Clinical Trial Results:
Effects of ivabradine on vascular function in individuals at increased risk of developing cardiovascular disease and with impaired endothelial function
An international, multicentre, randomised, double-blind, placebo-controlled study over 12 weeks.
Summary
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EudraCT number |
2012-000215-89 |
Trial protocol |
IT GB NL |
Global end of trial date |
18 Apr 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Jul 2016
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First version publication date |
31 Jul 2015
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Other versions |
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 |
CL2-16257-099
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Institut de Recherches Internationales Servier (I.R.I.S.)
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Sponsor organisation address |
50, rue Carnot, Suresnes, France, 92284
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Public contact |
Therapeutic Innovation Pole, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
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Scientific contact |
Therapeutic Innovation Pole, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.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 |
18 Apr 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Apr 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Apr 2014
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To demonstrate the beneficial effect of ivabradine compared with placebo on endothelial function as measured by flow mediated dilation (FMD) of the brachial artery at 12 weeks of treatment
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Protection of trial subjects |
Before randomisation, a patient was to be withdrawn from the study when the investigator
was aware that a selection/non-selection criterion or an inclusion/non-inclusion criterion was
not verified.
The IMP was prematurely discontinued in the following circumstances:
-IMP not tolerated: occurrence of any suspected adverse reaction that caused the patient
discomfort and led to interruption of usual activities or in the case of a suspected adverse
reaction that was considered by the investigator as a safety issue. An example of such a
situation could be the occurrence or persistence of symptomatic bradycardia while the
lower IMP dose-regimen (ivabradine 5 mg bid or matching placebo) was administered.
-IMP no longer appropriate: occurrence of prolonged loss of sinus rhythm (for example
persistent atrial fibrillation).
-IMP considered as contra-indicated: e.g. sick sinus syndrome or sino-atrial block.
-Need of treatment not allowed during the study: e.g. strong CYP3A4 inhibitor.
-Major protocol deviation which, in the opinion of the investigator, made it unsafe for the
patient to continue to take the test drug and to stay in the study.
-Non-medical reason: e.g. patient’s personal decision to stop treatment, withdrawal of
consent etc…
-Lost to follow-up: when the investigator had no news of the participant, he/she made every
effort to contact him/her, to establish the reason for the discontinuation of treatment, and to
suggest the participant came to an end-of-study visit. If all these attempts to contact the
participant failed, the investigator was to declare the participant “lost to follow-up”. The
investigator documented all these attempts in the corresponding medical file.
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Background therapy |
The treatment received by the study participants should be optimal according to the investigator’s judgement and in accordance to guidelines | ||
Evidence for comparator |
Placebo | ||
Actual start date of recruitment |
06 Dec 2013
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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: 1
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Country: Number of subjects enrolled |
Germany: 3
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Worldwide total number of subjects |
4
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EEA total number of subjects |
4
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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) |
3
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
15 centres were "opened" and trained. Only 10 centres in DEU and NLD screened patients (total of 53 patients) 9 patients were selected (5 in DEU and 4 in NLD). A total of 4 patients were included and randomly assigned: 2 in the ivabradine group and 2 in the placebo group. No patient completed the study since it was terminated prematurely | |||||||||
Pre-assignment
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Screening details |
Men or postmenopausal women aged 21-74 years, in sinus rhythm with resting HR superior or equal to 75 bpm, at increased risk of subsequent cardiovascular disease (documented by the presence of at least two cardiovascular risk factors such as diabetes, hypertension, smoking, hypercholesterolemia) and impaired FMD (<5.0%), signed an informed consent | |||||||||
Period 1
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Period 1 title |
Overall study (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 | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ivabradine | |||||||||
Arm description |
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Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Ivabradine
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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 |
During the treatment period after randomisation, the IMP (double-blind ivabradine or
matching placebo) was taken orally twice daily, at 12-hour intervals in the morning and in the
evening, during meals. Three doses were used: 5 mg, 7.5 mg or 10 mg tablets ivabradine or
matching placebo.
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Arm title
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Placebo | |||||||||
Arm description |
- | |||||||||
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 |
During the treatment period after randomisation, the IMP (double-blind ivabradine or
matching placebo) was taken orally twice daily, at 12-hour intervals in the morning and in the
evening, during meals. Three doses were used: 5 mg, 7.5 mg or 10 mg tablets ivabradine or
matching placebo.
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Baseline characteristics reporting groups
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Reporting group title |
Overall study
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Randomised Set
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Subject analysis set type |
Intention-to-treat | |||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
No statistical analysis plan was written because of the small sample size.
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End points reporting groups
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Reporting group title |
Ivabradine
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Reporting group description |
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Reporting group title |
Placebo
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Reporting group description |
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Subject analysis set title |
Randomised Set
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
No statistical analysis plan was written because of the small sample size.
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End point title |
No primary endpoint [1] | |||||||||
End point description |
The primary endpoint was the absolute percentage change in FMD of the brachial artery from baseline to 12 weeks for ivabradine compared with placebo. However, because of the premature study termination, no FMD was performed under or after treatment intake.
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End point type |
Primary
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End point timeframe |
The primary endpoint was the absolute percentage change in FMD of the brachial artery from baseline to 12 weeks for ivabradine compared with placebo. However, because of the premature study termination, no FMD was performed under or after treatment intake
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoint was the absolute percentage change in FMD of the brachial artery from baseline to 12 weeks for ivabradine compared with placebo. However, because of the premature study termination, no FMD was performed under or after treatment intake. |
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Notes [2] - Because of the premature study termination, no FMD was performed under or after treatment intake. [3] - Because of the premature study termination, no FMD was performed under or after treatment intake. |
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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 |
the overall study
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Assessment type |
Systematic | |||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
- | |||||||||||||||||||||
Reporting group title |
Ivabradine
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Reporting group description |
- | |||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||
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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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28 Feb 2014 |
Amendment No. 1, dated 28 February 2014, was applicable in all countries. It concerned
mainly:
The modification of the study selection criteria to allow the inclusion of patients with
“minor and stable cardiovascular disease” (the HR requirement of ≥ 75 bpm was left
unchanged).
The minimal time between selection and inclusion visits is reduced from 12 to 6 days.
The amendment did not require any changes to the patient information sheet or informed
consent form. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
At the end of March 2014, I.R.I.S., in agreement with the Scientific Board, took the decision to prematurely discontinue this study in view of the difficulties in the recruitment process and the strategic objectives for ivabradine. |