Clinical Trial Results:
Dual Antiplatelet Therapy to Inhibit Coronary Atherosclerosis and Myocardial Injury in Patients with Necrotic High-risk Coronary Plaque Disease
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Summary
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EudraCT number |
2014-000952-26 |
Trial protocol |
GB |
Global end of trial date |
03 Apr 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Mar 2019
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First version publication date |
27 Mar 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
14/SS/0089
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02110303 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University of Edinburgh & NHS Lothian
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Sponsor organisation address |
Old College, South Bridge, Edinburgh, United Kingdom, EH8 9YL
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Public contact |
Professor David Newby, University of Edinburgh, d.e.newby@ed.ac.uk
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Scientific contact |
Professor David Newby, University of Edinburgh, d.e.newby@ed.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
31 Jul 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Apr 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To determine if ticagrelor (a blood thinning medication) reduces the levels of plasma high-sensitivity cardiac troponin I (a protein in the blood that is associated with increased risk of heart attacks in the future) in patients with stable heart disease but evidence of high-risk features on heart scans.
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Protection of trial subjects |
This clinical trial was carried out with the approval of the national research ethics committee in accordance with the Declaration of Helsinki (2000), under a Clinical Trial Authorisation from the Medicine and Healthcare Products Regulatory Authority (MHRA, United Kingdom), and the written informed consent of all participants.
The CT and PET scans involved the administration of contrast 'dye' which can cause kidney problems or allergic reactions so patients who had significant kidney disease or a history of allergic reactions to contrast dye were excluded from the trial. The PET scan involved the administration of a injected radioactive tracer chemical (18F-NaF). This type of chemical tracer is routinely used in PET-CT scans and a well developed protocol was in place to minimise radiation exposure to the patient and to ensure safe handling and administration of the tracer. To avoid an excessive risk of bleeding patients who were already taking blood thinning medications other than aspirin (e.g. warfarin, clopidogrel) were excluded from the study. There is a small bleeding risk associated with taking ticagrelor so patients who were at high risk or had a history of serious bleeding problems were also excluded from the trial.
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Background therapy |
All subjects in both arms were receiving aspirin on recruitment to the trial. They were mandated in the protocol to be maintained on aspirin 75 mg once daily during the trial and were also to be maintained on the maximally tolerated dose of statin. Subjects were encouraged to be maintained on maximally tolerated doses of angiotensin-converting enzyme inhibition and beta-blocker therapy as clinically indicated and in accordance with local guidelines. | ||
Evidence for comparator |
A matched placebo comparator was used to ensure blinding in the trial and so avoid potential for systematic biases in outcome measures. | ||
Actual start date of recruitment |
13 Mar 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 202
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Worldwide total number of subjects |
202
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EEA total number of subjects |
202
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
79
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From 65 to 84 years |
123
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients with stable coronary disease were recruited from Royal Infirmary of Edinburgh, Scotland. Recruitment to the study commenced on the 13th March 2015. The first participant was randomised on the 30th March 2015 and the last patient was randomised on 25th April 2017. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 361 patients were approached to participate in the study and 220 were consented. The other 141 patients declined to participate, were ineligible, or were already taking part in another CTIMP. Eighteen of those who were consented subsequently changed their mind about participating or became ineligible, so 202 patients were randomised. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||||||||||||||
Blinding implementation details |
A matched placebo comparator was supplied by the drug manufacturer to ensure the subject and clinical research team were blinded to the allocated treatment. An indication of treatment allocation could have potentially been apparent from the platelet-monocyte aggregate testing, so this testing was performed by an unblinded technician who was distinct from the clinical team and the results were not released to the research team until the end of the trial.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ticagrelor | |||||||||||||||||||||
Arm description |
Ticagrelor 90 mg tablet twice daily for 12 months | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Ticagrelor
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Investigational medicinal product code |
ATC Code: B01AC24
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
One 90 mg tablet twice daily for 12 months
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Matched placebo tablet twice daily for 12 months | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
One tablet twice daily for 12 months
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Baseline characteristics reporting groups
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Reporting group title |
Ticagrelor
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Reporting group description |
Ticagrelor 90 mg tablet twice daily for 12 months | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Matched placebo tablet twice daily for 12 months | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects in sub-group of the per protocol population who had increased coronary 18F-NaF uptake on baseline PET-CT scan and received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Placebo (Per Protocol With Coronary 18F-NaF Uptake)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects in sub-group of the per protocol population who had increased coronary 18F-NaF uptake on baseline PET-CT scan and received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects in sub-group of the per protocol population who did not have increased coronary 18F-NaF uptake on baseline PET-CT scan and received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects in sub-group of the per protocol population who did not have increased coronary 18F-NaF uptake on baseline PET-CT scan and received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Ticagrelor (Per Protocol)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects in per protocol population who received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Placebo (Per Protocol)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects in per protocol population who received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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End points reporting groups
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Reporting group title |
Ticagrelor
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Reporting group description |
Ticagrelor 90 mg tablet twice daily for 12 months | ||
Reporting group title |
Placebo
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Reporting group description |
Matched placebo tablet twice daily for 12 months | ||
Subject analysis set title |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects in sub-group of the per protocol population who had increased coronary 18F-NaF uptake on baseline PET-CT scan and received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Placebo (Per Protocol With Coronary 18F-NaF Uptake)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects in sub-group of the per protocol population who had increased coronary 18F-NaF uptake on baseline PET-CT scan and received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects in sub-group of the per protocol population who did not have increased coronary 18F-NaF uptake on baseline PET-CT scan and received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from the pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects in sub-group of the per protocol population who did not have increased coronary 18F-NaF uptake on baseline PET-CT scan and received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Ticagrelor (Per Protocol)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects in per protocol population who received ticagrelor. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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Subject analysis set title |
Placebo (Per Protocol)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Subjects in per protocol population who received placebo. Per protocol population pre-specified as subjects with measurement of plasma high sensitivity cardiac troponin I at 30 day visit and ≥80% compliance as calculated from pill count at 30 day visit. If a subject forgot to bring their pill bottles to 30 day visit then compliance was calculated from pill count at 3 month visit or based on other information and pill counts at subsequent visits.
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End point title |
Plasma high sensitivity cardiac troponin I concentration at 30 days | ||||||||||||
End point description |
Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
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End point type |
Primary
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End point timeframe |
Concentration from blood sample at 30 day visit
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Statistical analysis title |
Troponin at 30 days (PP with 18F-NaF uptake) | ||||||||||||
Statistical analysis description |
General linear model for log transformed troponin concentrations at 30 days with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values at 30 days.
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Comparison groups |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.32 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||
Point estimate |
1.11
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.9 | ||||||||||||
upper limit |
1.36 | ||||||||||||
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End point title |
Plasma high sensitivity cardiac troponin I concentration at 30 days | ||||||||||||||||||||
End point description |
Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
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End point type |
Secondary
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End point timeframe |
Concentration from blood sample at 30 day visit
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Statistical analysis title |
Troponin at 30 days (PP without 18F-NaF uptake) | ||||||||||||||||||||
Statistical analysis description |
general linear model for log transformed troponin concentrations at 30 days with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values at 30 days.
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Comparison groups |
Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) v Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
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Number of subjects included in analysis |
71
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.87 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||||||||||
Point estimate |
1.02
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
0.8 | ||||||||||||||||||||
upper limit |
1.31 | ||||||||||||||||||||
Statistical analysis title |
Troponin at 30 days (PP) | ||||||||||||||||||||
Statistical analysis description |
General linear model for log transformed troponin concentrations at 30 days with age, sex, log transformed troponin concentration, increased coronary 18F-NaF uptake, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values at 30 days.
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Comparison groups |
Ticagrelor (Per Protocol) v Placebo (Per Protocol)
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Number of subjects included in analysis |
191
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.37 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||||||||||
Point estimate |
1.07
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
0.92 | ||||||||||||||||||||
upper limit |
1.26 | ||||||||||||||||||||
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End point title |
Area under plasma high sensitivity cardiac troponin I concentration curve over 1 year | ||||||||||||||||||||||||||||
End point description |
Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
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||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Concentrations from blood samples at 30 day, 3 month, 6 month, 9 month, and 12 month visits
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
Statistical analysis title |
AUC over 1 year (PP with 18F-NaF uptake) | ||||||||||||||||||||||||||||
Statistical analysis description |
General linear model for log transformed area under troponin concentration curve over 1 year with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values of AUC.
|
||||||||||||||||||||||||||||
Comparison groups |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
|
||||||||||||||||||||||||||||
Number of subjects included in analysis |
115
|
||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||
P-value |
= 0.33 | ||||||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||||||||||||||||||
Point estimate |
0.86
|
||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||
lower limit |
0.63 | ||||||||||||||||||||||||||||
upper limit |
1.17 | ||||||||||||||||||||||||||||
Statistical analysis title |
AUC over 1 year (PP without 18F-NaF uptake) | ||||||||||||||||||||||||||||
Statistical analysis description |
General linear model for log transformed area under troponin concentration curve over 1 year with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values of AUC.
|
||||||||||||||||||||||||||||
Comparison groups |
Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) v Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
|
||||||||||||||||||||||||||||
Number of subjects included in analysis |
68
|
||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||
P-value |
= 0.7 | ||||||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||||||||||||||||||
Point estimate |
1.04
|
||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||
lower limit |
0.84 | ||||||||||||||||||||||||||||
upper limit |
1.28 | ||||||||||||||||||||||||||||
Statistical analysis title |
AUC over 1 year (PP) | ||||||||||||||||||||||||||||
Statistical analysis description |
General linear model for log transformed area under troponin concentration curve over 1 year with age, sex, log transformed baseline troponin concentration, increased coronary 18F-NaF uptake, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed values of AUC.
|
||||||||||||||||||||||||||||
Comparison groups |
Ticagrelor (Per Protocol) v Placebo (Per Protocol)
|
||||||||||||||||||||||||||||
Number of subjects included in analysis |
183
|
||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||
P-value |
= 0.42 | ||||||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||||||||||||||||||
Point estimate |
0.92
|
||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||
lower limit |
0.74 | ||||||||||||||||||||||||||||
upper limit |
1.13 | ||||||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Ratio of total calcium mass in coronary arteries at 1 year to baseline | ||||||||||||||||||||
End point description |
Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Calcium mass from CT scans at baseline and 12 month visits
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Total calcium mass (PP with 18F-NaF uptake) | ||||||||||||||||||||
Statistical analysis description |
General linear model for log transformed ratio of mass at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
|
||||||||||||||||||||
Comparison groups |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
|
||||||||||||||||||||
Number of subjects included in analysis |
112
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.14 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||||||||||
Point estimate |
0.94
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.87 | ||||||||||||||||||||
upper limit |
1.02 | ||||||||||||||||||||
Statistical analysis title |
Total calcium mass (PP without 18F-NaF uptake) | ||||||||||||||||||||
Statistical analysis description |
General linear model for log transformed ratio of mass at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
|
||||||||||||||||||||
Comparison groups |
Ticagrelor (Per Protocol Without Coronary 18F-NaF Uptake) v Placebo (Per Protocol Without Coronary 18F-NaF Uptake)
|
||||||||||||||||||||
Number of subjects included in analysis |
67
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.26 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||||||||||
Point estimate |
0.89
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.73 | ||||||||||||||||||||
upper limit |
1.09 | ||||||||||||||||||||
|
|||||||||||||
End point title |
Ratio of calcium mass at 1 year to baseline in coronary artery segment with increased 18F-NaF uptake at baseline | ||||||||||||
End point description |
Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Calcium mass from CT scans at baseline and 12 month visits
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Calcium mass in segment with 18F-NaF uptake | ||||||||||||
Statistical analysis description |
General linear model for log transformed ratio of mass at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
|
||||||||||||
Comparison groups |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.36 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||
Point estimate |
0.92
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.76 | ||||||||||||
upper limit |
1.11 | ||||||||||||
|
|||||||||||||
End point title |
Ratio of calcium mass at 1 year to baseline in coronary artery segment without increased 18F-NaF uptake at baseline | ||||||||||||
End point description |
Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Calcium mass on CT scans at baseline and 12 month visits
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Calcium mass in segment without 18F-NaF uptake | ||||||||||||
Statistical analysis description |
General linear model for log transformed ratio of mass at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
|
||||||||||||
Comparison groups |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
|
||||||||||||
Number of subjects included in analysis |
110
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.95 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||
Point estimate |
1.01
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.85 | ||||||||||||
upper limit |
1.18 | ||||||||||||
|
|||||||||||||
End point title |
Ratio of calcium volume at 1 year to baseline in coronary artery segment with increased 18F-NaF uptake at baseline | ||||||||||||
End point description |
Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Calcium volume from CT scans at baseline and 12 month visits
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Calcium volume in segment with 18F-NaF uptake | ||||||||||||
Statistical analysis description |
General linear model for log transformed ratio of volume at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
|
||||||||||||
Comparison groups |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.27 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||
Point estimate |
0.91
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.77 | ||||||||||||
upper limit |
1.08 | ||||||||||||
|
|||||||||||||
End point title |
Ratio of calcium volume at 1 year to baseline in coronary artery segment without increased 18F-NaF uptake at baseline | ||||||||||||
End point description |
Measure of dispersion reported below is actually geometric standard deviation rather than standard deviation.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Calcium volume from CT scans at baseline and 12 month visits
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Calcium volume in segment without 18F-NaF uptake | ||||||||||||
Statistical analysis description |
General linear model for log transformed ratio of volume at 1 year to baseline with age, sex, log transformed baseline troponin concentration, and treatment as covariates. Estimate of ratio of geometric means (ticagrelor divided by placebo) and 95% confidence limits obtained by exponentiation of difference in means and confidence limits for log transformed ratio.
|
||||||||||||
Comparison groups |
Ticagrelor (Per Protocol With Coronary 18F-NaF Uptake) v Placebo (Per Protocol With Coronary 18F-NaF Uptake)
|
||||||||||||
Number of subjects included in analysis |
110
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 77 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||
Point estimate |
1.02
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.88 | ||||||||||||
upper limit |
1.19 | ||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All adverse events that occurred from consent until the last study visit were reported on the case report forms, but only those which started after randomisation have been included in these results.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Subjects were asked about the occurrence of AEs at each study visit through open-ended and non-leading verbal questioning. Any AEs which were identified via information from support departments, e.g. safety blood results, were also reported. All reported AEs were followed up until resolution of the event or until no longer medically indicated.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ticagrelor (Safety)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects who received any ticagrelor study medication, regardless of the group they were originally allocated to. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (Safety)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects who received some study medication but this was all placebo, regardless of the group they were originally allocated to. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
26 Aug 2016 |
Substantial Amendment 5: The Ticagrelor SPC was updated on 18 February 2016 to include new information from a large clinical trial involving the use of ticagrelor in patients with a history of prior myocardial infarction. The changes to the SPC resulted in an update to the reference safety information for the DIAMOND study. The study protocol was updated to remove the SPC link from Appendix 1. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
