Cardionics Belgium ECG systems for CRO

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The CARDIONICS systems for ECG Labs 1. ECG Centralisation software. The ECG data server allows the centralisation of the recordings and the centralisation of the information concerning the studies. The supervisor of the installation will define: The list of users The list of the current studies The type of access to the data’s.

For each study, the supervisor has to define the directory (source of the data’s). This means the place where the acquisition system (CardioPlug and/or CarTouch) will transfer the files. The supervisor can then define a specific arborescence with regard to the sequential access to the data’s. This allows making it obligatory to validate the data’s (confirmation of the measures by the cardiologist and/or the diagnostic help given by the automatic software’s) and to follow the evolution of the data’s.

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Here is an example of arborescence:

Another directory allows saving the configuration of the installation, and the database of the voluntaries taking part to studies. The voluntary is identified in using a barcode of an ID card. The information about the voluntary is recorded in an « Access » database .

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The Visit Management Software: The supervisor has also the possibility to define the planning of the visit for the study. For regular visits, the supervisor can define the time of the visit (absolute or relative to the drug delivery time), and ask for the automatic creation of a standard ECG linked to the visit (with or without the print).

Three types of visits are foreseen: Regular visits: defined with regard to the parameters of the study. Retest visits: allow to do a regular visit several times. Unscheduled visit: allow doing a visit which is not foreseen in the protocol of the study. The list of studies can be exported in a « *.vst » file and can be used during the configuration of the CarTouch device.

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2. ECG acquisition with the CardioPlug. The acquisition system CardioPlug allows to record standard ECG (12 leads, 10 seconds 500 Hz) and long term ECG (several minutes or several hours of recording).

The acquisition box CardioPlug is connected to the USB port of the computer. Then, the user chooses the current study and identifies the patient with a barcode. The 12 leads ECG traces are displayed on the screen during the recording session. This allows the user to check the trace in real time. He can ask for a print at any time (10 seconds of the 12 leads, or 2 minutes for 12/3/1 lead(s)).

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The user can record automatically or manually a basic ECG for each visit (12 leads, 10 seconds 500 Hz). These data files are recorded on the local disk and then transferred on the ECG data server according to its availability.

The user can also record the ECG in real time on the hard disk. Thus, in a transparent way for the volunteer and the user, the ECG’s data (12 leads 500Hz) are registered in data files at the format ISHNE. During the acquisition, the user can interrupt and then resume the recording to allow the volunteer to stay away for one moment. The data files’ size will depend on the duration of the recording (for information, one hour of registration corresponds to a data file of 27.5Mo). These data files are recorded on the local disk, and then transferred at the end of the recording on the online data-base service ECG, according to its availability.

A dialog box will appear for each visit during the recording of a standard ECG (12 leads, 10 seconds 500 Hz). This dialog box allows defining the type of the visit and the name of the visit. The software manages automatically the visits with regard to the volunteer, this: - Reduce the sources of error (concerning the visit realised). - Avoid the realisation of the same visit several times.

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During the acquisition of the lead (real time visualisation on the lead), it is possible to see the measures corresponding to the 10 seconds ECG selected. This will avoid printing this ECG.

CARDIONICS advise to record the plot ECG during the first administration to man, during a duration corresponding at least to the molecule’s half life. These long term recordings will permit a detailed study of the segment QT at the end of the study (retrospective analysis).

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3. CardioPlug: management of network workstations This application allows displaying on a central computer in real time the recorded leads which are displayed on the 12 other CardioPlug acquisition systems.

The user can, at a glance, follow the evolution of the leads. Moreover, from this screen, the user can: - Start up or interrupt the long term recording of one of the CardioPlug acquisition systems. - Ask for an immediate printing (10 seconds 12 leads) of one or all the CardioPlug acquisition

systems.

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4. CarTouch acquisition. The CarTouch recorder is a stand-alone 12 leads numeric electrocardiograph. Using the keyboard and the screen, the user can identify the patient (possibility to use an ID card), and carry out basic ECG (12 leads 10 seconds 500Hz). This recorder allows to carry out standard ECG (control visits) on the volunteers.

This CarTouch’s internal software allows especially: The recording of the patient’s identification in Flash memory. This avoids the re-capture the

patient identification at each exam. The visits’ management. Automatically, the system states the first available visit for the patient.

This will avoid eventual confusions. The saving of the registration in Flash memory. The memory of the device allows recording 53

ECG.

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4.1 ConfigTouch software: This software allows the configuration of the CarTouch device on PC according to the study requirements.

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4.2 TeleTouch : ECG transfer software In order to download the recordings realized on the CarTouch, the device can be connected on a microcomputer via the RS232 port. During this operation, the recordings are automatically analysed, can be printed and then transferred to the online data-base service.

• ECG file transmission by Modem to a remote PC:

Or:

• ECG file transmission by Internet to a FTP host:

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5. Validation and treatment computer The validation and treatment computer allows the users (ECG technicians, validating doctors, cardiologists) to re-examinate and/or to analyse the recordings. The possibilities of visualization are defined by the supervisor, and applied according to the user’s name and his password. These possibilities are adapted to each study. The analysis’objectives: - To cut out the long term recording in a sequence of raw file. - To analyse the raw file in order to measure especially the segment QT. - To quantize the variations of the QT measures.

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5.1. ISHNE Viewer: Software for processing the long term recordings This treatment’s aim is to cut out the long time recordings in a sequence of raw files (12 leads 10 seconds 500Hz). To do it, we use a specific visualisation software, which allows especially to display and print a long term data file.

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Pre-treatment can detect the QRS beats on the whole record. The beats found are classified according to the duration of the QRS (detection of the ventricular extrasystol) and the duration of the interval RR preceding the beat (detection of the supraventricular extrasystol). The visualization software allows to show off RR’s swing curve on the recording.

5.2 ISHNE Extractor: Several cut-out methods can be applied: We apply the visit plan as it is defined in the beginning of the study, and a basic ECG is created at

each visit. We use the visit plan as it is defined in the beginning of the study, for each visit, and by founding

upon the RR curve; we select a period of stable RR to create a basic ECG. We adjust the visit plan as it is defined in the beginning of the study in order to coincide it with the

concentration graph (adapted to the patient) with the molecule to use. For each adjusted visit, and by founding upon the RR curve, we select a period of stable RR to create a basic ECG.

ISHNE file

Visit planning RR curve Pharmacodynamic

Rest ECG(SCP file)

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5.3. ECG validation: Software of standard ECG treatment The basic ECG (12 leads 10 seconds 500Hz) are recorded in files at the SCP format. The software of automatic analysis allows: The detection and the classification of the QRS beats. The detection of the P waves on the 10 seconds recording. The calculation des 12 averaged leads. The detection of the markers of the beginning and the end of the waves (beginning/end of P,

beginning/end of QRS, end of T) on the averaged leads. The measure of the waves (duration and amplitude). The automatic analysis of the rhythm and the morphology.

Visualization software allows to re-examine this entire automatic analysis. The first screen allows to display the ECG plot, with the position of the QRS pointers.

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The doctor who validates the ECG can then visualise the result of the diagnostic help, with the possibility to modify this analysis either by using a pull-down menu, or by entering a free-text.

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5.4 QT analysis: averaged complex: The analysis of the QT segment can be realized on the 12 averaged leads. The software displays automatically the 12 superimposed averaged beats and the marker of the beginning and end of waves. The doctor who validates can then move these markers. Automatically, the global measures (PR, QRS, QT, QTcb et QTcf) are calculated.

This representation is very useful to define the beginning of QRS (first lead to be activated), the end of QRS (last) and the end of T. Conversely, the QT measure is global, that means that it depends on all derivations. Indeed, the beginning of QRS can be defined on dII, and at the end of T on V6.

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5.5 QT analysis: Tangent method: The analysis of the QT segment can also be realized on a unique lead. For this, the doctor chooses a lead, and the portion on which the analysis must be realized. The software will then place the cursors for three consecutive beats. The doctor who validates the result can move the cursors. Automatically, the global measures (PR, QRS, QT, QTcb et QTcf) are calculated.

The detection at the end of the T wave can be realized either by using the tangent method, or by returning to the baseline

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The final screen will gather all the results, give a general conclusion and archive the information in the SCP data file. This data file contains all the information relative to its access, and that allows a precise follow up of this access (audit trail).

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5.6 ECG exportation (ASCII, PDF & XML): The information contained in the SPC data file can be exported on three computer file formats: Text file ASCII: That will do the link with an external database (the IT system of the centre for

example). Graphic file PDF: this export allows to have a visual review of the measures and of the positions of

the markers. This file can be exploited without any specified Cardionics software and it also allows to give information to a sponsor.

Computer file XML: this file is used to send the results to the certification body (FDA).

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5.7 Software of results exploitation: currently in development. This software will, at the end of the study, display the evolution of the measures. The SCP data files which are validated by the cardiologist are archived in directories according to the identification number and/or the name (initials) of the volunteer. The software will then open the files related to the chosen volunteer, and then classify the measures according to the recording date and time. A visual presentation allows to see the evolution of the following measures: RR duration. Cardiac rate. PR duration. QRS duration. QT, QTcb and QTcf duration.

For each value, while positioning the mouse on the measure, the user can see the recording information (date and time, name of the visit) and can ask to display the corresponding ECG plot.