Clinical Trial Results:
Bivalirudin Infusion for Ventricular Infarction Limitation (BIVAL)
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Summary
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EudraCT number |
2012-002314-39 |
Trial protocol |
NL IT |
Global end of trial date |
14 Jun 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Jun 2017
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First version publication date |
08 Jun 2017
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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 |
MDCO-BIV-12-02
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02565147 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
The Medicines Company (Schweiz) GmbH
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Sponsor organisation address |
Talstrasse 59, Zurich, Switzerland, 8001
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Public contact |
Global Health Science Center, The Medicines Company, 41 044 828 1084, medical.information@themedco.com
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Scientific contact |
Global Health Science Center, The Medicines Company, 41 044 828 1084, medical.information@themedco.com
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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 |
17 Jan 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Jun 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Jun 2016
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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 |
The primary objective of this study is to determine whether treatment with bivalirudin, compared with treatment with heparin (unfractionated heparin [UFH]), for primary percutaneous coronary intervention (PPCI) in large ST-segment elevation myocardial infarction (STEMI) can reduce infarct size assessed by cardiac magnetic resonance (CMR) 5 days (defined as 5 days ±72 hours [h] from randomisation) after PPCI.
Results for all participants enrolled into this trial (BIVAL) are presented.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Dec 2014
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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 |
Netherlands: 43
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Country: Number of subjects enrolled |
France: 35
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Worldwide total number of subjects |
78
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EEA total number of subjects |
78
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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) |
48
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From 65 to 84 years |
26
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85 years and over |
4
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Screening occurred minutes prior to randomisation and included review of inclusion/exclusion criteria, signed informed consent, aspirin and P2Y12 administration when feasible, 12-lead electrocardiogram, clinical laboratory assessments, PPCI eligibility confirmation, flow assessment, and angiographic assessment for a large myocardial infarction. | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
BIVAL (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | |||||||||||||||||||||||||||
Roles blinded |
Assessor [1] | |||||||||||||||||||||||||||
Blinding implementation details |
The primary endpoint was evaluated by a core lab totally blinded to clinical information and the treatment groups.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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PPCI with Bivalirudin | |||||||||||||||||||||||||||
Arm description |
Bivalirudin was administered as a bolus (0.75 milligram [mg]/kilogram [kg]) and an infusion (1.75 mg/kg/h) for the duration of the PPCI and continued for the first 4 h after completion of the procedure. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Bivalirudin
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Investigational medicinal product code |
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Other name |
Angiomax, Angiox
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous bolus use , Intravenous use
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Dosage and administration details |
All participants randomised to the bivalirudin group received a bivalirudin bolus of 0.75 mg/kg and an infusion of 1.75 mg/kg/h for the duration of the procedure and the 4 h after the procedure.
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Arm title
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PPCI with Heparin | |||||||||||||||||||||||||||
Arm description |
UFH administered as a bolus according to standard of care for completion of PPCI per site. An activated clotting time (ACT) ≥250 seconds (s) at the end of the procedure was recommended. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Unfractionated Heparin
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Investigational medicinal product code |
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Other name |
Heparin
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous bolus use
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Dosage and administration details |
All participants randomised to the UFH group received a UFH bolus according to the standard of care for completion of PPCI per site. An ACT ≥250 s at the end of the procedure was recommended.
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| Notes [1] - The roles blinded appear inconsistent with a simple blinded trial. Justification: Despite the obvious benefits of a double-blind design, the logistics of a double-blind approach are exceedingly difficult in the emergent setting of PPCI. The open-label design did not add any logistical hurdles and therefore allowed for timely reperfusion in these STEMI participants. Furthermore, the primary endpoint was analysed by a core lab blinded to both the treatment and the clinical data, therefore the double-blind design was not considered necessary. |
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| Notes [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: The Per-Protocol (PP) population was defined as all enrolled participants in the randomised trial who underwent successful PPCI defined as TIMI Flow of 2 or 3, underwent CMR at 5 days, and were without major protocol deviations. A total of 64 participants (28 in the Bivalirudin Arm and 36 in the UFH Arm) were included in the PP population. The primary and secondary analyses were based on the PP population. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: The PP population was defined as all enrolled participants in the randomised trial who underwent successful PPCI defined as thrombolysis in myocardial infarction (TIMI) Flow of 2 or 3, underwent CMR at 5 days, and were without major protocol deviations. A total of 64 participants (28 in the Bivalirudin Arm and 36 in the UFH Arm) were included in the PP population. The primary and secondary analyses were based on the PP population. |
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Baseline characteristics reporting groups
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Reporting group title |
PPCI with Bivalirudin
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Reporting group description |
Bivalirudin was administered as a bolus (0.75 milligram [mg]/kilogram [kg]) and an infusion (1.75 mg/kg/h) for the duration of the PPCI and continued for the first 4 h after completion of the procedure. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PPCI with Heparin
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Reporting group description |
UFH administered as a bolus according to standard of care for completion of PPCI per site. An activated clotting time (ACT) ≥250 seconds (s) at the end of the procedure was recommended. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
PPCI with Bivalirudin
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Reporting group description |
Bivalirudin was administered as a bolus (0.75 milligram [mg]/kilogram [kg]) and an infusion (1.75 mg/kg/h) for the duration of the PPCI and continued for the first 4 h after completion of the procedure. | ||
Reporting group title |
PPCI with Heparin
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Reporting group description |
UFH administered as a bolus according to standard of care for completion of PPCI per site. An activated clotting time (ACT) ≥250 seconds (s) at the end of the procedure was recommended. | ||
Subject analysis set title |
Safety Population (Received Study Drug)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety Population includes all enrolled participants who received either bivalirudin or UFH.
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Subject analysis set title |
PP Population
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The PP population includes all enrolled participants who underwent successful PPCI and Day-5 CMR without major protocol deviations.
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Subject analysis set title |
Intent-to-Treat (ITT) Population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The ITT population includes all patients enrolled into the randomised trial. Analyses based on the ITT population were considered secondary and confirmatory.
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End point title |
CMR Assessment of Infarct Size At Day 5 | ||||||||||||
End point description |
Size of cardiac infarct, expressed as grams, as assessed by CMR. The use of CMR has dramatically improved the ability for accurate infarct size estimations and is therefore currently considered the gold standard. The number of participants and their mean reported infarct size, as grams, at Day 5 are presented.
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End point type |
Primary
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End point timeframe |
5 days post PPCI
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| Notes [1] - PP Population (enrolled participants with successful PPCI and CMR). [2] - PP Population (enrolled participants with successful PPCI and CMR). |
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Statistical analysis title |
Statistical Analysis: CMR Assessment of Infarct | ||||||||||||
Comparison groups |
PPCI with Bivalirudin v PPCI with Heparin
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Number of subjects included in analysis |
64
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.7505 | ||||||||||||
Method |
Wilcoxon rank sum test | ||||||||||||
Confidence interval |
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End point title |
CMR Assessment Of Myocardial Salvage Index (MSI) At Day 5 | ||||||||||||
End point description |
MSI is a CMR-derived parameter of myocardial recovery and treatment efficacy that allows comparisons among infarcts of different sizes. MSI is calculated as the difference between the area at risk (AAR) and the final infarct size, divided by the AAR, and it is expressed as a percentage of AAR. The number of participants and their mean-reported MSI at Day 5 are presented.
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End point type |
Secondary
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End point timeframe |
5 days post PPCI
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| Notes [3] - Per-Protocol Population and participants with a successful CMR assessment of MSI. [4] - Per-Protocol Population and participants with a successful CMR assessment of MSI. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
CMR Assessment Of Micro-vascular Obstruction (MVO) At Day 5 | ||||||||||||||||||
End point description |
Early and late assessment of MVO, expressed as grams, as assessed by CMR. MVO is an established complication of coronary reperfusion therapy for acute myocardial infarction. MVO occurs in the setting of reperfusion following prolonged myocardial ischemia and provides incremental prognostic information beyond infarct size, to which it is related. The number of participants and their mean reported MVO, as grams, at Day 5 are presented.
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End point type |
Secondary
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End point timeframe |
5 days post PPCI
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| Notes [5] - Per-Protocol Population and participants with successful CMR assessment of Early (23)/Late (27) MVO. [6] - Per-Protocol Population and participants with successful CMR assessment of Early (28)/Late (35) MVO. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
CMR Assessment Of Left Ventricular Ejection Fraction (LVEF) At Day 5 | ||||||||||||
End point description |
Percentage of cardiac LVEF as assessed by CMR. LVEF is a measurement of the percentage of blood ejected out of the left ventricle with each contraction. The number of participants and their mean reported LVEF, as a percentage of blood, at Day 5 are presented.
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End point type |
Secondary
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End point timeframe |
5 days post PPCI
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| Notes [7] - Per-Protocol Population (enrolled participants with successful PPCI and CMR). [8] - Per-Protocol Population (enrolled participants with successful PPCI and CMR). |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
CMR Assessment of LVEF at Day 90 | ||||||||||||
End point description |
Percentage of cardiac LVEF as assessed by CMR. LVEF is a measurement of the percentage of blood ejected out of the left ventricle with each contraction. The number of participants and their mean reported LVEF, as a percentage of blood, at Day 90 are presented.
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End point type |
Secondary
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End point timeframe |
90 days post PPCI
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| Notes [9] - Per-Protocol Population and participants with a successful CMR assessment of LVEF at Day 90. [10] - Per-Protocol Population and participants with a successful CMR assessment of LVEF at Day 90. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
TIMI Flow and Myocardial Blush Grade (MBG) at End of PPCI | ||||||||||||||||||
End point description |
TIMI flow (grade 0-3) is an angiographic determination of briskness of epicardial coronary blood flow: TIMI 0 flow (no perfusion); TIMI 1 flow (penetration without perfusion); TIMI 2 flow (partial reperfusion); TIMI 3 flow (complete perfusion/normal flow).
MBG (grade 0-3) is an angiographic method for determination of blood flow in the distal myocardial vascular bed. Blush grades: 0 = failure of dye to enter the microvasculature; 1 = dye slowly enters but fails to exit the microvasculature; 2 = delayed entry and exit of dye from the microvasculature; 3 = normal entry and exit of dye from the microvasculature. Blush that is only mildly intense throughout the washout phase, but fades minimally, is also classified as grade 3.
The number of participants and their mean reported TIMI flow and MBG grades at the end of PPCI are presented.
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End point type |
Secondary
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End point timeframe |
1 day (end of PPCI)
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| Notes [11] - Per-Protocol Population and participants with a TIMI Flow (28) and MBG (22) at the end of PPCI. [12] - Per-Protocol Population and participants with a TIMI Flow (36) and MBG (29) at the end of PPCI. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
In-Hospital Net Adverse Cardiac Events (NACE) At Day 5 | ||||||||||||
End point description |
The NACE at 5 days is the composite of major bleeding (Bleeding Academic Research Consortium Type 3 or greater [BARC type ≥3]), death, re-infarction, and ischaemia driven revascularization (IDR).
In brief, BARC ≥3 includes: Type 3a-3c, clinical, laboratory, and/or imaging evidence of bleeding; Type 4, coronary artery bypass grafting-related bleeding; Type 5, fatal bleeding that directly results in death that is either clinically suspicious or is confirmed as the cause of death.
A participant was defined to have a composite event if the participant experienced at least 1 of the components. If the participant did not have any of the components, then he or she did not have the composite endpoint. If a participant had more than 1 of the components, he or she was only counted once in the determination of the total number of participants experiencing the composite endpoint. The number of participants with NACE up to Day 5 is presented.
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End point type |
Secondary
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End point timeframe |
5 days post PPCI or at discharge, whichever occurs first
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| Notes [13] - Per-Protocol Population (enrolled participants with successful PPCI and CMR). [14] - Per-Protocol Population (enrolled participants with successful PPCI and CMR). |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Death At Day 90 | |||||||||
End point description |
Participant survival during the clinical follow-up period is presented as the number of participants with reported death at 90 days post PPCI.
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End point type |
Secondary
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End point timeframe |
90 days post PPCI
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| Notes [15] - Per-Protocol Population (enrolled participants with successful PPCI and CMR). [16] - Per-Protocol Population (enrolled participants with successful PPCI and CMR). |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Index Of Microcirculatory Resistance (IMR) | ||||||||||||
End point description |
IMR, a predictor of clinical outcome, is a readily available, quantitative, and reproducible method for invasively assessing coronary microvascular function. It is measured using the thermodilution technique and expressed as millimeters (mm) of mercury (Hg) multiplied by the mean hyperemic transit time (s) (mmHg·s). The number of participants and their mean reported IMR at the end of PPCI are presented.
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End point type |
Other pre-specified
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End point timeframe |
1 day (end of PPCI)
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| Notes [17] - IMR ITT population. [18] - IMR ITT population. |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to 5 days (±36 h) post randomisation/discharge
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
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Reporting groups
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Reporting group title |
PPCI with Bivalirudin
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Reporting group description |
Bivalirudin was administered as a bolus (0.75 mg/kg) and an infusion (1.75 mg/kg/h) for the duration of the PPCI and continued for the first 4 h after completion of the procedure. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PPCI with Heparin
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Reporting group description |
UFH was administered as a bolus according to standard of care for completion of PPCI per site. An ACT ≥250 s at the end of the procedure was recommended. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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24 Aug 2015 |
Amendment number 1 on 24-August-2015 included the following clinical changes to the protocol:
- An interim analysis was added to the protocol. The proposed interim analysis was performed to assess the assumptions used to evaluate the scientific validity of the hypothesis tested, and how this was affected by protocol deviations impacting the sensitive tool used to assess the infarct size (CMR). It was planned when approximately 66 evaluable participants (a third of the planned sample size) had their day 5 CMR data available for analysis.
- Changes were made to clarify clinical intent: in particular changes to the primary and secondary objectives, schedule and sequence of procedures and protocol deviations.
- Updates were made to ensure consistency throughout the protocol: in particular updates to the synopsis, Type/Design of Trial, Number of Subjects, schedule and sequence of procedures, and sample size.
- Other changes were made, including:
- addition of a new section, Reporting Events of Medication Errors, to clarify definition of medication errors and explain how to report them;
- addition of a new section, Screen Failures has been added to explain the procedure used, to account for screening failures.
These proposed changes were considered substantial but did not affect the benefit–risk assessment. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Since the measured difference in infarct size at Day 5 (by CMR) was <18%, the study was terminated for futility at the interim analysis as pre-defined in the protocol. | |||
