcome>
    <measure>Hospitalisation with heart failure</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Coded heart failure (ICD) from hospitalisation data</description>
  </other_outcome>
  <other_outcome>
    <measure>Death due to cancer (where cancer is the underlying cause of death)</measure>
    <time_frame>Average 4 years follow-up</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Major non traumatic lower limb amputation</measure>
    <time_frame>Average 4 years follow-up</time_frame>
    <description>Below or above knee amputation, coded (ICD) from hospitalisation data</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">25210</enrollment>
  <condition>Chronic Kidney Diseases</condition>
  <condition>Cardiovascular Diseases</condition>
  <condition>Bleeding</condition>
  <arm_group>
    <arm_group_label>Aspirin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>75mg of non enteric coated or dispersible aspirin once daily added to usual medications</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Usual care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Usual medications only</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aspirin</intervention_name>
    <description>75mg low dose non enteric coated or dispersible</description>
    <arm_group_label>Aspirin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females aged 18 years and over at the date of screening&#xD;
&#xD;
          -  .Subjects with CKD (reduced eGFR and/or albuminuria) defined as: • estimated&#xD;
             glomerular filtration rate [eGFR] &lt;60mL/min/1.73m2 for at least 90 days, and/or •&#xD;
             kidney disease code on the GP electronic patient AND most recent eGFR in CKD-defining&#xD;
             range (&lt;60mL/min/1.73m2), and/or • albuminuria or proteinuria (defined as urine&#xD;
             albumin:creatinine ratio [ACR] ≥3mg/mmol, and/or urine protein:creatinine ratio [PCR]&#xD;
             ≥15mg/mmol, and/or +protein or greater on reagent strip)&#xD;
&#xD;
          -  Subjects who are willing to give permission for their paper and electronic medical&#xD;
             records to be accessed by trial investigators&#xD;
&#xD;
          -  Subjects who are willing to be contacted and interviewed by trial investigators&#xD;
&#xD;
          -  Subjects who can communicate well with the investigator or designee, understand the&#xD;
             requirements of the study and understand and sign the written informed consent&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Subjects with CKD GFR category 5&#xD;
&#xD;
          -  Subjects with pre-existing cardiovascular disease (angina, myocardial infarction,&#xD;
             stroke, transient ischaemic attack (TIA), significant peripheral vascular disease,&#xD;
             coronary or peripheral revascularisation for atherosclerotic disease)&#xD;
&#xD;
          -  Subjects with a current pre-existing condition associated with increased risk of&#xD;
             bleeding other than CKD&#xD;
&#xD;
          -  Subjects currently prescribed anticoagulants or antiplatelet agent, or taking over the&#xD;
             counter (OTC) aspirin continuously&#xD;
&#xD;
          -  Subjects who are currently and regularly taking other drugs with a potentially serious&#xD;
             interaction with aspirin&#xD;
&#xD;
          -  Subjects with a known allergy to aspirin or definite previous clinically important&#xD;
             adverse reaction&#xD;
&#xD;
          -  Subjects with poorly controlled hypertension (systolic blood pressure [BP] ≥180 mmHg&#xD;
             and/or diastolic BP ≥105 mmHg)&#xD;
&#xD;
          -  . Subjects with other conditions which in the opinion of their General Practitioner&#xD;
             (GP) would preclude prescription of aspirin in routine clinical practice, for example&#xD;
             significant anaemia or thrombocytopenia&#xD;
&#xD;
          -  Subjects who are pregnant or likely to become pregnant during the study period&#xD;
&#xD;
          -  Subjects with malignancy that is life-threatening or likely to limit prognosis, other&#xD;
             life-threatening co-morbidity, or terminal illness&#xD;
&#xD;
          -  Subjects whose behaviour or lifestyle would render them less likely to comply with&#xD;
             study medication&#xD;
&#xD;
          -  Subjects in prison&#xD;
&#xD;
          -  Subjects currently participating in another clinical trial of an investigational&#xD;
             medicinal product or who have taken part in such a trial in the last three months&#xD;
             (Covid-19 vaccine studies are acceptable)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hugh Gallagher, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Epsom and St Helier University Hospitals NHS Trust</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Paul Roderick, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southampton</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jennifer Dumbleton</last_name>
    <phone>00441158231053</phone>
    <email>jennifer.dumbleton@nottingham.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Diane Stevenson</last_name>
    <phone>00441158231053</phone>
    <email>diane.stevenson@nottingham.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Nottingham Digestive Diseases Centre</name>
      <address>
        <city>Nottingham</city>
        <zip>NG72UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jennifer Dumbleton</last_name>
      <phone>00441158231053</phone>
      <email>jennifer.dumbleton@nottingham.ac.uk</email>
    </contact>
    <contact_backup>
      <last_name>Diane Stevenson</last_name>
      <phone>00441158231053</phone>
      <email>diane.stevenson@nottingham.ac.uk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>December 20, 2018</study_first_submitted>
  <study_first_submitted_qc>January 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>May 19, 2023</last_update_submitted>
  <last_update_submitted_qc>May 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
    <mesh_term>Cardiovascular Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03796156
org study id: 31844
nct id: NCT03796156
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study aims to find out whether people with chronic kidney disease [CKD] should take low
      dose aspirin to reduce the risk of first heart attack or stroke (cardiovascular disease
      [CVD]). CKD is common and is associated with an increased risk of CVD.

      CVD is caused by small blood clots and aspirin thins the blood to reduce the risk of such
      clots developing but it also increases the risk of bleeding.

      Aspirin is recommended to prevent further CVD in people who have already had a first CVD
      event (so called secondary prevention). Here the investigators want to study the use of
      aspirin as primary prevention in people with CKD who have not had a CVD to prevent the first
      event, to assess whether the potential benefits exceed the risks.

      Eligible patients will be recruited from their United Kingdom (UK) general practices and
      allocated by chance to be prescribed once daily low dose aspirin or usual care only.
      Follow-up will be for several years both electronically (for general practice, hospital and
      mortality data) and by annual questionnaires to ascertain CVD and bleeding events.
Aim To test the hypothesis that the addition of 75mg aspirin once daily to usual care reduces
      the risk of major vascular events in patients with chronic kidney disease (CKD) who do not
      have pre-existing cardiovascular disease (CVD)

      Design Open label, multi-centre randomised controlled trial

      Setting UK general practices

      Sample size 25,210 patients (12,605 per arm). A total of 1,827 major vascular events overall
      are required.

      Eligibility Inclusion Criteria

        1. Males and females aged 18 years and over at the date of screening

        2. Subjects with CKD (reduced eGFR and/or albuminuria) defined as: • estimated glomerular
           filtration rate [eGFR] <60mL/min/1.73m2 for at least 90 days, and/or • kidney disease
           code on the GP electronic patient AND most recent eGFR in CKD-defining range
           (<60mL/min/1.73m2), and/or • albuminuria or proteinuria (defined as urine
           albumin:creatinine ratio [ACR] ≥3mg/mmol, and/or urine protein:creatinine ratio [PCR]
           ≥15mg/mmol, and/or +protein or greater on reagent strip)

        3. Subjects who are willing to give permission for their paper and electronic medical
           records to be accessed by trial investigators

        4. Subjects who are willing to be contacted and interviewed by trial investigators

        5. Subjects who can communicate well with the investigator or designee, understand the
           requirements of the study and understand and sign the written informed consent

      Exclusion Criteria

        1. Subjects with CKD eGFR category 5

        2. Subjects with pre-existing cardiovascular disease (angina, myocardial infarction,
           stroke, transient ischaemic attack (TIA), significant peripheral vascular disease,
           coronary or peripheral revascularisation for atherosclerotic disease)

        3. Subjects with a current pre-existing condition associated with increased risk of
           bleeding other than CKD

        4. Subjects currently prescribed anticoagulants or antiplatelet agent, or taking over the
           counter (OTC) aspirin continuously

        5. Subjects who are currently and regularly taking other drugs with a potentially serious
           interaction with aspirin

        6. Subjects with a known allergy to aspirin or definite previous clinically important
           adverse reaction

        7. Subjects with poorly controlled hypertension (systolic blood pressure [BP] ≥180 mmHg
           and/or diastolic BP ≥105 mmHg)

        8. Subjects with other conditions which in the opinion of their General Practitioner (GP)
           would preclude prescription of aspirin in routine clinical practice, for example
           significant anaemia or thrombocytopenia.

        9. Subjects who are pregnant or likely to become pregnant during the study period

       10. Subjects with malignancy that is life-threatening or likely to limit prognosis, other
           life-threatening co-morbidity, or terminal illness

       11. Subjects whose behaviour or lifestyle would render them less likely to comply with study
           medication

       12. Subjects in prison

       13. Subjects currently participating in another clinical trial of an investigational
           medicinal product or who have taken part in such a trial in the last three months
           (Covid-19 vaccine studies are acceptable)

      Interventions Suitable participants will be randomised to receive: 75mg non-enteric coated or
      dispersible aspirin once daily in addition to their usual medication; or no additional
      treatment and avoidance of aspirin.

      Duration The trial will continue until at least 1,827 adjudicated primary endpoint events
      (major vascular events) have occurred, or before if the trial is discontinued after the
      internal pilot or for any other reason. It is anticipated that at least 6 years of
      recruitment (taking account a recruitment pause for the Covid-19 pandemic) and 2.5 years of
      follow-up will be required to complete the trial.

      Randomisation and blinding Eligible participants, based on results of routine blood and urine
      tests at screening, will be randomised (open label randomisation) 1:1 to general practitioner
      (GP) prescription of aspirin vs. no prescription, stratified by age, diabetes and CKD
      severity.

      Follow-up Data on potential CVD and bleeding outcomes will be collected electronically from
      GP records and national hospitalisation and mortality records. Adjudication panels (for CVD
      and for bleeding) will asses the information blind to allocation.

      Patients will complete an annual quality of life questionnaire (EQ5D).

      Outcomes. Primary outcome measure

      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 (MI), non-fatal
      stroke and cardiovascular death (excluding confirmed intracranial haemorrhage and other fatal
      cardiovascular haemorrhage).

      Secondary outcome measures (all time to event except 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); ii) other intracranial haemorrhage (adjudicated).
           Intra-cranial haemorrhage will be sub-categorised as traumatic or non-traumatic.

        3. Fatal and non-fatal (reported individually and as a composite) major extracranial
           haemorrhage: i) upper gastrointestinal; ii) lower gastrointestinal; iii)
           sight-threatening ocular; iv) multiple trauma; v) other (adjudicated).

        4. Clinically relevant non-major bleeding if hospitalised (adjudicated).

        5. Composite outcome of fatal and non-fatal major extracranial haemorrhage and clinically
           relevant non-major bleeding (if hospitalised).

      Tertiary (exploratory) outcome measures (all time to event except hospitalisation)

        1. Transient ischaemic attack

        2. Unplanned hospitalisation

        3. Hospitalisation with heart failure

        4. New diagnosis of cancer (colorectal/other)

        5. Death due to cancer (where cancer is the underlying cause of death)

        6. CKD progression

        7. New diagnosis of dementia

        8. Major non-traumatic lower limb amputation

      Statistical methods The primary outcome measure of time to first major vascular event will be
      analysed for the intention-to-treat (ITT) population. 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.

      All primary, secondary and tertiary time to event outcomes will be described using
      Kaplan-Meier curves or Cumulative Hazard plots for time to event outcomes involving competing
      risks for the ITT population. Analyses of time to event outcomes will be performed using Cox
      proportional hazards models or Competing Risk regression models, both unadjusted and adjusted
      for stratification factors: age, diabetes and CKD severity.

      The adjusted Competing Risk regression model for time to first major vascular event, with
      deaths from other causes (including fatal bleeding) treated as competing events, and patients
      who do not experience a major vascular event censored, will form the primary endpoint
      analysis model.

      Other secondary and tertiary endpoints will be assessed by arm using summary statistics (e.g.
      Pearson's χ² tests) in the ITT population.

      The amount of missing data and reasons for the incompleteness will be explored and presented
      overall i.e. not by group. If the amount of missing data is deemed too high and if
      appropriate (i.e. assuming the missing data is either missing at random [MAR] or missing
      completely at random [MCAR] and censoring assumed to be non-informative), multiple imputation
      will be performed accordingly, for which all covariates included in the multivariable model,
      together with the censoring/event indicator and the cumulative baseline hazard will be
      included in the multiple imputation model.

      Health economic analysis will also be undertaken.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Outcomes Assessor)
masking description: Adjudication of outcomes blinded
measure: Number of participants with a Major vascular event: Composite outcome of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death (excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage)
time frame: Over average 4 years follow-up
description: Acute MI defined according to the Third Universal Definition of myocardial infarction (MI).
Acute stroke defined in accordance with the World Health Organization (WHO) definition as "rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer, with no apparent cause other than of vascular origin". This excludes cases of primary cerebral tumour, cerebral metastasis, subdural haematoma, post-seizure palsy, brain trauma and TIA. Haemorrhagic stroke (fatal and non-fatal) including intracerebral haemorrhage and SAH which has been confirmed on appropriate imaging is excluded from the primary composite endpoint and included within the secondary endpoints.
measure: Number of participants dying from any cause
time frame: Average 4 years follow-up
description: Death from any cause
measure: Number of participants with major vascular events plus revascularisation
time frame: Average 4 years follow-up
description: Primary outcome plus coronary and non coronary arterial revascularisation. It will include open and percutaneous coronary and non-coronary (including carotid, aortic and limb) procedures (as defined in Office of Population Censuses and Surveys OPCS-4 procedure codes) and will be ascertained from Hospital Episode Statistics (HES) data.
measure: Number of participants with Non-fatal myocardial infarction
time frame: Average 4 years follow-up
description: Non-fatal myocardial infarction. Acute MI defined according to the Third Universal Definition of myocardial infarction (MI).
measure: Health-related quality of life, mean utility score
time frame: Average 4 years follow-up
description: Euroqol EQ-5D utility score derived from 5 states (scoring 1-5) converted to utility values using UK general population set
measure: Number of participants with intra-cranial haemorrhage, fatal and non fatal major extra cranial haemorrhage
time frame: Average 4 years follow-up
description: Intra-cranial haemorrhage includes intracerebral haemorrhage, subarachnoid haemorrhage, subdural haemorrhage, and extradural haemorrhage.
Extra-cranial haemorrhage is:
Fatal bleeding, or
Symptomatic bleeding in a critical area or organ, such as intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, or
Bleeding that leads to the transfusion of two or more units of whole blood or red cells
In particular, to be classified as major, bleeds in a critical area or organ should:
Be associated with a symptomatic clinical presentation (not following an incidental finding)
Be the cause of the symptoms
measure: Number of participants with Fatal and non-fatal intra-cranial haemorrhage
time frame: Average 4 years follow-up
description: Fatal and non-fatal intra-cranial haemorrhage as above It comprises primary haemorrhagic stroke(to distinguish from haemorrhagic transformation of ischaemic stroke) ii)other intra-cranial haemorrhage (adjudicated). Intra-cranial haemorrhage will be sub categorised as traumatic and non-traumatic.
measure: Number of participants with Fatal and non-fatal major extra-cranial haemorrhage
time frame: Average 4 years follow-up
description: Fatal and non-fatal major extra-cranial haemorrhage as above. Categorised as i) upper-gastro-intestinal ii) lower gastro-intestinal iii) sight threatening ocular iv)multiple trauma v) other
measure: Number of participants with Clinically relevant non major bleeding (hospitalised)
time frame: Average 4 years follow-up
description: Defined in accordance with the International Society on Thrombosis and Haemostasis (ISTH) as any sign or symptom of haemorrhage (e.g. more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria:
• Leading to hospitalisation
This definition excludes all minor bleeding episodes that lead to medical evaluation involving direct patient contact.
measure: Number of participants with Non-fatal stroke
time frame: Average 4 years follow-up
description: Non-fatal stroke excluding confirmed intracranial haemorrhage. Acute stroke defined in accordance with the World Health Organization (WHO) definition as "rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer, with no apparent cause other than of vascular origin". This excludes cases of primary cerebral tumour, cerebral metastasis, subdural haematoma, post-seizure palsy, brain trauma and TIA. Haemorrhagic stroke ( including intracerebral haemorrhage and sub-arachnoid haemorrhage) which has been confirmed on appropriate imaging is excluded.
measure: Number of participants with Cardiovascular death
time frame: Average 4 years follow-up
description: Cardiovascular death (excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage).
measure: Number of participants with fatal and non fatal major extra-cranial haemorrhage and clinically relevant non major bleed (if hospitalised)
time frame: Average 4 years follow-up
description: Definitions above
measure: Number of participants with transient ischaemic attack
time frame: Average 4 years follow-up
description: A transient episode of neurological dysfunction caused by focal brain spinal cord or retinal ischemia without acute infarction
measure: Number of Unplanned hospitalisations per participant
time frame: Average 4 years follow-up
description: Defined as an official admission that is for a duration greater than 24 hours or a minimum of 2 calendar days where exact time of stay is unavailable.
measure: Number of participants with new diagnosis of cancer
time frame: Average 4 years follow-up
description: Any new cancer diagnosis excluding non melanotic skin cancer
measure: Number of participants with CKD progression
time frame: Average 4 years follow-up
description: Defined as at least one of:
>30% fall in eGFR over two years, or
need for renal replacement therapy or 50% decline in eGFR, or
new eGFR<15mL/min/1.73m2, or
25% decline in GFR together with a drop in GFR category
measure: Number of participants with new diagnosis of dementia
time frame: Average 4 years follow-up
description: Coded dementia (ICD, Read) from linked GP and hospital data
measure: Hospitalisation with heart failure
time frame: Average 4 years follow-up
description: Coded heart failure (ICD) from hospitalisation data
measure: Death due to cancer (where cancer is the underlying cause of death)
time frame: Average 4 years follow-up
measure: Major non traumatic lower limb amputation
time frame: Average 4 years follow-up
description: Below or above knee amputation, coded (ICD) from hospitalisation data
arm group label: Aspirin
arm group type: Experimental
description: 75mg of non enteric coated or dispersible aspirin once daily added to usual medications
arm group label: Usual care
arm group type: No Intervention
description: Usual medications only
intervention type: Drug
intervention name: Aspirin
description: 75mg low dose non enteric coated or dispersible
arm group label: Aspirin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Hugh Gallagher, MD
role: Principal Investigator
affiliation: Epsom and St Helier University Hospitals NHS Trust
last name: Paul Roderick, MD
role: Principal Investigator
affiliation: University of Southampton
last name: Jennifer Dumbleton
phone: 00441158231053
email: jennifer.dumbleton@nottingham.ac.uk
last name: Diane Stevenson
phone: 00441158231053
email: diane.stevenson@nottingham.ac.uk
facility: 
status: Recruiting
contact: 
contact backup: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
mesh term: Cardiovascular Diseases
mesh term: Aspirin
sharing ipd: Undecided