InterNaTional rEgistry oN Sars-cov-2posItiVe nEuroendocrine Neoplasm Patients (INTENSIVE)
Conditions: Neuroendocrine Tumors, COVID-19
Sponsor: European Institute of Oncology

 
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Sponsor:  
 
Istituto Europeo di Oncologia 
Protocol Title: 
InterNaTional rEgistry oN Sars-cov-2 posItiVe nEuroendocrine 
neoplasm patients  
INTENSIVE 
 
(Registro internazionale di pazienti affetti da neoplasia 
neuroendocrina positivi per SARS-CoV-2) 
 
Protocol date and version 
11May2020 - Version 1.0 
 
 
Principal Investigator: 
 
 
Co-investigators : 
 
Nicola Fazio  
 
 
Dr. Francesca Spada 
Dr. Lorenzo Gervaso 
 
Data manager: 
 
 
Dr. Darina Tamayo 
Dr. Cristina Mazzon 
Statisticians: 
 
Prof. Vincenzo Bagnardi 
 
 

 
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Table of contents 
 
1. 
Background, rationale and objectives 
Pag. 3 
2. 
Study design and patient population 
Pag. 4 
3. 
Duration of the study 
Pag. 4 
4. 
Eligibility criteria 
Pag. 4 
5. 
Study Objective 
Pag. 5 
6. 
Statistical considerations 
Pag. 5 
7. 
Database management and CRF completion 
Pag. 6 
8. 
Ethical considerations 
Pag. 7 
9. 
Independents Ethical Committee and Legal Arrangements 
Pag. 7 
10. 
Enrollment 
Pag. 7 
11. 
Patient information and Consent 
Pag. 7 
12. 
Publications 
Pag. 8 
13. 
References 
Pag. 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. Background, rationale and objectives 
 
In late December 2019, a number of cases of pneumonia of unknown origin were epidemiologically 
linked to a seafood and wet animal wholesale market in Wuhan, Hubei Province, China. On 30 
December 2019, a previously unknown beta-coronavirus was identified with RT-PCR of samples got 
from a bronchoalveolar lavage of a patient with pneumonia of unknown etiology in Wuhan Jinyintan 
Hospital [1]. This new coronavirus, named 2019-nCoV, was later named SARS-CoV-2 due to its 
association with severe acute respiratory syndrome (SARS). The related disease, mainly pulmonary 
initially, was called coronavirus disease 19 (COVID-19). Information on the epidemic was notified to 
WHO on 3 January 2020. After that the outbreak spread outside China and the first western case 
occurred in Italy on January 30th. On 30 January 2020, the WHO declared COVID-19 as the sixth 
public health emergency of international concern. On 11 March 2020 the WHO general director, Dr 
Tedros Adhanom Ghebreyesus, said that SARS-CoV-2 outbreak became a pandemic. 
At the date of this version of the protocol just below 4 million of total confirmed cases of COVID-19 
have been recorded from 215 Countries all over the world, with roughly 270,000 deaths. 
As cancer patients are historically been considered at a higher risk of infection and related 
complications the main oncological Societies published general guidances on their websites. An 
international collaborative group proposed some practical measures for the management of cancer 
patients based on the available data [2]. 
It has been reported that cancer patients were more susceptible to viral infections, particularly 
SARS-CoV-2-related [3]. Furthermore, according to a recently published Chinese cohort, patients 
with cancer had a significantly higher risk of developing severe events (mainly intensive care unit - 
ICU - admissions) compared with patients without cancer (39% vs 8%, p=0·0003) [4].  
Some types of cancers, like the thoracic ones, and clinical underlying conditions, such as 
immunosuppressive concurrent therapies or immune-related comorbidities, are potentially at a 
higher risk for infection and complications of COVID-19 for cancer patients. 
However it is difficult to understand where and how to locate neuroendocrine neoplasms (NENs) 
patients within this context. It is well know that NENs represent a rare and heterogeneous group of 
malignancies and their clinical behavior and response to treatment is various. Some therapies, such 
as peptide receptor radionuclide therapy (PRRT), are specific of this disease. Prognosis can be very 
different between for instance a patient with a fast growing high burden neuroendocrine carcinoma 
(NEC) and a patient with an indolent metastatic small bowel neuroendocrine tumor (NET). 
Moreover in the first case is probable that the patient is receiving a conventional platinum-based 
chemotherapy whereas in the other case just a somatostatin analog (SSA). Therefore it is clear that 
global recommendations from scientific societies about NEN patients management during COVID-
19 pandemic should take into account all these difference.  
However at the moment there are not data about  the risk of infection, disease and complications 
of NEN patients during COVID-19 pandemic.  
In Italy according to the Istituto Superiore di Sanità (ISS)’s report on May 7th 2020 the 16% of patients 
had an active cancer over the past five years among the patients dead due to COVID-19. 
Unfortunately this information regards just 2,621 patients (out of 27,955) died for SARS-CoV-2 
infection, that is less than 10% of the total number of patients died so far. This information was 
extracted reviewing charts of patients died in hospital as reported in the online published document 
from ISS. 
On the basis of what above reported we think that it will be difficult to have reliable and 
reproducible data about the risk of infection and risk of disease/complications for cancer patients  
 

 
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and SARS-CoV-2. Other than difficult it is probably too early to find the ideal approach for cancer 
patients in the middle of the pandemic. Unfortunately the number of cancer patients COVID-19 
positive will increase and guidances will have to be updated. What it is clear so far is that the 
management of cancer patients must be dynamic and tailored to every patient’s condition, every 
hospital’s resources and every physician’s experience/expertise.  
All of this will be even more complex for NEN patients, because of the aforementioned 
heterogeneity and rarity. 
Therefore we propose a global collection of data through an international database to describe and 
monitor NEN patients with COVID-19. This retrospective/prospective collection of data can create a 
large basis to check frequence of events, clinical management, clinical outcome, demographic, 
geographical, clinical and biological correlations. All this will be helpful for the clinical and scientific 
community to get reliable information for a homogeneous clinical management of NEN patients 
during COVID-19 pandemic. 
 
This protocol will be submitted to the attention of the executive boards of the main NEN societies 
and international oncological societies for their endorsement. Furthermore each single center 
dealing with NEN patients all over the world will be welcome to participate into this global registry. 
The aim is to get the as wide as possible representativity of the world situation. 
 
 
2. Study design and patient population 
This is a retrospective and prospective observational international multicentric trial on Sars-CoV-2 
positive NEN patients. 
Centers all over the world will be invited to participate in this study filling in a web application 
(REDCap) which reports clinical characteristics of patients, NENs and COVID-19. Specific questions 
will address clinical management and outcome. 
During the revision of the clinical history and using the hospital chart, will be collected the following 
parameters in an electronic case report form: 
Age, sex, place of residence, Center, major comorbidities, ongoing therapies for comorbidities, 
diagnosis of NEN, type of NEN, stage of NEN, treatment of NEN, duration of treatment of NEN, NEN 
response status, date of RT-PCR diagnosis of COVID-19, symptoms/signs of COVID-19, COVID-19-
related CT-scan, therapy of COVID-19, biochemical exams regarding COVID-19, clinical behavior of 
NEN, clinical behavior of COVID-19, outcome of COVID-19, NEN-treatment management during 
COVID-19. 
 
 
3. Duration of the study 
The duration of the study will be approximately five months in total and four months for enrollment. 
 
 
4. Eligibility criteria  
 
Inclusion criteria 
Patients with a NEN of any type with an RT-PCR positive COVID-19 
 
Patients can have one of the following characteristics: 
 

 
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- 
Clinical symptoms/signs, including : fever (persistent T > 37.5 °C ) and/or reduced O2 
saturation and/or cough and/or rhynorrea and/or dyspnea at rest and/or extertional 
dyspnea and/or hypo-/anosmia and/or dys-/ageusia and/or diarrhea and/or myalgia and/or 
artralgia and/or conjunctivitis) 
- 
Radiological sings of COVID-19 pneumonia at CT-scan  
- 
No symptoms/signs, no radiological imaging or alterations 
- 
Signed written informed consent for patients enrolled in the prospective part 
 
Exclusion criteria 
- 
Patients with NEN and symptoms suspected for COVID-19 without an RT-PCR positivity 
confirmation 
 
 
5. Study Objective 
 
Endpoints 
- 
major demographic features; 
- 
prevalence of major comorbidities; 
- 
proportion of severe events overall including deaths; 
- 
proportion of NET patients who received chemotherapy; 
- 
proportion of NEC patients who received chemotherapy; 
- 
proportion of NET patients who received everolimus; 
- 
surgery, radiotherapy, immune check point inhibitors, chemotherapy, everolimus, in the last 
2 months before COVID-19. 
 
 
6. Statistical considerations 
 
Sample size 
This is mainly a descriptive study with no formal a priori hypothesis to be tested. As a consequence 
no formal statistical sample size has been computed. 
 
Data analysis 
Patients characteristics will be summarized by means of counts and percentages for categorical 
variables and by using the mean and standard deviation (DS) or median and quantiles for 
continuous variables. 
Parametric and non-parametric tests for comparisons between groups (i.e. the Pearson Chi- 
Square or the Fisher Exact test for comparisons between categorical variables, the Mann- Whitney 
or the Kruskal-Wallis test for comparisons between continuous and categorical variables) will be 
eventually performed with explorative purposes as well as the use of logistic regression with 
multiple explanatory variables. 
Time to event endpoints such as, DFS and OS will be mainly described by means of Kaplan-Meier 
curves. Multivariable regression models, such as the Cox model, will be eventually used with 
purely explorative intents. 
 
 
 

 
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7. Database management and CRF completion 
 
Data for this study will be collected in a REDCap® (Research Electronic Data Capture) database. 
REDCap is a secure web platform for building and managing online databases and surveys. REDCap's 
streamlined process for rapidly creating and designing projects offers a vast array of tools that can 
be tailored to virtually any data collection strategy. REDCap provides an intuitive user interface that 
streamlines project development and improves data entry through real-time validation rules (with 
automated data type and range checks). REDCap also provides easy data manipulation (with audit 
trails for reporting, monitoring and querying patient records) and an automated export mechanism 
to common statistical packages (SPSS, SAS, Stata, R/S-Plus). Investigators who have received 
appropriate institutional research approval (i.e., Institutional Review Board or Institutional Ethics 
Committee) will be given a web link with a survey where they can enter data about their specific 
patients. Guidelines about the data collection and to properly enter the data will be developed.  
The Promoter/Study Coordinator Centre is the legal owner of the collected data and has the right 
to manage it (including the data collected by the centers involved) 
in the case of a multi-site study, the sharing of data to any satellite centres is at the discretion of the 
Coordinator Centre under existing contractual agreements 
the regulation regarding protected health information (PHI) is also valid in Italy: it is therefore not 
possible to enter sensitive data of the subjects enrolled in the study or any other data (such as 
hospital codes/labels/SDO) that can lead to their identity; that's why when a subject is inserted into 
the platform, the system assigns it a unique identifier 
The id/name-lastname code decoding is the responsibility of the PI of each experimental center (and 
should not be shared with the Coordinator Center). Each experimental center will then be the only 
one to be able to decode the IDs assigned to the subjects managed by its center. 
For experimental studies, the date of birth is usually encoded by keeping only month and year or 
year only according to the specifics of the study; observational studies should follow the same rule 
but it is "borderline" as dynamic, even today the actual date of birth is often collected without 
particular criticism by the regulators 
As for the timing of data retention, it depends on the contract you have with the server on which it 
is collected; all web-based information transmission is encrypted. REDCap was developed 
specifically around HIPAA-Security guidelinesMore information about the consortium and system 
security can be found at http://www.projectredcap.org/. 
Investigators will access the medical record of their patient, enter required data into the database. 
The protected health information will not be reused or disclosed to any other person or entity, 
except as required by law, for authorized oversight of the research project. Future research, that is 
not defined in this protocol, wishing to access the REDcap database will need institutional review 
board/ethic review board approval before obtaining access to the REDcap database. 
The investigator will ensure the staff dedicated to the study is available so that CRF will be 
adequately completed, and in timely fashion. As much as possible queries will be resolved when 
needed.  
De-identified data only will be managed. Missing data will have to be carefully documented for 
patients who are lost to follow-up or with blocks or slides not available for the study. The database 
will contain information that enables the samples to be linked to personal data. 
 
 
 
 

 
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8. Ethical considerations 
 
All the study procedures will be in accordance with the precepts of Good Clinical Practice and the 
declaration of Helsinki. According to the regulation (EU) 2016/679 of the European Parliament and 
of the Council of 27 April 2016, the following requirements regarding personal data will be 
guaranteed: pseudonymisation and encryption, the confidentiality, integrity, availability and 
resilience of treatment systems and services, the ability to restore the availability and access of data 
in the event of a physical or technical accident. 
This study will be conducted in compliance with the protocol, adhering to the principles current 
local legislation. 
 
 
9. Independents Ethical Committee and Legal Arrangements 
 
All the documents required by the national law and any other informative documents that 
may be requested will be submitted for review to an independent Ethics Committee whose 
procedures and operations meet the national legal requirements. 
The Health Authorities according to the legal requirements will authorize the study. 
Selection of the patients will not start before approval of the Ethics Committee has been obtained 
and the study has been authorized by the Health Authorities. 
 
 
10. Enrollment 
  
For the prospective study all patients giving informed consent can be enrolled. When the informed 
consent is signed (signed and dated by the patient and the physician) the patient will be assigned a 
progressive number. 
All inclusion/exclusion criteria will be checked during the registration procedure. As soon as the 
eligibility is verified the patient is registered. 
 
 
11. Patient information and Consent 
 
Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained. In case report forms 
(CRF) and other study-related document subjects should be identified by their unique subject study 
number only. 
Source documents are original documents, data, and records from which the subject’s case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, radiographs, and correspondence.  Case report 
form entries may be considered source data if the case report form is the site of the original 
recording (ie, there is no other written or electronic record of data).  
For other patient the informed consent process is under investigator’s responsibility. 
The information and consent document will be made in duplicate: the original copy to be kept by 
the investigator, one copy will be given to the patient. 
 
 

 
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12. Publications 
 
Property of data is of the European Institute of Oncology, IEO, IRCCS; Milan, Italy. 
The main results of the clinical trial will be published in a peer-reviewed scientific journal.  
The final publication will be written on the basis of the final analysis performed by the European 
Institute of Oncology and Statistical Center. 
Organizational committee members will be co-authors. 
Investigators will be able to be included among the co-authors on the basis of the active recruitment 
of the center and/or their participation in the design and drawing up of the research project. 
All publications, abstract or presentations including data related to the present trial will be 
submitted for review to the Chair of the Study, who is the Director of Division of Gastrointestinal 
Medical Oncology and Neuroendocrine Tumors of European Institute of Oncology, prior to 
submission.  
Trial results will not be released before data maturity has been reached for the primary endpoint of 
the trial. Publication will be done in case of positive study results as well as negative results.  
 
 
13. References 
 
1. 
Zhu N, Zhang D, Wang W et al. A Novel Coronavirus from Patients with Pneumonia in China, 
2019. N Engl J Med 2020; 382: 727-733. 
2. 
Al-Shamsi HO, Alhazzani W, Alhuraiji A et al. A Practical Approach to the Management of 
Cancer Patients During the Novel Coronavirus Disease 2019 (COVID-19) Pandemic: An International 
Collaborative Group. Oncologist 2020. 
3. 
Yu J, Ouyang W, Chua MLK, Xie C. SARS-CoV-2 Transmission in Patients With Cancer at a 
Tertiary Care Hospital in Wuhan, China. JAMA Oncol 2020. 
4. 
Liang W, Guan W, Chen R et al. Cancer patients in SARS-CoV-2 infection: a nationwide 
analysis in China. Lancet Oncol 2020; 21: 335-337.