Clinical Trial Results:
A multi-center, open label, single group, observational study to investigate the effects of training on the administration of Cardioplexol (TM)
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Summary
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EudraCT number |
2018-002311-10 |
Trial protocol |
AT DE |
Global end of trial date |
18 Oct 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Nov 2022
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First version publication date |
03 Nov 2022
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Other versions |
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Summary report(s) |
Clinical Study Synopsis SCT-Cpx-004 |
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 |
SCT-Cpx-004
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Swiss Cardio Technologies AG
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Sponsor organisation address |
Blegistrasse 1, Rotkreuz ZG, Switzerland, CH – 6343
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Public contact |
Hendrik Tevaearai Stahel, Testa Logic GmbH, 0041 763804835, hendrik.tevaearai@gmail.com
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Scientific contact |
Hendrik Tevaearai Stahel, Testa Logic GmbH, 0041 763804835, hendrik.tevaearai@gmail.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 Oct 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Oct 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Oct 2021
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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 main objective is to explore the effects of a training program on the rate of correct application of Cardioplexol (TM) for cardioplegic cardiac arrest during cardiac surgical interventions.
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Protection of trial subjects |
The study was performed in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The planning and conduct of this clinical study followed the respective national laws of the participating country (competent authorities) and the principles and guidelines for Good Clinical Practice (GCP), Good Laboratory Practices (GLP) and Good Pharmacovigilance Practice (GVP).
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Background therapy |
None | ||
Evidence for comparator |
Not applicable. The main objective of this study was to explore the effects of a training program on the rate of correct application of Cardioplexol (TM) for cardioplegic cardiac arrest during cardiac surgical interventions. Hence, no comparator was used. | ||
Actual start date of recruitment |
19 Nov 2018
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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 |
Austria: 107
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Country: Number of subjects enrolled |
Germany: 33
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Country: Number of subjects enrolled |
Switzerland: 31
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Worldwide total number of subjects |
171
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EEA total number of subjects |
140
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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) |
72
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From 65 to 84 years |
99
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 29 surgeons and 171 patients were recruited over a period of approx. 3 years in Austria, Germany and Switzerland. Every patient who was a candidate for an elective surgical cardiac procedure was included in this study, provided the operation was being performed via a full or hemi sternotomy and under cardiac arrest and assistance of ECC. | ||||||||||||
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Pre-assignment
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Screening details |
A total of 25 surgeons was planned to be trained, accounting for a minimum of 150 patients to be operated in the study, including 50 patients in total in part I (i.e. 2 patients per surgeon), and 100 patients in total in part II (i.e. 4 patients per surgeon). The actual number of surgeons was 29, and a total of 171 patients were screened. | ||||||||||||
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Period 1
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Period 1 title |
Overall Trial Period
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Observational group | ||||||||||||
Arm description |
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Arm type |
Observational | ||||||||||||
Investigational medicinal product name |
Cardioplexol
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for cardioplegia
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Routes of administration |
Intracardiac use
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Dosage and administration details |
Administration of one single dose (100 ml) of Cardioplexol (TM). Further dose of Cardioplexol (TM) was applied in regular intervals depending on the duration of the cardiac surgery as well as individual factors.
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Period 2
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Period 2 title |
Overall Trial Period _Treated patients
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Is this the baseline period? |
No | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Observational group | ||||||||||||
Arm description |
All operated patients. Part I: Training Program: The training program was addressed to all cardiac surgeons and cardiotechnicians willing to operate patients in this study, and included one theoretical and one practical section. A total of 29 surgeons were recruited and 28 had successfully operated 2 patients each. One surgeon did not qualify to participate in part II of the study as he only operated one patient in part I. Hence, he was replaced by another surgeon by mutual agreement. During the training phase 57 patients were operated. Part II: Evaluation Part: A total of 28 surgeons participated in this phase and operated 100 patients using Cardioplexol. Parameters regarding the correct administration (primary efficacy endpoint) were collected during the surgical procedure. Secondary endpoints were mainly collected during the first 24 hours following myocardial reperfusion (i.e. after aortic unclamping). A second safety follow-up visit was performed 30 days after surgery. | ||||||||||||
Arm type |
Observational | ||||||||||||
Investigational medicinal product name |
Cardioplexol
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for cardioplegia
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Routes of administration |
Intracardiac use
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Dosage and administration details |
Administration of one single dose (100 ml) of Cardioplexol (TM). Further dose of Cardioplexol (TM) was applied in regular intervals depending on the duration of the cardiac surgery as well as individual factors.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial Period
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Training Set (TS)
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Statistical evaluation of the primary endpoint was done based on the Analysis Set (AS, n = 100, Phase II), whereas the evaluation of the secondary endpoints as well as the safety and tolerability variables were performed using the Full analysis (AS, n = 100) set and Safety Set (n = 157) (Training set (n = 57) and AS (n = 100).
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Subject analysis set title |
Analysis Set (AS)
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Statistical evaluation of the primary endpoint was done based on the Analysis Set (AS, n = 100, Phase II), whereas the evaluation of the secondary endpoints as well as the safety and tolerability variables were performed using the Full analysis (AS, n = 100) set and Safety Set (n = 157) (Training set (n = 57) and AS (n = 100).
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Subject analysis set title |
Safety Set (SS)
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Statistical evaluation of the primary endpoint was done based on the Analysis Set (AS, n = 100, Phase II), whereas the evaluation of the secondary endpoints as well as the safety and tolerability variables were performed using the Full analysis (AS, n = 100) set and Safety Set (n = 157) (Training set (n = 57) and AS (n = 100).
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End points reporting groups
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Reporting group title |
Observational group
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Reporting group description |
- | ||
Reporting group title |
Observational group
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Reporting group description |
All operated patients. Part I: Training Program: The training program was addressed to all cardiac surgeons and cardiotechnicians willing to operate patients in this study, and included one theoretical and one practical section. A total of 29 surgeons were recruited and 28 had successfully operated 2 patients each. One surgeon did not qualify to participate in part II of the study as he only operated one patient in part I. Hence, he was replaced by another surgeon by mutual agreement. During the training phase 57 patients were operated. Part II: Evaluation Part: A total of 28 surgeons participated in this phase and operated 100 patients using Cardioplexol. Parameters regarding the correct administration (primary efficacy endpoint) were collected during the surgical procedure. Secondary endpoints were mainly collected during the first 24 hours following myocardial reperfusion (i.e. after aortic unclamping). A second safety follow-up visit was performed 30 days after surgery. | ||
Subject analysis set title |
Training Set (TS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Statistical evaluation of the primary endpoint was done based on the Analysis Set (AS, n = 100, Phase II), whereas the evaluation of the secondary endpoints as well as the safety and tolerability variables were performed using the Full analysis (AS, n = 100) set and Safety Set (n = 157) (Training set (n = 57) and AS (n = 100).
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Subject analysis set title |
Analysis Set (AS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Statistical evaluation of the primary endpoint was done based on the Analysis Set (AS, n = 100, Phase II), whereas the evaluation of the secondary endpoints as well as the safety and tolerability variables were performed using the Full analysis (AS, n = 100) set and Safety Set (n = 157) (Training set (n = 57) and AS (n = 100).
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Subject analysis set title |
Safety Set (SS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Statistical evaluation of the primary endpoint was done based on the Analysis Set (AS, n = 100, Phase II), whereas the evaluation of the secondary endpoints as well as the safety and tolerability variables were performed using the Full analysis (AS, n = 100) set and Safety Set (n = 157) (Training set (n = 57) and AS (n = 100).
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End point title |
Number of major deviations from the application of Cardioplexol as determined by the pre-specified training procedure [1] | ||||||||
End point description |
The primary endpoint of the study was the number of major deviations from the application of Cardioplexol as determined by the pre-specified training procedure (incorrect volume of initial dose, incorrect volume of second/third/fourth dose, incorrect duration of injection of initial dose, incorrect timing of application of initial dose, incorrect timing of application of second/third/fourth dose).
The primary endpoint for each patient was considered to be fulfilled only if the application of Cardioplexol was correct in all of the following points: correct volume of initial dose, correct volume of second/third/fourth dose, correct duration of injection of initial dose, correct timing of application of initial dose, correct timing of application of second/third/fourth dose or if a detailed explanation by the surgeon was given why she/he deviated from the pre-specified training procedures.
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End point type |
Primary
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End point timeframe |
The variables of the primary endpoint (timing and volumes of initial, second, third and fourth doses of Cardioplexol) were documented in an intraoperative worksheet during surgery-visit.
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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 for the AS was analyzed by using the SAS FREQ Procedure with a two-sided 95% Clopper-Pearson (exact) confidence limits. No major deviation from the application of Cardioplexol as determined by the pre-specified training procedure was observed and the (95% (Clopper-Pearson (Exact)) confidence interval was [0.964; 1.000]. The performed training of surgeons, who had never used Cardioplexol before, resulted in a correct application of Cardioplexol in all100 patients of the AS. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Max values of Tnt during the first 24h following myocardial perfusion | ||||||||||||||||||||
End point description |
Secondary efficacy endpoints were analyzed by descriptive statistics for the Training Set (TS), the Analysis Set (AS) and the Safety Set (SS) population.
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End point type |
Secondary
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End point timeframe |
Measurements to evaluate maximal value of TnT were performed at 3, 6, 12, and 24 hours following myocardial reperfusion.
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Max values of CK-MB during the first 24h following myocardial perfusion | ||||||||||||||||||||
End point description |
Secondary efficacy endpoints were analyzed by descriptive statistics for the Training Set (TS), the Analysis Set (AS) and the Safety Set (SS) population.
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End point type |
Secondary
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End point timeframe |
Measurements to evaluate maximal value of CK-MB were performed at 3, 6, 12, and 24 hours following myocardial reperfusion.
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Time between the aortic cross-clamping and the complete cardiac arrest. | ||||||||||||||||||||
End point description |
Secondary efficacy endpoints were analyzed by descriptive statistics for the Training Set (TS), the Analysis Set (AS) and the Safety Set (SS) population.
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End point type |
Secondary
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End point timeframe |
The time between the aortic cross-clamping and the complete cardiac arrest was documented on a working sheet during surgery.
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Cumulative dose of catecholamines during aortic cross-clamping. | ||||||||||||||||||||
End point description |
Secondary efficacy endpoints were analyzed by descriptive statistics for the Training Set (TS), the Analysis Set (AS) and the Safety Set (SS) population.
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End point type |
Secondary
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End point timeframe |
The cummulative dose of catecholamines during surgery was documented on a working sheet during surgery.
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Defibrillation rate after aorta unclamping and coronary reperfusion | ||||||||||||||||
End point description |
Secondary efficacy endpoints were analyzed by descriptive statistics for the Training Set (TS), the Analysis Set (AS) and the Safety Set (SS) population.
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End point type |
Secondary
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End point timeframe |
The need for defibrillation and the intesnisty of defibrillation after aortic unclamping and coronary reperfusion were documented for each concerned patient.
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Cumulative dose of catecholamines during the first 24 hours following coronary reperfusion | ||||||||||||||||||||
End point description |
Secondary efficacy endpoints were analyzed by descriptive statistics for the Training Set (TS), the Analysis Set (AS) and the Safety Set (SS) population.
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End point type |
Secondary
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End point timeframe |
The cumulative dose of catecholamines during the first 24 hours following coronary reperfusion was documented for each patient.
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Duration of ICU stay | ||||||||||||||||||||
End point description |
Secondary efficacy endpoints were analyzed by descriptive statistics for the Training Set (TS), the Analysis Set (AS) and the Safety Set (SS) population.
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End point type |
Secondary
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End point timeframe |
The duration (hours) of ICU stay for each patient was documented.
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Mortality during the first 24 hours following coronary reperfusion | ||||||||||||||||
End point description |
Secondary efficacy endpoints were analyzed by descriptive statistics for the Training Set (TS), the Analysis Set (AS) and the Safety Set (SS) population.
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End point type |
Secondary
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End point timeframe |
No mortality during the first 24 hours following coronary repersufion was documented in this study.
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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 |
All adverse events (AEs) after signature of the informed consent form were recorded irrespective of whether or not they may be related to the study intervention. Investigators followed-up AEs until resolution or the end of the study (follow up visit)
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Adverse event reporting additional description |
At each assessment, all AEs either observed by the Investigator or one of his clinical collaborators or reported by the patient spontaneously or in response to a direct question were evaluated by the Investigator. Nature of each event, date and time (where appropriate) of onset, outcome, severity and relationship to administration were established.
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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 |
21.0
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Reporting groups
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Reporting group title |
Overall (Safety Set (SS))
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Reporting group description |
The safety set (SS) consisted of a total of 157 patients who were operated using Cardioplexol, of whom 156 patients (99.4%) experienced at least 1 AE starting on or after the day of study drug application (treatment emergent adverse event, TEAE). In general, there were 678 treatment emergent adverse events reported (i.e. all AEs which started after or on the same day as surgery). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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03 Apr 2019 |
Due to the request of the competent authority in Germany (BfArM) several amendments were done for the previous study protocol.
Exclusion criteria 11: Exclusion criteria updated to define anticoagulatory drugs more precisely
Footnote 6:Specification of safety laboratory parameters added
Footnote 7: More precise information on time windows were added
Footnote 8: More precise information on time windows were added
Footnote 9: Sponsor added this footnote to specify parameters more clearly
Footnote 10: Sponsor added this footnote to specify parameters more clearly
Footnote 11: More precise information on time windows were added
Footnote 12: Sponsor added this footnote to specify parameters more clearly
7.7 Safety related criteria for patient's discontinuation include (but are not limited to): Safety related criteria for discontinuation were added
7.8 Any anticoagulant and any other auxiliary medicinal product: Updated to be more precise regarding anticoagulatory drugs
8.4 Premature termination or temporarily suspension: Detailed description of discontinuation criteria added
10.9 The end of the study is defined as the date of the last visit last subject (LVLS): Exact specification of end of study was added
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20 Jan 2020 |
Page 9 & 24:
Inclusion Criterion 3:
The operation will be carried out via a full or a hemi sternotomy, under cardiac arrest and under the assistance of a heart lung machine;
Page 21:
The purpose of this study is to evaluate a training program addressed to all cardiac surgeons and cardiotechnicians who are unexperienced with the use of the cardioplegic solution Cardioplexol when operating patients via a full or a hemi sternotomy and who are willing to operate with Cardioplexol (TM) and aiming at increasing the efficacy of Cardioplexol (TM) administration while reducing the risk of false manipulations.
Due to ongoing discussions with the participating investigators, it was realized that the wording of inclusion criterion 3 “The operation can be carried out via a full sternotomy, under cardiac arrest and under the assistance of a heart lung machine”, Study Protocol, version 3.0 dated 03.04.2019, might lead to two different interpretations by the investigators. To harmonise the protocol and for better understanding inclusion criterion N°3 was updated. The update is also reflected I the objectives. The respective text can be found in the list of inclusion criteria on pages 9 and 24 of the study protocol, and further in the text on pages 21 and 24.
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17 Mar 2021 |
Page 21:
1.3.4. Risks
In the IB, contraindications for the use of the product are stated. These provisions were integrated in the clinical trial protocol according to the request of the authorities Swissmedic to have harmonized information in the two documents.
Page 24-25:
3.1 Training Program
It is described more in detail how the training of the surgeons is managed by the sponsor, as recommended by the Swiss Ethical Committee “Kantonale Ethik-kommission Zürich”.
Page 30:
6.2 Storage conditions
In the QIMP it is indicated that after mixing, the reconstituted solution has been shown to be stable for 6 hours at 5°C. The shelf-life of the reconstituted solution is determined as 6 hours. This information was integrated in the Protocol according to the request of the authorities Swissmedic to harmonize the information of the two documents.
Page 39 & 40
Chapter 8.2.1 Reporting of SAEs and AEs:
2nd and 3rd paragraphs:
It is clarified that the SAE reporting obligations of the investigator should be fulfilled “without delay” as noted by the authorities BfArM and demanded in GCP-V §12 (4).
Page 43-44:
3 new Sections 8.5, 8.6., 8.7 added in Chapter 8 “Safety Reporting
For the sake of completeness and clarification, as recommended by the Swiss Ethical Committee “Kantonale Ethikkommission Zürich”, a detailed description is given which Adverse Events are reported to Competent authorities and Ethics committees (8.5). It is also described which other safety reportings are performed (8.6 and 8.7). It is clarified that these obligations should be fulfilled “without delay” as noted by the authorities BfArM demanded in GCP-V §12 and §13 (8.5 and 8.7). Additionally, all adressees for immediate safety and protective measures are mentioned, as noted by the authorities BfArM.
Page 46
Chapter 10.1 “Research Ethics Committee and Regulatory Compliance” : For the sake of completeness, an explanation is given in which international register the clinical study is registered. |
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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. | |||
| None reported | |||
