PRospective Registry of Esophageal Motility
Conditions: Esophageal Diseases, Achalasia, Eosinophilic Esophagitis, Motility Disorder, GERD
Sponsor: IRCCS San Raffaele

 
 
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Prot. PREM vers 1.0 14-10-2025 
 
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CLINICAL STUDY PROTOCOL 
 
Study Code: PREM 
 
Title: PRospective registry of Esophageal Motility  
 
Principal Investigator: Dr. Barchi Alberto 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CLINICAL STUDY PROTOCOL 
Title: PRospective registry of Esophageal Motility  
 
DISCLAIMER 
This material is strictly private, confidential and property of the Sponsor. Its contents must not 
be disclosed or used except as authorized in writing by the Sponsor. 
 
 
 
 
Study Identifier 
PREM 
 
RSO number 
NA 
Other Protocol Codes 
NA 
Version 
Ver 1.1 
Date 
12-02-2026 
 
 
Sponsor 
IRCCS San Raffaele Hospital 
Co-Sponsor 
NA 
Authorized Sponsor 
Representative 
Prof. Silvio Danese 
U.O. Gastroenterology and Gastrointestinal Endoscopy 
Authorized Co-Sponsor 
Representative 
NA 
Funding Source(s) 
NA 
Principal Investigator 
Dr. Barchi Alberto 
Esophageal Motility and Eosinophilic GI disorders Unit, U.O. 
Gastroenterology and Gastrointestinal Endoscopy, San Raffaele 
Hospital 

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VERSION HISTORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
version n. 
Reason of changes 
Date issued 
1.0 
First Version submitted to the Ethics Committee (EC) 
12-11-2025 
1.1 
Integrations to EC 
12-02-2026 

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PROTOCOL SIGNATURE PAGE 
 
Study Title: “PRospective registry of Esophageal Motility” 
Study Identifier: PREM 
Protocol Version and Date: Ver 1.1 12-02-2026 
 
The undersigned has read and understood all the aspects of the protocol detailed within this 
document and agrees to supervise and conduct the study in accordance with the protocol, the 

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Declaration of Helsinki, Guideline for Good Clinical Practice ICH E6 (R2), and all applicable 
regulatory requirements. 
 
 
Dr. Barchi Alberto 
 
 
 
 
 
U.O. Gastroenterology and 
Gastrointestinal Endoscopy, 
IRCCS San Raffaele Hospital 
 
October 
14TH, 
2025 
Principal Investigator 
Name 
 
 
Signature 
 
Affiliation 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Silvio Danese, Prof. 
 
 
 
 
U.O. Gastroenterology 
and Gastrointestinal 
Endoscopy, IRCCS San 
Raffaele Hospital 
 
October 14TH , 
2025 
Authorized Sponsor 
Representative 
Name 
 
 
Signature 
 
Affiliation 
 
Date 

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TABLE OF CONTENTS 
1. 
KEY STUDY CONTACTS ................................................................................................................................................................... 8 
2. 
SYNOPSIS ................................................................................................................................................................................................ 8 
3. 
ABBREVIATIONS AND DEFINITIONS ......................................................................................................................................... 11 
3.1. 
Abbreviations ..................................................................................................................................................................... 11 
3.2. 
Definitions.............................................................................................................................................................................. 11 
4. 
BACKGROUND AND RATIONALE .............................................................................................................................................. 12 
5. 
OBJECTIVES AND ENDPOINTS ................................................................................................................................................... 12 
6. 
STUDY DESIGN .................................................................................................................................................................................... 13 
6.1. 
Study duration .................................................................................................................................................................. 13 
7. 
STUDY POPULATION ........................................................................................................................................................................ 13 
7.1. 
Study Participants.......................................................................................................................................................... 13 
7.2. 
Inclusion Criteria ............................................................................................................................................................. 13 
7.3. 
Exclusion Criteria ............................................................................................................................................................ 14 
7.4. 
Screening Failures ......................................................................................................................................................... 14 
8. 
STUDY OBJECT  .................................................................................................................................................................................. 14 
8.1. 
Study object description........................................................................................................................................... 14 
9. 
STUDY PROCEDURES ....................................................................................................................................................................... 15 
9.1. 
Informed Consent .......................................................................................................................................................... 16 
9.2. 
Subject Recruitment and Screening ............................................................................................................... 16 
9.3. 
Subject Identification .................................................................................................................................................. 16 
9.4. 
Baseline Assessments ................................................................................................................................................ 16 
9.5. 
Visits and Follow Up ...................................................................................................................................................... 17 
9.6. 
Definition of End of Study ......................................................................................................................................... 17 
9.7. 
Premature termination or suspension of a study ................................................................................. 17 
10. 
DISCONTINUATION AND WITHDRAWAL ........................................................................................................................ 17 
11. 
SAMPLE HANDLING ..................................................................................................................................................................... 17 
12. 
PATIENT SAFETY ............................................................................................................................................................................ 17 
13. 
DATA MANAGEMENT ................................................................................................................................................................. 17 
13.1. 
Definition of source data and source documents ............................................................................... 17 

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13.2. 
Documentation of data in Case Report Forms (CRFs) ...................................................................... 17 
13.3. 
Data Recording and Record Keeping ............................................................................................................. 18 
13.4. 
Data Protection ................................................................................................................................................................ 18 
14. 
STATISTICS ....................................................................................................................................................................................... 18 
14.1. 
Description of Statistical Methods .................................................................................................................... 18 
14.2. 
Sample Size Determination .................................................................................................................................... 18 
14.3. 
Analysis Populations .................................................................................................................................................... 18 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................................................................ 19 
15.1. 
Responsibilities of the Investigator(s) ............................................................................................................ 19 
15.2. 
Ethics Committee (EC) Approvals..................................................................................................................... 19 
15.3. 
Other Ethical Considerations ................................................................................................................................ 19 
16. 
GENDER MEDICINE IN RESEARCH PROTOCOL ........................................................................................................... 19 
17. 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................................................... 20 
17.1. 
Deviation from study protocol ............................................................................................................................. 21 
17.2. 
Surveillance for observational studies with additional procedure .......................................... 21 
18. 
FINANCE AND INSURANCE ..................................................................................................................................................... 21 
18.1. 
Funding .................................................................................................................................................................................. 21 
18.2. 
Patient Insurance ........................................................................................................................................................... 21 
19. 
END OF CLINICAL STUDY ......................................................................................................................................................... 21 
19.1. 
Summary of the results of the clinical study............................................................................................. 21 
20. 
INTELLECTUAL PROPERTY ........................................................................................................................................................ 21 
21. 
PUBLICATION POLICY ............................................................................................................................................................... 22 
22. 
REFERENCES ................................................................................................................................................................................... 22 
23. 
APPENDIX A:  AMENDMENT HISTORY .............................................................................................................................. 23 
24. 
APPENDIX B:  LIST OF CLINICAL SERVICES / LABORATORIES ........................................................................... 23 
25. 
APPENDIX C:  LIST OF ENROLLING SITES ........................................................................................................................ 23 
 
 
 

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1. 
KEY STUDY CONTACTS 
 
Sponsor 
Ospedale San Raffaele 
Via Olgettina, 60 
20132 – Milano, Italy 
Co-Sponsor 
NA 
Authorized Sponsor 
Representative 
Prof. Silvio Danese, PhD 
Director U.O. Gastroenterology and Gastrointestinal 
Endoscopy, IRCCS San Raffaele Hospital  
Via Olgettina, 60 – 20132 – Milano, Italy 
Tel 02-26430000 
Email: danese.silvio@hsr.it 
Authorized  
Co-Sponsor 
Representative 
NA 
Principal Investigator 
Alberto Barchi, MD 
U.O. Gastroenterology and Gastrointestinal Endoscopy, 
IRCCS San Raffaele Hospital  
Via Olgettina, 60 – 20132 – Milano, Italy 
Tel 02-26430000 
Email: barchi.alberto@hsr.it 
Study Clinical Unit  
Esophageal Motility and Eosinophilic GI disorders Unit, 
02.26432808, eosin@hsr.it 
Participant Clinical 
Units  
Alberto Barchi MD, barchi.alberto@hsr.it, 3348630784 
Edoardo Vespa MD, vespa.edoardo@hsr.it, 02.26432808 
Sandro Passaretti MD, Passaretti.sandro@hsr.it, 02.26432808 
Funding source(s) 
NA   
Clinical Trial Center 
Email: ctc.firstcontact@hsr.it; ctc.trialstartup@hsr.it; 
ctc.datamanagement@hsr.it; ctc.quality@hsr.it 
 
2. SYNOPSIS 
 
Study Identifier 
PREM 
Study Title 
PRospective registry of Esophageal Motility 
Protocol Version and Date 
Vers 1.1 12/02/2026 

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Sponsor  
IRCCS Ospedale San Raffaele 
Co-Sponsor  
NA 
Funding Source(s) 
NA 
Principal Investigator 
Dr. Alberto Barchi  
Study Description 
PRospective registry of Esophageal Motility 
Study Design 
Prospective  
Primary Objective 
To register clinical, endoscopic, 
physiologic, radiographic data 
on patients referred for 
esophageal 
motility/inflammatory 
disorders or reflux/obstructive 
esophageal symptoms at San 
Raffaele Hospital 
Primary Endpoint 
NA 
 Time point(s)  
NA 
 
Secondary Objectives 
NA 
Secondary Endpoints 
NA 
 
Time point(s)  
NA 
Exploratory Objectives 
NA 
Other 
NA 
 
Time point(s)  
NA 
 
Study Population 
Patients with reflux (typical or atypical) or obstructive 
esophageal symptoms on or off therapy, Barrett 
Esophagus patients, pts with eosinophilic esophagitis, 
gastroparesis, patients with primary motility esophageal 
disorders, patients undergone to foregut GI surgery 
procedures (esophageal myotomies, anti-reflux surgeries, 
bariatric procedures, gastroparesis surgery), Age > 18 
years 
Inclusion Criteria 
Age > 18 years, Patients with reflux (typical or atypical) or 
obstructive esophageal symptoms on or off therapy, 
Barrett Esophagus patients, pts with eosinophilic 
esophagitis, gastroparesis, patients with primary motility 
esophageal disorders, patients undergone to foregut GI 

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surgery procedures (esophageal myotomies, anti-reflux 
surgeries, bariatric procedures, gastroparesis surgery), 
Age > 18 years 
Exclusion Criteria 
Age < 18 years 
STUDY OBJECT: integrating and analyzing physiopathologic outcomes with clinical, 
demographic, endoscopic and radiographic data 
DRUG: No specific drug is evaluated in this protocol, aside the clinical practice 
Additional procedure NA 
MEDICAL DEVICE: NA 
PROCEDURE: NA 
Sample Size  
Every patients reaching out Digestive Physiopathology 
division of Gastroenterology and Digestive Endoscopy of 
San Raffaele Hospital 
Statistical Design 
NA 
Duration of the Study 
Duration of enrollment: 5 years 
Duration of subject participation: 10 years 
Duration of total study period: 15years 

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3. ABBREVIATIONS AND DEFINITIONS 
3.1. Abbreviations 
CIOMS 
Council for International Organization of Medical Science 
CRF 
Case Report Form 
CRO  
Contract Research Organization 
CTC 
Clinical Trial Center 
DPIA 
Data Protection Impact Assessment 
EC 
Ethics Committee 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
LVLP 
Last Visit of Last Patient 
MedDRA 
Medical Dictionary for Regulatory Activities 
OSR 
Ospedale San Raffaele 
PI 
Principal Investigator 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
EoE 
Eosinophilic Esophagitis 
 
 
3.2. Definitions 
 
 
 
 
 
 
 
 
 
 
 
 

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4. BACKGROUND AND RATIONALE 
Digestive physiopathology is a branch of gastroenterology aiming to study patients with upper 
GI 
symptoms, 
mainly 
gastro-esophageal, 
potentially 
indicating 
the 
presence 
of 
Gastroesophageal Reflux Disease (GERD)/Barrett Esophagus (BE) or obstructive esophageal 
motility disorders (achalasia being the most relevant), but including also other primary motility 
disorders such as Esophgago-Gastric Junction Outflow Obstruction (EGJOO), Hypercontractile 
Esophagus (HE), Distal Esophageal Spasm (DES) and other minor disorders. Physiopathological 
testing encompasses High-Resolution Manometry (HRM), 24-H esophageal pH-impedance 
testing, Functional Lumen Imaging Probe (FLIP) assessment. All these tests are designed to 
provide a clear phenotyping of esophago-gastric disorders related to reflux or obstructive 
esophageal symptoms, either in naïve patients, as well as after foregut surgery (particularly 
anti-reflux surgery, achalasia/primary motility disorders treatment).   
5. OBJECTIVES AND ENDPOINTS 
Primary objective of the study is to create a prospective/retrospective registry of all patients 
with > 18 years of age referring to the Digestive Physiopathology division of San Raffaele Hospital, 
in order to register clinical, endoscopic, radiologic data of these patients integrating them with 
physiopatology outcomes in order to shape disease management and treatment work-up, 
also in long-term follow-up of these patients. 
Primary endpoints are the Integration and analysis of association/correlation of physiologic 
with endoscopic, radiologic and clinical data. 
 
Objectives 
Endpoints 
Time point(s)  
Primary Objective 
To register clinical, endoscopic, 
physiologic, radiographic data 
on patients referred for 
esophageal 
motility/inflammatory disorders 
or reflux/obstructive 
esophageal symptoms at San 
Raffaele Hospital 
Primary Endpoint 
NA 
 Time point(s)  
NA 
Secondary Objectives 
NA 
 
Secondary Endpoints 
NA  
NA 
Exploratory Objectives 
NA  
Other 
NA  
 
NA  

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6. STUDY DESIGN 
PREM is a prospective registry recruiting patients retrospectively enrolled  aiming to include all 
clinical, endoscopic, radiological integrating them with physiopathology data of all patients 
referred to Digestive Physiopathology Division of San Raffaele Hospital, with the purpose of 
extracting data for prospective and retrospective analyses, in order to improve patients’ 
management and clinical research and empower diagnostic and therapeutic work-up 
 
6.1. 
Study duration  
Duration of enrollment: 5 years 
Duration of treatment: 10 years 
Duration of total follow-up: 10 years 
Duration of total study period: 15 years 
 
7. STUDY POPULATION 
7.1. Study Participants 
Patients with reflux (typical or atypical) or obstructive esophageal symptoms on or off therapy, 
Barrett Esophagus patients, pts with eosinophilic esophagitis, gastroparesis, patients with 
primary motility esophageal disorders, patients undergone to foregut GI surgery procedures 
(esophageal myotomies, anti-reflux surgeries, bariatric procedures, gastroparesis surgery), 
Age > 18 years 
7.2. Inclusion Criteria 
Inclusion criteria to be included in the registry are: 
1. 
Participant is willing and able to give informed consent for participation in the study.   
2. The procedures are the standard of care for the patient or the participant is taking the 
medicinal product according to clinical practice  
3. Aged > 18 years. 
4. Any typical (heartburn or regurgitation) or atypical reflux symptom (Laryngeal 
Cough, laryngitis, sub-glottic stenosis, globus, laryngeal cancer, vocal cord granuloma, vocal 
cord irritation, vocal cord polyps and post-nasal drip; Oropharyngeal: Dental erosion, 
pharyngitis, sore or burning throat, gingivitis and halitosis; Ears and sinuses: Earaches, otitis 
media and sinusitis; Pulmonary: Chronic bronchitis, pneumonia, aspiration, bronchiectasis, 
asthma and idiopathic pulmonary fibrosis; Cardiac: Arrhythmia, angina and myocardial 
infarction; Sleep: Sleep apnoea, sleep deprivation, insomnia, snoring, nightmare and sleep 
disturbance), but also any obstructive esophageal symptom potentially reflecting a primary 
Commentato [RT1]: Specificare che saranno inclusi solo 
pazienti arruolati retrospettivamente  

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or secondary motility disorder (oropharyngeal or esophageal dysphagia, chest pain, bolus 
impaction). Every patient with a diagnosis of esophageal inflammatory disorder (including 
EoE and others) or systemic rheumatological condition (scleroderma, systemic sclerosis, 
lichen planus and others), every patient previously undergone to any anti-reflux surgery, 
bariatric surgery, endoscopic or surgical esophageal or gastric myotomy (also for 
gastroparesis) may be included.   
5. Patients must be referred to the Digestive Physiopathology Unit of IRCCS San Raffaele 
Hospital for motility tests 
 
7.3. Exclusion Criteria 
1. 
Age < 18 years 
2. Not willing to provide informed consent to the inclusion in the registry 
7.4. Screening Failures 
NA 
8. STUDY OBJECT  
Integrating and analyzing physiopathologic outcomes with clinical, demographic, endoscopic 
and radiographic data registry 
 
8.1. Study object description 
 
NA

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9. STUDY PROCEDURES 
 
 
Enrollment 
Follow-Up 
Visits 
Procedures 
Day 
 
T0 
T1 (if 
available) 
Informed consent 
X 
X 
Demographics 
X 
X 
Medical history 
X 
X 
Eligibility assessment 
X 
X 
Physical examination 
(including height and weight) 
X 
X 
Radiologic/Imaging 
assessment 
x 
x 
Digestive Physiopathology 
tests 
x 
x 
Questionnaires (GERDQ, 
GERD-HRQL, RSI,ECKARDT, 
BED-Q, GSS)  
X 
X 

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9.1. Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
EC-approved, and the participant will be asked to read and review the document. The 
investigator (according to applicable regulatory requirements) or a person designated by the 
investigator, and under the investigator's responsibility, will explain the research study to the 
participant and answer any questions that may arise. A verbal explanation will be provided in 
terms suited to the participant’s comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their family or surrogates or 
think about it prior to agreeing to participate. The participant MUST sign the informed consent 
document prior to any procedures being done specifically for the study/any data is collected. 
Participants must be informed that participation is voluntary and that they may withdraw from 
the study at any time, without prejudice. A copy of the informed consent document will be given 
to the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the 
participant undergoes any study-specific procedure/ any data is collected. The rights and 
welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
9.2. Subject Recruitment and Screening  
Every patient as per clinical routine in our hospital will undergo a general outpatient 
consultation before the physiopathology tests and procedures, with eligibility criteria screening 
for the enrollment in the registry and the signature of the IC. 
9.3. Subject Identification 
Starting from the signature of the informed consent by the patient or patient’s legal tutor, the 
subjects is considered enrolled in the clinical study.  
A subject identification code will be assigned consecutively (i.e.: PREM_HSR_001) 
9.4. Baseline Assessments 
Baseline assessment is made during an outpatient consultation as per clinical routine and 
international guidelines with the collection of demographics, clinical, radiologic, endoscopic 
data and previous details on medical and treatment history, and of course overall assessment 
of the indication for the physiopathology procedures. Clinical questionnaires used are already 
used in clinical practice. 
 
Commentato [RT2]: Specificare che verranno eseguiti I 
questionari e che gli stessi sono già utilizzati da pratica clinica e 
inserire nella bibliografia la relativa validazione in italiano. 
Commentato [AB3R2]: Già inserite le relative bibliografie 
più avanti 

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9.5. Visits and Follow Up 
Follow-up visits and other follow-up physiopathology procedures could be undertaken if 
deemed necessary according to clinical decision-making. Therefore every patient is expected 
to attend the T0 assessment, while follow-up is optional. 
9.6. Definition of End of Study 
The study will end at the end of the last patient’s follow-up period 
9.7. Premature termination or suspension of a study 
NA 
10. DISCONTINUATION AND WITHDRAWAL 
Participants are free to withdraw from participation in the study at any time upon request. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
clinical records and in Case Report Form (CRF). Subjects who sign the informed consent form 
and subsequently withdraw, or are withdrawn or discontinued from the study, will not be 
replaced. 
 
11. SAMPLE HANDLING 
NA 
 
12. PATIENT SAFETY 
NA 
13. DATA MANAGEMENT   
Not performed by a CRO 
13.1. Definition of source data and source documents  
All parameters asked for in the case report form (CRF) should be documented in the source 
documents. 
 
13.2. Documentation of data in Case Report Forms (CRFs)  
All relevant data collected during the study for all of the patients enrolled in the study shall be 
entered in the CRF by the principal investigator or someone authorized by the investigator in a 
timely manner (as soon as possible after the information is collected) to ensure that they are 

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clear and legible. The physician shall confirm the completeness, correctness, plausibility, and 
compliance with the ICH guidelines and the institutional SOPs of the data by dated signature. 
An explanation must be provided for any and all missing data. The entries shall be made with 
black ballpoint pen. 
The properly filled in CRF will remain in the study site. 
For the study will be used an eCRF (REDcap) and a copy of all pages will be conserved in the 
study site. 
REDcap is a clinical electronic data capture system specifically developed around HIPAA-
Security guidelines; more information on the consortium and system security is available at 
https.//www.projectredcap.org/. 
13.3. Data Recording and Record Keeping 
The investigator shall arrange for the retention of Essential Documents for the Conduct of a 
Clinical study (e.g., patient files, other source data, and the Trial Master File/Investigator Site 
File) after the completion or discontinuation of the study according to institutional procedures 
and applicable laws. 
13.4. 
Data Protection  
The Investigator (or the Center that will receive the data) undertakes to: 
- use the data only for the purposes of the foreseen analyses and within the limits established 
by the study and approved by the competent EC; 
-  store data in a secure network system; 
-  prohibit unauthorised third parties from accessing, even partially, data. 
- guarantees to limit access to and processing of data only to its employees and collaborators 
who, upon appointment as an authorized person: 
1. need to process the data in order to carry out their work in relation to the study; 
2. have undertaken to maintain the confidentiality of the Data and of any information 
deriving from it or that is communicated to them. 
14. STATISTICS 
NA 
14.1. Description of Statistical Methods 
NA 
14.2. 
Sample Size Determination 
NA 
14.3. 
Analysis Populations  

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NA 
14.4 Statistical Design 
No statistical design needed. No sample size calculation was needed since the prospective 
registry nature of the study but nonetheless 10,000 patients will be enrolled 
15. ETHICAL AND REGULATORY CONSIDERATIONS 
This clinical study will be conducted in accordance with the principles laid down by the 18th 
World Medical Assembly (Helsinki, 1964) and all applicable amendments established by the 
World Medical Assemblies, and the ICH guidelines for Good Clinical Practice.  
This clinical study will be conducted in compliance with all international laws and regulations; 
national laws and regulations of the country in which the clinical study is performed; as well as 
any other applicable guidelines. 
15.1. Responsibilities of the Investigator(s) 
The Investigator(s) undertake(s) the responsibility to perform the study in accordance with this 
Protocol, Good Clinical Practice, and the applicable regulatory requirements. The Investigator 
is required to ensure compliance with the investigational product schedule, visits schedule, and 
procedures required by the protocol. The Investigator agrees to provide all information 
requested in the Case Report Form (CRF) in an accurate and legible manner. The investigator 
may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to study subjects without prior EC approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and, if appropriate, the proposed 
protocol amendment(s) should be submitted. The investigator must have available an 
adequate number of qualified staff and adequate facilities for the foreseen duration of the 
study to conduct the study properly and safely. 
15.2. 
Ethics Committee (EC) Approvals  
This clinical study protocol as well as the Informed Consent are to be submitted to the 
appropriate Ethics Committee, and it is mandatory to obtain the written and dated approval, 
signed by the chairman with Ethics Committee(s) composition. 
The clinical study the documents reviewed, the list of voting members and their qualifications, 
and the date of the review should be clearly stated on the written Ethics Committee approval. 
15.3. 
Other Ethical Considerations 
NA 
16.  GENDER MEDICINE IN RESEARCH PROTOCOL 

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The concept of Gender Medicine relies on the idea that health differences between men and 
women are not only due to their biological attributes and reproductive functions (as defined by 
biological sex), but also to environmental, social, cultural, and relational factors (as defined by 
the term gender). According to the Italian Plan for Gender Medicine, accounting for sex and 
gender in health research is a necessary tool to achieve excellent, rigorous, and reproducible 
results for the benefit of everybody. When evaluating and treating diseases, in addition to 
biological sex other parameters such as age, gender, ethnicity, cultural background, 
religion, sexual orientation, socio-economic status, need to be considered to optimize 
prevention, diagnosis, therapy and care appropriately. Under this perspective special attention 
needs to be paid to critical health issues relative to transgender and intersexual people.  
During the development of research questions, investigators should use the correct 
terminology, and report (where relevant) whether sex and/or gender may be important 
variables and differences may be expected at the light of current literature. Thus, investigators 
should report how sex and/or gender were taken into account in study design and statistics or 
clarify the reasons for not using a gender medicine approach. 
Methodological choices about sex and gender in relation to study population and analytical 
approach should be reported and justified in the same way as other methodological choices. 
The population of the study should be appropriate to capture gender and/or sex-based factors. 
The inclusion and exclusion criteria should be well justified with respect to sex and/or gender.  
Considerations about anatomical and physiological differences between men and women 
(height, weight, body mass, cell counts, hormonal cycles, etc.) and social and cultural variables 
(socio-economic status, education, etc.) should be applied whenever relevant to the topic of 
the study. 
Data on enrolment, participation, dropout, discontinuation and loss-to-follow up should be 
reported disaggregated by sex and gender (whenever possible). 
 
For guidance, see NIH Policy on Sex as a Biological Variable and SAGER (SexAndGenderEquity in 
Research) Guidelines. 
17. QUALITY ASSURANCE AND QUALITY CONTROL 
The study will be conducted in accordance with the current approved protocol, GCP, relevant 
regulations, and standard operating procedures. Investigators involved in the study will permit 
study-related audits, EC review, and regulatory inspections by providing direct access to all 
study records.  
Study audits can be conducted by or on behalf of CTC, according to OSR quality standards. 
Data will be evaluated for compliance with the protocol and accuracy in relation to source 
documents. Following written standard operating procedures, the auditors will verify that the 

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clinical study is conducted, and data are generated, documented, and reported in compliance 
with the protocol, GCP, and the applicable regulatory requirements. 
The Investigator should notify the CTC promptly of any inspection scheduled by any regulatory 
authorities and will promptly forward copies of any inspection reports received. 
Not performed by a CRO 
17.1. Deviation from study protocol 
A deviation from the protocol is an unintended departure from the procedures or processes 
described in the protocol and approved by the EC.  
The Investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol.  
Every deviation from the study protocol must be specified and documented separately for each 
patient. The investigator should discuss the type and extent of deviation as well as the possible 
consequences for further participation of the patient in the study.  
17.2. Surveillance for observational studies with additional procedure 
• 
NA 
 
18. FINANCE AND INSURANCE 
18.1. Funding 
NA 
18.2.Patient Insurance 
NA 
19. END OF CLINICAL STUDY 
In accordance with applicable regulation, ICH GCP and SOPs, the PI shall notify the end of the 
clinical study within 15 days from the end of the clinical study and the reasons for such action. 
19.1. Summary of the results of the clinical study 
Irrespective of the outcome of a clinical study, within one year from the end of a clinical study, 
the PI shall submit a summary of the results of the clinical study.  
 
20. INTELLECTUAL PROPERTY  

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As Sponsor of the study, the sole owner of the data and results deriving from this study is IRCCS 
Ospedale San Raffaele. 
21. PUBLICATION POLICY 
NA 
22. REFERENCES 
1. 
Yadlapati R, Kahrilas PJ, Fox MR, Bredenoord AJ, Prakash Gyawali C, Roman S, et al. 
Esophageal motility disorders on high-resolution manometry: Chicago classification version 
4.0©. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc. gennaio 2021;33(1):e14058.  
2. 
Carlson DA, Kahrilas PJ, Lin Z, Hirano I, Gonsalves N, Listernick Z, et al. Evaluation of 
Esophageal Motility Utilizing the Functional Lumen Imaging Probe. Am J Gastroenterol. dicembre 
2016;111(12):1726–35.  
3. 
Salvador R, Pandolfino JE, Costantini M, Gyawali CP, Keller J, Mittal S, et al. The Role of 
High-Resolution Manometry Prior to and Following Antireflux Surgery: The Padova Consensus. 
Ann 
Surg 
[Internet]. 
12 
aprile 
2024 
[citato 
20 
settembre 
2024]; 
Disponibile 
su: 
http://dx.doi.org/10.1097/SLA.0000000000006297 
4. 
Jones R, Junghard O, Dent J, Vakil N, Halling K, Wernersson B, et al. Development of the 
GerdQ, a tool for the diagnosis and management of gastro-oesophageal reflux disease in 
primary care. Aliment Pharmacol Ther. 15 novembre 2009;30(10):1030–8.  
5. 
Cisternas D, Taft T, Carlson DA, Glasinovic E, Monrroy H, Rey P, et al. Validation and 
psychometric evaluation of the Spanish version of Brief Esophageal Dysphagia Questionnaire 
(BEDQ): Results of a multicentric study. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc. 
aprile 2021;33(4):e14025.  
6. 
Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index 
(RSI). J Voice Off J Voice Found. giugno 2002;16(2):274–7.  
7. 
Eckardt VF. Clinical presentations and complications of achalasia. Gastrointest Endosc 
Clin N Am. aprile 2001;11(2):281–92, vi.  
8. 
Velanovich V. The development of the GERD-HRQL symptom severity instrument. Dis 
Esophagus Off J Int Soc Dis Esophagus. 2007;20(2):130–4.  
9. 
Röjler L, Glimberg I, Walker MM, Garber JJ, Ludvigsson JF. Validation of the diagnosis of 
eosinophilic esophagitis based on histopathology reports in Sweden. Ups J Med Sci. 2021;126.  

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10. 
Chan WW, Schroeder M, Richardson A, Shah N, Muftah M, Muftah S, et al. Validation of 
Esophageal Global Symptom Severity as a Patient-Reported Outcome for Evaluation of Reflux 
Symptoms. Am J Gastroenterol. 23 aprile 2025;120(8):1760–9.  
 
APPENDIX A:  AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Rationale 
Study 
status 
Details of Changes  
 
 
 
 
 
 
 
23. APPENDIX B:  LIST OF CLINICAL SERVICES / LABORATORIES 
Name 
Institution 
Responsible 
person 
Activity/service 
Notes 
 
 
 
 
 
 
24. APPENDIX C:  LIST OF ENROLLING SITES 
NA