Urgences C.A.T

Technical File Attachment
D-Heart
Protocol of Clinical Investigation
Name Date Signature
Author N.Maurizi 11/03/2016
Reviewer E. Bisson 11/03/2016
Approver N. Briante 11/03/2016
Manufacturer
D-HEART SRL
Via C. R. Ceccardi 1/17 16121
Genova (GE) - Italy
D-Heart srl Title: Protocol of Clinical Investigation
Published: 11/03/2016
Changelog
Date Revision Changes

11/03/2016 00 Initial Revision
Doc ID: D-Heart Protocol of Clinical Investigation Product: D-Heart Pag. 2 / 16

PROTOCOL
CLINICAL INVESTIGATION WITH MEDICAL DEVICE
Study Title: Comparative analysis of multiple leads
smartphone electrocardiograph (D-Heart®)
versus standard 12-leads electrocardiograph in
patients with Hypertrophic Cardiomyopathy: a
non-inferiority study
Number of Referral of the SPE 16.221

investigation:
Version number of the protocol: Version 2
Date: 11th March 2016
Device identification D-Heart® Electrocardiograph
ponsor Manufacturer and Sponsor: D-Heart Srl, Via R.

C. Ceccardi 1/17, 16121 Genova, Italia
Scientific Responsable Iacopo Olivotto M.D., Director,

Cardiomyopathy Unit, Careggi University
Hospital.
Other Researcher Dott. Mattia Targetti, Cardiomyopathy Unit,
Careggi University Hospital.
Dott.ssa Anna Arretini, Cardiomyopathy Unit,
Careggi University Hospital
Dott.ssa Silvia Passantino, Cardiomyopathy
Unit, Careggi University Hospital
Dott.ssa Ilaria Tanini, Cardiomyopathy Unit,
Katia Baldini, Cardiomyopathy Unit, Careggi
University Hospital
Alessia Tomberli, Cardiomyopathy Unit,
Fausto Barlocco, Cardiomyopathy Unit,
Centers Involved: Cardiomyopathy Unit, Careggi University

Hospital

Contact Informations
Sponsor contact and name D-Heart Srl Via R. C. Ceccardi 1/17 16121
Genova Italia
Sponsor name for medical Niccolo’ Maurizi M.D., Chief Medical Officer,
device surveillance D-Heart Srl Via R.C. Ceccardi 1/17 16121
Genova Italia Tel. +39010 532505; +39 349 548
6091
Nicolo’ Briante, CEO D-Heart Srl, Via R.C.
Ceccardi 1/17 16121 Genova Italia Tel. +39010
532505
The researchers:
- Approve the present protocol;
- Declare that the study will be held according to the Good Clinical Practice (UNI EN ISO
14155:2012) and following what is reported in the present protocol.
___________________ ___________11/03/2016_______
Dott. Iacopo Olivotto Date
___________________ _________11/03/2016_________
Dott. Mattia Targetti Date
___________________ __________11/03/2016________
Dott. Anna Arretini Date
___________________ _________11/03/2016_________
Dott. Silvia Passantino Date
___________________ ________11/03/2016__________
Dott. Ilaria Tanini Date
___________________ _________11/03/2016_________
Katia Baldini Date
___________________ ________11/03/2016__________
Alessia Tomberli Date
___________________ _______11/03/2016___________
Fausto Barlocco Date

Table of Contents
I. Information on the medical device ...................................................................................... 6

II. Analisi della letteratura e razionale dell’indagine clinica ...................................................... 8
III. Obiettivi dello studio.................................................... Errore. Il segnalibro non è definito.
IV. Ethical Considerations ................................................................................................... 10
V. Modality of informed consent acquisition ......................................................................... 10
VI. Vulnerable population and use in emergency setting ..................................................... 10
VII. Preclinical Studies and previous similar experiences ...................................................... 10
VIII. Information about the clinical study .............................................................................. 10
IX. Monitoring Plan of the Clinical Investigation ................................................................. 13
X. Deviations from the Clinical Evaluation Plan...................................................................... 14
XI. Quality Control, Procedure Control, Data Management, documentation conservation ... 14
XII. Deviation from the Clinical Evaluation Plan ................................................................... 14
XIII. Adverse events ............................................................................................................. 15
XIV. Amendament of the Clinical Evaluation Plan ................................................................. 15
XV. Early study termination and suspension of clinical evaluation ........................................ 15
XVI. Statistica ....................................................................................................................... 15
XVII. Data publication policy .............................................................................................. 16
XVIII. Bibliography .............................................................................................................. 16

I. Information on the medical device
The D-Heart portable ECG (D-Heart ECG) is a 6 electrodes ECG designed to be worn at the neck (Fig. 1)
that monitors the electrical activity of the heart and transfers the collected data to a Smartphone via Bluetooth
Low Energy (BLE).
Figure 1: wearing the D-Heart ECG

A dedicated App processes the data received from the ECG and plots an 8-leads electrocardiogram in run
time (Fig. 2). The App can connect to a dedicated Cloud application for the management of the users and for
the connection to remote medical reporting services (Telecardiology).
Fig. 2: 8-leads electrocardiogram based on D-Heart ECG
The D-Heart is battery operated. The battery is charged via wireless technology. A wireless charger is
provided as an accessory of the D-Heart.
In order to operate, the D-Heart is connected to the human body by means of 6 sockets that are connected
to disposable electrodes (Fig, 5), glued to the skin of the body:

• 4 sockets are placed on retractable cables (Fig. 3);
Fig. 3: 4 retractable cables
• 2 sockets are fixed in the chassis (back side, Fig. 4-1, 4-2).
Fig. 4-1, 4-2: fixed sockets in the chassis
Fig. 5: disposable electrode
A power button (Fig. 6) is placed in the center of the chassis (front side) to switch on/off the device.
The power button hosts a LED to signal the device status to the user.

Fig. 6: Power button with integrated LED
When switched on, the D-Heart monitors the electrical activity of the heart by means of dedicated chipsets
that convert the analog electrical signal generated by the heart into a digital bit stream; the correct
connection to the human body and the presence of meaningful signals are automatically checked. The bit
stream is then transferred - in real time - to a Smartphone via a BLE link.
The D-Heart is battery (Li-Ion) operated. The battery charge level is transferred to the Smartphone in real
time.
The battery is recharged by wireless technology. The D-Heart hosts a wireless receiver connected to a coil.
To enable the battery charging, the D-Heart is placed on an external wireless charger (provided as accessory)
Fig. 8 shows the block diagram of the D-Heart device, with the indication of the main components.
II. Literature analysis and clinical investigation rationale
Mobile health (mHealth) technologies are revolutionizing the practice of cardiovascular medicine. The global
diffusion of smartphone devices is producing profound changes in diagnostics, as much relevant data could
nowbe generated locally by the patient rather than centrally by providers [1].While high-income countries
remain at the forefront of developing the latestmobile technologies used in healthcare, the rate of penetration

of such technologies in low- and middle-income countries has recently exceeded that of their wealthier
neighbors [2]. In general, low- and middle-income countries have major restrictions on their
healthcare capacities due to the lack of infrastructures, human resources and logistics. Smartphone technology
may overcome several of these limitations by providing an easy and affordable access to accurate diagnostic
and monitoring methods [2]. The importance of non-communicable diseases – and especially of cardiovascular
related morbidity and mortality [3,4] – is rising steeply in low-income countries, unmasking new unmet needs
for risk assessment and early diagnosis [5]. In such setting, widespread availability of accurate ECG screening
would represent a major step in the right direction [6,7]. However, a low-cost, user-friendly smartphone-based
electrocardiograph, enabling the acquisition of multiple lead electrocardiograms (ECG) with a reliability
comparable to the standard ECG, is still lacking. D-Heart® electrocardiograph has been recently developed
with this specific aim, both for iOS and Android operative systems, enabling the acquisition of surface
electrical signals through 6 electrodes, capturing 3 peripheral and 2 precordial lead (V2-V5), and their
transmission to the smartphone via Bluetooth technology (Fig. 1).
The use of the 6 electrodes settings (instead of the canonical 10) is based on more than 20 years of literature
trying to identify the best compromise between usability and clinical reliability (8) In acute ischemia setting,
a study (9) has shown that the mere presence of 4 electrodes on the patient's body (two bipolar, one unipolar
and one to download) were able to have a specificity and sensitivity that is statistically comparable to a track
obtained with 10 electrodes. In the D-Heart configuration the 3 peripheral electrodes are associated with two
precordials, which ensure an even better coverage of the various cardiac anterior and posterior cardiac
"territories".
For this validation study, a paradigmatic pathology was chosen such as hypertrophic cardiomyopathy (HCM),
characterized by young patients with very varied and often marked electrocardiographic alterations (10). HCM
is the most common heart disease and is a common cause of sudden cardiac death, especially in young athletes
(10). Electrocardiogram is considered to be an excellent tool for screening and monitoring the time of this type
of patient (11) and is even more sensitive than ultrasonography in the identification of affected family members
(10). A large variety of electrocardiographic anomalies have been described in HCM (12). These not only
guide the physician in identifying HCM risk subjects in the general population (12) but specifically correlate
with the severity of the individual patient's phenotype (13). Since HCM is the most common cause of sudden
death in young athletes, the possibility of screening ECG populations as wide as possible (and hence not just
those of competitive relevance currently evaluated) to include, for example, schools or gyms, appears highly
desirable given the high sensitivity of the ECG for this pathology. Such a strategy is, however, unreliable with
traditional methods for logistics and cost. The pilot study proposed here is intended to determine whether in
patients with concurrent HCM the sensitivity and specificity of D-Heart ECG readings is comparable to that
of standard ECG 12-derived, as a pre-action step for larger population studies.
III. Objectives of the Study
The primary objective of the study is to assess the concordance between D-Heart® ECG readings
and standard 12 lead electrocardiographs (assumed as the gold standard) readings. Concordance
would be assessed by: the weighted kw-Cohen index, with its relative significance, taking as the
endpoint variable the 12 lead ECG group. The secondary objective is to assess the accuracy of D-
Heart ECG intervals as compared to the 12 lead ECG (taken as the gold standard) with the use of
Bland-Altman method, with a 95% confidence level, for the PR and QRS interval measurements.
Since differences between the two measurements do not follow a normal distribution, a non-
parametric approach (median value and 2.5^ and 97.5^ percentiles) was used to determine the
limits of agreement.
The D-Heart device is designed for remote control of patients with chronic heart disease. Since it
would be classified as Class IIA device with a technology to minimize possible dangers, the risks

associated with its use are infinitely small. In addition, compared to standard outpatient
electrocardiographs, both the smartphone and the D-Heart electrocardiograph are powered by
battery and are not connected to power source when used on the patient.
IV. Ethical Considerations

The requirements of the Helsinki Declaration will be respected.
The study will be reviewed by the Review Board of the participating center. Informed consent of the patient
will be required. An information on the treatment of data will be delivered to the patient.
V. Modality of informed consent acquisition

The Informed Consent will be obtained during the scheduled monitoring visit to the Center,
following an exhaustive interview with the Principal Investigator.
Being an outpatient clinic following chronic patients is not envisaged any type of emergency
enrollment or in patients who cannot fully express their will.
VI. Vulnerable population and use in emergency setting
Not applicable.
The device and its application procedure do not involve acute risks. The study will be carried out
in a hospital outpatient setting: if medical intervention becomes necessary, the staff and
equipment of the facility itself will be used.
As an electrocardiographic screening in chronic outpatients, no emergency procedure would be
required.
VII. Preclinical Studies and previous similar experiences

The present study is the first clinical trial for the D-Heart Electrocardiograph and as protocol for
non-CE approved devices, the regular application to the Italian Ministry of Health will be submitted
upon receipt of the notification of a deposit at the Ethics Committee of the Area Vasta AOUC.
There are numerous reports in the literature of single lead electrocardiographic devices for
smartphones (Journal of Electrocardiography 2013, Smartphone ECG for evaluation of STEMI)
mainly used in identification in the post-ablation of atrial fibrillation (AliveCor ECG, a derivation,
HRS 2013) . Such devices cannot provide a morphological diagnosis of the tracing, such as D-
Heart, but only of the rhythm.
VIII. Information about the clinical study
Description of the clinical investigation

D-Heart Clinical Investigation Protocol is a prospective comparative study.
Among the purposes of this investigation are both the CE marking of the device and the further development
and refinement of the D-Heart Electrocardiograph device.
Obiettivi primari e secondari

Primary Objective of the Study

The primary objective of the study is to assess the concordance between D-Heart® ECG readings
and standard 12 lead electrocardiographs (assumed as the gold standard) readings. Concordance
would be assessed by: the weighted kw-Cohen index, with its relative significance, taking as the
endpoint variable the 12 lead ECG group.
Secondary Objective of the Study

The secondary objective is to assess the accuracy of D-Heart ECG intervals as compared to the 12
lead ECG (taken as the gold standard) with the use of Bland-Altman method, with a 95% confidence
level, for the PR and QRS interval measurements. Since differences between the two measurements
do not follow a normal distribution, a non-parametric approach (median value and 2.5^ and 97.5^
percentiles) was used to determine the limits of agreement.
Endpoint
Primary End-Point
Kappa cohen’s test agreement > 0.81 (as sign of high agreement as suggest by Landis and Koch
(14)).
Secondary End-point
Differences between PR and QRS measurement from both technique within median value between
+/- 30 ms and +/- 20 ms for QRS.
Variables to be mesaured
D-Heart® and 12-lead recordings were subsequently obtained (within 2–5min) in each subject.
Severity of ECG abnormalities was defined by a semi-quantitative score based on the sum of 9
criteria (based on reference 13): abnormal cardiac rhythm, QRS duration ≥ 100 ms, Romhilt–
Estes (R-E) score ≥ 5, fascicular block and/or bundle-branch block, ST-T abnormalities, ST-T
segment elevation ≥ 0.2 mV, prolonged QTc interval, pathological Q waves and absence of normal
Q wave. Four ECG groups were identified: normal (0 criteria); mildly abnormal (1–3 criteria);
moderately abnormal (4–6 criteria); markedly abnormal (7–9 criteria). ECGs from D heart® were
assessed by two independent observers (S.P. and M.T.) that categorized in a separate database the
ECG abnormalities, whereas two other independent observers (I.T. and A.A.) analyzed the tracings
from standard 12-lead electrocardiograph.
As far as the secondary objective, each observer measured PR and QRS intervals.
The measurement of the continuous variables will be done with three identical models (each
equipped with an observer) of rulers for measurements of intervals (ms), voltage (mV) and length
(mm).
Systematical errors - bias

The design involves a set of consecutive patients referred to the Cardiomyopathy Unit for routine
visits, inclusion criteria have been specified in the "Patient Selection" section, and the evaluation
of electrocardiographic trails will be performed by two experienced observers and will be filed by a
third impartial observer which will win doubt cases.
We therefore believe that this can minimize the possibility of bias.
Patient Selection
Inclusion Criteria

1) Patients with Hypertrophic Cardiomyopathy

2) Patients reaching at least 18 years or more, with the will to sign the Informed Consent for participation in
the study.
Exclusion Criteria
1) Patients who are pursuing intense sports activities (> 6h per week), even if not professional.
2) Patient who does not want or is unable to sign authorization for use and disclosure of Health Data or
Conscious Information.
3) Patients carrying a Pacemaker or Pacing ICD functioning at the time of the ECG.
Number of patients who are expected to enroll

To obtain a level of tolerance β (probability of judging the measurements incorrectly discordant) equal to
0.99 with a first type error of 0.05, at least 90 cases are required. Considering a 20% drop out, a total of at
least 110 people will need to be recruited. In definitive was established, taking into account the
aforementioned sample computation of 150 patients total with the diagnosis of HCM (15)). The beginning
of patient enrollment is scheduled for April 2016. The duration of the phase of the enrollment will be 12
months and the study will end in May 2017 or at the expected number of patients.
Enrollment Point
Each patient who meets the inclusion criteria from the Reference Center for Cardiomyopathy is
considered enrolled in the clinical trial if he signs the informed consent and the Data Treatment
Information Form.
Number of experimental medical devices that are expected to be used

The number of experimental medical devices that is expected to be used in this study is 2 units.
Duration of the study

The duration of the phase of the enrollment will be 12 months and the study will end in May 2017 or at the
expected number of patients.
Medical-surgical procedures and follow-up study
Patients with HCM diagnoses referred to the Cardiomyopathy Unit of Univerisity Hospital of Careggi from
April 2016 to May 2017 during their routine follow up visit to and after being enrolled in the study, they will
receive electrocardiographic screening both with D-Heart electrocardiographs and standard 12 lead
electrocardiograph (MyCardio Pad, Esaote).
The diagnosis of HCM will be a priori defined on the presence of a two - dimensional echocardiographic
evidence of a left ventricular hypertrophic and non-dilated (max. parietal thickness ≥ 15 mm), in the
absence of other cardiac or systemic pathologies that produce such hypertrophy (11). Electrodes will be
placed by nursed or medical personnel properly trained. All ECG records from both devices should include
at least 4 consecutive QRS complexes. D-Heart device would be used with a dedicated Iphone 6 provided
by the sponsor with the sole function of acquiring ECGs without connection card
Each ECG coming from both the D-Heart device and Esaote MyCardioPad will be saved with an anonymous
ID and saved in a special protected folder. In order to guarantee more anonymity to patient data, there is
the possibility of encrypting the data using Adavanced Encryption Standart techniques using a symmetric
key algorythm. This is characterized by the property that, given the encryption key "e", is easily accessible
calculate the decryption key "d". The strength of symmetric encryption is thus secured in the secrecy of the
only key used by the two interlocutors who use it, in addition to the size of the key space, in choosing a
good key and algorithm resistance to crittal attacks.
At the time of data analysis, all electrocardiographic recordings should be printed in scale 1: 1. The printed
ECGs. All the procedures of this study will be held exclusively at the Cardiomyopathy Unit of Careggiu

University Hospital. No medication, treatment or medical device alternative to the ones above will come
used or administered in the study. Patients will be able to take any medication during it study and will not
have the need to bring it back to the investigators.
The D-Heart device is designed in such a way as to minimize the risks of creating
electromagnetic fields that could affect the operation of other devices (ICD and PM carrier are however
exclued from the study).
Known or predictable factors that may compromise results and interpretation of results
There are no known factors that may compromise the interpretation of results.
Investigators will report malfunctions of the devices or the manufacturer or National Competent Authority,
according to national practice. The manufacturer must inform the Competent National Authority of the
malfunction and corrective measures are to be taken. The manufacturer is responsible for investigating
accidents and for not taking any corrective action on it.
Interruption and withdrawal of subjects from clinical investigation
If a subject officially withdraws from the study, after signing the Informed Consent, the reason will be
documented, indicating any report on the retirement of the study. Retraction of a subject will be
documented in the Electronic Case Reporting Report (e-CRF).
All deviations of the study must be recorded in the e-CRF. A deviation of the study is defined as an event
that internally in the study does not occur as in the Clinical Investigation Plan. Study aberrations must be
reported as soon as somebody realizes the need to decline. Deviations can be discovered through various
resources, including CRF reworking. Common examples include problems associated with informed consent,
the approval of IRBs and the omission of tests or procedures required by the Clinical Investigation Plan.
Specific examples include, but are not limited to:
• Not obtaining informed consent before participating in the study
• Incorrect version of consent delivered to the subject
• Patients who do not comply with inclusion / exclusion criteria
• Measurements and tests not performed but required by the Clinical Investigation Plan
• Measurements and tests not performed correctly but required by the Clinical Investigation Plan
• Permanent Data Loss (Tables, Disks, etc.)
IX. Monitoring Plan of the Clinical Investigation

The monitoring will be carried out by Dr. Niccolò Maurizi, I. Quality assurance, control procedures,
data management and documentation retention
The investigator is responsible for the preparation (control and signature) and preservation
preparation (control and signature) and submission to the sponsor of all CRFs. These documents
must be collected in the Investigation File Sites, ie provided by the investigator's organizer to the
investigators. The following documents will be inspected and must be kept for a period of two years
(or greater if local law or the hospital administration so requests) from the end of the study.
-That's all about the survey.
-The anonymous traces acquired for each patient and in addition the signed Consensus Information;
all relevant observations; documentation of the dates and reasons for any deviation from the
protocol.
-The Consent signed by the Investigator and the current CV.
- IRB documentation.

X. Deviations from the Clinical Evaluation Plan

All deviations of the study must be recorded in the e-CRF. A deviation of the study is defined as
an event that internally in the study does not occur as in the Clinical Investigation Plan. Study
aberrations must be reported as soon as somebody realizes the need to decline.
Deviations can be discovered through various resources, including CRF reworking. Common
examples include problems associated with informed consent, the approval of IRBs and the
omission of tests or procedures required by the Clinical Investigation Plan.
• Permanent Data Loss Tables, Tracks, etc.)
Such monitoring should be aimed at:

- Safeguarding the rights and well-being of individuals according to the principles of the
Helsinki Declaration;
- Check that collected data is accurate, complete and verifiable;
- Ensure that the study is conducted in accordance with the rules of good clinical practice
(GCP), protocol and applicable legislation.
The moments when monitoring will be two:
- A start of study study whose aim will be to educate the Experimental Staff;
-Search Closing Examination, whose purpose will be to resolve the issues unresolved by the
Experiment Center.
XI. Quality Control, Procedure Control, Data Management, documentation

conservation
The investigator is responsible for the preparation (control and signature) and preservation
preparation (control and signature) and submission to the sponsor of all CRFs. These documents
must be collected in the Investigation File Sites, ie provided by the investigator's organizer to the
investigators. The following documents will be inspected and must be kept for a period of two years
(or greater if local law or the hospital administration so requests) from the end of the study.
-That's all about the survey.
-The anonymous traces acquired for each patient and in addition the signed Consensus Information;
all relevant observations; documentation of the dates and reasons for any deviation from the
protocol.
-The Consent signed by the Investigator and the current CV.
- IRB documentation.
XII. Deviation from the Clinical Evaluation Plan

All deviations of the study must be recorded in the e-CRF. A deviation of the study is defined as
an event that internally in the study does not occur as in the Clinical Investigation Plan. Study
aberrations must be reported as soon as somebody realizes the need to decline.
Deviations can be discovered through various resources, including CRF reworking. Common
examples include problems associated with informed consent, the approval of IRBs and the
omission of tests or procedures required by the Clinical Investigation Plan.


• Permanent Data Loss (Tables, Tracks, etc.)
You must describe the procedures for recording and reporting any deviation from the clinical
protocol.
XIII. Adverse events

The Center must adhere to the requirements set out by its IRB and must report malfunctions of the
devices or the manufacturer or National Competent Authority, according to national practice. The
manufacturer must inform the Competent National Authority of the malfunction and corrective
measures. The manufacturer is responsible for investigating incidents and for not taking any
corrective action.
XIV. Amendament of the Clinical Evaluation Plan
Not applicable, since no amendments are planned for the clinical evaluation plan
XV. Early study termination and suspension of clinical evaluation

If the number of 110 patients enrolled before May 2017 is reached, the study, as described above,
will end with the enrollment of the entire desired population.
In case of temporary suspension of the study, a new insurance policy will be stipulated.
This policy will cover the remaining period of time required to complete the enrollment.
XVI. Statistics
This is a transverse study with a medical device. Consequently, only data will be collected
categorical and continuous on:
- Demographic Allocation of Patients
- Characteristics of electrocardiographic traces acquired with D-Heart Electrocardiograph
and Standard 12 Lead Electrocardiograph.
Primary Statistical Method:
As far as the primary objective is concerned, the primary objective of the study is to assess the
concordance between D-Heart® ECG readings and standard 12 lead electrocardiographs (assumed
as the gold standard) readings. Concordance would be assessed by: the weighted kw-Cohen index,
with its relative significance, taking as the endpoint variable the 12 lead ECG group. The secondary
objective is to assess the accuracy of D-Heart ECG intervals as compared to the 12 lead ECG (taken
as the gold standard) with the use of Bland-Altman method, with a 95% confidence level, for the
PR and QRS interval measurements. Since differences between the two measurements do not
follow a normal distribution, a non-parametric approach (median value and 2.5^ and 97.5^
percentiles) was used to determine the limits of agreement.

XVII. Data publication policy

Once the data analysis is complete, the results of the trial will be included in the EudraCT Database
in accordance with Article 11 (1) of Directive 2001/20 / EC.
In addition, the data will be made available to investigators for publication on peer-reviewed
scientific journals.
XVIII. Bibliography
1) S. Kuma, W.J. Nilsen, A. Abernethy, et al., Mobile health technology evaluation: the mHealth evidence
workshop, Am. J. Prev. Med. 45 (2013) 228-23.
2) A. Bastawrous, M.J. Armstrong, Mobile health use in low-and high-income countries: an overview of the
peer-reviewed literature, J. R. Soc. Med. 106 (4) (2013) 130–142.
3) D.O. Abegunde, C.D. Mathers, T. Adam, M. Ortegon, K. Strong, The burden and costs of chronic diseases in
low-income and middle-income countries, Lancet 370 (9603) (2007) 1929–1938.
4) M.H. Forouzanfar, L. Alexander, H.R. Anderson, et al., Global, regional, and national comparative risk
assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in
188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013, Lancet 386
(10010) (2015) 2287–2323.
5) P.A.Modesti, P. Agostoni, C. Agyemang, et al., Cardiovascular risk assessment in lowresource settings: a
consensus document of the European Society of Hypertension Working Group on Hypertension and
Cardiovascular Risk in Low Resource Settings, J. Hypertens. 32 (5) (2014) 951–960.
6) P. Greenland, J.S. Alpert, G.A. Beller, et al., 2010 ACCF/AHA guideline for assessment of cardiovascular risk
in asymptomatic adults: executive summary: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines, Circulation 122 (2010) 2748–
2764.
7) R. Chou, B. Arora, T. Dana, R. Fu, M.Walker, L. Humphrey, Screening Asymptomatic Adults for Coronary
Heart Disease with Resting or Exercise Electrocardiography Systematic Review to Update the 2004 U.S.
Preventive Services Task Force Recommendation(Rockville MD) 2011.
8) Nelwan, S. P., Kors, J. A., Meij, S. H., van Bemmel, J. H., & Simoons, M. L. (2004). Reconstruction of the
12-lead electrocardiogram from reduced lead sets. Journal of electrocardiology, 37(1), 11-18.
9) Nelwan, Stefan P., Suzanne W. Crater, Cynthia L. Green, Per Johanson, Teus B. van Dam, Simon H. Meij,
Maarten L. Simoons, and Mitchell W. Krucoff. "Assessment of derived 12-lead electrocardiograms using
general and patient-specific reconstruction strategies at rest and during transient myocardial ischemia." The
American journal of cardiology 94, no. 12 (2004): 1529-1533.
10) Maron, Barry J. "Hypertrophic cardiomyopathy: a systematic review." Jama 287, no. 10 (2002): 1308-
1320.
11) McLeod, C.J., Ackerman, M.J., Nishimura, R.A., Tajik, A.J., Gersh, B.J. and Ommen, S.R., 2009. Outcome of
patients with hypertrophic cardiomyopathy and a normal electrocardiogram. Journal of the American
College of Cardiology, 54(3), pp.229-233.
12) Gersh, B.J., Maron, B.J., Bonow, R.O., Dearani, J.A., Fifer, M.A., Link, M.S., Naidu, S.S., Nishimura, R.A.,
Ommen, S.R., Rakowski, H. and Seidman, C.E., 2011. 2011 ACCF/AHA guideline for the diagnosis and
treatment of hypertrophic cardiomyopathy. Circulation, pp.CIR-0b013e318223e2bd.
13) S.D. Delcrè, P. Di Donna, S. Leuzzi, S. Miceli, M. Bisi, M. Scaglione, D. Caponi, M.R. Conte, F. Cecchi, I.
Olivotto, F. Gaita, Relationship of ECG findings to phenotypic expression in patients with hypertrophic
cardiomyopathy: a cardiac magnetic resonance study, Int. J. Cardiol. 167 (3) (2013 Aug 10) 1038–1045.
14) Landis, J.R.; Koch, G.G. (1977). "The measurement of observer agreement for categorical
data". Biometrics. 33 (1): 159–174
15) Jason J. Z. Liao, Sample size calculation for an agreement study, Pharmaceutical Statistic; 9: 125-132 (2010

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Technical File Attachment

Name Date Signature

Author N.Maurizi 11/03/2016

Reviewer E. Bisson 11/03/2016

Approver N. Briante 11/03/2016

Date Revision Changes

Doc ID: D-Heart Protocol of Clinical Investigation Product: D-Heart Pag. 2 / 16

Number of Referral of the SPE 16.221

Version number of the protocol: Version 2

Date: 11th March 2016

Device identification D-Heart® Electrocardiograph

ponsor Manufacturer and Sponsor: D-Heart Srl, Via R.

Scientific Responsable Iacopo Olivotto M.D., Director,

Centers Involved: Cardiomyopathy Unit, Careggi University

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I. Information on the medical device ...................................................................................... 6

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I. Information on the medical device

Figure 1: wearing the D-Heart ECG

Fig. 2: 8-leads electrocardiogram based on D-Heart ECG

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• 4 sockets are placed on retractable cables (Fig. 3);

Fig. 3: 4 retractable cables

Fig. 4-1, 4-2: fixed sockets in the chassis

Fig. 5: disposable electrode

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Fig. 6: Power button with integrated LED

II. Literature analysis and clinical investigation rationale

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III. Objectives of the Study

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IV. Ethical Considerations

V. Modality of informed consent acquisition

VI. Vulnerable population and use in emergency setting

VII. Preclinical Studies and previous similar experiences

VIII. Information about the clinical study

Description of the clinical investigation

Obiettivi primari e secondari

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Secondary Objective of the Study

Systematical errors - bias

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1) Patients with Hypertrophic Cardiomyopathy

Number of patients who are expected to enroll

Number of experimental medical devices that are expected to be used

Duration of the study

Medical-surgical procedures and follow-up study

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Interruption and withdrawal of subjects from clinical investigation

IX. Monitoring Plan of the Clinical Investigation

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X. Deviations from the Clinical Evaluation Plan

Such monitoring should be aimed at:

XI. Quality Control, Procedure Control, Data Management, documentation

XII. Deviation from the Clinical Evaluation Plan

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Specific examples include, but are not limited to:

XIII. Adverse events

XIV. Amendament of the Clinical Evaluation Plan

XV. Early study termination and suspension of clinical evaluation

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XVII. Data publication policy