Usefulness of Deep-Learning Image Reconstruction for Cardiac Computed Tomography Angiography - a Prospective, Non-randomized Observational Trial
Phase: NA
Conditions: Coronary Artery Disease
Sponsor: University of Zurich

usz 
Universitäts 
Spital Zürich 
Clinical Study Protocol 
Usefulness of Deep-Learning Image Reconstruction for 
Cardiac Computed Tomography Angiography - a 
Prospective, Non-randomized Observational Trial 
DLIR in CCTA 
Study Type: 
Study Categorisation: 
Study Registration: 
Study ldentifier: 
Intervention with CE approved Medical Device (IMD) 
Clinical Trial with IMD Category A 
This study will be registered in the Swiss Federal 
Complementary Database ("Portal") and in the international trial 
registry ClinicalTrials.gov (clinicaltrials.gov) 
DUR in CCTA 
Sponsor, Sponsor-lnvestigator or 
PD Dr. rned. Ronny Ralf Büchel 
Principal lnvestigator: 
Address: University Hospital Zurich 
lnvestigational Product: 
Protocol Version and Date: 
CONFIDENTIAL 
Nuklearmedizin NUK C 42 
Rämistrasse 100, 8091 Zürich 
Email: ronny.buechel@usz.ch 
Tel: 044 255 10 59 
(IIT: Sponsor and Project Leader is the same person) 
Deep-learning image reconstruction from GE Healthcare 
1.1 
The information contained in this document is confidential and the property of the Department of Nuclear 
Medicine of the University Hospital Zurich The information may not - in full or in part - be transmitted, 
reproduced, published, or disclosed to others than the applicable Competent Ethics Committee and 
Regulatory Authority without prior written authorisation from the sponsor except to the extent necessary 
to obtain informed consent from those who will participate in the study. 

Signature Page 
Study number 
Study Title 
2019-00533 
Usefulness of Deep-Learning Image Reconstruction for Cardiac 
Computed Tomography Angiography - a Prospective, Non-
randomized Observational Trial 
The Sponsor-lnvestigator and trial statistician have approved the protocol version [1 .1 (dated 
23.04.2019)], and confirm hereby to conduct the study according to the protocol, current version of the 
World Medical Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable 
and the local legally applicable requirements. 
Sponsor-I nvestigator: 
PD Dr. med. Ronny R. Buechel 
Place/Date 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 2 of 28 

Local Principal lnvestigator at study site: 
1 have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
Site 
Principal investigator 
University Hospital Zurich 
Nuklearmedizin NUK C 42 
. Rämistrasse 100, 8091 Zürich 
PD Dr. med. Ronny R. Buechel 
b,;e,,L 1 ~~-l\ . i 5 
Place/Date 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 3 of28 

Table of Contents 
STUDY SYNOPSIS ................................................................................................................................. 6 
ABBREVIATIONS ................................................................................................................................... 8 
STUDY SCHEDULE ................................................................................................................................ 9 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 10 
1.1 
Sponsor, Sponsor-! nvestigator .................................................................................................... 1 O 
1.2 
Principal lnvestigator(s) ............................................................................................................... 10 
1.3 
Statistician ("Biostatistician") ....................................................................................................... 1 O 
1.4 
Monitoring Institution ................................................................................................................... 10 
1.5 
Data Safety Monitoring Committee .............................................................................................. 1 O 
2. 
ETHICAL AND REGULATORY ASPECTS ................................................................................... 11 
2.1 
Study registration ......................................................................................................................... 11 
2.2 
Categorisation of study ................................................................................................................ 11 
2.3 
Competent Ethics Committee (CEC) ........................................................................................... 11 
2.4 
Competent Authorities (CA) ......................................................................................................... 11 
2.5 
Ethical Conduct of the Study ....................................................................................................... 11 
2.6 
Declaration of interest. ................................................................................................................. 11 
2.7 
Patient Information and lnformed Consent. ................................................................................. 11 
2.8 
Participant privacy and confidentiality ......................................................................................... 12 
2.9 
Early termination of the study ...................................................................................................... 12 
2.10 Protocol amendments .................................................................................................................. 12 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 13 
3.1 
Background and Rationale .......................................................................................................... 13 
3.2 
lnvestigational Product (treatment, device) and lndication ......................................................... 13 
3.3 
Clinical Evidence to Date ............................................................................................................. 13 
3.4 
Explanation for choice of comparator ( or placebo ) ...................................................................... 13 
3.5 
Risks / Benefits ............................................................................................................................ 13 
3.6 
Justification of choice of study population ................................................................................... 14 
4. 
STUDY OBJECTIVES ................................................................................................................... 15 
4.1 
Overall Objective ......................................................................................................................... 15 
4.2 
Primary Objective ........................................................................................................................ 15 
4.3 
Secondary Objectives .................................................................................................................. 15 
4.4 
Safety Objectives ......................................................................................................................... 15 
5. 
STUDY OUTCOMES ...................................................................................................................... 16 
5.1 
Primary Outcome ......................................................................................................................... 16 
5.2 
Secondary Outcomes .................................................................................................................. 16 
5.3 
Other Outcomes of lnterest ......................................................................................................... 16 
5.4 
Safety Outcomes ......................................................................................................................... 16 
6. 
STUDY DESIGN ............................................................................................................................. 17 
6.1 
General study design and justification of design ......................................................................... 17 
6.2 
Methods of minimising bias ......................................................................................................... 17 
6.2.1 Randomisation .................................................................................................................... 17 
6.2.2 Blinding procedures ............................................................................................................. 17 
6.3 
Unblinding Procedures (Code break) .......................................................................................... 17 
7. 
STUDY POPULATION ................................................................................................................... 18 
7 .1 
Eligibility criteria ........................................................................................................................... 18 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 4 of 27 

7.2 
Recruitment and screening .......................................................................................................... 18 
7.3 
Assignment to study groups ........................................................................................................ 18 
7.4 
Criteria for withdrawal / discontinuation of participants ............................................................... 18 
8. 
STUDY INTERVENTION ............................................................................................................... 19 
8.1 
ldentity of lnvestigational Products (treatment/ medical device) ................................................ 19 
8.1.1 Experimental Intervention .................................................................................................... 19 
8.1 .2 Control Intervention ............................................................................................................. 19 
8.2 
Administration of experimental and control interventions ........................................... _. ......... .... ... 19 
8.2.1 
Experimental Intervention .................................................................................................... 19 
8.2.2 Control Intervention ...................................................................................................... .... ... 19 
8.3 
Dose/ Device modifications ........................................................................................................ 19 
8.4 
Data Collection and Follow-up for withdrawn participants .......................................................... 19 
8.5 
Trial specific preventive measures .............................................................................................. 19 
8.6 
Concomitant Interventions (treatments) ...................................................................................... 19 
8. 7 
Study Drug / Medical Device Accountability ................................................................................ 19 
8.8 
Return or Destruction of Study Drug / Medical Device ................................................................ 19 
9. 
STUDY ASSESSMENTS ............................................................................................................... 20 
9.1 
Study flow chart(s) / table of study procedures and assessments .............................................. 20 
9.2 
Assessments of outcomes ........................................................................................................... 20 
10. SAFETY ......................................................................................................................................... 21 
10.1 Medical Device Category A studies ............................................................................................. 21 
10.1 .1 Definition and Assessment of safety related events ........................................................... 21 
10.1.2 Reporting of Safety related events ...................................................................................... 22 
11. STATISTICAL METHODS ............................................................................................................. 23 
11.1 
Hypothesis ................................................................................................................................... 23 
11 .2 Determination of Sample Size .............................................. ........ ............................................... 23 
11 .3 Planned Analyses ........................................................................................................................ 23 
11.4 Handling of missing data and drop-outs ...................................................................................... 23 
12. QUALITY ASSURANCE AND CONTROL .................................................................................... 24 
12.1 
Data handling and record keeping / archiving ............................................................................. 24 
12.1.1 Gase Report Forms ............................................................................................................. 24 
12.1.2 Specification of source documents ..................................................................................... 24 
12.1. 3 Record keeping / archiving .................................................................................................. 25 
12.2 Monitoring .................................................................................................................................... 25 
12.3 Audits and lnspections ................................................................................................................ 25 
12.4 Confidentiality, Data Protection ................................................................................................... 25 
12.5 Storage of biological material and related health data ................................................................ 25 
13. PUBLICATION AND DISSEMINATION POLICY .......................................................................... 25 
14. FUN DING AND SUPPORT ............................................................................................................ 26 
14.1 
Funding ........................................................................................................................................ 26 
14.2 Other Support .............................................................................................................................. 26 
15. INSURANCE .................................................................................................................................. 26 
16. REFERENCES ............................................................................................................................... 27 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 5 of 27 

STUDY SYNOPSIS 
p 
.d 
rovI e a structure d svnopsIs contammq a Important m ormatIon, pre era IV m ta u ar vIew: 
. f 
f 
bl . 
b 1 
Sponsor/ Sponsor-
PD Dr. med. Ronny R. Buechel 
lnvestigator 
Study Title: 
Usefulness of Deep-Learning Image Reconstruction for Cardiac 
Computed Tomography Angiography - a Prospective, Non-randomized 
Observational Trial 
Short Title / Study 1D: 
DUR in CCTA / not yet available 
Protocol Version and 
1.1 / 23.04.2019 
Date: 
Trial registration: 
The study will be registered in the Swiss Federal Complementary 
Database ("Portal") and in the international trial registry ClinicalTrials.gov 
( clinicaltrials.qov) 
Study category and 
Clinical study with IMD Category A 
Rationale 
Clinical Phase: 
Phase of development: CE-marked, pre-commercial use 
Background and 
Cardiac CT allows the assessment of coronary artery disease by ionising 
Rationale: 
radiation. Although radiation exposure was significantly reduced in recent 
years, further technological refinements with artificial intelligence (deep-
learning image reconstruction, DUR) suggest improved post-processing 
of imaqes with reduction of imaqe noise. 
Objective(s): 
The present study assesses the impact of a DUR algorithm on image 
noise, image contrast, image quality and evaluation of coronary plaques 
and lesion severity 
Outcome(s): 
-
Subjective image quality obtained from the experimental 
intervention with the control intervention 
-
Agreement of signal, noise, signal-to-noise ratio and contrast-to-
noise ratio 
-
Comparison of dose-length products and radiation exposure in 
mSv 
-
Impact on assessment of coronary plaques and lesion severity 
-
Applicability and performance of established software (e.g. for 
quantitative plaque analysis, for calculation of endothelial shear 
stress or CTFFR) in images reconstructed with DUR 
-
The results of further diagnostic tests (e.g. invasive coronary 
angiography, myocardial perfusion imaging) that are triggered by 
the clinical coronary CT scan will be compared to the findings of 
the control and interventional coronarv CT scan. 
Study design: 
Open-labe!, non-randomised 
lnclusion / Exclusion 
lnclusion 
criteria: 
- Patients referred for cardiac CT angiography 
-Age;,: 18 years 
- Written informed consent 
Exclusion 
- Pregnancy or breast-feeding 
- Enrollment of the investigator, his/her family members, employees and 
other dependent persons 
- Renal insufficiency (GFR below 35 ml/min/1. 73 m2 ) 
DUR in CCTA, Version 1.1 of 23.04.2019 
Page 6 of 27 

Measurements and 
The intervention is an additional cardiac CT angiography scan with 20-
procedures: 
50% lower radiation exposure immediately after the clinical scan 
Study Product / 
Deep-learning image reconstruction 
Intervention: 
Control Intervention 
Clinically indicated cardiac CT angiography 
(if applicable): 
Number of 
50 patients 
Participants with 
Considering the impact of gender, body habitus, BMI and heart rate a 
Rationale: 
broad spectrum of patients should be scanned. Based on clinical 
experience and previous publication, 50 patients should provide valid 
results 
Study Duration: 
2 months 
Study Schedule: 
Start (first patient): May 1 st 2019 
End (last patient, last visit): June 9th 2019 
lnvestigator(s): 
See separate staff list 
Study Centre(s): 
Single-centre 
Statistical 
The statistical analysis will include correlation analysis and Bland-Altman 
Considerations: 
analysis. Outcomes will be compared using Wilcoxon signed ranktest or 
other suitable tests. A P-value <0.05 will be considered statistically 
sionificant. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as 
far as applicable) as well as all national legal and regulatory requ_irements. 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 7 of 27 

ABBREVIATIONS 
AE 
CA 
CEC 
ClinO 
CRF 
eCRF 
CCTA 
CTCAE 
DUR 
HO 
H1 
IMD 
ISF 
ITT 
LHR 
PI 
SAE 
SDV 
SNCTP 
SOP 
TMF 
Adverse Event 
Competent Authority (e.g. Swissmedic) 
Competent Ethics Committee 
Clinical Trials Ordinance 
Case Report Form 
Electronic Case Report Form 
Coronary Computer Tomography Angiography 
Common terminology criteria for adverse event 
Deep-learning image reconstruction 
Null hypothesis 
Alternative hypothesis 
lnvestigational Medical Device 
lnvestigator Site File 
Intention to Treat 
Law on human research 
Principal lnvestigator 
Serious Adverse Event 
Source Data Verification 
Swiss National Clinical Trial Portal 
Standard Operating Procedure 
Trial Master File 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 8 of 27 

STUDY SCHEDULE 
1 
Day 1 
(Scanning) 
Participant Information and lnformed 
✓ 
Consent 
lnclusion- and Exclusion Criteria 
✓ 
Demographie Data 
✓ 
Medical 
History 
I 
Concomitant 
✓ 
Diseases 
Serious Events 
✓ 
Non-contrast enhanced cardiac CT 
✓ 
examination (clinically indicated) 
Contrast 
enhanced 
cardiac 
CT 
✓ 
examination (clinically indicated) 
Lower-dose 
contrast 
enhanced 
✓ 
cardiac CT examination (study scan) 
DL/Rin CCTA, Version 1.1 of23.04.2019 
Page 9 of 27 

1. STUDY ADMINISTRATIVE STRUCTURE 
1.1 
Sponsor, Sponsor-lnvestigator 
PD Dr. med. Ronny Ralf Büchel 
Address: University Hospital Zurich 
Nuklearmedizin NUK A 12 
Rämistrasse 100, 8091 Zürich 
Email: ronny.buechel@usz.ch 
Tel: 044 255 10 59 
Fax: 044 255 44 14 
Dr. med. R. Büchel will be involved in the screening process, obtaining informed consent, data 
analysis, statistics, quality control and furthermore he will be involved in the writing process. 
1.2 Principal lnvestigator(s) 
Same as sponsor 
1.3 
Statistician ("Biostatistician") 
The statistical analysis will be performed by the members of our research group. 
1.4 Monitoring Institution 
Monitoring will be performed through the study coordination office according to our internal SOP's. 
1.5 
Data Safety Monitoring Committee 
There is no need for a data safety monitoring committee because the patient are referred for a 
clinically indicated cardiac CT and the additional CT scans are performed identically to the clinical 
standard CT except with a lower radiation dose. 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 10 of27 

2. 
ETHICAL AND REGULATORY ASPECTS 
Before this study will be conducted, the investigation plan, the proposed participant information and 
consent form as weil as other study-specific documents will be submitted to a properly constituted 
Competent Ethics Committee (CEC) in agreement with local legal requirements, for formal approval. 
Any amendment to the investigation plan must as weil be approved. 
The decision of the CEC concerning the conduct of the study will be made in writing to the Sponsor-
lnvestigator before commencement of this study. The clinical study can only begin once approval from 
all required authorities has been received. Any additional requirements imposed by the authorities shall 
be implemented. 
2.1 
Study registration 
The study will be registered in the Swiss Federal Complementary Database (,,Portal") and in the 
international trial registry ClinicalTrials.gov (clinicaltrials.gov). 
2.2 
Categorisation of study 
Category A: 
• 
The deep-learning image reconstruction which is used in this study is CE marked and 
• 
CT scans are performed according to the specialized information and clinical routine, but with 
lower tube current and/or tube voltage resulting in a lower radiation dose exposure. However, 
all scan parameters will lie within the specifications of the CE-marked CT Revolution scanning 
device. 
2.3 
Competent Ethics Committee (CEC} 
Approval from the appropriate constituted Competent Ethics Committee is sought for each study site in 
the clinical trial. The reporting duties and allowed time frame are respected. No substantial changes are 
made to the investigation plan without prior Sponsor, CEC, CA approval, except where necessary to 
eliminate apparent immediate hazards to study participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of the study 
is reported to the CEC within 90 days, the final study report shall be submitted within one year after 
study end. Amendments are reported according to chapter 2.10. 
2.4 Competent Authorities (CA} 
No approval from Swissmedic is necessary for this category A clinical trial. 
2.5 
Ethical Conduct of the Study 
The study will be carried out in accordance with principles enunciated in the European Directive on 
medical devices 93/42/EEC and the ISO Norm 14155 and ISO 14971, the Swiss Law and Swiss 
regulatory authority's requirements. CEC will receive annual safety and interim reports and be informed 
about study stopfend in agreement with local requirements. 
2.6 
Declaration of interest 
The department of nuclear medicine holds a research contract with GE Healthcare. 
2.7 
Patient Information and lnformed Consent 
The investigator must explain to each participant the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits and any discomfort it may entail. Each 
participant must be informed that the participation in the study is voluntary and that he/she may withdraw 
from the study at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment. 
The participant must be informed that his/her medical records may be examined by authorized 
individuals other than their treating physician. 
All participants for this study will be provided a participant information sheet and a consent form 
describing this study and providing sufficient information for participants to make an informed decision 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 11 of27 

about their participation in this study. 
The participant information sheet and the consent form will be submitted with the investigation plan for 
review and approval for the study by the CEC. The formal consent of a participant, using the approved 
consent form, must be obtained before that participant is submitted to any study procedure. 
The participant should read and consider the statement before signing and dating the informed consent 
form, and should be given a copy of the signed document. The consent form must also be signed and 
dated by the investigator (or his designee) and it will be retained as part of the study records. 
2.8 
Participant privacy and confidentiality 
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals. 
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilizing subject 
identification code numbers to correspond to treatment data in the computer files. 
Such medical information may be given to the participant's personal physician or to other appropriate 
medical personnel responsible for the participant's welfare, if the patient has given his/her written 
consent to do so. 
For data verification purposes, authorized representatives of the Sponsor (-lnvestigator), a competent 
authority (e.g. Swissmedic), or an ethics committee may require direct access to parts of the medical 
records relevant to the study, including participants' medical history. 
2.9 
Early termination of the study 
Provide a statement that the Sponsor-lnvestigator may terminate the study prematurely according to 
certain circumstances. 
The Sponsor-lnvestigator may terminate the study prematurely according to certain circumstances, e.g.: 
• 
when the safety of the participants is doubtful or at risk, respectively, 
• 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise, 
• 
early evidence of benefit or harm of the experimental intervention 
2.10 Protocol amendments 
lf an amendment to the investigational plan is to be made, it will be initiated by the PI and communicated 
to the investigators and all other involved persons through a short instructional meeting or if minor 
changes need to be implemented it could be done by e-mail. 
Under emergency circumstances, deviations from the investigation plan to protect the rights, safety and 
well-being of human participants may proceed without prior approval of the sponsor and the CEC/CA. 
Such deviations shall be documented and reported to the sponsor and the CEC/CA as soon as possible. 
All Non-substantial amendments are communicated to the CA as soon as possible if applicable and to 
the CEC within the Annual Safety Report (ASR). 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 12 of27 

3. 
BACKGROUND AND RATIONALE 
3.1 
Background and Rationale 
Cardiac CT allows the assessment of the heart and of the coronary arteries by use of ionising 
radiation. Although radiation exposure was significantly reduced in recent years (1 }, further decrease 
in radiation exposure is limited by increased image noise and deterioration in image quality (2). Recent 
evidence suggests that further technological refinements with artificial intelligence allows improved 
post-processing of images with reduction of image noise (3). 
The present study aims at assessing the potential of a deep-learning image reconstruction algorithm in 
a clinical setting. Specifically, after a standard clinical scan, patients are scanned with lower radiation 
exposure and reconstructed with the DLIR algorithm. This interventional scan is then compared to the 
standard clinical scan. 
3.2 
lnvestigational Product (treatment, device) and lndication 
Medical Device (MD): TrueFidelity (Deep Learning Image Reconstruction, DLIR) software by GE 
Healthcare. 
The medical device in question is a novel reconstruction algorithm for raw CT data which is based on 
artificial intelligence approaches, namely deep-learning iterative reconstruction (DLIR). This DLIR 
algorithm will be installed on the console of the CT Revolution scanning device, which is in routine 
clinical use for cardiac CT scans at the Department of Nuclear Medicine at the University Hospital 
Zurich. Purpose of this installation is the assessment of the performance of the DLIR algorithm du ring 
a limited time span of six weeks. 
The algorithm will be CE-marked at the time of installation and use (statement by GE Healthcare 
provided separately). lts intended use is the reconstruction of CT datasets. 
Of note, the novel DLIR algorithm will not substitute any clinical routine procedures currently in use. 
That is, diagnosis will still be made using the standard reconstruction algorithms. 
3.3 
Clinical Evidence to Date 
Several studies have demonstrated the value of deep-learning in low-dose image reconstruction of CT 
scans (3). Several techniques of artificial intelligence were demonstrated to significantly reduce noise. 
Most promising are neural convolution networks. However, no study has yet been performed in a 
clinical setting of cardiac CT scanning. 
3.4 Explanation for choice of comparator (or placebo) 
The comparator is the clinically indicated, routinely performed CT using standard radiation dose. 
3.5 
Risks / Benefits 
The cumulative additional radiation dose exposure arising from participation in this study is estimated 
to lie in the range of 0.4 mSv. In this range of radiation exposure, there is no known association with the 
risk of cancer. As the exposure is about 10% of background radiation exposure in Switzerland, it can be 
regarded as safe. Additionally, a second dose of iodinated contrast agent will be applied with the same 
volume used as for standard cardiac CT scanning. Depending on body habitus, the additional amount 
of contrast agent will lie in the range of 40-60 ml. Adverse reactions to iodinated contrast agents are 
allergic reactions and contrast-induced nephropathy. Regarding contrast reactions, there is no dose-
dependent association. Hence, the risk for an allergic reaction is not expected to increase after the 
experimental scan. lf patients show signs or symptoms of allergic reactions after the clinical scan, the 
experimental scan will not be performed. In contrast, a dose-dependent risk for contrast-induced 
nephropathy has been described in high-risk patients (4). However, in the present study, patients with 
reduced renal function (GFR below 35 ml/min/1. 73 m2) will be excluded. Furthermore, by applying a 
low-dose contrast protocol at our institution (5), the total volume of contrast agent applied after the 
clinical and experimental scan will be comparable to clinical routine in most institutions in Switzerland 
(i.e. 80-120 ml). Taken together, the additional exposure to the contrastagent can be considered as 
safe. Finally, the time needed to perform the additional CT scan is expected to be less than five minutes. 
There is no immediate benefit for the participating patient. But the study results will allow us to implement 
in the future a scan protocol with a substantially lower radiation dose exposure which will ensure to the 
benefit of future patients referred for cardiac CT. 
DUR in CCTA, Version 1.1 of 23.04.2019 
Page 13 of 27 

There are no anticipated adverse device effects according to EN ISO 14971 as the device itself is a 
post-processing tool. There are no possible interactions anticipated with concurrent medical 
interventions or with other competing trials. 
3.6 Justification of choice of study population 
All patients referred for a clinically indicated cardiac CT will in advance be informed by mail about the 
study. Written informed consent will be obtained on the day of examination prior to scanning. 
For inclusion the patients must be ~18 years of age. Pregnant or breast feeding females are excluded. 
In the event of a participant incapable of judgment, or showing signs that he is unwilling to participate in 
the study will result in the patient being excluded from participation. 
DL/Rin CCTA, Version 1.1 of23.04.2019 
Page 14 of 27 

4. 
STUDY OBJECTIVES 
4.1 
Overall Objective 
The overall objective is whether a deep-learning image reconstruction algorithm may improve image 
noise to the extent that radiation exposure can be lowered without impact on quantitative and qualitative 
image parameters. 
4.2 
Primary Objective 
The primary objective is whether subjective image quality differs between the clinical and the 
interventional study CT scan. 
4.3 
Secondary Objectives 
The secondary objective includes other measures related to image quality (e.g. image noise, image 
contrast) as weil as further imaging parameters (e.g. radiation exposure, dose-length-product [DLP]) 
and assessment of coronary plaques and lesion severity differences between the clinical and the 
interventional CT scan. 
4.4 Safety Objectives 
As the additional CT scan is performed with less radiation dose but otherwise do not differ from the 
clinical routine, no safety concerns must be anticipated. 
DL/Rin CCTA, Version 1.1 of23.04.2019 
Page 15 of 27 

5. 
STUDY OUTCOMES 
The present study assesses the impact of a deep-learning image reconstruction algorithm on image 
noise, image contrast, image quality and evaluation of coronary plaques and lesion severity. 
5.1 
Primary Outcome 
Subjective image quality obtained from the experimental intervention with the control intervention. 
5.2 
Secondary Outcomes 
Other measures related to image quality (e.g. image noise, image contrast) 
Further imaging parameters (e.g. radiation exposure, DLP) 
Impact on assessment of coronary plaques and lesion severity 
5.3 
Other Outcomes of lnterest 
Applicability and performance of established software (e.g. for quantitative plaque analysis, for 
calculation of endothelial shear stress or CTFFR) in images reconstructed with DLIR 
The results of further diagnostic tests (e.g. invasive coronary angiography, myocardial perfusion 
imaging) that are triggered by the clinical coronary CT scan will be compared to the findings of the 
control and interventional coronary CT scan. 
5.4 Safety Outcomes 
None 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 16 of 27 

6. 
STUDY DESIGN 
6.1 
General study design and justification of design 
The above described study is an observational non randomized study, because the population eligible 
for this study is referred for a clinically indicated cardiac CT. All study patients will receive the same 
intervention and differences between standard and low dose protocol will be assessed for non-
inferiority. Methods of minimising bias 
The reconstructed images will have no annotations and therefore the clinicians evaluation the images 
will be blinded to scan settings. 
6.2.1 
Randomisation 
Not applicable 
6.2.2 
Blinding procedures 
The evaluation of the images will be blinded by switching the annotations of the images off. 
6.3 
Unblinding Procedures (Code break) 
Afteranalysis annotation will be recovered and screenshots are saved with annotations. 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 17 of 27 

7. STUDY POPULATION 
The study population consists of patients =::18 years of age who are referred for cardiac CT. 
7 .1 
Eligibility criteria 
Subjects, who will fulfil all the following inclusion criteria, may be included into this project: 
- Patients referred for coronary CT angiography 
- Age >18 years 
- Written informed consent 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
- Pregnancy or breast-feeding 
- Enrolment of the investigator, his/her family members, employees and other dependent persons 
- Renal insufficiency (GFR below 35 ml/min/1 . 73 m2 ) 
7 .2 
Recruitment and screening 
Patients referred for a clinically indicated cardiac CT will receive prior to the date of their clinical exam 
the written patient information by mail. On the date of the clinical exam the patients will be consulted by 
a trained physician who will check again the eligibility criteria of the each patient and will explain again 
the purpose and the consequences of the study to the patient. lf the patients still agree they will be 
asked to sign the informed consent form before scanning. The patients will not receive any financial 
compensation. 
7 .3 
Assignment to study groups 
Not applicable because there is only one single group. 
7 .4 Criteria for withdrawal / discontinuation of participants 
Early withdrawal of the subject will occur upon patient request to not further participate in the study or if 
the CT images acquired during the study cannot be analyzed due to technical or other reasons. lf 
discontinuation of a patient occurs he can be replaced by another subject. 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 18 of 27 

8. 
STUDY INTERVENTION 
8.1 
ldentity of lnvestigational Products (treatment / medical device) 
The deep-learning image reconstruction by GE Healthcare is CE marked but not yet clinically available. 
8.1.1 
Experimental Intervention 
The experimental intervention is an additional CT scan with a lower dose (about 20 to 50% decrease) 
and a similar contrast agent administration that is reconstructed with a deep-learning image 
reconstruction immediately after the clinical CT scan. The additional time required is about 5 minutes. 
8.1.2 
Control Intervention 
The control intervention consists of the routinely performed cardiac CT datasets reconstructed with a 
standard iterative reconstruction algorithm (ASIR-V). Median radiation dose is about 0.5 mSv, range 
between about 0.2 and 1.2 mSv; median contrast agent administration about 45 ml, range between 35 
and 55 ml. 
8.2 Administration of experimental and control interventions 
8.2.1 
Experimental Intervention 
The experimental intervention is an additional CT scan with a lower dose (about 20 to 50% decrease) 
and a similar contrast agent administration immediately after the clinical CT scan. The reconstruction 
by a deep-learning image reconstruction is performed after the scan at our department. 
8.2.2 
Control Intervention 
The control intervention consists of the routinely performed cardiac CT datasets reconstructed with a 
standard iterative reconstruction algorithm (ASIR-V). Median radiation dose about 0.5 mSv, range 
between about 0.2 and 1.2 mSv; median contrast agent administration about 45 ml, range between 35 
and 55 ml. 
8.3 
Dose/ Device modifications 
No modification to CE marked device application. 
8.4 
Data Collection and Follow-up for withdrawn participants 
lf a patient withdraws from the study after the acquisition of the images, the images will still be evaluated. 
In none of the participating patients a clinical follow-up will be performed which is in accordance with 
our clinical routine. The patients are clinically followed by their referring physicians. 
8.5 
Trial specific preventive measures 
A urinary pregnancy test for warnen in childbearing age will be performed prior to study inclusion. 
Warnen with ovarectomy with or without hysterectomy and postmenopausal women (>12 months) are 
not considered as being in "childbearing age". 
8.6 
Concomitant Interventions (treatments) 
Not applicable 
8.7 
Study Drug / Medical Device Accountability 
The medical device, namely the reconstruction software will be installed by engineers of the providing 
company GE Healthcare to ensure proper functionality and compliance with all regulatory aspects, 
including CE-marking of the device. 
8.8 
Return or Destruction of Study Drug / Medical Device 
After the assessment phase of 6 weeks, the reconstruction software will be de-installed from our 
scanner systems until its official and commercial release. 
DUR in CCTA. Version 1.1 of23.04.2019 
Page 19 of27 

9. 
STUDY ASSESSMENTS 
9.1 
Study flow chart(s) / table of study procedures and assessments 
Time course: 
1. 
Information of patient and written informed consent. 
2. 
Evaluation of patient demographics, medical history (incl. risk factors, current symptoms, 
medication) and cardiac medical therapy are primarily based upon referral documents of the 
referring physician. 
3. 
Body measurements (pulse, weight and height) 
4. 
Urinary pregnancy test (for warnen in childbearing age*). 
5. 
Check for inclusion and exclusion criteria. 
6. 
Clinically indicated standard non-contrast CT image acquisition on the Revolution CT (GE 
Healthcare). 
8. 
Clinically indicated cardiac CT scan according to clinical routine. 
9. 
Followed by an additional study CT scan with a lower dose (about 20 to 50% decrease) and a 
similar contrast agent administration. This datasets will then be reconstructed with the DUR 
algorithm. 
10. 
Vital parameters (e.g., heart rate) and scanning parameters will be recorded. 
11 . 
After post-processing with the novel DUR algorithm, parameters of image quality will be 
obtained from the reconstructed images along with exploratory analysis of additional image 
parameters. Additionally, applicability and performance of established softwares in images 
reconstructed with DUR will be assessed, and the findings of the clinical and study CT will be 
compared to triggered other diagnostic tests. 
* Warnen with ovarectomy with or without hysterectomy and postmenopausal warnen (>12 months) are 
not considered as being in "childbearing age". 
The majority of the above mentioned measures are performed according to clinical routine. The only 
additional measures is the additional CT scan with lower dose and reconstruction with DUR. 
9.2 Assessments of outcomes 
The Sponsor-lnvestigator is implementing and maintaining quality assurance and quality control 
systems with written SOPs and Working lnstructions to ensure that research is conducted and data are 
generated, documented (record), and reported in compliance with the protocol, GCP, and applicable 
regulatory requirement(s). 
All documents of the study will be stored for 10 years after the end of the study. Image data is stored 
and archived in the PACS system of the University Hospital Zurich according to clinical guidelines (10 
years). Similarly, clinical data are stored in the patient information system (KISIM) o the University 
Hospital Zurich. 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 20 of 27 

10. SAFETY 
The Sponsor's SOPs provide more detail on safety reporting. 
During the entire duration ofthe study, all serious adverse events (SAEs) are collected, fully investigated 
and documented in source documents. Study duration encompassed the time from when the participant 
signs the informed consent until the last investigation plan-specific procedure has been completed, and 
will end when the patient is leaving the nuclear department. 
10.1 Medical Device Category A studies 
Device deficiencies and all adverse events (AE) including all serious adverse events (SAE) are 
collected, fully investigated and documented in the source document and appropriate case report form 
(CRF) during the entire study period, i.e. from patient's informed consent until the last protocol-specific 
procedure, including a safety follow-up period. Documentation includes dates of event, treatment, 
resolution, assessment of seriousness and causal relationship to device and/or study procedure [ISO 
14155, 6.4.1 .]. 
Information on AEs is collected by clinical safety assessment at the study visit, as applicable and 
clinically justified in the context of the specific protocol. However, there are no foreseeable serious 
adverse events as a result of the DUR. 
Foreseeable serious adverse events due to the clinically indicated CT scan are allergic reactions to 
contrast agents or drop in blood pressure due to administration of betablocker and nitroglycerine after 
the clinically indicated scan. These rare events are treated as clinically indicated. 
10.1.1 Definition and Assessment of safety related events 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including 
an abnormal laboratory finding) in participants, users or other persons whether or not related to the 
investigational medical device [ISO 14155: 3.2]. 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device [ISO 14155: 3.1 ]. 
Serious Adverse Event (SAE) [European regulation on medical devices 2017/745, art. 58]. 
Any adverse event that led to any of the following: 
(a) death, 
(b) serious deterioration in the health of the subject that resulted in any of the following: 
(i) life-threatening illness or injury, 
(ii) permanent impairment of a body structure or a body function, 
(iii) hospitalisation or prolongation of patient hospitalisation, 
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
(v) chronic disease, 
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect. 
Device deficiency 
lnadequacy of a medical device related to its identity, quality, durability, reliability, safety or performance, 
such as malfunction, misuse or use error and inadequate labelling [ISO 14155: 3.15]. 
Health hazards that require measures 
Findings in the trial that may affect the safety of study participants and, which require preventive or 
corrective measures intended to protect the health and safety of study participants SAE [ClinO Art. 37]. 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 21 of 27 

Causal Relationship of SAE [MEDDEV 2.7/3 revision 3, May 2015]. 
A causal relationship towards the medical device or study procedure should be rated as follows: 
• 
Not related: The relationship to the device or procedures can be excluded. 
• 
Unlikely: The relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained. 
• 
Possible: The relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible. 
• 
Probable: The relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably explained by another cause. 
• 
Causal relationship: The serious event is associated with the investigational device or with 
procedures beyond reasonable doubt. 
Device deficiencies that might have led to an SAE are always related to the medical device. 
10.1.2 Reporting of Safety related events 
Reporting to Sponsor-lnvestigator: 
Health hazard that require measures are reported to the Sponsor-lnvestigator within 24 hours upon 
becoming aware of the event: 
Pregnancies 
Pregnancies are reported within a maximum of 24 hours to the Sponsor-lnvestigator. Pregnant 
patients are withdrawn. 
Reporting to Authorities: 
In Category A studies, the sponsor is subject to the notification requirements specified in Art. 15 of the 
MedDO of 17 October 2011 (SR 812.213). 
lt is the lnvestigator's responsibility to report to the Ethics Committee via BASEC device deficiencies 
that could have led to serious adverse events if suitable action had not been taken, intervention had not 
been made, or circumstances had been less fortunate within 7 days [ClinO Art. 42]. 
Health hazards that require measures are reported to the Ethics Committee via BASEC within 2 days 
[ClinO Art. 37]. 
Periodic safety reporting: 
A yearly safety update-report is submitted by the lnvestigator to the Ethics Committee via BASEC. 
A report is submitted to Swissmedic by the Sponsor-lnvestigator, as defined in Art. 15a,b of the MedDO 
of 17 October 2011 (SR 812.213). 
DL/Rin CCTA, Version 1.1 of23.04.2019 
Page 22 of 27 

11. STATISTICAL METHODS 
11.1 Hypothesis 
The hypothesis is that parameters of qualitative and quantitative image assessment do not differ 
between the clinical and the interventional scan. 
11.2 Determination of Sample Size 
Considering the impact of gender, body habitus, BMI and heart rate a broad spectrum of patients should 
be scanned. Based on clinical experience and previous publication, 50 patients should provide valid 
results (5). 
11.3 Planned Analyses 
The statistical analysis - performed in-hause - will include correlation analysis and Bland-Altman 
analysis. Outcomes will be compared using Wilcoxon signed ranktest or other suitable tests. A P-value 
<0.05 will be considered statistically significant. 
11.4 Handling of missing data and drop-outs 
lncomplete datasets will be analyzed separately if occurring. Differences to main population might be 
analyzed using appropriate measure post-hoc, depending on amount of examination with missing data. 
DUR in CCTA, Version 1.1 of 23.04.2019 
Page 23 of 27 

12. QUALITY ASSURANCE AND CONTROL 
The Sponsor-lnvestigator is implementing and maintaining quality assurance and quality control 
systems with written SOPs and Working lnstructions to ensure that trials are conducted and data are 
generated, documented (record), and reported in compliance with the protocol, EN ISO 14155, and 
applicable regulatory requirement(s). 
Monitoring and Audits will be conducted du ring the course of the study for quality assurance purposes. 
12.1 Data handling and record keeping / archiving 
The study will strictly follow the investigation plan. lf any changes become necessary, they must be laid 
down in an amendment to the investigation plan. All amendments of the investigation plan must be 
signed by the Sponsor-lnvestigator and submitted to CEC. 
12.1.1 Case Report Forms 
All patient data will be stored electronically in the form of an electronic Gase Report Form (eCRF) within 
Redcap®. One form for each enrolled study participant, to be filled in with all relevant data pertaining 
to the participant during the study. All participants who either entered the study or were considered not-
eligible or were eligible but not enrolled into the study additionally have tobe documented on a screening 
log. The investigator will document the participation of each study participant on the Enrolment Log. 
A declaration ensuring accuracy of data recorded in the case report forms must be signed by the 
investigator. 
eCRFs must be kept current to reflect participant status at each phase during the course of study. 
Participants must not to be identified in the eCRF by name. Appropriate coded identification (e.g. 
Participant Number) must be used. 
lt must be assured that any authorized person, who may perform data entries and changes in the CRF, 
can be identified. A list with signatures and initials of all authorized persons will be filed in the study site 
file (included in the trial master file). 
The investigators assure to perform a complete and accurate documentation of the participant data in 
the eCRF. Essential documents must be retained for at least 10 years after the regular end or a 
premature termination of the respective study (KlinV Art. 45). 
Any patient files and source data must be archived for the langest possible period of time according to 
the feasibility of the investigational site, e.g. hospital, institution or private practice. 
12.1.2 Specification of source documents 
The following documents are considered source data, including but not limited to: 
SAE worksheets 
Medical records from other department(s), or other hospital(s), or discharge letters and 
correspondence with other departments/hospitals, 
Clinical information system (KISIM) entries (including ECG information) 
Image data from the scanners or analysis stations, stored in the intern PACS. 
Source data must be available at the site to document the existence of the study participants and 
substantiate the integrity of study data collected. Source data must include the original documents 
relating to the study, as weil as the medical treatment and medical history of the participant. 
The following information (at least but not limited to) should be included in the source documents: 
• Demographie data (age, sex) 
• lnclusion and Exclusion Criteria details 
• Participation in study and signed and dated lnformed Consent Forms 
• Visit date 
• Medical history 
• Results of relevant examinations 
• Reason for premature discontinuation 
Following data are considered for direct data entry into the CRF without separate source data: 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 24 of27 

Current symptoms 
Medication and other medical therapies 
Risk factors 
Plaque characteristics and stenosis severity 
Image quality 
12.1.3 Record keeping / archiving 
All study data must be archived for a min im um of 10 years after study termination or premature 
termination of the clinical trial. 
12.2 Monitoring 
Regular quality control visits at the investigator's site prior to the start and du ring the course of the study 
will help to follow up the progress of the clinical study, to assure utmost accuracy of the data and to 
detect possible errors at an early time point. Because the current study is considered low risk, we will 
organize the quality control within our department. lt will be conducted via study coordination office of 
our department which is not directly involved in this study. 
All original data including all patient files, progress notes and copies of laboratory and medical test 
results must be available for quality control. Before study start a quality control plan will be set-up 
according to our standard procedures. 
12.3 Audits and lnspections 
A quality assurance audit/inspection of this study may be conducted by the competent authority or CEC, 
respectively. The quality assurance auditor/inspector will have access to all medical records, the 
investigator's study related files and correspondence, and the informed consent documentation that is 
relevant to this clinical study. 
The investigator will allow the persons being responsible for the audit or the inspection to have access 
to the source data/documents and to answer any questions arising. All involved parties will keep the 
patient data strictly confidential. 
12.4 Confidentiality, Data Protection 
Direct access to source documents will be permitted for purposes of monitoring, audits and inspections. 
Only study team members and quality control team members have access to study related source data 
unless relevant for clinical routine. 
12.5 Storage of biological material and related health data 
Not applicable 
13. PUBLICATION AND DISSEMINATION POLICY 
After the statistical analysis of this trial the sponsor will make every endeavor to publish the data in a 
medical journal. Trial results will not be communicated to the individual participant. 
DL/Rin CCTA, Version 1.1 of23.04.2019 
Page 25 of27 

14. FUNDING AND SUPPORT 
14.1 Funding 
The project will not be funded by external sources. lt will be funded by the department of Nuclear 
Medicine. 
14.2 Other Support 
The Nuclear Medicine Department and UZH holds a general research contract with GE healthcare, but 
not direct monetary support for this study is given. 
15. INSURANCE 
lnsurance is covered by "Versicherung für klinische Versuche und nichtklinische Versuche" by Zürich 
Versicherungs-Gesellschaft AG (Policy no.: 15.369.591 ). 
Any damage developed in relation to study participation is covered by this insurance. So as not to forfeit 
their insurance cover, the participants themselves must strictly follow the instructions of the study 
personnel. Medical emergency treatment must be reported immediately to the investigator. The 
investigator must also be informed instantly, in the event of health problems or other damages during 
or after the course of study intervention. 
The investigator will allow delegates of the insurance company to have access to the source 
data/documents as necessary to clarify a case of damage related to study participation. All involved 
parties will keep the patient data strictly confidential. 
A copy of the insurance certificate will be placed in the lnvestigator's Site File. 
DUR in CCTA, Version 1.1 of 23.04.2019 
Page 26 of 27 

16. REFERENCES 
1. 
Benz DC, Gräni C, Hirt Mach B et al. Minimized Radiation and Contrast Agent Exposure for 
Coronary Computed Tomography Angiography: First Clinical Experience on a Latest 
Generation 256-slice Scanner. Acad Radiol 2016;23: 1008-14. 
2. 
Benz DC, Fuchs TA, Gräni C et al. Head-to-head comparison of adaptive statistical and model-
based iterative reconstruction algorithms for submillisievert coronary CT angiography. Eur Heart 
J Cardiovasc lmaging 2017. 
3. 
Sahiner B, Pezeshk A, Hadjiiski LM et al. Deep learning in medical imaging and radiation 
therapy. Med Phys 2019;46:e1-e36. 
4. 
Toprak 0. Conflicting and new risk factors for contrast induced nephropathy. J Urol 
2007; 178:2277-83. 
5. 
Benz DC, Gräni C, Hirt Mach B et al. A low-dose and an ultra-low-dose contrast agent protocol 
for coronary CT angiography in a clinical setting: quantitative and qualitative comparison to a 
standard dose protocol. Br J Radiol 2017;90:20160933. 
DUR in CCTA, Version 1.1 of23.04.2019 
Page 27 of 27