Reducing Cardiac Radiation Dose in Continuous Positive Airway Pressure (CPAP) Assisted Radiotherapy in Breast Cancer: a Prospective Non-Randomized Clinical Trial
Phase: PHASE2
Conditions: Breast Cancer Early Stage Breast Cancer (Stage 1-3)
Sponsor: Universitaire Ziekenhuizen KU Leuven

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023  
Page 1 of 45                             Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
   
 
 
 
 
 
 
CLINICAL INVESTIGATION PLAN (CIP) 
 
Reducing Cardiac Radiation Dose in CPAP-assisted Radiotherapy in 
Breast Cancer: a Prospective Non-Randomized Clinical Trial 
 
CPAP-assisted Radiotherapy in Breast Cancer 
 
Version number: v1.5   68702   –  Date 11/04/2025 
Clinical Investigation number: S68702 
Single Identification Number (SIN): [SIN Nr] 
Sponsor 
University Hospitals Leuven (UZ Leuven) 
Herestraat 49, B-3000 Leuven 
 
Coordinating Investigator 
Prof. Dr. Caroline Weltens 
(in case of monocentric Trial, the Principal Investigator is the same as the Coordinating Investigator) 
 
 
Sub Investigators 
Prof. Dr. Maarten Lambrecht 
Prof. Dr. Lucas Van Aelst 
Dr. Aline Van der Vorst 
Dr. Johanna Jacobs 
Confidentiality Statement 
The information in this document is strictly confidential and is available for review to Investigators, potential 
Investigators and appropriate Ethics Committees, Institutional Review Boards or Competent Authorities. No 
disclosure should take place without written authorization from the Sponsor. 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 2 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
LIST OF PARTICIPATING SITES 
(if applicable) 
List Of Participating Sites 
Principal Investigator 
University Hospitals Leuven (UZ Leuven) 
Prof. Dr. Caroline Weltens 
 
 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 3 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
SIGNATURES 
 
Title: Reducing Cardiac Radiation Dose in CPAP-assisted Radiotherapy in Breast Cancer: a 
Prospective Non-Randomized Clinical Trial 
CIP: CPAP-assisted Radiotherapy in Breast Cancer 
 
The undersigned confirm that the following CIP has been acknowledged and accepted and that they 
agree to conduct the Investigation in compliance with the approved CIP (and any subsequent 
amendments if applicable) and will adhere to the principles outlined in the Declaration of Helsinki, 
applicable Good Clinical Practices and regulations (e.g., the EU Medical Device Regulation 2017/745 
(MDR), EU General Data Protection Regulation 2016/679 (GDPR)) and ISO 14155:2020), the 
appropriate local legislation(s) and all other applicable legal and regulatory requirements as amended. 
The most stringent requirements, guidelines or regulations must always be followed. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the Investigation without the prior written 
consent of the Sponsor. 
I also confirm that I will make the findings of the Investigation publicly available through publication or 
other dissemination tools, in accordance with this CIP without any unnecessary delay and that an 
honest accurate and transparent account of the Investigation will be given; and that any discrepancies 
from the Investigation as planned in this CIP will be explained. 
Coordinating Investigator 
 
Prof. Dr. Caroline Weltens 
 
 
 
 
 
………………………… 
………………………… 
………………………… 
 
Name & Title 
Signature 
Date 
 
Principal Investigator (Participating Site) (in case of monocentric Trial, the Principal Investigator is the 
same as the Coordinating Investigator) 
Prof. Dr. Caroline Weltens 
 
 
 
 
………………………… 
………………………… 
………………………… 
 
Name & Title 
Signature 
Date 
 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 4 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
TABLE OF CONTENTS 
 
CLINICAL INVESTIGATION PLAN (CIP) ................................................................................................................... 1 
LIST OF PARTICIPATING SITES .................................................................................................................................... 2 
SIGNATURES ....................................................................................................................................................................... 3 
TABLE OF CONTENTS .................................................................................................................................................... 4 
LIST OF ABBREVIATIONS ............................................................................................................................................... 7 
FUNDING AND THIRD PARTIES ................................................................................................................................. 9 
ROLES AND RESPONSIBILITIES .................................................................................................................................. 10 
CIP SYNOPSIS .................................................................................................................................................................... 11 
STUDY FLOWCHART .................................................................................................................................................... 14 
1 
Background and Rationale ...................................................................................................................................... 15 
2 
Objectives and Design ............................................................................................................................................. 17 
2.1 
Study objectives and hypotheses ................................................................................................................ 17 
2.2 
Primary Endpoints .......................................................................................................................................... 17 
2.3 
Secondary Endpoints ...................................................................................................................................... 17 
2.4 
Design of the Clinical Investigation ............................................................................................................ 18 
2.5 
Justification for the design of the Investigation ....................................................................................... 19 
2.6 
Expected Duration of the Investigation .................................................................................................... 19 
3 
Eligibility Criteria ....................................................................................................................................................... 20 
3.1 
Inclusion criteria.............................................................................................................................................. 20 
3.2 
Exclusion criteria ............................................................................................................................................ 20 
4 
Study Procedures ...................................................................................................................................................... 21 
4.1 
Selection of Participants / Recruitment ..................................................................................................... 21 
4.2 
Investigation assessments and procedures ............................................................................................... 21 
4.2.1 
Participant consent and withdrawal of consent ................................................................................. 21 
4.2.2 
Randomization Procedure (if applicable) ............................................................................................. 21 
4.2.3 
Other Investigation assessments and procedures ............................................................................. 21 
4.3 
Premature discontinuation ........................................................................................................................... 22 
5 
Investigational Medical Device (IMD) .................................................................................................................. 22 
5.1 
Intended use ..................................................................................................................................................... 23 
5.2 
Identification and description of the IMD ................................................................................................. 23 
5.3 
Device Accountability .................................................................................................................................... 23 
6 
Safety reporting ......................................................................................................................................................... 24 
6.1 
Definitions ........................................................................................................................................................ 24 
6.1.1 
Adverse Event (AE) ................................................................................................................................... 24 
6.1.2 
Serious Adverse Event (SAE) .................................................................................................................. 24 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 5 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
6.1.3 
Adverse Device Effect (ADE) ................................................................................................................. 24 
6.1.4 
Serious Adverse Device Effect (SADE) ................................................................................................ 24 
6.1.5 
Device Deficiency (DD) ........................................................................................................................... 24 
6.1.6 
Adverse Events of Special Interest ........................................................................................................ 24 
6.2 
Adverse Events that do not require reporting ........................................................................................ 24 
6.3 
Recording and reporting of Adverse Events ............................................................................................ 25 
6.3.1 
Assessment .................................................................................................................................................. 25 
6.3.2 
Timelines for reporting ............................................................................................................................ 26 
6.3.3 
Follow-up ..................................................................................................................................................... 27 
6.3.4 
Death ............................................................................................................................................................ 27 
6.4 
Recording and reporting of Device Deficiencies .................................................................................... 27 
6.5 
Reporting requirements to Ethics Committees (EC’s) ......................................................................... 27 
6.5.1 
Sponsor’s reporting of Serious Adverse Events and Device Deficiencies ................................... 28 
6.6 
Sponsor’s reporting of Materiovigilance to Competent Authorities (CA’s) ................................... 28 
6.7 
Overview reporting requirements ............................................................................................................. 28 
6.8 
Data Safety Monitoring Board (DSMB) ..................................................................................................... 29 
7 
Statistics and Data Analysis .................................................................................................................................... 29 
7.1 
Sample Size Determination .......................................................................................................................... 29 
7.2 
Statistical Analysis ........................................................................................................................................... 29 
7.2.1 
Efficacy Analysis .......................................................................................................................................... 30 
7.2.2 
Other Analysis ............................................................................................................................................ 30 
7.3 
Interim Analysis and Final Database Lock ................................................................................................ 31 
8 
Data handling ............................................................................................................................................................. 31 
8.1 
Data Collection Tools and Source Document Identification .............................................................. 31 
8.1.1 
Operational aspects................................................................................................................................... 31 
8.1.2 
Legal requirements .................................................................................................................................... 33 
8.2 
Audits and Inspections................................................................................................................................... 33 
8.3 
Monitoring ........................................................................................................................................................ 33 
8.4 
Archiving ........................................................................................................................................................... 34 
9 
Ethical and Regulatory Considerations ................................................................................................................ 34 
9.1 
Ethics Committee (EC) review & reports ................................................................................................ 34 
9.2 
Peer review ...................................................................................................................................................... 34 
9.3 
Regulatory Compliance ................................................................................................................................. 34 
9.4 
CIP / GCP compliance ................................................................................................................................... 34 
9.5 
Data protection and participant confidentiality ...................................................................................... 35 
9.6 
Insurance ........................................................................................................................................................... 35 
9.7 
Amendments .................................................................................................................................................... 35 
9.8 
Post-Study activities ....................................................................................................................................... 36 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 6 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
10 Research Registration, Dissemination of Results and Publication Policy .................................................... 36 
11 Intellectual Property ................................................................................................................................................. 36 
12 References .................................................................................................................................................................. 37 
Appendices .......................................................................................................................................................................... 41 
13 Appendix 1: Clinical Investigation Plan history .................................................................................................. 42 
14 Appendix 2: Patient Questionnaires .................................................................................................................... 44 
15 Appendix 3: [Funding – Myny-Vanderpoorten fonds and AIR LIQUIDE MEDICAL nv - VitalAire 
Grant] ................................................................................................................................................................................... 45 
 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 7 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
(e)CRF 
(electronic) Case Report Form 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BC 
Breast Cancer 
CA 
Competent Authority 
CI 
Coordinating Investigator 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CM 
Concomitant Medication 
CPAP 
Continuous Positive Airway Pressure 
CT 
Computed Tomography 
DD 
Device Deficiency 
DIBH 
Deep Inspiration Breath Hold 
DMP 
Data Management Plan 
Dmax 
Maximum radiation dose a specific organ at risk is receiving (expressed in Gy) 
Dmean 
Mean radiation dose a specific organ at risk is receiving (expressed in Gy) 
DPA 
Data Processing Annex 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EUDAMED 
European Database for Medical Devices 
FB 
Free Breathing 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice (latest version of ICH E6) 
GDPR 
EU General Data Protection Regulation 2016/679 
Gy 
Gray, unit of radiation dose 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IFU 
Instructions For Use 
IMD 
Investigational Medical Device 
IMRT 
Intensity Modulated Radiotherapy 
ISF 
Investigator Site File 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 8 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
IUD 
Intrauterine devices 
LPLV 
Last Patient Last Visit 
MBC 
Multidisciplinary Breast Centre 
MDR 
EU Medical Device Regulation 2017/745 
MHD 
Mean Heart Dose 
MSP 
Median Supraclavicular Parasternal 
NTCP 
Normal Tissue Complication Probabilities 
OAR 
Organs At Risk 
OSAS 
Obstructive Sleep Apnea Syndrome 
PI 
Principal Investigator (Participating Site) 
PRO 
Patient Reported Outcome 
PT 
Proton Therapy 
RNI 
Regional Nodal Irradiation 
RT 
Radiotherapy 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIN 
Single Identification Number 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File 
TNM 
Tumor-Node-Metastasis 
VMAT 
Volumetric Modulated Arc Therapy 
VXGy 
Volume of the organ at risk receiving X Gy radiation dose (expressed in %), 
e.g. V5Gy of the heart is the volume of the heart receiving 5 Gy radiation 
dose (expressed in %).  
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 9 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
FUNDING AND THIRD PARTIES 
Funder or service provider 
Type of Support 
Myny-Vanderpoorten Fonds  
Financial support  
AIR LIQUIDE MEDICAL nv - 
VitalAire 
Grant for acquisition of essential CPAP equipment solely 
No additional travel reimbursement or other compensation is foreseen for the Investigation participants, 
because travel reimbursement is already provided for radiotherapy patients in standard of care.  
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 10 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
 
ROLES AND RESPONSIBILITIES 
The Principal Investigator (PI) is responsible for the conduct of the Investigation at her Participating Site, 
and for protecting the rights, safety and well-being of the participants. As such the PI must ensure adequate 
supervision of the Investigation conduct at the Participating Site. If any tasks are delegated, the PI will 
maintain a log of appropriately qualified persons to whom she has delegated specified Investigation-related 
duties. The PI will ensure that adequate training is provided and documented for all Investigation staff, prior 
to conducting assigned Investigation-related activities.  
It is the CI’s responsibility to supervise the general conduct (e.g., study progress, communication, CIP 
training and support of the participating sites, annual reporting to the EC, end of Investigation notification(s) 
and results reporting…) of the Investigation. The CI fulfils both Investigator and Sponsor responsibilities, 
as outlined in ISO 14155:2020 and applicable regulations. 
PI and CI shall each be referred to as «Investigator(s)». 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 11 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
CIP SYNOPSIS 
 
Title of clinical Investigation 
(«Investigation») 
Reducing Cardiac Radiation Dose in CPAP-assisted Radiotherapy in 
Breast Cancer: a Prospective Non-Randomized Clinical Trial 
CIP Short Title 
Acronym 
CPAP-assisted Radiotherapy in Breast Cancer 
Sponsor name 
University Hospitals Leuven (UZ Leuven) 
Coordinating Investigator 
Prof. Dr. Caroline Weltens 
           Contact Address CI 
Herestraat 49, 3000 Leuven  
           Contact Email CI 
caroline.weltens@uzleuven.be  
           Contact Phone CI 
016 347665  
SIN number 
[SIN Nr] 
Other 
public 
database 
number  
Not Applicable 
Medical condition or disease 
under investigation 
Breast Cancer 
Study rationale  
Decreasing cardiac radiation doses by using a continuous positive airway 
pressure (CPAP) device during radiotherapy (RT) for breast cancer (BC) 
patients  
Primary objective 
To demonstrate a decrease of approximately 0.5 Gy Mean Heart Dose 
(MHD) by using CPAP-assisted RT compared to the standard protocol 
in 4 cohorts of BC patients (right-sided, left-sided without RNI, left-sided 
with RNI(<70y/o) and left-sided with RNI (70-80 years old)).  
Secondary objective(s) 
- 
To compare target volume coverage between standard and 
CPAP-assisted RT in 4 cohorts of BC patients (right-sided, left-
sided without RNI, left-sided with RNI (<70y/o) and left-sided 
with RNI (70-80 years old)) 
- 
To determine which patients benefit the most from CPAP-
assisted RT based on dosimetric outcomes for different organs 
at risk (OAR) in 4 cohorts of BC patients (right-sided, left-sided 
without RNI, left-sided with RNI(<70y/o) and left-sided with 
RNI (70-80 years old)): 
o 
Whole heart   
o 
Cardiac substructures (large vessels, atria, ventricles, 
valves, conduction nodes, coronary arteries, coronary 
artery calcifications, heart base) 
o 
Lungs  
o 
Ipsilateral lung  
o 
Contralateral breast  
o 
Liver  
- 
To determine patient comfort and tolerance of CPAP-assisted 
RT by analysing patient questionnaires 
- 
To compare reproducibility and accuracy between standard and 
CPAP-assisted RT by using surface scanning and daily cone beam 
CT (CBCT) parameters 
- 
To compare DIBH performance between standard and CPAP-
assisted RT for left-sided BC by using surface scanning and daily 
CBCT parameters 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 12 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
- 
To compare time-effectiveness between standard and CPAP-
assisted RT 
o 
Set-up time 
o 
Matching time 
o 
Radiation time 
- 
To compare cost-analysis between standard and CPAP-assisted 
RT 
- 
To compare normal tissue complication probabilities (NTCP) 
from various NTCP models (Darby et al. and models developed 
in study s68508) between standard and CPAP-assisted RT 
Clinical Investigation Design 
Prospective Non-randomized Clinical Trial 
Endpoints 
Primary endpoint: Difference in MHD in Gy between standard and 
CPAP-assisted RT in 4 cohorts of BC patients (right-sided, left-sided 
without RNI, left-sided with RNI(<70y/o) and left-sided with RNI (70-80 
years old)): 
Secondary endpoints:  
- 
Differences in target volume coverage between standard and 
CPAP-assisted RT in 4 cohorts of BC patients (right-sided, 
left-sided without RNI, left-sided with RNI(<70y/o) and left-
sided with RNI (70-80 years old)): 
- 
Differences in OAR dosimetric parameters between standard 
and CPAP-assisted RT in 4 cohorts of BC patients (right-sided, 
left-sided without RNI, left-sided with RNI(<70y/o) and left-
sided with RNI (70-80 years old)): 
o 
Whole heart  
o 
Cardiac substructures (large vessels, atria, ventricles, 
valves, conduction nodes, coronary arteries, coronary 
artery calcifications, heart base) 
o 
Lungs 
o 
Ipsilateral lung  
o 
Contralateral breast  
o 
Liver 
o 
  
- 
Likert scale scores from patient questionnaires 
- 
Differences in mean deviation of surface, OAR and target 
volume positions per fraction (in mm) in standard vs CPAP-
assisted RT (reproducibility: day-to-day variation in surface, 
OAR and target volume position) 
- 
Differences in average surface, OAR and target volume 
maximum shift observed during each fraction (in mm) in 
standard RT vs CPAP-assisted RT (accuracy: difference of daily 
surface, OAR and target volume position versus planning 
position) 
- 
Differences in RT duration between standard and CPAP-
assisted RT (minutes)  
o 
Set-up time 
o 
Matching time 
o 
Radiation time 
- 
Differences in DIBH duration between standard and CPAP-
assisted RT (seconds) 
- 
Differences in total treatment costs between standard and 
CPAP-assisted RT (euro) 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 13 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
- 
Differences in normal tissue complication probabilities (NTCP) 
from various NTCP models (Darby et al. and models developed 
in study s68508) between standard and CPAP-assisted RT 
Sample Size 
73 patients (Approximately 83 participants will be screened to achieve 
an estimated total of 73 evaluable participants.) 
IMD 
CPAP device 
Comparator device(s) 
Not Applicable 
Maximum duration of 
treatment and Follow Up of 
a Participant 
4-5 weeks  
Anticipate First Patient First 
Visit (FPFV) 
01-02-2025 
Anticipate Last Patient Last 
Visit (LPLV) 
01-02-2026 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023  
Page 14 of 45                             Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
STUDY FLOWCHART 
Schedule of Events – Study specific Procedures / Assessments 
  Please indicate in the flowchart with different colors whether a procedure is performed as part of the standard of care or specifically for the Investigation. 
I : Informed Consent process should take place prior to all other study-related procedures at the screening visit 
2 : … 
 
Procedures/ 
Assessment 
Screening 
 
Treatment period 
Visits / Contacts 
Visit 1 
Consultation 
Visit 2 
CT 
Simulation 
Visit 3-18 
Radiation Treatment 
End of Treatment period / 
Early Termination 
Unscheduled Visit 
Timing (weeks) 
 
0 
[2] 
 
 
Visit Window (days) 
-28 to -1 
 
±[14-35] days 
± [35] Days 
 
Informed consent 
X 1 
 
 
 
 
Inclusion 
/ 
Exclusion 
criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Cardiovascular risk profile 
(through questionnaires) 
X 
 
 
 
 
Physical examination 
X 
 
 
 
 
Use 
of 
investigational 
device  
 
X 
X (when CPAP-assisted RT is 
chosen as treatment of choice) 
 
 
Radiological Assessments 
(CT) without CPAP 
 
X 
 
 
 
Radiological Assessments 
(CT) with CPAP 
 
X 
 
 
 
Patient 
experience 
questionnaire 
 
X 
X (every 7 days when CPAP-
assisted RT is chosen as treatment 
of choice) 
 
 
Reason for discontinuation 
 
 
 
(X) 
 
(Serious) Adverse event 
(S)(AE) assessment 
X 
X 
X 
X 
X 
Concomitant 
Medication 
(CM) 
X 
 
 
 
 
 
 
 
 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 15 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
1 Background and Rationale 
Breast cancer (BC) remains the most prevalent cancer in women worldwide with the highest mortality 
rate among all female cancers in Europe and second highest mortality rate among all female cancers in the 
United States of America 1,2. Despite it being the most common cancer in women with a persistent rising 
incidence, the overall prognosis is already relatively good with a 5 year overall survival (OS) of 
approximately 80-90% in the Western world and these numbers still seem to improve because of earlier 
diagnosis and more recent advances in treatment strategies 1. Because of these long-term survivors, it is 
becoming increasingly important to strive for a high quality of life after BC curation. Therefore, toxicity 
following different treatment modalities becomes a crucial part of BC research. 
Adjuvant local / locoregional radiotherapy (RT) has proven to increase OS and local control rates after 
breast conserving surgery (BCS) and also after mastectomy in some more advanced clinical cases 3,4. 
Therefore, approximately 70% of BC patients are treated with adjuvant RT as a crucial component of 
curative treatment 5. However, it is important to note that radiation treatment in the thoracic region is 
also known to be potentially cardiotoxic, particularly after a long latency period of more than 10 years 
(although earlier cardiotoxicity has also been reported). 
BC patients treated with RT had a 1.76-fold (95% confidence interval: 1.34 to 2.31) higher risk of dying of 
cardiac disease than those who did not receive RT 6. Various cardiac conditions have been associated to 
radiation injury. Most importantly heart failure, ischemic cardiac disease and atrial fibrillation have been 
reported after BC RT, but association with pericardial disease, arrhythmia and cardiac death have also been 
demonstrated 7–20.  As a result, research on radiation-induced cardiotoxicity has become a significant focus 
within the field of breast cancer research, aiming to minimize treatment-related cardiac toxicity. 
In the past, various studies reported a dose-response relationship for radiation-induced cardiac toxicity. 
Not only mean heart dose (MHD) but also radiation doses to cardiac substructures such as coronary 
arteries and the ventricles for example have been associated with increased risk of developing cardiac 
adverse events 7,20–29. On the other hand, patient-related characteristics such as pre-existing cardiac risk 
factors also play an important role 30,31.  
To reduce radiation-induced cardiac toxicity numerous cardiac-sparing RT techniques have been developed 
in the past years, such as modern RT techniques (Intensity Modulated Radiotherapy (IMRT)/ Volumetric-
Modulated Arc Therapy (VMAT)), deep inspiration breath hold (DIBH), prone RT and lately the use of 
proton 
therapy 
has 
also 
been 
investigated 
in 
this 
perspective 
32–38.  
Since these techniques have shown obvious cardiac dose reductions, several investigations have been 
initiated to fine-tune and optimize them, potentially reducing cardiac doses even further. For example, 
prone and DIBH radiotherapy have been combined together showing dosimetric advantages 39–42. 
Moreover, various respiration-assisting devices have been investigated for their role in facilitating DIBH, 
not only to improve dosimetry parameters but also to enhance accuracy, reproducibility, and ultimately, 
patient comfort. For example, the use of mechanically assisted ventilation in DIBH has been shown to 
deliver high irradiation accuracy while better protecting the organs at risk (OAR) 43. In a small retrospective 
study the use of a continuous positive airway pressure (CPAP) device has also been investigated in 
combination with DIBH in left-sided BC patients showing clear dosimetric advantages on cardiac radiation 
doses 44. Additionally, some smaller retrospective and non-randomized prospective studies also showed 
decreased cardiac doses when CPAP was used in a free breathing (FB) setting, for example in patients not 
able to perform DIBH 45–49. The same CPAP-assisted strategy has been investigated in RT for other thoracic 
malignancies showing similar results confirming larger lung volumes and some also demonstrating decreased 
cardiac doses with CPAP 50–52. These potential dosimetric advantages with CPAP could be a consequence 
of combined increased lung volume and also inferior displacement of the heart, resulting in a larger distance 
between the heart and the RT target volume. In summary, preliminary evidence and proof of concept 
indicating potential advantages of using CPAP in BC RT already exists from small, mostly retrospective 
studies. This makes CPAP a promising technique deserving further exploration through large-scale and 
prospective investigations. For example, there is currently no data on the potential benefits of CPAP in 
patients with right-sided breast cancer, and critical factors such as patient compliance, accuracy, and stability 
need assessment before implementation of CPAP in clinical practice. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 16 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
 
The aim of this specific study is thus to prospectively confirm and investigate the potential benefits of 
CPAP in optimizing RT for BC patients and assess its clinical performance in daily radiation oncology 
practice.  
In this study, each patient will undergo an initial CT simulation scan according to the standard protocol 
(without CPAP support), followed by another CT simulation scan with CPAP respiratory assistance. For 
right-sided BC patients standard protocol implies Free Breathing conditions. For left-sided BC patients 
standard protocol covers CT in Deep Inspiration Breath Hold (DIBH), except for patients unable to 
perform DIBH or older than 70 years old, these will use Free Breathing as standard protocol. In the 
further course of the protocol, the term 'standard RT' will be used to denote these configurations. The 
second scan thus includes a CPAP-assisted Free Breathing for right-sided BC patients and left-sided BC 
patients unable to perform DIBH. In the left-sided BC group the second CT scan covers a CPAP-assisted 
DIBH. These configurations are further referred to as ‘CPAP-assisted RT’. A dedicated medical radiation 
physicist or dosimetrist will then make radiation plans for both scenarios. The radiation oncologist will 
then evaluate both plans, selecting the one with the most favorable dosimetric results for the effective 
irradiation of the patient. 
This study will be different than previously published work in various ways. Firstly, we will not only 
include patients with left-sided BC, but also right-sided BC patients will be included, more specifically 
right-sided BC patients who require a locoregional radiation treatment including RT of the elective 
regional lymph node regions (e.g. median supraclavicular region, internal mammary nodes and/or axillary 
lymph nodes). In these patients, maintaining cardiac and pulmonal radiation doses bellow generally 
accepted dose constraints can be challenging. Therefore, radiation oncologists often partially omit 
radiation of the regional lymph nodes to reduce cardiac and pulmonal doses, possibly resulting in more 
oncological failure. Using CPAP assisted RT in these patients could potentially improve radiation 
dosimetry, consequently improving the quality of radiation treatment and, in turn, potentially leading to 
improved oncological outcomes. Secondly, we will investigate which BC patients benefit the most from 
CPAP assisted RT by comparing dosimetric results in 4 cohorts of BC patients (right-sided, left-sided 
without RNI, left-sided with RNI(<70y/o) and left-sided with RNI (70-80 years old)):. Thereafter, patient 
compliance and tolerance of CPAP assisted RT will be assessed using patient questionnaires. Accuracy, 
reproducibility and DIBH performance of CPAP-assisted RT will also be studied by using data from the 
surface scanning system and daily cone beam CT (CBCT). Additionally, a comparison of radiation 
treatment times will be performed, to ensure time-efficiency of CPAP-assisted RT. Finally, a cost-analysis 
will be set up. 
 
Additionally, we aim to compare normal tissue complication probabilities (NTCP) for cardiac toxicities 
between standard radiation therapy and CPAP-assisted radiation therapy, using NTCP models from Darby 
et al. and those developed in study s6850877. These models incorporate dosimetrical data and clinical 
variables to predict a patient’s risk of developing cardiac toxicity. The ultimate goal is not only to compare 
the dosimetrical differences between the two approaches, but also to assess their clinical significance by 
estimating the actual reduction in cardiac toxicity risk. 
 
In summary, we expect a reduction in cardiac and/or pulmonal radiation doses in CPAP-assisted RT 
compared to standard RT (without CPAP), potentially also leading to a decrease in long-term radiation-
induced cardiotoxicity (and or pulmonal toxicity). Additionally, this study may offer preliminary evidence 
suggesting CPAP as a viable alternative to DIBH for patients unable to perform DIBH. We also aim to 
develop a patient selection model based on laterality and extent of the irradiation field for identifying those 
who would benefit the most from CPAP-assisted RT. Furthermore, this research will assess clinical 
performance of CPAP-assisted RT in daily practice and provide guidelines for its clinical implementation in 
BC RT, encompassing considerations of accuracy, reproducibility, efficacy and cost-analysis. Additionally, 
patient compliance will be reported. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 17 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
2 Objectives and Design 
2.1 Study objectives and hypotheses 
The study hypothesizes that using a CPAP device during RT for BC patients will decrease cardiac (and or 
pulmonal) radiation doses compared to standard RT (without CPAP-assistance). 
The primary objectives is thus to demonstrate a decrease of approximately 0.5 Gy MHD by using CPAP-
assisted RT compared to standard RT (without CPAP) in 4 cohorts of BC patients (right-sided, left-sided 
without RNI, left-sided with RNI(<70y/o) and left-sided with RNI (70-80 years old)):.  
The secondary objectives include:  
- 
To compare target volume coverage between standard and CPAP-assisted RT in 4 cohorts of BC 
patients (right-sided, left-sided without RNI, left-sided with RNI(<70y/o) and left-sided with RNI (70-80 
years old)): 
-           To determine which patients benefit the most from CPAP-assisted RT by comparing dosimetric 
parameters on different OARs in 4 cohorts of BC patients (right-sided, left-sided without RNI, left-sided 
with RNI(<70y/o) and left-sided with RNI (70-80 years old)): 
o 
Whole heart  
o 
Cardiac substructures (large vessels, atria, ventricles, valves, conduction nodes, coronary 
arteries, coronary artery calcifications, heart base) 
o 
Lungs  
o 
Ipsilateral lung  
o 
Contralateral breast  
o 
Liver 
o 
  
- 
To determine patient comfort and tolerance of CPAP-assisted RT by analysing patient 
questionnaires 
- 
To compare reproducibility and accuracy between standard and CPAP-assisted RT by using 
surface scanning parameters and daily CBCT information.  
- 
To compare DIBH performance between standard and CPAP-assisted RT by using surface 
scanning parameters and daily CBCT information. 
- 
To compare time-effectiveness between standard and CPAP-assisted RT 
o 
Set-up time 
o 
Matching time 
o 
Radiation time 
- 
To compare cost-analysis between standard and CPAP-assisted RT  
-           To compare normal tissue complication probabilities (NTCP) from various NTCP models (Darby 
et al. and models developed in study s68508) between standard and CPAP-assisted RT 
 
2.2 Primary Endpoints 
Difference in MHD in Gy between standard RT (without CPAP) and CPAP-assisted RT in 4 cohorts of BC 
patients (right-sided, left-sided without RNI, left-sided with RNI(<70y/o) and left-sided with RNI (70-80 
years old)): 
2.3 Secondary Endpoints 
- 
Differences in target volume coverage between standard and CPAP-assisted RT 
- 
Differences in cardiac dosimetry (whole heart and cardiac substructures) + other OAR dosimetry 
(lungs, ipsilateral lung, contralateral breast, liver) between standard and CPAP-assisted RT 
- 
Likert scale scores from patient questionnaires  
- 
Difference in mean deviation of surface, OAR and target volume positions per fraction (in mm) in 
standard vs CPAP-assisted RT (encompasses reproducibility: day-to-day variation in surface, OAR 
and target volume position) 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 18 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
- 
Difference in average surface, OAR and target volume maximum shift observed during each 
fraction (in mm) in standard RT vs CPAP-assisted RT (encompasses accuracy: difference of daily 
surface, OAR and target volume treatment position versus planning position)   
- 
Difference in RT duration between standard and CPAP-assisted RT (minutes)  
o 
Set-up time 
o 
Matching time 
o 
Radiation time 
- 
Difference in DIBH duration between standard and CPAP-assisted RT (seconds) 
- 
Difference in total treatment costs between standard and CPAP-assisted RT (euro) 
- 
Difference in normal tissue complication probabilities (NTCP) from various NTCP models (Darby 
et al. and models developed in study s68508) between standard and CPAP-assisted RT 
2.4 Design of the Clinical Investigation 
Prospective Non-Randomized Clinical Trial 
 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 19 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
2.5 Justification for the design of the Investigation 
Previously published results have shown dosimetric benefits of the use of CPAP in RT for BC and other 
thoracic malignancies. A small retrospective study investigated the use of a CPAP device in combination 
with DIBH in left-sided BC patients showing clear dosimetric advantages on cardiac radiation doses 44. 
Additionally, some small retrospective and non-randomized prospective studies also showed decreased 
cardiac doses when CPAP was used in a free breathing (FB) setting, for example in patients not able to 
perform DIBH 45–49. The same CPAP-assisted strategy has been investigated in RT for other thoracic 
malignancies showing similar results confirming larger lung volumes and some also demonstrating 
decreased cardiac doses with CPAP 50–52. One study in lung cancer patients did not show a dosimetric 
benefit on the heart, probably because of the use of a relatively low airway pressure and a nose mask 
instead of a nose and mouth mask 53.  
In summary, preliminary evidence indicating potential advantages in RT dosimetry when using CPAP in 
BC RT exists. However, the evidence is limited by small sample sizes and/or the retrospective nature of 
most previous studies. To address this limitation, the primary objective of this study is to prospectively 
examine the impact of CPAP in optimizing RT in a large BC cohort to enhance the robustness of these 
findings.  Moreover, to determine which patients benefit the most from CPAP-assisted RT we will 
compare dosimetric parameters in 4 cohorts of BC patients (right-sided, left-sided without RNI, left-
sided with RNI(<70y/o) and left-sided with RNI (70-80 years old)). The rationale behind this is twofold. 
Firstly, the anatomical left-sided position of the heart, suggests a potential for more significant cardiac 
benefits from CPAP-assisted RT in left-sided BC patients. Secondly, patients undergoing irradiation of the 
RNI, including the internal mammary and subclavian glandular chain, may experience increased advantages 
with CPAP-assisted RT due to the otherwise close proximity of the RT target volume to multiple OARs. 
Due to these two factors, right-sided BC patients only requiring local breast RT (without RNI) will not 
be included in this study, because the presumed benefit of CPAP-assisted RT is too small.  
Furthermore, we will also assess clinical performance of CPAP-assisted RT in daily practice and provide 
guidelines for its clinical implementation in BC RT, encompassing considerations of accuracy, 
reproducibility, efficacy and cost-analysis.   
2.6 Expected Duration of the Investigation 
The study duration for a single patient aligns with the standard radiation treatment course for BC, 
commencing with a CT simulation scan, typically followed by the initiation of RT approximately 2 weeks 
thereafter. The complete course consists of 15 radiation treatment fractions, administered at a frequency 
of 4 to 5 sessions per week, resulting in an average duration of slightly less than 4 weeks for the entire RT 
process. If a boost dose to the tumor bed is administered, this will be given in a simulteaneous way 
(integrated in the radiation of the breast/regional lymph nodes). No study-specific follow-up is provided 
after termination of RT.  
Anticipated enrolment of patients is expected to take 1 year, followed by an additional year allocated for 
data analysis and subsequent publication of the results. Consequently, the anticipated timeframe for the 
study's completion is two years. 
The end of the Investigation is defined as Last Patient Last Visit (LPLV). The CI shall notify the end of the 
Investigation to the EC within 15 days. The CI will submit a final report with the results of the Investigation, 
including any publications/abstracts, within one year of the end of the clinical investigation or within three 
months in case of an early termination. In absence of EUDAMED, the Clinical Investigation Report (CIR) 
shall be submitted to the involved EC. 
The Sponsor, EC or authorized regulatory authority can decide to halt or prematurely terminate the 
Investigation when new information becomes available whereby the rights, safety and well-being of 
participants can no longer be assured, when the integrity of the Investigation has been compromised, or 
when the scientific value of the Investigation becomes obsolete and/or unjustifiable. In case the Sponsor 
decides to temporary halt or prematurely end the Investigation, or to close a Participating Site in case of 
major non-compliance and/or critical safety issues, the Sponsor will notify the concerned EC within 15 days 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 20 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
of early termination or temporary halt, providing a justification of the event. In the event that the sponsor 
has temporarily halted or early terminated the Investigation on safety grounds, the Sponsor will inform the 
EC within 24 hours of the event. In absence of EUDAMED, local guidelines with regards to notifications 
and submissions to the concerned EC will be followed. 
Circumstances requiring premature treatment interruption or discontinuation of the Investigation, include 
but are not limited to:  
• 
Safety concerns related to IMD or unacceptable intolerability 
3 Eligibility Criteria 
3.1 Inclusion criteria 
Participants eligible for inclusion in this Investigation have to meet all of the following criteria: 
1. Voluntary written informed consent of the participant or their legally authorized representative 
has been obtained prior to any screening procedures 
2. At least 40 years of age and 80 years or younger at the time of signing the Informed Consent 
Form (ICF) 
3. Female patients 
4. Patients that underwent breast conserving surgery (BCS) 
5. Left-sided invasive BC / in situ carcinoma with indication for adjuvant RT (<70 years old) 
6. Left-sided invasive BC with indication for adjuvant locoregional RT (including RT of the regional 
lymph nodes) (70-80 years old) 
7. Right-sided invasive BC with indication for adjuvant locoregional RT (including RT of the regional 
lymph nodes) 
8. Prior chemotherapy allowed 
9. Prior immunotherapy allowed 
10. Prior / concomitant hormonal therapy allowed 
11. Prior / concomitant HER2-targeted therapy allowed 
All participants that are considered for Investigation participation per the above criteria, will be 
documented via applicable log forms in Investigator Site File (including Screen Failures).  
3.2 Exclusion criteria 
Participants eligible for this Investigation must not meet any of the following criteria: 
1. Patient has active bullous lung disease, bypassed upper airway, pneumothorax, cerebral spinal fluid 
leaks, abnormalities of the cribriform plate (contra-indications for the use of CPAP) 
2. Patient has history of major head trauma and/or pneumocephalus (contra-indications for the use 
of CPAP) 
3. Any disorder, which in the investigator’s opinion might jeopardise participant’s safety or 
compliance with the CIP. 
4. Female who is pregnant, breast-feeding or intends to become pregnant (which is a contra-
indication for RT in general) 
5. Male BC patients 
6. Patients that underwent mastectomy Patients whose initial tumor was located just beneath the 
skin (defined as being less than 28mm below the breast surface), indicating the need for an electron 
boost 
7. Patients requiring RT boost on positive lymph nodes 
8. Distant metastasis 
9. Breast implants in situ 
10. Right-sided in situ carcinoma 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 21 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
11. Right-sided invasive BC only requiring local adjuvant RT (without irradiation of the regional lymph 
nodes, because the presumed benefit on cardiac doses of local right-sided breast irradiation is 
assumed to be rather small because of the left anatomical position of the heart) 
12. Bilateral BC 
13. Concomitant use of chemotherapy during RT 
14. Substantial comorbidities, incompatible with RT or CPAP use, estimated by the treating radiation 
oncologist 
15. Insufficient arm mobility to perform comfortable arm positioning in radiation treatment position, 
evaluated by the treating radiation oncologist 
16. Other active oncological disease / treatment with the exception of non-melanoma skin cancer 
17. Previous RT with overlapping RT fields with actual target volume 
Participants who meet one or more of the above exclusion criteria must not proceed to be 
enrolled/randomized in the Trial and will be identified via applicable log forms in Investigator Site File. 
4 Study Procedures 
4.1 Selection of Participants / Recruitment 
Potential participants will be identified and recruited during patient consultations in one of the participating 
sites. No additional recruitment material (such as for example flyers, social media advertising, audio/video 
recordings) will be used. 
4.2 Investigation assessments and procedures 
Trial procedures and their timing are summarized in the Study Flowchart. 
 
4.2.1 
Participant consent and withdrawal of consent 
The Investigation will be conducted only on the basis of prior informed consent by the participants and/or 
their legally authorized representative(s). As such, no Investigation-related procedures will be conducted 
prior to obtaining written informed consent from potential participants. 
The process for obtaining and documenting initial and continued informed consent from potential 
participants will be conducted in accordance with ISO 14155:2020, applicable regulatory requirements and 
internal Standard Operating Procedures (SOPs). 
All originally signed obtained Informed Consent Forms (ICFs) must be retained/archived in the ISF at the 
Participating Site and must not be destroyed (even when a scanned copy is available) before expiration of 
the legal archiving term as defined in the CIP section entitled “Archiving”.  
Participants may voluntarily withdraw consent to participate in the Investigation for any reason at any time. 
The participant’s request to withdraw from the Investigation must always be respected without prejudice 
or consequence to further treatment. Consent withdrawal will be documented in the participant’s medical 
record. 
Study data and samples collected before withdrawal can be used in the study. No new study data or samples 
will be collected after withdrawal of the participant. 
4.2.2 
Randomization Procedure (if applicable) 
Not Applicable 
4.2.3 
Other Investigation assessments and procedures 
Additional information to the anticipated investigations taking place within this study: 
Consultation:  
The treating physician will meet the patient to discuss side effects and other concerns about the condition 
and treatment. A consultation may be accompanied by a (focused) clinical examination.  
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 22 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
CT scan:  
A CT simulation scan is used to plan and optimize radiation treatment.  
 
Patient-reported questionnaires:  
During and after treatment, we will ask patients to answer some questions regarding side effects and quality 
of life by using validated questionnaires. 
4.3 Premature discontinuation 
Participants may voluntarily discontinue from the Investigation treatment and/or prematurely end their 
participation in the Investigation for any reason at any time. In such case the Investigator must make a 
reasonable effort to contact the participant (e.g., via telephone, e-mail, letter) in order to document the 
primary reason for this decision. 
The Investigator may also decide at any time during the course of the Investigation, to temporarily interrupt 
or permanently discontinue the treatment if it is deemed that continuation would be detrimental to, or 
not in the best interest of the participant.  
Circumstances requiring premature treatment interruption or discontinuation of the Investigation, include 
but are not limited to:  
• 
Investigation participation while in violation of the inclusion and/or exclusion criteria 
• 
Pregnancy 
• 
Intention of becoming pregnant 
• 
< Safety concerns related to IMD or unacceptable intolerability> 
In any such case of early termination and/or treatment interruption/discontinuation, the Investigator will 
continue to closely monitor the participant’s condition and ensure adequate medical care and follow-up. It 
is recommended that follow-up information will be collected as follows: 
If a patient withdraws from the study while undergoing RT, we will highlight the crucial medical importance of finishing 
the radiation course for effective oncological disease control and provide the opportunity to resume the radiation treatment 
according to standard of care as soon as possible. 
Since no study-specific follow-up is provided after termination of RT, participant discontinuation of the study after 
completing RT does not affect study protocol, hence no different follow-up is provided in this case.  
For participants whose status is unclear because they fail to appear for visits without stating an intention 
to discontinue or withdraw, the Investigator must make every effort to demonstrate “due diligence" by 
documenting in the source documents which steps have been taken to contact the participant to clarify 
their willingness and ability to continue their participation in the Investigation (e.g., dates of telephone calls, 
registered letters, etc.). 
A participant should not be considered lost to follow-up until due diligence has been completed. 
5 Investigational Medical Device (IMD)  
Investigational Medical Device 
Name (& company brand) 
CE 
mark 
(Y – N - NA) 
Used 
within 
Indication (Y or N) 
Manufacturer of the 
device 
Philips Respironics DreamStation 1 
Y 
Y 
Philips 
F&P Evora™ Full Face mask  
Y 
Y 
Fisher 
& 
Paykel 
Healthcare  
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 23 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
5.1 Intended use 
The Philips Respironics DreamStation system delivers positive airway pressure therapy in spontaneously 
breathing patients weighing over 30 kg. It is developed for use at home or in a hospital/institutional 
environment. It is most commonly used for the treatment of Obstructive Sleep Apnea Syndrome (OSAS) 
(https://www.documents.philips.com/doclib/enc/11405972/DreamStation_CPAP_User_Manual.pdf).  
5.2 Identification and description of the IMD 
The Philips Respironics DreamStation system delivers positive airway pressure therapy in spontaneously 
breathing patients weighing over 30 kg. It is developed for use at home or in a hospital/institutional 
environment. It is most commonly used for the treatment of Obstructive Sleep Apnea Syndrome (OSAS) 
(https://www.documents.philips.com/doclib/enc/11405972/DreamStation_CPAP_User_Manual.pdf). It will 
be used in combination with The F&P Evora™ Full Face mask. This device is intended to be used by 
adults weighing ≥ 30 kg who have been prescribed non-invasive positive airway pressure therapy such as 
CPAP (https://resources.fphcare.com/content/ui-618441.pdf) .   
In our study, this DreamStation 1 CPAP device will be used to provide positive airway pressure, in order 
to assist and enhance spontaneous breathing and DIBH during RT for BC patients. It will be used in 
combination with a F&P Evora Full compact full-face PAP mask to cover both nose and mouth.  
Patients will be educated about the use of the CPAP device and mask in a coaching session of 30 minutes, 
prior to CT simulation. As a first step, the patient will be educated about the use of the system by our 
RT nurse or the treating RT physician. Next, fitting of the full-face mask is provided, since correct fitting 
is very important to prevent leakage of pressure. Subsequently, the patient will be connected to the 
CPAP device, and the airway pressure will be gradually elevated from 7 cmH20 to 15 cmH20 over a ten-
minute interval to acclimate to breathing with the device. Throughout this duration, the patient will have 
the opportunity to communicate whether the final pressure of 15 cmH20 is both comfortable and 
sustainable. Once the patient has adequately adapted to breathing with the device, the commencement of 
the effective preparation for RT will start, while continuing breathing with the CPAP device. 
5.3 Device Accountability 
For both the Philips Respironics DreamStation 1 and the F&P Evora™ Full Face mask preparation is not 
applicable. 5 DreamStation 1 study devices will be available for the duration of the entire study. All of these 
will be labelled as followed:  
- 
“DreamStation1_Philips_RT_Sim1” (this device will be stored at CT simulation 1 UZ Leuven) 
- 
“DreamStation1_Philips_RT_Toestel1” (this device will be stored at LINAC 1 UZ Leuven) 
- 
“DreamStation1_Philips_RT_Toestel2” (this device will be stored at LINAC 2 UZ Leuven) 
- 
“DreamstationI_Philips_RT_Toestel3” (this device will be stored at LINAC 3 UZ Leuven) 
- 
“DreamStation1_Philips_RT_Reserve” (this device will serve as a spare device in the event of 
defects in other devices, ensuring that the repair of one device does not disrupt the workflow of 
the study. This device will be stored at CT simulation 1 UZ Leuven) 
The devices should be stored at room temperature, away from any heating or cooling equipment.  
Sterilization of the devices is unnecessary; thorough cleaning with a Trionic wipe after each use is deemed 
sufficient. 
For every individual patient randomized to the investigational arm an individual F&P Evora™ Full Face mask 
and connecting tube will be purchased with study budget of the available funding. The mask and tube will 
be used by a single patient during the entire radiation treatment and will be stored at the radiation 
treatment console, labelled as followed: “Mask_PatientSurname_PatientDateOfBirth”. After completion of 
the entire radiation treatment all masks and tubes will be collected together and will be stored at CT 
simulation 1 of UZ Leuven until completion of the study. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 24 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
6 Safety reporting 
6.1 Definitions 
The definitions and reporting requirements adopted in this CIP are based on the MDR, ISO 14155:2020 
and the MDCG 2020-10/1 European guideline and the vigilance provisions. 
6.1.1 
Adverse Event (AE) 
An AE is any untoward medical occurrence, unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory finding) in subjects, users or other persons, in the context of a clinical 
investigation, whether or not related to the investigational medical device.  
 
Note: 
a. This definition includes events related that are anticipated as well as unanticipated events  
b. This definition includes events occurring in the context of a clinical investigation related to the 
investigational device, the comparator or the procedures involved.  
 
6.1.2 
Serious Adverse Event (SAE) 
A SAE is any adverse event that led to any of the following:  
a)  death, 
b)  serious deterioration in health of the subject, that resulted in any of the following:  
 
- life-threatening illness or injury,  
 
- permanent impairment of a body structure or a body function, 
 
- hospitalisation or prolongation of patient hospitalisation,  
- medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
- chronic disease, 
c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect.  
 
6.1.3 
Adverse Device Effect (ADE) 
An ADE is an adverse event related to the use of an investigational medical device or a comparator.  
 
6.1.4 
Serious Adverse Device Effect (SADE) 
A SADE is an adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event.  
An Unanticipated Serious Adverse Device Effect is any SADE of which the nature, severity or outcome is 
not consistent with the reference safety information. 
 
6.1.5 
Device Deficiency (DD) 
A DD is any inadequacy in the identity, quality, durability, reliability, safety or performance of an 
investigational device, including malfunction, use errors or inadequacy in information supplied by the 
manufacturer.  
6.1.6 
Adverse Events of Special Interest (AESI) 
The following events should be reported within the same timelines as SAEs: 
- 
Not Applicable 
 
6.2 Adverse Events that do not require reporting 
In general, the following should not be reported as AEs: 
• 
Pre-existing conditions, including those found as a result of screening (these should be reported 
as medical history or concomitant illness, unless the pre-existing condition appears to be 
worsened). 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 25 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
• 
Pre-planned procedures, unless the condition for which the procedure was planned has worsened 
from the first investigation-related activity after the subject has signed the informed consent. 
 
The following events are commonly observed and are therefore not considered as adverse events for the 
purpose of the investigation: 
• 
Radiation-induced erythema/epidermolysis/oedema of the irradiated skin 
• 
Radiation-induced oesophagitis 
• 
Radiation-induced fatigue  
Although these events should not be reported to the Sponsor, these should be recorded in the patient’s 
medical notes according to routine practice.  
The following events not to be considered as SAEs are: 
• 
Pre-planned hospitalisations unless the condition for which the hospitalisation was planned has 
worsened from the first trial-related activity after the subject has signed the informed consent.  
• 
Hospitalisation as part of a standard procedure for protocol therapy administration. However, 
hospitalisation or prolonged hospitalisation for a complication of therapy administration will be 
reported as an SAE. 
• 
Hospitalisation or prolongation of hospitalisation for technical, practical, or social reasons, in 
absence of an AE. 
 
6.3 Recording and reporting of Adverse Events  
Investigators will seek information on AEs during each patient contact. All events, whether reported by the 
patient or noted by trial staff, will be recorded in the patient’s medical record and in the (e)CRF within a 
reasonable time after becoming aware. If available, the diagnosis should be reported on the AE form, rather 
than the individual signs or symptoms. If no diagnosis is available, the Investigator should record each sign 
and symptom as individual AEs using separate AE forms. 
The following minimum information should be recorded for each AE: 
- AE description 
- start and stop date of the AE 
- severity 
- seriousness 
- causality assessment to the Investigational Medical Device (IMD) and/or study procedures 
- outcome 
 
6.3.1 
Assessment  
All AEs must be evaluated by an Investigator as to: 
 
• 
Seriousness: whether the AE is an SAE. See above for the seriousness criteria. 
 
• 
Severity:  
o 
Severity must be evaluated by an Investigator according to the following definitions: 
▪ 
Mild – no or transient symptoms, no interference with the subject’s daily activities 
▪ 
Moderate – marked symptoms, moderate interference with the subject’s daily 
activities 
▪ 
Severe – considerable interference with the subject’s daily activities, unacceptable 
• 
Causality: 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 26 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
 
Not related 
Relationship to the device, comparator or procedures can be excluded when: 
- the event has no temporal relationship with the use of the investigational device, or the 
procedures related to application of the investigational device 
- the serious adverse event does not follow a known response pattern to the medical device 
(if the response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious adverse event; 
- the event involves a body-site or an organ that cannot be affected by the device or 
procedure; 
- the serious adverse event can be attributed to another cause (e.g. an underlying or 
concurrent illness/ clinical condition, an effect of another device, drug, treatment or other 
risk factors); 
- the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
 
In order to establish the non-relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious adverse event. 
Possible 
The relationship with the use of the investigational device or comparator, or the relationship 
with procedures, is weak but cannot be ruled out completely. Alternative causes are also 
possible (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of another 
device, drug or treatment). Cases where relatedness cannot be assessed, or no information 
has been obtained should also be classified as possible. 
Probable 
The relationship with the use of the investigational device or comparator, or the relationship 
with procedures, seems relevant and/or the event cannot be reasonably explained by another 
cause. 
Causal relationship The serious adverse event is associated with the investigational device, comparator or with 
procedures beyond reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
- the event has a temporal relationship with investigational device use/application or 
procedures; 
- the event involves a body-site or organ that 
• the investigational device or procedures are applied to; 
• the investigational device or procedures have an effect on; 
- the serious adverse event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious adverse event (when clinically feasible); 
- other possible causes (eg, an underlying or concurrent illness/clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the investigational device used for diagnosis, 
when applicable; 
In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious adverse event. 
 
6.3.2 
Timelines for reporting 
- 
After informed consent has been obtained but prior to first use of the IMD, only adverse events 
caused by a study specific procedure should be reported  

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 27 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
- 
After first use of the IMD, adverse events will be reported as follows:  
o 
All AEs and SAEs related to a study procedure or the IMD, AESIs and Device Deficiencies 
will be reported until last (follow-up) visit.  
All SAEs and AESI as defined in the protocol must be reported to the Sponsor within 24 hours of the trial 
staff becoming aware of the event. The immediate report shall be followed by detailed, written reports. 
The immediate and follow-up reports shall identify subjects by code numbers. 
 SAE details will be reported by the Investigator to the sponsor:  
• 
By completing the SAE form in the (e)CRF  
If an authorised Investigator from the reporting site is unavailable, initial reports without causality 
assessment should be submitted to the Sponsor by a healthcare professional within 24 hours of becoming 
aware of the SAE, but must be followed-up by medical assessment as soon as possible thereafter. 
6.3.3 
Follow-up  
The Investigator must record follow-up information by updating the patient’s medical records and the 
appropriate forms in the (e)CRF. The worst case severity and seriousness of an event must be kept 
throughout the trial. 
SAE follow-up information should only include new (e.g. corrections or additional) information and must 
be reported within 24 hours of the Investigator’s first knowledge of the information. This is also the case 
for previously non-serious AEs which subsequently become SAEs. 
• 
All SAEs must be followed up until the outcome of the event is ‘recovered’, ‘recovered with 
sequelae’, ‘not recovered’ (in case of death due to another cause) or ‘death’ (due to the SAE) and 
until all related queries have been resolved, or until end of trial (whichever occurs first). 
• 
Non-serious AEs must be followed up until the patient’s last study visit, and/or until all related 
queries have been resolved. 
 
SAEs after the end of the investigation: If the Investigator becomes aware of an SAE with suspected 
causal relationship to the IMD or experiment after the subject has ended the investigation, the Investigator 
should report this SAE within the same timelines as for SAEs during the investigation. 
 
6.3.4 
Death 
All deaths will be reported without delay to the sponsor (irrespective of whether the death is related to 
disease progression, the IMD, study procedure or is an unrelated event). If considered a reportable event, 
the sponsor must notify the EC(s) and CA(s) for materiovigilance as soon as possible after becoming aware.  
6.4 Recording and reporting of Device Deficiencies 
Each Device Deficiency must be documented by the Investigator in the source documents and reported to 
the Sponsor on a Device Deficiency form. 
If the Device Deficiency leads to the occurrence of a (S)ADE, the (S)ADE must also be reported by the 
Investigator to the Sponsor on the appropriate forms and within the specified timelines. 
6.5 Reporting requirements to Ethics Committees (EC’s) 
The Investigator is responsible for ensuring that all safety events are recorded in the (e)CRF and reported 
to the Sponsor in accordance with instructions provided below. 
The Sponsor will promptly evaluate all SAEs, AESIs and Device Deficiencies against medical experience to 
identify and expeditiously communicate possible new safety findings to Investigators and applicable EC’s 
based on applicable legislation. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 28 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
6.5.1 
Sponsor’s reporting of Serious Adverse Events and Device Deficiencies 
The Sponsor is responsible to report to the EC’s where the clinical investigation has commenced: 
- 
Any SAE that has a causal relationship with the device, the comparator or the investigation 
procedure* or where such causal relationship is reasonably possible; 
- 
Any Device Deficiency that might have led to a SAE if: 
a) Appropriate action had not been taken or, 
b) Intervention had not occurred or, 
c) If circumstances had been less fortunate 
- 
New findings/update in relation to already reported reportable events. 
*a study-specific procedure related to the use of the investigational device or comparator (outside the standard of care). 
 
These ‘reportable events’ must be reported within the following timelines: 
• 
A reportable event which results in imminent risk of death, serious injury, or serious illness that 
requires prompt remedial action for other patients/subjects, users or other persons or a new finding 
to it must be reported immediately, but not later than 2 calendar days after awareness by the sponsor 
of a new reportable event or of new information in relation with an already reported event. 
• 
Any other reportable event or a new finding/update to it must be reported immediately, but not later 
than 7 calendar days following the date of awareness by the sponsor of the new reportable event or 
of new information in relation with an already reported event. 
 
6.6 Sponsor’s reporting of Materiovigilance to Competent Authorities (CA’s) 
Serious incidents or potential serious incidents related to the use of a CE marked device used 
within its intended purpose should be reported to the CA according to the materiovigilance 
provisions.  
 
The following should be notified as soon as possible:  
 
- Any dysfunction or any change of the characteristics and/or performance of a device, and any inadequacy 
in the labelling or instructions, which might lead to or have led to death or serious relapse in the state of 
health of a patient, a user or a third party. 
- Any incident that might have resulted in one of the following clinical implications:  
• death 
• life-threatening injury 
• permanent or significant impairment of a body structure or a body function 
• hospitalisation or prolongation of patient hospitalization 
• need for medical or surgical intervention 
• congenital physical or mental impairment, foetal distress or foetal death 
• delayed or incorrect diagnosis or treatment 
• transfusion of improper materials 
 
This also includes any risk of a serious incident that could be prevented by the actions and interventions 
of the involved persons. 
 
6.7 Overview reporting requirements 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 29 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
 
WHAT 
HOW 
TO 
TIMELINES 
Investigator 
AE 
AE form 
sponsor 
as defined in CIP 
SAE 
SAE form 
sponsor 
asap, but no later than 3 calendar 
days after awareness 
Device Deficiency 
(DD) 
DD form  
+ AE/SAE form   
(if applicable) 
sponsor 
as defined in CIP  
(exception: within 3 calendar days 
if considered reportable event) 
death 
SAE form 
sponsor 
asap 
Sponsor 
all reportable events 
(of all participating 
sites) 
EU SAE report 
form (excel)1 
- Ethics Committee(s) 
asap, but no later than 
- 2 calendar days (in case of risk of 
death or serious injury/illness that 
requires prompt remedial action 
for other patients, users or other 
persons)  
- 7 calendar days                              
(all other reportable events) 
Materiovigilance 
Meddev report 
form2 
- CA for Belgium -> 
FAGG: via mail to 
vigilance.meddev@fagg-
afmps.be  
asap 
1The SAE report form in excel format can be downloaded from the following web page: 
https://ec.europa.eu/health/sites/health/files/md_sector/docs/md_mdcg_2020-10-
2_guidance_safety_report_form_en.xlsx?web=1 
2The 
Meddev 
report 
form 
can 
be 
downloaded 
form 
the 
following 
web 
page: 
https://www.fagg.be/sites/default/files/content/notification_incident_nl_0.pdf  
6.8 Data Safety Monitoring Board (DSMB) 
After a thorough evaluation of the potential risks to Investigation participants and considering the nature, 
design and complexity of the clinical Investigation, the Sponsor has determined not to establish a DSMB. 
This decision is grounded in our conclusion that this is a low risk clinical Investigation in which the IMD 
has a CE mark and is used within indication. In addition, the potential risks associated to the study 
procedures and protocol design are comparable to that of standard medical care. 
The Investigation is committed to ensuring the safety and well-being of all participants at all times by 
adhering to the latest version of ISO 14155:2020 and other relevant and applicable standards and 
legislations. 
7 
Statistics and Data Analysis 
Statistical analysis will be performed in accordance with ICH E9; a detailed description of the analysis is 
provided in the study-specific Statistical Analysis Plan (SAP). ICH E3 and E8 will guide the structure and 
content of the clinical study report. 
7.1 Sample Size Determination 
Approximately 83 participants will be screened to achieve an estimated total of 73 evaluable participants. 
7.2 Statistical Analysis 
<SAMPLE SIZE  

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 30 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
Our aim is to evaluate whether CPAP-assisted radiation treatment improves cardiac radiation doses in 3 
cohorts of BC patients (right-sided BC, left-sided BC without RNI, left-sided BC with RNI). A decrease of 
0.5 Gy Mean Heart Dose (MHD) by using CPAP-assisted RT compared to a standard protocol was deemed 
clinically relevant. Retrospective data provided the following information on means and standard deviation 
(SD) of MHD in the first 3 cohorts: right-sided BC Mean MHD 1.03, SD 0.52; left-sided BC without RNI 
Mean MHD 1.15, SD 0.71, left-sided BC with RNI Mean MHD 2.29, SD 0.82. No information was available 
on the correlation between paired measurement of MHD with and without CPAP. A correlation of 0.5 
was assumed for the sample size calculation, leading to sample sizes of 11 (right-sided BC), 18 (left-sided 
BC without RNI), and 24 (left-sided BC with RNI) patients, or 53 patients in total. The sample size 
calculation was performed assuming a two-sided paired t-test, adopting a 5% test-wise significance level, 
and 80% of power. To account for the uncertainty on the assumed correlation between paired 
measurements, a blinded sample size recalculation will be performed after inclusion of approximately 50% 
of the patients. The correlation between paired measurements will be calculated and the sample size will 
be re-estimated with the observed correlation. In case the correlation turns out lower than previously 
anticipated, the sample size will be increased. For the additional subgroup of 70- to 80-year-old patients 
with left-sided breast cancer and an indication for RNI, no baseline data on MHD were available. Therefore, 
we estimate to include approximately 20 patients in this group, extrapolated from the sample sizes used 
for the other subgroups. Since a sample size recalculation is planned, a specific calculation for this subgroup 
will also be performed at that time. In conclusion, with the inclusion of this final group, we anticipate a total 
sample size of approximately 73 patients. 
STATISTICAL ANALYSIS 
Descriptive statistics on the sample will be provided presenting categorical variables by frequencies and 
percentages, and continuous variables by mean with standard deviation, median and quartiles. > 
7.2.1 
Efficacy Analysis 
Endpoint 
Statistical Analysis Methods 
Primary 
For each of the three cohorts, the following analysis is planned: A two-sided paired t-
test will be performed to compare the difference in MHD between the standard 
protocol and CPAP. The mean difference will be estimated with 95% confidence 
interval. A 5% significance level will be adopted for the analysis in each of the 4 cohorts.  
Secondary 
The comparison between standard protocol and CPAP with regards to dosimetric 
outcomes for different organs at risk (OAR) will be analyzed in analogy with the 
primary outcome analysis. 
Patient comfort and tolerance of CPAP-assisted RT by assessed by patient questionnaires 
will be analyzed descriptively. 
A Bland-Altman analysis will be performed to analyze agreement of surface scanning 
parameters obtained with CPAP or standard protocol. 
DIBH performance, time effectiveness, cost analysis and NTCP differences will be 
compared between standard and CPAP-assisted RT for left-sided BC on surface scanning 
and CBCT parameters using the same approach as the primary outcome analysis. 
The focus of the secondary analyses will be on the estimation of effect sizes with 95% 
confidence intervals. Formal tests performed will adopt a 5% significance level, 
nevertheless p-values will be interpreted carefully, recognizing the risk inflated type I 
error rate. Conclusions will be drawn as hypothesis-generating. 
We expect negligible missing observations as almost all outcome measurements are taken 
at Visit 2 and collected by clinical staff. 
 
Exploratory 
Not applicable 
7.2.2 
Other Analysis 
Not applicable 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 31 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
7.3 Interim Analysis and Final Database Lock 
Not applicable 
8 
Data handling  
Redcap will be used to capture study related data. Data will be stored on KULeuven/UZ Leuven hardware 
and servers, thus protected by its firewalls. The patient data will be coded. There will be a coding file using 
a study number with the matched EAD number. This coding file will only be accessible by Prof. Weltens 
(principle investigator), Prof. Van Aelst, Prof. Lambrecht, dr. Aline Van der Vorst and dr. Johanna Jacobs 
(co-investigators). 
8.1 Data Collection Tools and Source Document Identification 
8.1.1 
Operational aspects  
Data collection, handling, processing and transfer for the purpose of this Investigation will be performed in 
compliance with applicable regulations, guidelines for clinical trials and internal procedures, as follows: 
8.1.1.1 
Data collection  
Source data will be collected and recorded in the participant’s files/medical records. 
If applicable, worksheets may be used for capturing some specific data in order to facilitate completion of 
the (e)CRF. Any such worksheets will become part of the participant's source documentation and will be 
filed together with or as part of the medical records (during but also following completion of the 
Investigation). 
It remains the responsibility of the Investigator to check that all data relating to the Investigation, as 
specified in the CIP, are entered into the (e)CRF in accordance with the instructions provided and that the 
forms are filled out accurately, completely and in a timely manner. 
Redcap will be used as eCRF to capture study related data.  
(e)CRFs are provided by the Sponsor for each participant. The Investigation data will be transcribed from 
the source records (i.e., participant’s medical file or study-specific source data worksheets) into an (e)CRF 
by study staff. Transcription to the (e)CRF will be done as soon as possible after a participant visit and in a 
pseudonymized manner using a unique identifier assigned by the Sponsor. 
The following data will be collected in the (e)CRF : 
- 
Patient characteristics: sex, date of birth, age, weight, length 
- 
Medical history 
- 
Cardiovascular risk factors 
- 
Oncological data 
o 
Tumour laterality: left / right breast 
o 
Tumour Stage: clinical and pathological Tumor-Node-Metastasis (TNM) 
o 
Date of cancer diagnosis 
o 
Pathological characteristics: tumour size, nodal status, histological subtype, histological 
grade, hormone and HER2 receptor positivity, Ki67 
o 
Surgical therapy 
▪ 
Type of surgery 
• 
BCS 
• 
Sentinel node procedure 
• 
Axillary dissection 
o 
Systemic therapy 
▪ 
Chemotherapy regimen: scheme, setting neoadjuvant/adjuvant, start therapy, 
cycles planned, cycles received, dose used 
▪ 
Her2-directed regimen: setting neoadjuvant/adjuvant, start therapy, cycles 
planned, cycles received, dose used 
▪ 
Hormonal therapy: setting neoadjuvant/adjuvant, start therapy, cycles planned, 
cycles received, dose used 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 32 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
▪ 
Immunotherapy: setting neoadjuvant/adjuvant, start therapy, cycles planned, 
cycles received, dose used 
o 
Radiation therapy 
▪ 
Radiation field 
• 
Breast 
• 
Regional lymph nodes (level I, II, III, IV, rotter, internal mammary 
nodes) 
▪ 
Radiation dose 
• 
Total dose 
• 
Dose per fraction 
• 
Target volume coverage 
• 
Dosimetry parameters of different OAR 
o 
Whole heart  
o 
Cardiac Substructures 
o 
Lungs  
o 
Ipsilateral lung  
o 
Contralateral breast  
o 
Liver 
o 
  
▪ 
Administration of a boost to the tumour bed 
• 
Total dose 
• 
Dose per fraction  
• 
Location of boost: inner/outer, upper/lower quadrant 
▪ 
Application of DIBH technique: yes or no  
▪ 
Application of CPAP-assisted RT: yes or no 
▪ 
Radiation technique: 3D conformal radiotherapy, IMRT, VMAT, PT, combination  
o 
If applicable, date and cause of death  
▪ 
Oncological 
▪ 
Cardiovascular 
▪ 
Infectious 
▪ 
Other 
▪ 
Unknown 
- 
Differences in normal tissue complication probabilities (NTCP) from various NTCP models (Darby 
et al. and models developed in study s68508) between standard and CPAP-assisted RT 
- 
 
 
We expect negligible missing observations as almost all outcome measurements are known at Visit 2 and 
collected by clinical staff. 
 
8.1.1.2 
Data Validation  
All data relating to the Investigation must be prepared and validated by the Investigator. Any (e)CRF entries, 
corrections and alterations must be made by the Investigator or other authorized study staff.  
Proper audit trails must be available to demonstrate the validity of the Investigation data collected. This 
includes historical records of original data entries, by whom and when the data was entered, as well as 
detailed records of any corrections or additions made to the original data entry (i.e., who made the 
correction/addition, when and why), without obliterating the original data entry information. 
8.1.1.3 
Data Management 
The Study Data Manager will perform extensive consistency checks on the received data. Queries will be 
issued in case of inconsistencies in accordance with internal procedures. A DMP will be developed to map 
data flows, data validation measures that will be taken, how (interim) database lock(s) will be managed and, 
as applicable, the role and responsibilities of the DSMB. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 33 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
8.1.1.4 
Data Transfer 
Any participant records or datasets that are transferred to the Sponsor or any partners of the Sponsor 
will contain the study-specific participant identifier only; participant names or any information which would 
make the participant identifiable will not be transferred. All pseudonymized data relating to the Investigation 
must be transmitted in a secure manner to the Sponsor or any partners of the Sponsor (see 8.1.2. legal 
requirements). 
8.1.2 
Legal requirements 
All source data will be kept at a secured location with restricted access at all times. These data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with applicable 
data protection laws and regulations and more in particular the GDPR, and relevant national laws 
implementing the GDPR. Appropriate technical and organizational measures to protect the data against 
unauthorized disclosure or access, accidental or unlawful destruction, or accidental loss or alteration must 
be established. Study staff whose responsibilities require access to personal data agree to keep the data 
confidential. 
The Investigator and the Participating Site(s) (as applicable) shall treat all information and data relating to 
the Investigation disclosed to them as confidential and shall not disclose such information to any third 
parties or use such information for any purpose other than the objectives of the Investigation as described 
in this CIP. The collection, processing and disclosure of personal data, such as participant health and medical 
information, is subject to compliance with applicable laws and regulations regarding personal data 
protection and the processing of personal data. 
The Investigator will maintain all source documents and completed (e)CRFs that support the data collected 
from each participant, and will maintain a TMF/ISF containing all study documents, as specified in ISO 
14155:2020 Annex E entitled “Essential clinical investigation documents”, and as specified by applicable 
regulatory requirement(s). The Investigator will take appropriate measures to prevent accidental or 
premature destruction of these documents. 
Transfer of the pseudonymized data will be performed via a secured method of transfer taking into account 
all applicable security arrangements and regulations (such as the GDPR).  
8.2 Audits and Inspections 
The Investigator will permit direct access to study data and documents for the purpose of monitoring, 
audits and/or inspections by authorized entities, such as but not limited to: the Sponsor or its designees 
and competent regulatory or health authorities. As such, (e)CRFs, source records and other study related 
documentation (e.g., ISF, TMF, pharmacy records, etc.) must be kept current, complete and accurate at all 
times. 
8.3 Monitoring 
In accordance with ISO 14155:2020, the Sponsor is responsible for monitoring the Investigation to ensure 
compliance with GCP and current legislation, and to verify, among other requirements, that proper written 
informed consent has been obtained and documented, that the study procedures have been followed as 
shown in the approved CIP, and that relevant study data have been collected and reported in a manner 
that assures data integrity.  
UZ Leuven Clinical Trial Center (CTC) performs a risk analysis to determine the monitoring strategy. 
Based on this risk assessment, the clinical trial was classified as ‘low risk’ as the potential risks associated 
to study procedures and protocol design are comparable to that of standard medical care since the IMD 
has a CE label and is used within indication.  
Based on the above risk assessment and as permitted by GCP, the Sponsor of the trial accepts the minimal 
risks associated with this trial and determines that monitoring activities (as defined by GCP) by a qualified 
individual, independent of the study team, is not necessary as it will provide little or no added value in 
protecting the safety of trial participants and assuring the integrity of collected trial data. Nonetheless, the 
UZ Leuven study team will take all possible measures to assure the quality and integrity of trial data and to 
safeguard the safety and wellbeing of trial participants, in accordance with the requirements set out in GCP 
and ISO:14155. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 34 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
8.4 Archiving  
As specified in ISO 14155:2020 section 8.6, the Sponsor and Investigator/Participating Site will maintain a 
record of the location(s) of all respective Essential Clinical Investigation Documents (including but not 
limited to Source Documents, completed and final (e)CRF and ISF/TMF). The Sponsor should ensure that 
the Investigator has control of and continuous access to the (e)CRF data reported to the Sponsor during 
the Investigation. 
The Investigator/Participating Site should have control of all Essential Documents and records generated 
by the Investigator/Participating Site before, during and following termination of the Investigation. 
The Sponsor and Investigator is responsible for archiving study specific documentation (such as but not 
limited to the CIP, any amendments thereto, the final Clinical Investigation Report (CIR) and the study 
database), according to ISO 14155:2020. Source data and site-specific study documents (such as but not 
limited to the original signed ICFs) will be archived by the Participating Site(s) according to local practice, 
and for a period of at least 10 years after the clinical Investigation with the device in question has ended, 
or, in the event that the device is subsequently placed on the market, at least 10 years after the last device 
has been placed on the market.1 Archived data may be held on electronic record, provided that media 
back-up exists, hard copies can be obtained, if required and measures are taken to prevent accidental or 
premature loss or destruction of data. Destruction of Essential Documents prior to, during or upon 
completion of the required archival period, will require written authorisation from the Sponsor. 
9 
Ethical and Regulatory Considerations 
9.1 Ethics Committee (EC) review & reports  
Before the start of the Investigation, this CIP and other related documents (e.g., ICF, advertisements, IB, 
etc.) will be submitted for review to the EC for authorization. The Investigation shall not commence until 
such approval have been obtained and until other relevant essential Investigation documents, such as duly 
signed contract agreements, evidence of adequate financing etc. are in place.. 
9.2 Peer review  
This CIP was peer reviewed by 3 independent experts. Peer review was conducted by expert referees to 
the professional and scientific standards expected for clinical studies.  
9.3 Regulatory Compliance 
The Investigation will be conducted in compliance with the principles outlined in the requirements for the 
conduct of clinical investigations in the EU, as provided for in the MDR, as applicable, and any subsequent 
amendments, as well as in compliance with ISO 14155:2020, other GxP guidelines, the most recent version 
of the Declaration of Helsinki, the Belgian law of May 7th, 2004 regarding experiments on the human person 
(as amended), or the Belgian law of December 22nd, 2020 concerning medical devices, as applicable, the 
Belgian royal decree of May 18th, 2021 concerning clinical investigations of medical devices,  and with the 
GDPR, the relevant Belgian laws implementing the GDPR, the Belgian Law of August 22nd, 2002 on patient 
rights, and all other applicable legal and regulatory requirements. 
9.4 CIP / GCP compliance 
The Investigation must be performed in accordance with the CIP, ISO 14155:2020, and applicable 
regulatory and country-specific requirements. ISO 14155:2020 is an international ethical and scientific 
quality standard for designing, conducting, recording and reporting clinical investigations that involve the 
participation of human participants. Compliance with this standard provides public assurance that the rights, 
safety and well-being of participants are protected, consistent with the principles that originated in the 
Declaration of Helsinki, and that the study data are credible, reliable and reproducible. 
The Investigator and study team acknowledge and agree that prospective, planned deviations or waivers to 
the CIP are not permitted under applicable regulations on clinical investigations. However, should there be 
 
1 According to UZ Leuven policy, Study documents will be archived for at least 25 years following termination of 
Investigation. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 35 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
an accidental CIP- deviation, such deviation shall be adequately documented in the source documents and 
on the relevant forms and reported to the CI and Sponsor. Deviations should also be reported to the EC 
as part of the EC’s continued review of the Investigation. Protocol deviations which are found to frequently 
recur, will require (immediate) action. The Investigator acknowledges that such recurring protocol 
deviations could potentially be classified as a major protocol deviation. 
The Investigator is expected to take any immediate action required to protect the safety of any participant 
included in the Investigation, even if this action represents a deviation from the CIP. In such cases, the 
Sponsor should be notified of this action and the EC should be informed according to local procedures and 
regulations. 
The Sponsor has performed a risk assessment to reduce anticipated risks with regards to the safety, 
wellbeing and rights of the participants as well as with regards to the reliability and robustness of the clinical 
Trial data. 
9.5 Data protection and participant confidentiality 
The Investigation will be conducted in compliance with the requirements of the GDPR, the relevant Belgian 
laws implementing the GDPR, including the Belgian Privacy Act of July 30th, 2018 on the protection of 
privacy in relation to the processing of personal data. Any collection, processing and disclosure of personal 
data, such as participant health and medical information is subject to compliance with the aforementioned 
personal data protection laws (cfr. Data Processing Annex (DPA) in Appendix). In case personal data is 
transferred outside the European Economic Area, safeguards will be taken to ensure that appropriate 
protection travels with the data in accordance with the GDPR (https://ec.europa.eu/info/law/law-
topic/data-protection/international-dimension-data-protection/rules-international-data-
transfers_en#documents) 
Any personal data shall be treated as confidential at all times including during collection, handling and use 
or processing, and the personal data (including in any electronic format) shall be stored securely at all times 
and with all technical and organizational security measures that would be necessary for compliance with 
EU and national data protection legislation (whichever is more stringent). The Sponsor shall take 
appropriate measures to ensure the security of all personal data and guard against unauthorized access 
thereto or disclosure thereof or loss or destruction while in its custody. 
9.6 Insurance 
The Sponsor, Participating Site and the Investigator shall have and maintain in full force and effect during 
the term of this Investigation, and for a reasonable period following termination of the Investigation, 
adequate insurance coverage for: (i) medical professional and/or medical malpractice liability, and (ii) general 
liability. 
For Belgian Participating Sites 
Article 32 of the Belgian Law concerning medical devices dated December 22nd, 2020 applies. Prior to the 
start of the Investigation, the Sponsor shall enter into an insurance contract in order to adequately cover 
participants from Belgian Participating Sites in accordance with Article 32 of the said law. 
 
For non-Belgian Participating Sites 
The Participating Site shall have and maintain in full force and effect during the term of this Investigation 
(and for a reasonable period following termination of the Investigation), adequate insurance coverage for 
other possible damages resulting from the Investigation at the Participating Site, as required by local law. 
Each such insurance coverage shall be in amounts appropriate to the conduct of the services of the 
Participating Site under this Investigation. The Participating Site and Sponsor shall be solely responsible 
for any deductible or self-insured retention under any such policies.  
9.7 Amendments 
As specified in ISO 14155:2020 section 7.5.1, amendments must not be implemented prior to EC review 
and/or approval, as applicable. Under emergency circumstances, deviations from the CIP to protect the 
rights, safety or well-being of human subjects may proceed without prior approval of the sponsor and the 
EC. Such deviations shall be documented and reported to EC as soon as possible. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 36 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
In accordance with the Belgian law of December 22nd, 2020 concerning medical devices, the Sponsor may 
develop a non-substantial amendment at any time during the Investigation. If a substantial amendment is 
introduced to the CIP, or the documents that supported the original application for the clinical 
Investigation, authorisation is needed, the Sponsor must submit a valid substantial amendment for approval 
to the EC. The EC will provide a response in accordance with timelines defined by applicable law. It is the 
Sponsor’s responsibility to assess whether an amendment is substantial or non-substantial. In absence of 
EUDAMED, local guidelines with regards to notifications and submissions to the concerned EC will be 
followed. 
Amendments to the Investigation are regarded as ‘substantial’ when they are likely to have a substantial 
impact on the safety, health or rights of the subjects or on the robustness or reliability of the clinical data 
generated by the investigation.  
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf  
9.8 Post-Study activities 
After completing the study, the acquired data will undergo initial analysis and subsequent publication. If 
this study confirms the anticipated advantages of CPAP-assisted RT, validation through larger-scale 
studies in independent RT centres is suggested before its integration into standard of care. Meanwhile, 
BC patients will retain access to current standard of care RT treatment.  
10 Research Registration, Dissemination of Results and 
Publication Policy 
The Declaration of Helsinki (most recent version) and European and Belgian regulations require that every 
research involving human participants be registered in a publicly accessible database before recruitment of 
the first participant. The CI is responsible for registering the Study.  
In addition, the CI will fulfil its ethical obligation to disseminate and make the research results publicly 
available. As such, the CI is accountable for the timeliness, completeness and accuracy of the reports. 
Researchers, authors, sponsors, editors and publishers must adhere to accepted guidelines for ethical 
reporting. Negative and inconclusive, as well as positive results, must be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in 
publication.  
Publications will be coordinated by the CI. Authorship to publications will be determined in accordance 
with the requirements published by the International Committee of Medical Journal Editors, and in 
accordance with the requirements of the respective medical journal. 
For multicentre Investigations, it is anticipated that the primary results of the overall Investigation shall be 
published in a multicentre publication. 
Participating Sites are not allowed to publish any subset data or results from the Investigation prior to such 
multicentre publication. 
Any publication by a Participating Site must be submitted to the Sponsor for review at least 30 calendar 
days prior to submission or disclosure. Sponsor shall have the right to delay the projected publication for 
a period of up to 3 months from the date of first submission to the Sponsor in order to enable the Sponsor 
to take steps to protect its intellectual property rights and know-how. 
11 Intellectual Property 
Any know how, inventions, methods, developments, innovations, discoveries and therapies, whether 
patentable or not, arising from the Investigation or made in the performance of the CIP (“Inventions”) shall 
vest in the Sponsor. If the Investigation is multicentric, the Participating Site, its employees and 
Investigator(s) shall promptly disclose to the Sponsor any such Inventions. The Sponsor and the 
Participating Site have expressly agreed that any and all study data as collected and prepared in the 
performance of the CIP shall be the sole property of the Sponsor, unless otherwise agreed in the 
Investigation agreement between the Sponsor and the Participating Site. 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 37 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
12 References 
1. Cancer burden statistics and trends across Europe | ECIS [Internet]. [cited 2023 Nov 3]. Available from: 
https://ecis.jrc.ec.europa.eu/ 
2. 
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin [Internet]. 2023 
Jan [cited 2023 Oct 16];73(1):17–48. Available from: https://pubmed.ncbi.nlm.nih.gov/36633525/ 
3. 
Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, et al. Effect of radiotherapy after 
breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of 
individual patient data for 10,801 women in 17 randomised trials. Lancet [Internet]. 2011 Nov 1 [cited 2023 
Oct 16];378(9804):1707–16. Available from: https://pubmed.ncbi.nlm.nih.gov/22019144/ 
4. 
McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, et al. Effect of radiotherapy after 
mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis 
of individual patient data for 8135 women in 22 randomised trials. Lancet [Internet]. 2014 Jan 1 [cited 2023 
Oct 16];383(9935):2127–35. Available from: https://pubmed.ncbi.nlm.nih.gov/24656685/ 
5. 
Maliko N, Stam MR, Boersma LJ, Vrancken Peeters MJTFD, Wouters MWJM, KleinJan E, et al. 
Transparency in quality of radiotherapy for breast cancer in the Netherlands: a national registration of 
radiotherapy-parameters. Radiat Oncol [Internet]. 2022 Dec 1 [cited 2023 Nov 8];17(1). Available from: 
https://pubmed.ncbi.nlm.nih.gov/35413924/ 
6. 
Bouillon K, Haddy N, Delaloge S, Garbay JR, Garsi JP, Brindel P, et al. Long-term cardiovascular 
mortality after radiotherapy for breast cancer. J Am Coll Cardiol [Internet]. 2011 Jan 25 [cited 2023 Oct 
9];57(4):445–52. Available from: https://pubmed.ncbi.nlm.nih.gov/21251585/ 
7. 
Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Brønnum D, et al. Risk of ischemic 
heart disease in women after radiotherapy for breast cancer. N Engl J Med [Internet]. 2013 Mar 14 [cited 
2023 Oct 9];368(11):987–98. Available from: https://pubmed.ncbi.nlm.nih.gov/23484825/ 
8. 
Errahmani MY, Locquet M, Spoor D, Jimenez G, Camilleri J, Bernier MO, et al. Association Between 
Cardiac Radiation Exposure and the Risk of Arrhythmia in Breast Cancer Patients Treated With 
Radiotherapy: A Case-Control Study. Front Oncol [Internet]. 2022 Jul 4 [cited 2023 Oct 13];12. Available 
from: https://pubmed.ncbi.nlm.nih.gov/35860581/ 
9. 
Marinko T. Pericardial disease after breast cancer radiotherapy. Radiol Oncol [Internet]. 2018 
[cited 2023 Oct 13];53(1):1–5. Available from: https://pubmed.ncbi.nlm.nih.gov/30840590/ 
10. 
Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ, Harris EE. Coronary artery findings after left-
sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol [Internet]. 
2007 Jul 20 [cited 2023 Oct 6];25(21):3031–7. Available from: https://pubmed.ncbi.nlm.nih.gov/17634481/ 
11. 
Milo MLH, Thorsen LBJ, Johnsen SP, Nielsen KM, Valentin JB, Alsner J, et al. Risk of coronary artery 
disease after adjuvant radiotherapy in 29,662 early breast cancer patients: A population-based Danish 
Breast Cancer Group study. Radiother Oncol [Internet]. 2021 Apr 1 [cited 2023 Oct 9];157:106–13. 
Available from: https://pubmed.ncbi.nlm.nih.gov/33515670/ 
12. 
Nilsson G, Holmberg L, Garmo H, Duvernoy O, Sjog̈ren I, Lagerqvist B, et al. Distribution of 
coronary artery stenosis after radiation for breast cancer. J Clin Oncol [Internet]. 2012 Feb 1 [cited 2023 
Oct 9];30(4):380–6. Available from: https://pubmed.ncbi.nlm.nih.gov/22203772/ 
13. 
Tagami T, Almahariq MF, Balanescu D V., Quinn TJ, Dilworth JT, Franklin BA, et al. Usefulness of 
Coronary Computed Tomographic Angiography to Evaluate Coronary Artery Disease in Radiotherapy-
Treated Breast Cancer Survivors. Am J Cardiol [Internet]. 2021 Mar 15 [cited 2023 Oct 9];143:14–20. 
Available from: https://pubmed.ncbi.nlm.nih.gov/33359199/ 
14. 
Lim YJ, Koh J. Heart-related mortality after postoperative breast irradiation in patients with ductal 
carcinoma in situ in the contemporary radiotherapy era. Sci Rep [Internet]. 2021 Dec 1 [cited 2023 Oct 
13];11(1). Available from: https://pubmed.ncbi.nlm.nih.gov/33531527/ 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 38 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
15. 
Roychoudhuri R, Robinson D, Putcha V, Cuzick J, Darby S, Møller H. Increased cardiovascular 
mortality more than fifteen years after radiotherapy for breast cancer: a population-based study. BMC 
Cancer [Internet]. 2007 [cited 2023 Oct 9];7. Available from: https://pubmed.ncbi.nlm.nih.gov/17224064/ 
16. 
Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer 
after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER 
cancer registries. Lancet Oncol [Internet]. 2005 Aug [cited 2023 Oct 9];6(8):557–65. Available from: 
https://pubmed.ncbi.nlm.nih.gov/16054566/ 
17. 
Jacobs JEJ, L’Hoyes W, Lauwens L, Yu YL, Brusselmans M, Weltens C, et al. Mortality and Major 
Adverse Cardiac Events in Patients With Breast Cancer Receiving Radiotherapy: The First Decade. J Am 
Heart 
Assoc 
[Internet]. 
2023 
Apr 
18 
[cited 
2023 
Oct 
5];12(8). 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/37026536/ 
18. 
Harris EER, Correa C, Hwang WT, Liao J, Litt HI, Ferrari VA, et al. Late cardiac mortality and 
morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol [Internet]. 
2006 Sep 1 [cited 2023 Oct 9];24(25):4100–6. Available from: https://pubmed.ncbi.nlm.nih.gov/16908933/ 
19. 
Laugaard Lorenzen E, Christian Rehammar J, Jensen MB, Ewertz M, Brink C. Radiation-induced risk 
of ischemic heart disease following breast cancer radiotherapy in Denmark, 1977-2005. Radiother Oncol 
[Internet]. 
2020 
Nov 
1 
[cited 
2023 
Oct 
9];152:103–10. 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/32858067/ 
20. 
Saiki H, Petersen IA, Scott CG, Bailey KR, Dunlay SM, Finley RR, et al. Risk of Heart Failure With 
Preserved Ejection Fraction in Older Women After Contemporary Radiotherapy for Breast Cancer. 
Circulation [Internet]. 2017 Apr 11 [cited 2023 Oct 9];135(15):1388–96. Available from: 
https://pubmed.ncbi.nlm.nih.gov/28132957/ 
21. 
Jacobse JN, Duane FK, Boekel NB, Schaapveld M, Hauptmann M, Hooning MJ, et al. Radiation 
Dose-Response for Risk of Myocardial Infarction in Breast Cancer Survivors. Int J Radiat Oncol Biol Phys 
[Internet]. 
2019 
Mar 
1 
[cited 
2023 
Oct 
9];103(3):595–604. 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/30385276/ 
22. 
Chung SY, Oh J, Chang JS, Shin J, Kim KH, Chun KH, et al. Risk of Cardiac Disease in Patients 
With Breast Cancer: Impact of Patient-Specific Factors and Individual Heart Dose From Three-Dimensional 
Radiation Therapy Planning. Int J Radiat Oncol Biol Phys [Internet]. 2021 Jun 1 [cited 2023 Oct 
9];110(2):473–81. Available from: https://pubmed.ncbi.nlm.nih.gov/33421556/ 
23. 
Van Den Bogaard VAB, Ta BDP, Van Der Schaaf A, Bouma AB, Middag AMH, Bantema-Joppe EJ, 
et al. Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast 
Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac 
Substructures. J Clin Oncol [Internet]. 2017 Apr 10 [cited 2023 Oct 6];35(11):1171–8. Available from: 
https://pubmed.ncbi.nlm.nih.gov/28095159/ 
24. 
Holm Milo ML, Slot Møller D, Bisballe Nyeng T, Hoffmann L, Dahl Nissen H, Jensen I, et al. 
Radiation dose to heart and cardiac substructures and risk of coronary artery disease in early breast cancer 
patients: A DBCG study based on modern radiation therapy techniques. Radiother Oncol [Internet]. 2023 
Mar 1 [cited 2023 Oct 6];180. Available from: https://pubmed.ncbi.nlm.nih.gov/36642388/ 
25. 
Jacob S, Camilleri J, Derreumaux S, Walker V, Lairez O, Lapeyre M, et al. Is mean heart dose a 
relevant surrogate parameter of left ventricle and coronary arteries exposure during breast cancer 
radiotherapy: a dosimetric evaluation based on individually-determined radiation dose (BACCARAT study). 
Radiat 
Oncol 
[Internet]. 
2019 
Feb 
7 
[cited 
2023 
Oct 
9];14(1). 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/30732640/ 
26. 
Taylor C, McGale P, Brønnum D, Correa C, Cutter D, Duane FK, et al. Cardiac Structure Injury 
After Radiotherapy for Breast Cancer: Cross-Sectional Study With Individual Patient Data. J Clin Oncol 
[Internet]. 
2018 
Aug 
1 
[cited 
2023 
Oct 
9];36(22):2288–96. 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/29791285/ 
27. 
van Velzen SGM, Gal R, Teske AJ, van der Leij F, van den Bongard DHJG, Viergever MA, et al. AI-
Based Radiation Dose Quantification for Estimation of Heart Disease Risk in Breast Cancer Survivors After 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 39 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
Radiation Therapy. Int J Radiat Oncol Biol Phys [Internet]. 2022 Mar 1 [cited 2023 Oct 9];112(3):621–32. 
Available from: https://pubmed.ncbi.nlm.nih.gov/34624460/ 
28. 
Finnegan R, Lorenzen EL, Dowling J, Jensen I, Berg M, Thomsen MS, et al. Analysis of cardiac 
substructure dose in a large, multi-centre danish breast cancer cohort (the DBCG HYPO trial): Trends 
and predictive modelling. Radiother Oncol [Internet]. 2020 Dec 1 [cited 2023 Oct 9];153:130–8. Available 
from: https://pubmed.ncbi.nlm.nih.gov/32916238/ 
29. 
Piroth MD, Baumann R, Budach W, Dunst J, Feyer P, Fietkau R, et al. Heart toxicity from breast 
cancer radiotherapy : Current findings, assessment, and prevention. Strahlenther Onkol [Internet]. 2019 
Jan 21 [cited 2023 Oct 9];195(1). Available from: https://pubmed.ncbi.nlm.nih.gov/30310926/ 
30. 
Meattini I, Poortmans PM, Aznar MC, Becherini C, Bonzano E, Cardinale D, et al. Association of 
Breast Cancer Irradiation With Cardiac Toxic Effects: A Narrative Review. JAMA Oncol [Internet]. 2021 
Jun 1 [cited 2023 Oct 13];7(6):924–32. Available from: https://pubmed.ncbi.nlm.nih.gov/33662107/ 
31. 
Gaasch A, Schönecker S, Simonetto C, Eidemüller M, Pazos M, Reitz D, et al. Heart sparing 
radiotherapy in breast cancer: the importance of baseline cardiac risks. Radiat Oncol [Internet]. 2020 May 
24 [cited 2023 Oct 13];15(1). Available from: https://pubmed.ncbi.nlm.nih.gov/32448164/ 
32. 
Hou PY, Hsieh CH, Wu LJ, Hsu CX, Kuo DY, Lu YF, et al. Modern Rotational Radiation Techniques 
with Volumetric Modulated Arc Therapy or Helical Tomotherapy for Optimal Sparing of the Lung and 
Heart in Left-Breast Cancer Radiotherapy Plus Regional Nodal Irradiation: A Comparative Dosimetric 
Analysis. Cancers (Basel) [Internet]. 2021 Oct 1 [cited 2023 Oct 13];13(20). Available from: 
https://pubmed.ncbi.nlm.nih.gov/34680189/ 
33. 
Zhang N, Liu X, Tao D, Wang Y, Wu Y, Zeng X. Optimal radiotherapy modality sparing for cardiac 
valves in left-sided breast cancer. Ann Transl Med [Internet]. 2023 Jan [cited 2023 Oct 13];11(2):46–46. 
Available from: https://pubmed.ncbi.nlm.nih.gov/36819565/ 
34. 
Milo MLH, Thorsen LBJ, Johnsen SP, Nielsen KM, Valentin JB, Alsner J, et al. Risk of coronary artery 
disease after adjuvant radiotherapy in 29,662 early breast cancer patients: A population-based Danish 
Breast Cancer Group study. Radiother Oncol [Internet]. 2021 Apr 1 [cited 2023 Oct 6];157:106–13. 
Available from: https://pubmed.ncbi.nlm.nih.gov/33515670/ 
35. 
Loap P, Tkatchenko N, Goudjil F, Ribeiro M, Baron B, Fourquet A, et al. Cardiac substructure 
exposure in breast radiotherapy: a comparison between intensity modulated proton therapy and 
volumetric modulated arc therapy. Acta Oncol [Internet]. 2021 [cited 2023 Oct 5];60(8):1038–44. Available 
from: https://pubmed.ncbi.nlm.nih.gov/33788665/ 
36. 
Li G, Xia YF, Huang YX, Okat D, Qiu B, Doyen J, et al. Cost-effectiveness of using protons for 
breast irradiation aiming at minimizing cardiotoxicity: A risk-stratification analysis. Front Med (Lausanne) 
[Internet]. 2022 Aug 25 [cited 2023 Oct 13];9. Available from: https://pubmed.ncbi.nlm.nih.gov/36091675/ 
37. 
Speleers BA, Belosi FM, De Gersem WR, Deseyne PR, Paelinck LM, Bolsi A, et al. Comparison of 
supine or prone crawl photon or proton breast and regional lymph node radiation therapy including the 
internal mammary chain. Sci Rep [Internet]. 2019 Dec 1 [cited 2023 Oct 6];9(1). Available from: 
https://pubmed.ncbi.nlm.nih.gov/30894606/ 
38. 
Smyth LM, Knight KA, Aarons YK, Wasiak J. The cardiac dose-sparing benefits of deep inspiration 
breath-hold in left breast irradiation: a systematic review. J Med Radiat Sci [Internet]. 2015 Mar 1 [cited 
2023 Oct 17];62(1):66–73. Available from: https://pubmed.ncbi.nlm.nih.gov/26229669/ 
39. 
Mulliez T, Veldeman L, Speleers B, Mahjoubi K, Remouchamps V, Van Greveling A, et al. Heart 
dose reduction by prone deep inspiration breath hold in left-sided breast irradiation. Radiother Oncol 
[Internet]. 
2015 
Jan 
1 
[cited 
2023 
Oct 
6];114(1):79–84. 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/25497557/ 
40. 
Speleers B, Schoepen M, Belosi F, Vakaet V, De Neve W, Deseyne P, et al. Effects of deep 
inspiration breath hold on prone photon or proton irradiation of breast and regional lymph nodes. Sci Rep 
[Internet]. 
2021 
Dec 
1 
[cited 
2023 
Oct 
24];11(1). 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/33727599/ 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 40 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
41. 
Mulliez T, Van de Velde J, Veldeman L, De Gersem W, Vercauteren T, Speleers B, et al. Deep 
inspiration breath hold in the prone position retracts the heart from the breast and internal mammary 
lymph node region. Radiother Oncol [Internet]. 2015 Dec 1 [cited 2023 Oct 24];117(3):473–6. Available 
from: https://pubmed.ncbi.nlm.nih.gov/26455452/ 
42. 
Goyal U, Saboda K, Roe D, Gonzalez VJ. Prone Positioning With Deep Inspiration Breath Hold for 
Left Breast Radiotherapy. Clin Breast Cancer [Internet]. 2021 Aug 1 [cited 2023 Oct 30];21(4):e295–301. 
Available from: https://pubmed.ncbi.nlm.nih.gov/33358601/ 
43. 
Vander Veken L, Van Ooteghem G, Razavi A, Da Rita Quaresma S, Longton E, Kirkove C, et al. 
Voluntary versus mechanically-induced deep inspiration breath-hold for left breast cancer: A randomized 
controlled trial. Radiother Oncol [Internet]. 2023 Jun 1 [cited 2023 Oct 6];183. Available from: 
https://pubmed.ncbi.nlm.nih.gov/36898583/ 
44. 
Reckhow J, Kaidar-Person O, Ben-David MA, Ostrovski A, Ilinsky D, Goldstein J, et al. Continuous 
positive airway pressure with deep inspiration breath hold in left-sided breast radiation therapy. Med Dosim 
[Internet]. 
2021 
Jun 
1 
[cited 
2023 
Oct 
6];46(2):127–31. 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/33020023/ 
45. 
Kil WJ, Lee IJ, Pham T, Cho IH. Practical Heart Sparing Breast Cancer Radiation Therapy Using 
Continuous Positive Airway Pressure (CPAP) in Resource-Limited Radiation Oncology Clinics. Am J Clin 
Oncol 
[Internet]. 
2019 
Oct 
1 
[cited 
2023 
Oct 
6];42(10):797–801. 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/31503062/ 
46. 
Allen AM, Ceder YK, Shochat T, Fenig E, Popovtzer A, Bragilofsky D, et al. CPAP (Continuous 
Positive Airway Pressure) is an effective and stable solution for heart sparing radiotherapy of left sided 
breast cancer. Radiat Oncol [Internet]. 2020 Mar 6 [cited 2023 Oct 6];15(1). Available from: 
https://pubmed.ncbi.nlm.nih.gov/32143658/ 
47. 
Kil WJ, Pham T, Hossain S, Casaigne J, Jones K, Khalil M. The impact of continuous positive airway 
pressure on radiation dose to heart and lung during left-sided postmastectomy radiotherapy when deep 
inspiration breath hold technique is not applicable: a case report. Radiat Oncol J [Internet]. 2018 Mar 1 
[cited 2023 Oct 24];36(1):79–84. Available from: https://pubmed.ncbi.nlm.nih.gov/29506325/ 
48. 
Ko H, Chang JS, Moon JY, Lee WH, Shah C, Shim JS, et al. Dosimetric Comparison of Radiation 
Techniques for Comprehensive Regional Nodal Radiation Therapy for Left-Sided Breast Cancer: A 
Treatment Planning Study. Front Oncol [Internet]. 2021 Apr 12 [cited 2023 Oct 30];11. Available from: 
https://pubmed.ncbi.nlm.nih.gov/33912459/ 
49. 
Choi MS, Chang JS, Park RH, Kwon YJ, Kim YB, Moon JY, et al. Heart-Sparing Capability and 
Positional Reproducibility of Continuous Positive Airway Pressure in Left-Sided Breast Radiation Therapy. 
Pract Radiat Oncol [Internet]. 2022 Sep 1 [cited 2023 Oct 30];12(5):e368–75. Available from: 
https://pubmed.ncbi.nlm.nih.gov/35151923/ 
50. 
Goldstein JD, Lawrence YR, Appel S, Landau E, Ben-David MA, Rabin T, et al. Continuous Positive 
Airway Pressure for Motion Management in Stereotactic Body Radiation Therapy to the Lung: A Controlled 
Pilot Study. Int J Radiat Oncol Biol Phys [Internet]. 2015 Oct 1 [cited 2023 Oct 31];93(2):391–9. Available 
from: https://pubmed.ncbi.nlm.nih.gov/26264628/ 
51. 
Jacobson G, Lawrence YR, Appel S, Weiss I, Ben Ayun M, Akiva Ben-David M, et al. Benefits of 
Continuous Positive Airway Pressure (CPAP) During Radiation Therapy: A Prospective Trial. Int J Radiat 
Oncol Biol Phys [Internet]. 2021 Aug 1 [cited 2023 Oct 6];110(5):1466–72. Available from: 
https://pubmed.ncbi.nlm.nih.gov/33965269/ 
52. 
Liang E, Dolan JL, Morris ED, Vono J, Bazan LF, Lu M, et al. Application of Continuous Positive 
Airway Pressure for Thoracic Respiratory Motion Management: An Assessment in a Magnetic Resonance 
Imaging-Guided Radiation Therapy Environment. Adv Radiat Oncol [Internet]. 2022 May 1 [cited 2023 Oct 
6];7(3). Available from: https://pubmed.ncbi.nlm.nih.gov/35198838/ 
53. 
Di Perri D, Colot A, Delor A, Ghoul R, Janssens G, Lacroix V, et al. Effect of continuous positive 
airway pressure administration during lung stereotactic ablative radiotherapy: a comparative planning study. 
Strahlenther Onkol [Internet]. 2018 Jun 1 [cited 2023 Oct 6];194(6):591–9. Available from: 
https://pubmed.ncbi.nlm.nih.gov/29450589/> 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 41 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
Appendices 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 42 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
13 Appendix 1: Clinical Investigation Plan history 
 
Original CTP version: 
1.0 dated 11/04/2025 
 
Amendment #1: 
<1.3> dated 11/04/2025 
Modifications made / Reason for amendment: 
Secondary endpoints 
Addition of comparison of dosimetrical differences on cardiac substructures, as well as addition of comparison of normal tissue 
complication probabilities between standard and CPAP-assisted RT. Furthermore accuracy and reproducibility will be assessed in terms 
of surface, OAR and target volume changes on surface scannings and CBCT parameters.  
In -and exclusion criteria  Post-mastectomy irradiation, electron boost delivery (for superficial tumor beds) and nodal boosts were excluded to improve 
comparability between groups and ensure a more homogeneous patient population. 
Identification and description 
of the IMD 
 The positive airway pressure will be increased in two stages, rather than three, from 7 cmH2O to 15 cmH2O over 10 minutes, as the 
CPAP device can be programmed to automatically deliver this pressure adjustment. This approach minimizes the need for manual 
intervention by the nurses and ensures accurate implementation. 
< CIP section reference> 
<describe modifications made> 
 
Amendment #2: 
<CIP version number> dated 11/04/2025 
Modifications made / Reason for amendment: 
Inclusion criteria 
Broadening of the inclusion criteria from 50-70 years old to 40-70 years old 
< CIP section reference> 
<describe modifications made> 
< CIP section reference> 
<describe modifications made> 
< CIP section reference> 
<describe modifications made> 
 
Amendment #3: 
<1.5> dated 11/04/2025 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 43 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
Modifications made / Reason for amendment: 
Inclusion criteria 
Addition of a patient subgroup: 70-80 year old left-sided breast cancer patients with an indication of regional nodal irradiation 
< CIP section reference> 
<describe modifications made> 
< CIP section reference> 
<describe modifications made> 
< CIP section reference> 
<describe modifications made> 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023  
Page 44 of 45                             Protocol template for clinical 
investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
14 Appendix 2: Patient Questionnaires 
  
Tolerance of CPAP-assisted RT for right-sided patients 
Likert scale 
Strongly 
disagree 
Disagree 
Neutral 
Agree 
Strongly 
agree 
1. The CPAP mask fits perfectly under my 
nose and mouth. 
 
 
 
 
 
2. The CPAP mask is straining too hard on 
my face. 
 
 
 
 
 
3. Wearing the CPAP mask is comfortable 
for me. 
 
 
 
 
 
4. The 15 minutes preparation before the 
simulation / irradiation are beneficial to get 
used to breathing with the mask. 
 
 
 
 
 
5. The speed at which the air pressure 
increases during the preparation is 
tolerable. 
 
 
 
 
 
6. In general, using the CPAP mask for 
breathing is well tolerated. 
 
 
 
 
 
7. With each use, breathing through the 
CPAP mask becomes progressively easier. 
 
 
 
 
 
8. The setup for each radiation session 
with the CPAP device proceeds smoothly. 
 
 
 
 
 
 
Tolerance of CPAP-assisted RT for left-sided patients 
Likert scale 
Strongly 
disagree 
Disagree 
Neutral 
Agree 
Strongly 
agree 
1. The CPAP mask fits perfectly under my 
nose and mouth. 
 
 
 
 
 
2. The CPAP mask is straining too hard on 
my face. 
 
 
 
 
 
3. Wearing the CPAP mask is comfortable 
for me. 
 
 
 
 
 
4. The 15 minutes preparation before the 
simulation / irradiation are beneficial to get 
used to breathing with the mask. 
 
 
 
 
 
5. The speed at which the air pressure 
increases during the preparation is 
tolerable. 
 
 
 
 
 
6. In general, using the CPAP mask for 
breathing is well tolerated. 
 
 
 
 
 
7. With each use, breathing through the 
CPAP mask becomes progressively easier. 
 
 
 
 
 
8. The setup for each radiation session 
with the CPAP device proceeds smoothly. 
 
 
 
 
 
9. Performing Deep Inspiration Breath 
Hold with the CPAP-mask is tolerable. 
 
 
 
 
 
 
 
 
 

UZ Leuven – KU Leuven 
 
 
Protocol: CPAP-assisted Radiotherapy in Breast Cancer 
Internal Ref.: S68702 
 
 
Version: 1.5_11April2025 
 
CTC GEN-TMP-004-2.0_25Oct2023 
Page 45 of 45                              Protocol template for clinical investigation 
                                                                                   Confidential & Proprietary                                   with IMD, used within CE-label 
15 Appendix 3: [Funding - Myny-Vanderpoorten Fonds and AIR 
LIQUIDE MEDICAL nv - VitalAire Grant] 
Financial support for this study is provided by the Myny-Vanderpoorten Fonds. Professor Caroline 
Weltens serves as the administrator of this fund.  
AIR LIQUIDE MEDICAL nv - VitalAire offered a Grant for acquisition of essential CPAP equipment 
solely.