Randomised Controlled Trials to Assess Approved SARS-CoV-2 Vaccines in Immunocompromised Patients: A Master Protocol for the Set-up of a Swiss Cohorts Based Trial Platform
Phase: PHASE3
Conditions: Immunocompromised Patients
Sponsor: University Hospital, Basel, Switzerland

Clinical Study Master-protocol 
Randomised 
controlled 
trials 
to 
assess 
approved 
SARS-CoV-2 
vaccines 
in 
immunocompromised patients: A master protocol for the set-up of a Swiss Cohorts Based Trial 
Platform  
Short title: Immunocompromised Swiss Cohorts Based Trial Platform 
Acronym: COVERALL (COrona VaccinE tRiAL pLatform) 
Study Type: 
Clinical trial with Investigational Medicinal Product (IMP) 
Study Categorisation: 
Category A (reassessment will be done in separate sub-
protocols) 
Study Registration: 
Clinicaltrials.gov: NCT04805125Planned:  kofam 
Study Identifier: 
COVERALL 
Sponsor, Sponsor-Investigator or 
Principal Investigator: 
University Hospital Basel 
Prof. Heiner C. Bucher MD MPH  
Basel Institute for Clinical Epidemiology & Biostatistics 
University Hospital Basel 
Spitalstrasse 12 
4056 Basel 
Switzerland 
Phone: +41 (0)61 328 61 01 
Email: heiner.bucher@usb.ch 
Investigational Product: 
In Switzerland approved SARS-CoV-2 vaccines (i.e. vaccines 
with market authorisation by Swissmedic). Investigated vaccines 
are specified in, a separate sub-protocol  and submitted to the 
EKNZ via BASEC. 
Protocol Version and Date: 
Version 2.1; 07.04.2021 
CONFIDENTIAL 
The information contained in this document is explicitly not confidential. We will make all study protocols (including 
master protocol, sub-protocols, as well as amendments) publicly available on Open Science Framework 
(https://osf.io/) 

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Signature pages 
 
 
 

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Authors of the study protocol: 
 
Benjamin Speich, PhD 
Prof. Heiner C. Bucher MD MPH 
PD Michael Koller, PhD 
Prof. Nicolas Müller MD 
Prof. Huldyrch Günthard MD PhD 
Prof. Andri Rauch MD PhD 
Prof. Matthias Briel MD, PhD, MSc 
PD Lars G. Hemkens, MD, MPH 
 
Trial statistician: 
Frédérique Chammartin, PhD 
 
Data Management: 
Katharina Kusejko, PhD 
Daniel Smith 
 
 
 
 

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Table of Contents 
STUDY SYNOPSIS ............................................................................................................................... 16 
ABBREVIATIONS ................................................................................................................................. 25 
STUDY SCHEDULE .............................................................................................................................. 27 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 28 
1.1 
Sponsor-Investigator ................................................................................................................... 28 
1.2 
Local Principal Investigator(s) ..................................................................................................... 28 
1.3 
Statistician ("Biostatistician") ....................................................................................................... 29 
1.4 
Laboratory ................................................................................................................................... 29 
1.5 
Co-investigators .......................................................................................................................... 29 
1.6 
Monitoring institution ................................................................................................................... 30 
1.7 
Data Safety Monitoring Committee ............................................................................................. 30 
1.8 
Any other relevant Committee, Person, Organisation, Institution ............................................... 31 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 32 
2.1 
Study registration ........................................................................................................................ 32 
2.2 
Categorisation of study................................................................................................................ 32 
2.3 
Competent Ethics Committee (CEC) .......................................................................................... 32 
2.4 
Competent Authorities (CA) ........................................................................................................ 32 
2.5 
Ethical Conduct of the Study ....................................................................................................... 32 
2.6 
Declaration of interest ................................................................................................................. 33 
2.7 
Patient Information and Informed Consent ................................................................................. 33 
2.8 
Participant privacy and confidentiality ......................................................................................... 33 
2.9 
Early termination of the study ...................................................................................................... 33 
2.10 Protocol amendments ................................................................................................................. 34 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 35 
3.1 
Background and Rationale .......................................................................................................... 35 
3.2 
Investigational Product (treatment, device) and Indication ......................................................... 35 
3.3 
Preclinical Evidence .................................................................................................................... 36 
3.4 
Clinical Evidence to Date ............................................................................................................ 36 
3.5 
Dose Rationale / Medical Device: Rationale for the intended purpose in study (pre-market 
MD) 36 
3.6 
Explanation for choice of comparator (or placebo) ..................................................................... 36 
3.7 
Risks / Benefits ............................................................................................................................ 36 
3.8 
Justification of choice of study population ................................................................................... 36 
4. 
STUDY OBJECTIVES ................................................................................................................... 37 
4.1 
Overall Objective ......................................................................................................................... 37 
4.2 
Objectives related to platform trial set-up and feasibility of cohort based patient recruit, trial 
inclusion and data collection.................................................................................................................. 37 
4.3 
Objectives related to a platform based nested pilot trial to investigate the comparative 
effectiveness of vaccines against Sars-CoV-2 ...................................................................................... 37 
4.4 
Safety Objectives ........................................................................................................................ 37 
5. 
STUDY OUTCOMES ..................................................................................................................... 38 
5.1 
Immunological Outcomes ............................................................................................................ 38 
5.2 
Clinical Outcomes ....................................................................................................................... 38 
5.3 
Other Outcomes of Interest ......................................................................................................... 39 
5.4 
Safety Outcomes ......................................................................................................................... 39 

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6. 
STUDY DESIGN ............................................................................................................................ 39 
6.1 
General study design and justification of design ......................................................................... 39 
6.2 
Methods of minimising bias ......................................................................................................... 40 
6.2.1 Randomisation .................................................................................................................... 40 
6.2.2 Blinding procedures ............................................................................................................ 40 
6.2.3 Other methods of minimising bias ....................................................................................... 40 
6.3 
Unblinding Procedures (Code break) .......................................................................................... 41 
7. 
STUDY POPULATION .................................................................................................................. 42 
7.1 
Eligibility criteria ........................................................................................................................... 42 
7.2 
Recruitment and screening ......................................................................................................... 42 
7.3 
Assignment to study groups ........................................................................................................ 43 
7.4 
Criteria for withdrawal / discontinuation of participants ............................................................... 44 
8. 
STUDY INTERVENTION ............................................................................................................... 45 
8.1 
Identity of Investigational Products (treatment / medical device) ................................................ 45 
8.1.1 Experimental Intervention (treatment / medical device) ...................................................... 45 
8.1.2 Control Intervention (standard/routine/comparator treatment / medical device) ................ 45 
8.1.3 Packaging, Labelling and Supply (re-supply) ..................................................................... 45 
8.1.4 Storage Conditions.............................................................................................................. 45 
8.2 
Administration of experimental and control interventions ........................................................... 45 
8.2.1 Experimental Intervention ................................................................................................... 45 
8.2.2 Control Intervention ............................................................................................................. 45 
8.3 
Dose / Device modifications ........................................................................................................ 45 
8.4 
Compliance with study intervention ............................................................................................. 45 
8.5 
Data Collection and Follow-up for withdrawn participants .......................................................... 46 
8.6 
Trial specific preventive measures .............................................................................................. 46 
8.7 
Concomitant Interventions (treatments) ...................................................................................... 46 
8.8 
Study Drug / Medical Device Accountability ............................................................................... 46 
8.9 
Return or Destruction of Study Drug / Medical Device ............................................................... 46 
9. 
STUDY ASSESSMENTS ............................................................................................................... 47 
9.1 
Study flow chart(s) / table of study procedures and assessments .............................................. 47 
9.2 
Assessments of outcomes .......................................................................................................... 47 
9.2.1 Assessment of feasibility outcomes .................................................................................... 47 
9.2.2 Assessment of immunological endpoints ............................................................................ 48 
9.2.3 Assessment of clinical endpoints ........................................................................................ 48 
9.2.4 Assessment of safety outcomes ......................................................................................... 49 
9.2.5 Assessments in participants who prematurely stop the study ............................................ 50 
9.3 
Procedures at each visit .............................................................................................................. 50 
9.3.1 Eligibility (and eventual enrolment  randomisation) ............................................................ 50 
9.3.2 Enrolment and randomisation ............................................................................................. 50 
9.3.3 Follow-up 1 week 12 ........................................................................................................... 50 
9.3.4 Follow-up 2 week 48 ........................................................................................................... 50 
10. SAFETY ......................................................................................................................................... 51 
10.1 Drug studies ................................................................................................................................ 51 
10.1.1 Reporting of serious adverse events (SAE) and other safety related events ..................... 52 
10.1.2 Follow up of (Serious) Adverse Events ............................................................................... 52 
10.2 Medical Device Category C studies ............................................................................................ 53 

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10.3 Medical Device Category A studies ............................................................................................ 53 
10.4 Assessment, notification and reporting on the use of radiation sources ..................................... 53 
11. STATISTICAL METHODS ............................................................................................................. 54 
11.1 Hypothesis ................................................................................................................................... 54 
11.2 Determination of Sample Size ..................................................................................................... 54 
11.3 Statistical criteria of termination of trial ....................................................................................... 54 
11.4 Planned Analyses ........................................................................................................................ 54 
11.4.1 Datasets to be analysed, analysis populations ................................................................... 54 
11.4.2 Feasibility analysis .............................................................................................................. 54 
11.4.3 Analyses of immunological and clinical outcomes .............................................................. 54 
11.4.4 Interim analyses .................................................................................................................. 55 
11.4.5 Safety analysis .................................................................................................................... 55 
11.4.6 Deviation(s) from the original statistical plan ...................................................................... 55 
11.5 Handling of missing data and drop-outs...................................................................................... 55 
12. QUALITY ASSURANCE AND CONTROL .................................................................................... 56 
12.1 Data handling and record keeping / archiving ............................................................................. 56 
12.1.1 Case Report Forms ............................................................................................................. 56 
12.1.2 Specification of source documents ..................................................................................... 56 
12.1.3 Record keeping / archiving ................................................................................................. 56 
12.2 Data management ....................................................................................................................... 56 
12.2.1 Data Management System ................................................................................................. 56 
12.2.2 Data security, access and back-up ..................................................................................... 56 
12.2.3 Analysis and archiving ........................................................................................................ 57 
12.2.4 Electronic and central data validation ................................................................................. 57 
12.3 Monitoring .................................................................................................................................... 57 
12.4 Audits and Inspections ................................................................................................................ 57 
12.5 Confidentiality, Data Protection ................................................................................................... 58 
12.6 Storage of biological material and related health data ................................................................ 58 
13. PUBLICATION AND DISSEMINATION POLICY.......................................................................... 59 
14. FUNDING AND SUPPORT ............................................................................................................ 60 
14.1 Funding ....................................................................................................................................... 60 
14.2 Other Support .............................................................................................................................. 60 
15. INSURANCE .................................................................................................................................. 60 
16. REFERENCES ............................................................................................................................... 61 
17. APPENDICES ................................................................................................................................ 63 
 
 
 

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STUDY SYNOPSIS  
 
Sponsor / Sponsor-
Investigator 
Prof. Heiner C. Bucher MD MPH 
 
Basel Institute for Clinical Epidemiology & Biostatistics  
University Hospital Basel 
Spitalstrasse 12 
4056 Basel 
Switzerland 
 
Phone: +41 (0)61 328 61 01 
Email: heiner.bucher@usb.ch 
Study Title: 
Randomised controlled trials to assess approved SARS-CoV-2 vaccines in 
immunocompromised patients: A master protocol for the set-up of an Swiss 
Cohorts Based Trial Platform 
Short Title / Study ID: 
Immunocompromised Swiss Cohorts Based Trial Platform 
Protocol Version and 
Date: 
Version 2.0; 23 .01.2021   
Trial registration: 
Clinicaltrials.gov: NCT04805125Planned:  kofam 
Study category and 
Rationale 
We plan to set up a flexible trial platform using two existing national cohorts of 
immunocompromised patients (i.e. Swiss HIV Cohort Study [SHCS] and Swiss 
Transplant Cohort Study [STCS]) to assess the comparative effectiveness and 
safety of approved SARS-CoV-2 vaccines in immunocompromised patients. 
Nesting this trial into cohorts with highly standardized data collection allows for a 
rapid, efficient and cost-saving trial conduct while addressing a highly relevant 
research question. With the current pandemic situation of SARS-CoV-2 infection, 
our focus is on vaccines in immunocompromised hosts. 
 
We will test this platform in the frame of an exploratory pilot trial and we will set-up 
a framework to conduct a larger, flexible, randomized controlled trial (RCT) to test 
approved SARS-CoV-2 vaccines to prevent SARS-CoV-2 infections. The pilot trial 
will be a category A trial as all used vaccines will be approved in Switzerland and 
entails only minimal risks. The actual vaccines tested, including more specific 
inclusion and exclusion criteria and dosing will be defined in separate sub-protocols 
that will be submitted as soon as vaccines are licensed in Switzerland. 
Clinical Phase: 
Phase 3/4 

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Background and 
Rationale: 
A new highly contagious corona virus SARS-CoV-2 has emerged in late 2019 in 
Wuhan, China, and caused in a two month period a pandemic with the highest 
disease burden in elderly and people with pre-existing medical conditions. In a 
situation with no known therapy against SARS-CoV-2 clinical research in 
Switzerland was ill-prepared at the beginning of the pandemic for launching clinical 
trials for the rapid evaluation of investigative drugs with postulated in vitro activities 
against SARS-CoV-2. Use of routinely collected data for nesting trials into cohort 
studies with highly standardized data collection systems and platform trials allows 
for rapid patient recruitment and efficient and cost-saving data collection for the 
simultaneous evaluation of several treatment options, features which can expedite 
trial protocol development and trial implementation in an epidemic situation.  
The advantage of using the existing infrastructure of two well-established cohorts 
is that eligible patients most urgently at need for vaccines or therapies can be more 
rapidly identified and recruited to trials during regular cohort visits, or by calls. Due 
to rigorous follow-up monitoring and collection of high-quality phenotypic data the 
cohort data can be used to define trial baseline data but also for outcome 
assessment for those parameters that are routinely collected like for example 
hospitalisations, pneumonia, or death. The use of highly standardized routinely 
collected data for conducting intervention trials is a highly efficient and economic 
approach for trial conduct as exemplified by previous groups. Furthermore, a well-
established trial platform would allow us to react quickly in case of any future 
outbreak, meaning that fewer hurdles need to be overcome to implement a clinical 
trial. 
At present (December 08 2020) Switzerland has still around 4000 new SARS-CoV-
2 infections per day. Hospitalisations and deaths due to SARS-CoV-2 are high with 
18 hospitalisations per 100`000 inhabitants and 11 per 100’000 deaths and the 
reproduction 
rate 
is 
still 
around 
1 
(https://www.covid19.admin.ch/de/overview/hospitalisationen?detTime=14d). 
It 
remains unclear whether the current reproduction rate of SARS-CoV-2 can be 
further lowered and kept during this winter season.  
According to the University of Oxford (November 25, 2020, https://www.covid-
19vaccinetracker.org/) 40 vaccines against SARS-CoV-2 are in clinical evaluation, 
and of those, 10 vaccines are in phase III (including one non-replicating viral vector, 
three inactivated vaccines, one LNP-encapsulated mRNA, and one 3 LNP-mRNAs) 
and 237 candidate vaccines are under preclinical investigation. Two vector based 
mRNA vaccines by Pfizer/BioNTech and Moderna have been approved December 
19, 2020 and January 12, 2021 by Swissmedic and vaccination programs start to 
be rolled out in Switzerland. The Swiss Federal Government has acquired large 
stocks of both vaccines. 
These vaccines and others to come use new vector based vaccine strategies that 
have never been used in humans. In particular, safety and efficacy data in immune 
compromised patients is only existing in a very limited amount or not at all. 
Therefore, it is paramount to compare new emerging vaccines for safety and 
efficacy in those individuals who are at increased risk of complicated Sars-CoV-2 
infection and are likely to have reduced vaccine induced immunity like elderly and 
immune compromised patients. 
The here presented revised master protocol describes the set-up of the trial platform 
which is nested into two cohorts and the annexed first sub-study protocol details 
the pilot RCT which intends to compare the immune response, clinical effectiveness 
and safety of the first two in Switzerland approved mRNA vaccines against Sars-
Cov_2 in immunocompromised patients. We had submitted the master protocol of 
the trial platform December 15, 2020 to the Leitethikkommission EKZN without a 
sub-study protocol as at that time point no vaccine had achieved market 
authorisation by Swissmedic in order  to start a potential trial in a timely manner. 
The pilot study will primarily assess the functionality of the trial platform and early 
immunogenicity, efficacy and safety data. At a later stage, the platform might also 
be used to enlarge the pilot trial or to develop sub-protocols to deal with patients 
with no or insufficient immune response to Sars-CoV-2 vaccines.  

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Objective(s): 
The overall objective is to use existing resources from two established national 
cohorts (i.e. SHCS and STCS) to build a flexible trial platform and to test this 
platform in the frame of a randomised pilot trial by comparing induced immunity of 
the two first vaccines that are licensed in Switzerland to prevent SARS-CoV-2 
infections and related complications in immunocompromised patients.  
 

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Outcome(s): 
For the conduct of this pilot trial we will assess the feasibility of conducting a RCT 
in Switzerland based on our newly developed platform.  
Specific endpoints related to trial conduct feasibility within the cohort and trial 
platform infrastructure will be the following: 
• Duration of RCT set up (i.e. time from deciding which interventions will be tested until the 
first patient is randomised). 
• Time of patient recruitment (i.e. from activation of first study site until (i) 40 patients and 
(ii) 380 patients are randomised) 
• Patient consent rate (i.e. proportion of patients giving informed consent out of approached 
eligible patients) 
• Proportion of missing data for all baseline variables from routinely collected cohort data 
(baseline variables are listed under “Measurements and procedures”) 
• Proportion of missing data for all clinical outcomes from routinely collected cohort data 
and outcome data that is collected in the trial platform (clinical outcomes are listed below) 
 
Specific SARS-CoV-2 related outcomes will be collected during the sub-study pilot phase. 
These will be the following: 
Immunological outcome (primary endpoint) : 
We will measure SARS-CoV-2–specific antibodies and titers with established assays, in all 
participants at three months after vaccination. We will use a commercial pan-IgG antibody 
assay against the receptor binding domain (RBD) against the nP and spike 1 subunits and 
an in-house assay developed by the Institute of Medical Virology, University of Zurich which 
can detect multiple viral epitopes.  
 
Clinical outcomes (secondary endpoints): 
The clinical effectiveness endpoints are (according to FDA recommendations for phase III 
Covid-19 vaccine licensing trials) the following:  
- 
Newly PCR-confirmed asymptomatic Covid-19 infection (identified by the 
presence of anti–SARS-CoV-2 nucleocapsid antibodies, or SARS-CoV-“ PCR or 
rapid antigen test) and no related symptoms [(i.e. fever or chills, cough, shortness 
of breath or difficulty breathing, fatigue, muscle or body aches, headache, new 
loss of taste or smell, sore throat, congestion or runny nose nausea or vomiting, 
and diarrhea]) at any time points within 48 weeks  follow-up  
- 
Newly PCR-confirmed symptomatic Covid-19 infection with at least one of the 
following symptoms (i.e. fever or chills, cough, shortness of breath or difficulty 
breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, 
sore throat, congestion or runny nose nausea or vomiting, and diarrhea) within 48 
week follow-up  
- 
Severe COVID-19 infection with respiratory failure, evidence of shock (as 
diagnosed by a treating physician), clinically significant acute renal, hepatic, or 
neurologic dysfunction; admission to an intensive care unit; or death within 48 
week follow-up. 
- 
Covid-19 burden of diseases (BOD), a composite of the above endpoints. The 
BOD will be scored as by using 0 for no COVID-19, 1 for non-severe COVID-19, 
and 2 for severe COVID-19. 
 
An additional clinical effectiveness endpoint is patient reported symptomatic or 
symptomatic infections of household members.  
 
All clinical outcomes will be measured in the trial database during a follow-up period of 12 
months after vaccination.   
 
Safety outcomes: 
Collection of solicited local and systemic adverse events will for feasibility reasons be 
reduced to: 
 
Any local symptom (redness or swelling or prolonged pain at injection side) 
limiting the continuation of normal daily activities during the first 7 days after 
vaccination  
 
Any systemic symptom (fever, generalized muscle or joint pain) limiting the 
continuation of normal daily activities during the first 7 days after vaccination  

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 
Any vaccine related symptom leading to contacting a physician during the first 7 
days after vaccination 
. 
Study design: 
Cohort embedded platform with a first sub-study pilot trial of two arms comparing 
licensed vaccines against SARS-CoV-2. The platform design allows to expand the 
pilot trial into a larger trial by sub-protocols to add or drop vaccine arms or to add 
further sub-protocols for re-randomization of patients with no immune response to 
a vaccine booster or new vaccines   
The interventions are further specified in the separate sub-protocol.   
Inclusion / Exclusion 
criteria: 
Inclusion criteria 
- Aged ≥18 years 
- Patients registered with informed consent from participating cohorts  
- Additional consent for participation in the specific sub-protocol 
 
Exclusion criteria  
- Acute symptomatic SARS-CoV-2 infection, influenza or other acute respiratory 
tract infection 
-Known allergy or contra-indications for vaccines or any vaccine components 
- Any emergency condition requiring immediate hospitalization for any condition 
 
Inclusion and exclusion criteria (e.g. pregnancy) are specified further in the 
separate sub-protocol. 

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Measurements and 
procedures: 
Baseline characteristics will be measured and used from routinely collected cohort 
data. Baseline data from SHCS patients will include the following: Age, sex, 
education, 
working 
status, 
co-morbities 
diabetes 
mellitus, 
hypertension, 
dyslipidemia, coronary heart diseases angioplasties, bypass surgery and strokes, 
body mass index, depression, smoking, alcohol and illicit drug use, current 
antiretroviral therapy and any co-medication, first HIV antibody test or inclusion into 
cohort, CD4 cell nadir, latest CD4 cell count & HI viral load, glomerular filtration rate, 
hepatitis C virus (HCV) and chronic hepatitis B virus (HBV) infection, hematogram 
and blood chemistry including GFR, contact with a person with a documented 
SARS-CoV-2 infection, past documented SARS-CoV-2 infection by either SARS-
CoV-2 PCR or antibodies (IgG).  
 
Baseline data from STCS patients will include the following: Age, sex, ethnicity, 
history of transplantation, organ-specific pre-transplant history, hospitalization 
duration for the actual transplantation, patient medical history (cardiopulmonary 
diseases, metabolic diseases, endocrine diseases, kidney diseases, history of 
cancer and other events and diseases), history of infectious diseases, infectious 
diseases 
at 
baseline 
(viral, 
bacterial, 
fungal, 
parasite, 
unindentified), 
immunosuppressive treatment, lab data (chemistry and hematology), immunology, 
serology (HBV, HCV, CMV, HIV, EBV, Toxo, Tpha, HSV, VZV), HLA typing, 
allograft 
biopsy 
(date 
and 
ID), 
drugs 
(induction, 
maintenance 
of 
immunosuppression and infectious diseases prophylaxis, plus other important 
treatments), education,  work status , smoking history, drug addiction,  depression. 
The baseline data will also serve for the identification of eligible patients who are at 
highest risk of complications from SARS-CoV-2 infection.  
Clinical trial endpoints and serious adverse events will be continuously collected by 
clinicians of participating clinical cohort centres and entered by the local clinicians 
and local cohort data managers into the clinical outcome trial platform database.  
The data centres and local data managers of the SHCS and STCS will manage and 
control the trial platform database and will be responsible for data monitoring. The 
cohort data centres will check for consistency of all outcome data that is entered in 
parallel into the routine cohort database and into the trial outcome database (e.g. 
clinical information on any or SARS-CoV-2 related hospitalization and exact 
reasons of death). 
Study Product / 
Intervention:  
We will primarily assess the feasibility of conducting a randomised vaccine trial that 
is nested in two cohorts in Switzerland with the purpose to measure the specific 
endpoints related to trial conduct feasibility, and the immunological and clinical 
endpoints in regard to vaccine efficacy and safety.. 
The first in Switzerland approved SARS-CoV-2 vaccine will constitute the trial study 
intervention (and will be described in a separate sub-protocol following the licensing 
of the vaccines). 
Control Intervention 
(if applicable): 
The second approved SARS-CoV-2 vaccine will constitute the trial control group.  
Number of 
Participants with 
Rationale: 
To pilot the trial and test the functionality of the trial platform we plan to enrol 380 
patients over 3 months in 4 cohort centers (with multiple transplantation programs 
for the STCS). 
Study Duration: 
Vaccines by Pfizer / BioNTech and Moderna have been approved December 19, 
2020 and January 12, 2021.Extended follow-up for patient reported outcomes that 
are collected within the ongoing cohort data collection is feasible and will be done 
for 48 weeks.  

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Study Schedule: 
First-patient-in (planned): March 2021 
Last-patient-in (planned): July 2021  
Last patient out (planned 48 week visit): July 2022 
We anticipate that 3 months of recruitment will be sufficient for a pilot study focusing 
on the specific endpoints  
All follow-ups will be conducted in the frame of the ongoing cohort studies (i.e. 
SHCS and STCS). 

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Investigator(s): 
Principal investigator: 
Prof. Heiner C. Bucher MD MPH 
Basel Institute for Clinical Epidemiology & Biostatistics  
Universitätsspital Basel und Universität Basel  
Spitalstrasse 12 
4031 Basel, Switzerland 
Phone: +41 (0)61 328 61 01 
Email: heiner.bucher@usb.ch  
 
Investigators: 
Benjamin Speich, PhD 
Basel Institute for Clinical Epidemiology & Biostatistics  
Universitätsspital Basel und Universität Basel  
Spitalstrasse 12 
4031 Basel 
Email: benjamin.speich@usb.ch   
 
PD Michael Koller, MD MSc 
Transplantationsimmunologie und Nephrologie, Datenzentrum Swiss Transplant 
Cohort Study  
Universitätsspital Basel und Universität Basel  
Spitalstrasse 12 
4031 Basel 
Switzerland 
Email: Michael.koller@usb.ch 
 
Prof. Nicolas Müller MD  
Klinik für Infektionskrankheiten und Spitalhygiene 
Universitätsspital Zürich und Universität Zürich 
Rämistrasse 100 
8091 Zürich 
Email: nicolas.mueller@usz.ch 
 
Prof. Huldyrch Günthard MD PhD 
Universitätsspital Zürich und Universität Zürich 
Rämistrasse 100 
8091 Zürich 
Email: huldrych.guenthard@usz.ch 
Spitalstrasse 12 
4056 Basel 
Switzerland 
 
Prof. Andri Rauch MD PhD 
Inselspital, Universitätsspital Bern 
Freiburgstr. 16p 
3010 Bern 

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Email: andri.rauch@insel.ch  
 
Prof. Matthias Briel MD, PhD, MSc 
Basel Institute for Clinical Epidemiology & Biostatistics  
Universitätsspital Basel und Universität Basel  
Spitalstrasse 12 
4031 Basel  
Email: matthias.briel@usb.ch 
 
PD Lars G. Hemkens, MD, MPH 
Basel Institute for Clinical Epidemiology & Biostatistics  
Universitätsspital Basel und Universität Basel  
Spitalstrasse 12 
4031 Basel 
Email: lars.hemkens@usb.ch  
 
Trial statistician: 
Frédérique Chammartin, PhD 
Basel Institute for Clinical Epidemiology & Biostatistics  
University Hospital Basel 
Spitalstrasse 12 
4056 Basel 
Switzerland 
Email: frederique.chammartin@usb.ch 
 
 
Study Centre(s): 
A multi-center study of 4 study centres of the SHCS and STCS (with multiple 
transplantation programs at centers within the STCS).   
Statistical 
Considerations: 
All specified outcomes will be descriptively summarized for the two vaccine arms, 
as well as for important subgroups. This is a pilot study. Once relevant sub-group 
results of the phase III licensing vaccine trials pertinent to patients of this trial are 
published we will explore whether powering the trial for non-inferiority of the second 
licensed vaccine compared to the first licensed vaccine  is feasible.  
GCP Statement: 
This study will be conducted in compliance with the protocol, the current version of 
the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as 
well as all national legal and regulatory requirements.  
 
 
 

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ABBREVIATIONS 
 
AE 
Adverse Event  
BASEC 
Business Administration System for Ethical Committees, 
(https://submissions.swissethics.ch/en/) 
BOD 
Burden of disease 
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
Competent Ethics Committee 
COVID 
Corona virus diseases 
CRF 
Case Report Form  
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin, in Italian: OSRUm) 
CONSORT 
Consolidated Standards of Reporting Trials 
eCRF 
Electronic Case Report Form  
CTCAE 
Common terminology criteria for adverse events 
DSUR 
Development safety update report 
FDA 
Food and drug administration 
GCP 
Good Clinical Practice  
GMT 
Geometric mean titers 
IB 
Investigator’s Brochure 
Ho 
Null hypothesis 
H1 
Alternative hypothesis 
HIV 
Human Immunodeficiency Virus 
HRA 
Federal Act on Research involving Human Beings (in German: HFG, in French: 
LRH, in Italian: LRUm) 
IMP 
Investigational Medicinal Product 
IIT 
Investigator-initiated Trial 
ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
MD 
Medical Device  
MedDO 
Medical Device Ordinance (in German: MepV, in French: ODim) 
PI 
Principal Investigator  
RBD 
Receptor binding domain 
RECORD 
REporting of studies Conducted using Observational Routinely-collected Data 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SDV 
Source Data Verification  
SHCS 
Swiss HIV Cohort Study 
SOP 
Standard Operating Procedure 
SPC 
Summary of product characteristics 

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SPIRIT 
Standard Protocol Items: Recommendations for Interventional Trials 
STCS 
Swiss Transplant Cohort Study 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File  
 
 
 

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STUDY SCHEDULE  
 
 
STUDY PERIOD 
 
 
Eligibility 
Enrolment, 
randomisation 
& vaccination 
Post-randomisation 
TIMEPOINT 
Approximately 
-12 weeks 
Day 0 
Week 12 
(±7 
days) 
Week 48 
(±7 
days) 
Continuous 
follow-up 
in 
the frame of 
the cohort  
ENROLMENT: 
Eligibility screena 
Eligibility assessment 
Informed consent 
Allocation 
 
 
 
 
 
Xa 
 
 
 
 
X 
 
 
 
 
 
Xa 
X b 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
Group A: Vaccine 1 
 
X 
 
 
 
Group B: Vaccine 2 
 
X 
 
 
 
ASSESSMENTS: 
 
 
 
 
 
BASELINE 
VARIABLES 
(will 
be 
exported from routine cohort data) 
Baseline blood sample  
X 
 
 
 
 
IGG neutralizing antibodies post 
randomisation 
but 
prior 
to 
vaccination 
 
X 
 
 
 
CLINICAL OUTCOMES: 
Xe 
Xe 
 
 
 
- Immune response IgG neutralizing 
antibodies  
 
X 
xc 
 
 
- Newly confirmed asymptomatic 
SARS-CoV-2 infection 
 
 
xc 
xc,d 
x d 
-Newly 
confirmed 
symptomatic 
SARS-CoV-2 infection  
 
 
xc 
xc,d 
x d 
- Severe COVID-19 infection with 
respiratory failure, evidence of 
shock, organ failure, admission to 
ICU, or death 
 
 
xc 
xc,d 
x d 
- Adverse events from vaccines 
 
 
xc 
 
 
-Serious adverse events  
 
 
xc 
xc,d 
x d 
- PCR confirmed symptomatic 
infections of household members 
 
 
xc 
xc.d 
x d 
aContinuous assessment and selection from routinely collected cohort data 
bEnrolment and concealed allocation of patients with informed consent will be performed during the same visit when the study is 
explained to the patient, or, if preferred, during a separate arranged study visit. 
cAssessed in separate data entry form for the trial  
d Assessed by routine data collection from cohort database 
eBaseline blood samples will be taken from previous cohort visits (no longer than 6 months) or during cohort and randomisation 
visits at day 0.  
 
 

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1. STUDY ADMINISTRATIVE STRUCTURE  
A safety committee consisting of two infectiologists not otherwise involved in the trial and a biostatistician 
will be formed to oversee patient enrolment and efficacy and safety issues in regard to vaccines used 
during the pilot trial.  
 
1.1 Sponsor-Investigator  
 
University Hospital Basel 
Prof. Heiner C. Bucher MD MPH 
Basel Institute for Clinical Epidemiology & Biostatistics  
University Hospital Basel 
Spitalstrasse 12 
4056 Basel 
Switzerland 
Phone: +41 (0)61 328 61 01 
Email: heiner.bucher@usb.ch 
 
1.2 Local Principal Investigator(s)  
Dr. Marcel P. Stoeckle 
Basel HIV Cohort 
Div. of Infectious Dieseases and Hospital Epidemiology 
University Hospital Basel 
Petersgraben 4 
4031 Basel 
 
Prof. Huldrych Günthard 
Zürich HIV Cohort 
Klinik für Infektionskrankheiten und Spitalhygiene  
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
Dr. Anna Lena Eichenberger 
Bern HIV Cohort 
Universitätsklinik für Infektiologie 
Freiburgstrasse 16p, Haus 5, Stock E 
3010 Bern 
 
PD Dr. Macé Schuurmans 
STCS Zürich (Lung-transplantations) 
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
Prof. Thomas Müller 
STCS Zürich (Kidney transplantation) 
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
PD Dr Oriol Manuel 
STCS CHUV Lausanne (Solid organ transplantations) 
CHUV 
Service des maladies infectieuses 
Rue du Bugnon 46 
CH-1011 Lausanne, Vaud 
 
Prof. Matthias Cavassini 

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CHUV Lausanne HIV 
CHUV 
Service des maladies infectieuses 
Rue du Bugnon 46 
CH-1011 Lausanne, Vaud 
 
Prof. Thomas Müller 
STCS (Kidney) Zürich 
Klinik für Nephrologie  
Universitätsspital Zürich 
Rämistrasse 100 
8091 Zürich 
 
Prof. Michael Tamm 
STCS (Lung) Basel 
Universitätsspital Basel 
Pneumologie 
Petersgraben 4 
4051 Basel 
 
Prof. Michael Dickenmann  
STCS (Kidney) Basel 
Universitätsspital Basel 
Transplantationsimmunologie & Nephrologie 
Petersgraben 4 
4051 Basel 
 
1.3 Statistician ("Biostatistician")  
 
Dr. Frédérique Chammartin 
Basel Institute for Clinical Epidemiology & Biostatistics  
University Hospital Basel 
Spitalstrasse 12 
4056 Basel 
Switzerland 
Email: frederique.chammartin@usb.ch 
 
1.4 Laboratory 
Dr. sc.nat. Dr.med. Irene A. Abela 
Institut für medizinische Virologie 
Universität Zürich 
Winterthurerstrasse 190 
8057 Zürich 
 
1.5 Co-investigators  
PD Michael Koller, PhD 
Transplantationsimmunologie und Nephrologie, Datenzentrum Swiss Transplant Cohort Study  
Universitätsspital Basel und Universität Basel  
Spitalstrasse 12 
4031 Basel 
Switzerland 
Email: Michael.koller@usb.ch 
 

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Dr. Speich, Benjamin, PhD 
PD Dr. med. Hemkens, Lars G. 
Prof. Matthias Briel MD, PhD, MSc 
Basel Institute for Clinical Epidemiology and Biostatistics 
Departement Klinische Forschung 
University Hospital Basel 
Switzerland 
 
Prof. Nicolas Müller MD  
Klinik für Infektionskrankheiten und Spitalhygiene 
Universitätsspital Zürich und Universität Zürich 
Rämistrasse 100 
8091 Zürich 
Email: nicolas.mueller@usz.ch 
 
Prof. Huldyrch Günthard MD PhD 
Universitätsspital Zürich und Universität Zürich 
Rämistrasse 100 
8091 Zürich 
Email: huldrych.guenthard@usz.ch 
Spitalstrasse 12 
4056 Basel 
Switzerland 
 
Prof. Andri Rauch MD PhD 
Inselspital, Universitätsspital Bern 
Freiburgstr. 16p 
3010 Bern 
Email: andri.rauch@insel.ch 
 
 
1.6 Monitoring institution 
 
No external monitoring is planned during the pilot study. Central monitoring of data entry into the trial 
platform and cohort database will be done within the routine procedures by the local cohort data 
managers and the biostatistician responsible for the sub-study pilot trial.  
 
1.7 Data Safety Monitoring Committee  
An independent data safety monitoring board (IDSMB) will be established which will be advisory to the 
Trial Committee that constitutes of the PI and the co-investigators. The IDSMB will be regularly informed 
by the primary investigator, the primary co-investigator, and the trial biostatistician on any safety aspects 
and on serious adverse events from vaccinations from the first sub-study protocol.  
For future sub-study protocols that may involve adding or dropping of study arms based on results from 
interim analyses a detailed action plan, an analysis with stopping rules for harm, benefit and futility will 
be established. The IDSMB has to decide which data from the interim analyses has to be shared with 
the trial committee. Prior to a (first) interim analysis the IDSM and the Trial Committee will meet to review 
potential scenarios following the interim analysis and will agree on the communication prior and after 
the interim analysis to trial sites and study participants. The following independent scientists have 

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agreed to be part of the IDSMB: 
- 
Tracy Glass, PD, PhD; Biostatistician at the Swiss Tropical and Public Health Institute (Swiss 
TPH) 
- 
Prof. Andreas Widmer, former vice head of department for Infectious Diseases & Hospital 
Epidemiology at the University Hospital Basel 
- 
Prof. Pietro Vernazza, Head of the department for Infectious Diseases, Kantonal Hospital St. 
Gallen. 
 
1.8 Any other relevant Committee, Person, Organisation, Institution  
Not applicable. 
 
1.9 Authors contributions 
Heiner Bucher (HB); Michael Koller (MK); Matthias Briel (MB); Lars Hemkens (LG); Frédérique 
Chammartin (FC); and Benjamin Speich (BS) designed the study. Nicolas Müller (NM); Huldyrch 
Günthard (HG); Andri Rauch (AR); Daniel Smith (DS) and Katharina Kusejko (KK) gave scientific input. 
BS and HB wrote the first draft of the protocol. All authors critically revised and approved the final version 
of the study protocol. HB acquired funding for the trial.  
 

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2. ETHICAL AND REGULATORY ASPECTS  
Before the study will be conducted, the master protocol, as well as the sub-protocol (which defines the 
actual intervention plus additional inclusion and exclusion criteria) will be submitted to a properly 
constituted Competent Ethics Committee (CEC). The decision of the CEC will be made in writing to the 
Sponsor-Investigator before commencement of this study. The study will not start recruiting patients 
before receiving ethical approval. We have contacted Swissmedic for a “Pre-assessment clinical trial 
with complex design”. Swissmedic rated a pilot trial of licensed vaccines as category A study with no 
further need of approval from Swissmedic (see separately submitted document: Email exchange with 
Swissmedic). All sub-study protocol and changes to the master-protocol are subject to additional ethical 
approval. 
 
2.1 Study registration  
 
The trial platform and sub-studies protocols is registered with the U.S. National Institutes of Health 
(www.clinicaltrials.gov) under NCT04805125. The trial platform and sub-studies protocols will also be 
registered with the Koordinationsstelle Forschung am Mensch (kofam).  
 
2.2 Categorisation of study  
 
Category A. This study will use vaccines against SARS-CoV-2, which have been licensed by 
Swissmedic in accordance with the prescribing information approved by Swissmedic and which - by 
guidelines from  the BAG and Kommission für Impffragen - may be used in immune suppressed 
individuals when considering the individual benefits and risks.  
 
2.3 Competent Ethics Committee (CEC)  
 
The Principle/Sponsor Investigator will ensure that approval from an appropriately constituted 
Competent Ethics Committee (CEC) is sought for the study.  
Changes of the protocol will be implemented, unless to prevent immediate danger, without prior Sponsor 
and Ethics committee approval.  
Premature study end or interruption of sub-study protocols will be reported within 15 days. The regular 
end of the sub-study protocol and the trial platform is reported to the CEC within 90 days, the final study 
report shall be submitted within one year after study end. Amendments are reported according to chapter 
2.10. 
2.4 Competent Authorities (CA)  
 
To obtain approval from Swissmedic is not planned as this will be a Category A study (see also “2. 
Ethical and regulatory aspects” and “2.2. Categorisation of study”). 
2.5 Ethical Conduct of the Study 
 
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki (1), the guidelines of Good Clinical Practice (GCP) issued by ICH, 
in case of medical device: the European Directive on medical devices 93/42/EEC and the ISO Norm 
14155 and ISO 14971, the Swiss Law and Swiss regulatory authority’s requirements. The CEC and 
regulatory authorities will receive annual safety and interim reports and be informed about study 
stop/end in agreement with local requirements.  
All staff involved in the trial will have to fulfil requirements in regard to training, data management and 
data analysis. 
Writing of protocol and final manuscripts will be in adherence with reporting standards of SPIRIT (2), 

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CONSORT (3) and RECORD (4). 
2.6 Declaration of interest  
 
This investigator-initiated trial will be conducted with public support by Swiss National Science 
Foundation grant #177499 (Swiss HIV Cohort Study), grant # 31CA30_196245 (COVID-19 call) and 
33CS30_134267/1 (Swiss Transplant Cohort Study). The sponsor of this trial is the University Hospital 
of Basel. All participating investigators and authors declare no conflict of interests. 
2.7 Patient Information and Informed Consent 
Cohort participants will be contacted by the local centers and invited to get an appointment at the site 
vaccination center for a vaccination against SARS-CoV-2 or get information about vaccines and the trial 
during cohort visits. When a potentially eligible patient is visiting a local cohort centre, the investigators 
will explain the nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits and any discomfort it may entail. Each participant will be informed that the 
participation in the study is voluntary and that he/she may withdraw from the study at any time and that 
withdrawal of consent will not affect his/her subsequent medical assistance and treatment. Only patients 
who do want to get vaccinated independently of the trial will be approached for trial participation. Patients 
will have sufficient time to ask questions and to consent to trial participation. Patients are allowed to 
consider trial participation at a sub-sequent visit and to have time to consider trial participation.  
Participants have already provided written informed consent that their data, stored plasma and blood 
cell samples that are routinely collected within the Swiss HIV Cohort Study and the Swiss Transplant 
Cohort Study are used by authorised researchers of both cohorts other than their treating physician in 
the frame of the ongoing cohort studies. 
All participants for the study will be provided with a participant information sheet which can be handed 
out to patients during or prior to cohort visits or by mailing. The consent form describing the trial and 
providing sufficient information for participants to make an informed decision about their participation in 
the study will be given to patients during cohort visits. The patient information sheet as well as the 
consent sheet will be submitted to the CEC for review and approval. Based on the patient’s preferences 
the random assignment will be done during the same visit or at a later time point (i.e. within the next 14 
days).  
The formal consent of a participant, using the approved consent form, must be obtained before the 
participant is submitted to any study procedure.   
The participant should read and consider the statement before signing and dating the informed consent 
form, and should be given a copy of the signed document. The consent form must also be signed and 
dated by the investigator (or his/her designee) at the same time as the participant signs, and it will be 
retained as part of the study records. 
 
2.8 Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study (including sub-studies) is 
considered confidential and disclosure to third parties is prohibited. Subject confidentiality will be further 
ensured by utilising subject identification code numbers to correspond to treatment data in the computer 
files. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator), a competent 
authority (e.g. Swissmedic), or an ethics committee may require direct access to parts of the medical 
records relevant to the study, including participants’ medical history. 
 
2.9 Early termination of the study  
The Sponsor-Investigator may terminate the trial platform and/or a sub-study prematurely according to 
certain circumstances, for example: 
 
ethical concerns, 

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 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, 
 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise,  
 
evidence of harm from investigated vaccines  
 
2.10 Protocol amendments 
Substantial amendments are only implemented after being discussed amongst the study investigators 
and after approval of the CEC. The start or closure of a sub-study will be added to the master-protocol 
as an amendment and are reported to the CEC.  
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-
being of human subjects may proceed without prior approval of the sponsor and the CEC. Such 
deviations shall be documented and reported to the sponsor and the CEC as soon as possible. 
All minor amendments that have no direct effect on the study conduct and are of primarily administrative 
nature will be recorded. These changes will be reported to the CEC on the Principal Investigator 
discretion. All changes will be documented in the final results publication of the pilot study.  
 
 
 
 

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3. BACKGROUND AND RATIONALE  
3.1 Background and Rationale  
A new highly contagious corona virus SARS-CoV-2 has emerged in late 2019 in Wuhan, China, and caused in a 
two months period a pandemic with the highest disease burden in elderly and people with pre-existing medical 
conditions (5-7). HIV positive individuals are suffering from multiple comorbidities in particular cardiovascular 
disease and diabetes due to aging, risk factors for chronic diseases and life style factors, which put them at higher 
risk of complicated Sars-CoV-2 infection (8). Whether poor immune recovery in the presence of antiretroviral 
therapy is associated with increased risk of Sars-CoV-2 infection and complicated infection is unclear. End of 
October 2020 100 Sars-CoV-2 infections 22 hospitalisations and 2 deaths due to Sars-CoV-2 were noted in the 
SHCS. 
Likewise solid organ transplanted patients are suffering from multiple chronic conditions like cardiovascular disease 
and diabetes and treated with immunosuppressive drugs putting them at risk of multiple infections and severe 
infection related complications.  
On the April 3rd 2020 21 patients had a documented Covid-19 infection. Twenty patients were hospitalized, 5 were 
transferred to the ICU, 4 of them required mechanical ventilation and two renal transplant recipients died. An update 
of the number of confirmed SARS-CoV-2 infections by end of August revealed 30 confirmed cases, of which 24 
were hospitalized and 6 patients had died. 
In a situation with no known therapy against SARS-CoV-2 clinical research in Switzerland was ill-prepared at the 
beginning of the pandemic for launching clinical trials for the rapid evaluation of investigative drugs with postulated 
in vitro activities against SARS-CoV-2. Use of routinely collected data for nesting trials into cohort studies with highly 
standardized data collection systems and platform trial design allow rapid patient recruitment and efficient and cost-
saving data collection for the simultaneous evaluation of several treatment options, features which can expedite 
trial protocol development and trial implementation in an epidemic situation (9-13).  
The advantage of using the existing infrastructure of two well-established cohorts is that the processes of rigorous 
follow-up monitoring and collection of high-quality phenotype data is already well established and will be performed 
entirely within the existing cohorts (14, 15). The use of highly standardized routinely collected data for conducting 
intervention trials is a highly efficient and economic approach for trial conduct as exemplified by previous groups. 
Furthermore, a well established trial platform would allow us to react quickly in case of any future outbreak, meaning 
that fewer hurdles need to be overcome to implement a clinical trial. 
At present (December 08 2020) Switzerland has still around 4000 new SARS-CoV-2 infections per day (16). 
Hospitalisations and deaths due to SARS-CoV-2 are high with 18 hospitalisations per 100`000 inhabitants and 11 
per 100’000 deaths and the reproduction rate is still around 1 (16). It remains unclear whether the reproduction rate 
of SARS-CoV-2 can be constantly be kept below 1 during the upcoming winter season.  
According to the Oxford University based vaccines tracker (237 vaccines against Sars-coV-2 are in development 
and 38 are actually undergoing clinical testing (17). Of those 10 vaccines are in phase III (including one non-
replicating viral vector, three inactivated vaccines, one LNP-encapsulated mRNA, and one 3 LNP-mRNAs).  
For example, in the UK, the first vaccine by Pfizer was already approved and others are expected to be evaluated 
soon (18). Hence, it is possible, that one or more SARS-COV-2 vaccines are approved in Switzerland within the 
next weeks. This trial platform with the corresponding master protocol will outline a pilot RCT to test approved 
vaccine candidates in immunocompromised patients. The platform is developed within the infrastructure of two well-
established cohorts in Switzerland, the Swiss HIV Cohort Study (14) and the Swiss Transplant Cohort Study (15) 
and allows to nest trials into the existing cohort data infrastructure. This allows for more efficient patient recruitment, 
and the use of cohort baseline data and for the collection of long-term patient relevant outcome data by taking 
advantage of the routinely collected clinical outcome data. At present, it appears most likely that vaccines by 
BioNTech/Pfizer, Moderna and Oxford University/Astra Zeneca will first FDA emergency act approval and 
accelerated approval by Swissmedic as the Swiss government has already acquired large stocks of these vaccines.  
The trial platform will be ready (before vaccine candidates are available in Switzerland (i.e. vaccines with market 
authorisation by Swissmedic). Therefore, we intend to have the trial platform approved by ethics committee prior to 
authorisation of vaccines in order to accelerate the preparation of the trial. The specific vaccines interventions will 
be approved by supplementary trial sub-protocols. These procedures have been approved by our application to 
Swissmedic which has created a review process for drug approval trials with complicated design. This will allow us 
to start a potential trial in a timely manner when vaccines are available (i.e. after approval of specific sub-protocols). 
The pilot study will assess the functionality of the trial platform and the comparative effectiveness in terms of 
antibody response, clinical and safety outcomes of the first two approved vaccines against Sars-CoV-2 At a later 
stage, the platform can serve for a larger comparative vaccine trial of or can be enriched by new study protocol that 
investigate the comparative effectiveness for example in vaccinated individuals in the cohort that did not achieve 
an immune response after the first vaccine. 
3.2 Investigational Product (treatment, device) and Indication  
Only SARS-CoV-2 vaccines which have market authorisation by Swissmedic will be selected. As soon 
as two potential investigational products are identified, they will be described in detail in a separate sub-
protocol which will also be submitted to the CEC for review and approval. 

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3.3 Preclinical Evidence  
Not applicable as the intervention is not yet selected. As soon as a potential investigational product is 
identified, it will be described in detail in a separate sub-protocol which will also be submitted to the CEC 
for review and approval. 
 
3.4 Clinical Evidence to Date  
Not applicable as the intervention is not yet selected. As soon as a potential investigational product is 
identified, it will be described in detail in a separate sub-protocol which will also be submitted to the CEC 
for review and approval. 
 
3.5 Dose Rationale / Medical Device: Rationale for the intended purpose in 
study (pre-market MD)  
We will use the exact same vaccine dose or doses as described in the Swiss market authorisation by 
Swissmedic.  
 
3.6 Explanation for choice of comparator (or placebo)  
The first two vaccines (Pfizer/BioNTech and Moderna) against Sars-CoV-2 have  been licensed in 
Switzerland on December 21, 2020 and January 12,  2021. For logistic reasons not all patients can be 
vaccinated immediately after licensing. Some vaccines require storage at low temperature (-600 C) 
which makes vaccination at centres necessary. Therefore, it is unlikely that the vast majority from the 
two cohorts will be routinely vaccinated during the time when only one vaccine is available. As soon as 
a second vaccine is approved in Switzerland, we will start our pilot randomised controlled trial, using 
dynamic randomisation technique of minimisation to minimise imbalance allocation to one of two active 
vaccines.  
3.7 Risks / Benefits  
 
Any adverse events will be collected within the trial database which is linked to the two cohort databases.  
Severely immunocompromised patients with a chronic HIV infection or solid organ transplant and 
immunosuppressive drug intake are at higher risk of complications from SARS-CoV-2 infection. 
Therefore, we anticipate that this population is very likely to profit from a SARS-COV-2 vaccine. No 
safety or efficacy data of any vaccine from these populations is currently available, and it is unknown 
whether vaccine related complications in these populations might be increased.  
 
3.8 Justification of choice of study population  
According to the Swiss Federal Office of Public Health, individuals with a condition or therapies that 
weaken the immune system are at especially high risk to have a severe case of COVID-19 disease (19). 
Hence, according to the guidelines from the BAG and Kommission für Impffragen the vaccines may be 
used in immune suppressed individuals when considering the individual benefits and risks in Switzerland, 
we have two national cohorts including such patients, namely the Swiss HIV cohort study (SHCS) (14) 
and the Swiss Transplant Cohort Study (STCS) (15). Combining these two cohorts in the frame of an 
established trial platform is an excellent opportunity to assess the comparative effectiveness and side 
effects of emerging vaccines against SARS-CoV-2. The trial platform will also allow for rapid evaluation 
by an experimental study design of other future interventions.  
 
 

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4. STUDY OBJECTIVES  
4.1 Overall Objective 
The overall objective is to use existing prospectively and routinely collected data from two established 
national cohorts (i.e. SHCS and STCS), to build a flexible trial platform and to test this platform in the 
frame of a randomised comparative effectiveness pilot trial of licensed vaccines against SARS-CoV-2 
in regard to immunogenicity, and efficacy to prevent  infections and related Covid-19 complications in 
immunocompromised patients. The main goals refer to 1) investigating the feasibility for setting up such 
a nested trial platform which makes use of routinely collected highly quality cohort data for patient 
identification, recruitment and outcome assessment and to 2) conducting a pilot trial of licensed vaccines 
against Sars-CoV-2. Such an infrastructure may allow for the accelerated set-up of randomized 
controlled clinical trials which are crucial for the rapid evaluation of new interventions in the situation of 
a pandemic.  
4.2 Objectives related to platform trial set-up and feasibility of cohort based 
patient recruitment, trial inclusion and data collection 
The study seeks to determine the feasibility for the set-up of a trial platform which is nested into the 
existing cohort infrastructures. This setting should guarantee a more efficient identification and 
recruitment of eligible immune compromised patients for intervention trials. For this we will assess a 
number of process parameters that relate to feasibility and recruitment of eligible patients within the pilot 
trial. The parameters of interest are  
  
 
Duration of RCT set up (i.e. time from deciding which interventions will be tested, achieving ethical approval 
until the first patient is randomized). 
 
Time of patient recruitment (i.e. from activation of first study site until (i) 40 and (ii) 380 patients are 
randomized) 
 
Patient consent rate (i.e. proportion of patients giving informed consent out of approached eligible patients) 
 
Proportion of missing data for all baseline variables from routinely collected cohort data (baseline variables 
are listed under “Measurements and procedures”) compromising future co-factor adjust in trial efficacy 
evaluations 
 
Proportion of missing data for all clinical outcomes from routinely collected cohort data and outcome data that 
is collected in the trial platform (clinical outcomes are listed below) 
 
 
4.3 Objectives related to a platform based nested pilot trial to investigate the 
comparative effectiveness of vaccines against Sars-CoV-2 
The study seeks to determine the following SARS-CoV-2 related objectives (for detailed definitions see 
under 5 study endpoints) which are all developed according to FDA recommendations for phase III 
Covid-19 vaccine licensing trials (20)): 
 
Immune response (pan-Ig antibodies against the receptor binding domain (RBD) in the S1 
subunit of the spike protein (pan-Ig anti–S1-RBD) of SARS-CoV-2. 
 
newly PCR-confirmed asymptomatic SARS-CoV-2 infection,  
 
newly PCR-confirmed symptomatic SARS-CoV-2 infection   
 
severe COVID-19 infection,  
 
COVID-19 burden of diseases (BOD)   
 
Patient reported asymptomatic or symptomatic infections of household members.  
 
Safety parameters 
o 
Adverse events from vaccines and  
o 
Serious adverse events  
4.4 Safety Objectives 
To evaluate the safety of vaccines in immunocompromised patients and risks for adverse events (AEs) 
and serious adverse events (SAEs). 
 
 
 

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5. STUDY OUTCOMES  
Due to the exploratory nature of the pilot study, no specific primary objective is defined. We distinguish 
three type of endpoints: immunological endpoints, clinical vaccine related effectiveness endpoints and 
vaccine related safety endpoints. 
 
5.1 Immunological Outcomes  
 
The best predictor of antibody mediated protection is assessed with neutralisation assays, in which the 
ability of patient serum to prevent virus infection in in-vitro assays is measured. These assays, however, 
are too labour intense for the purpose of this trial. The binding antibody response against the S1 (RBD) 
of spike protein of SARS-CoV-2 as assessed serological tests show a high correlation with neutralisation 
titers (21, 22).  
Therefore, we will use a commercial immunoassay Elecsys® Anti-SARS-CoV-2 S for the in vitro 
quantitative determination of antibodies to the SARS-CoV-2 spike (S) protein receptor binding domain 
(RBD) in human serum and plasma (23). This assay detects pan-Ig antibody response (pan-Ig anti–S1-
RBD) and allows for a quantitative assessment of the serological response of the participants at baseline 
and three months after vaccination. Additionally, we will qualitatively measure anti-Nucleocapsid (N) 
responses with Elecsys® Anti-SARS-CoV-2 N assay to gain a broader insight on the immune response 
of the participants. 
Finally, we will assess SARS-CoV-2-binding antibody responses of the participants by analyzing the 
IgM, IgA and IgG responses to a wider range of SARS-CoV-2 proteins (S1, S2, RBD and N using an in-
house method (ABCORA 2.0) established at the Institute of Medical Virology (IMV), UZH). The ABCORA 
2.0 test has an advantage over commercial available tests, as it allows a parallel assessment of IgG, 
IgM and IgA reactivity to multiple antigens enabling a high-dimensional temporal resolution of antibody 
responses and a dissection between humoral responses to an infection and vaccination.  
 
5.2 Clinical Outcomes 
 
The clinical effectiveness endpoints are (according to FDA recommendations for phase III Covid-19 
vaccine licensing trials (20)) of the following:  
- 
Newly PCR-confirmed asymptomatic COVID-19 infection (identified by the presence of anti–
SARS-CoV-2 nucleocapsid antibodies or Sars-Cov-2 PCR or rapid antigen test) and no related 
symptoms [(i.e. fever or chills, cough, shortness of breath or difficulty breathing, fatigue, 
muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny 
nose nausea or vomiting, and diarrhea]) at any time point in within 48 weeks following 
randomisation.   
- 
Newly PCR-confirmed symptomatic COVID-19 infection with at least one of the following 
symptoms (i.e. fever or chills, cough, shortness of breath or difficulty breathing, fatigue, 
muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny 
nose nausea or vomiting, and diarrhea at any time point in within 48 weeks following 
randomisation 
- 
Severe COVID-19 infection with respiratory failure, evidence of shock (as diagnosed by a 
treating physician), clinically significant acute renal, hepatic, or neurologic dysfunction; 
admission to an intensive care unit; or death at any time point in within 48 weeks following 
randomisation. 
- 
COVID-19 burden of diseases (BOD), a composite of the above endpoints. The BOD is will be 
scored as by using 0 for no COVID-19, 1 for non-severe COVID-19, and 2 for severe COVID-
19. 
 
An additional clinical effectiveness endpoint is patient reported asymptomatic or symptomatic 
infections of household members.  
 
All clinical outcomes will be measured in the trial database during a follow-up period of 48 weeks after 
randomisation and vaccination.   
 

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5.3 Other Outcomes of Interest 
None. 
  
5.4 Safety Outcomes 
 
5.4.1 Collection of solicited local and systemic adverse events will for feasibility reasons be reduced 
to: 
 
any local symptom (redness or swelling or prolonged pain at injection side) limiting 
continuation of normal daily activities during the first 7 days after vaccination  
 
any systemic symptom (fever, generalized muscle or joint pain) limiting continuation of normal 
daily activities during the first 7 days after vaccination  
 
any vaccine related symptom leading to contacting a physician during the first 7 days after 
vaccination 
6. STUDY DESIGN  
6.1 General study design and justification of design  
 
This is a pilot trial which is based on a trial platform that is integrated into the ongoing routine prospective 
data collection of two national cohorts, the SHCS and STCS. Eligibility of trial participants will be 
checked from routinely collected cohort data. Baseline data collection is done within cohorts. 
Randomisation and follow-up data collection of clinical trial endpoint data is done within the trial platform 
which is linked to the cohort database. The trial platform is overseen and managed by the two data 
centres of the SHCS and STCS.  
A parallel two-arm open-label randomized controlled exploratory pilot trial comparing the first approved 
SARS-CoV-2 vaccines is planned to compare the immunogenicity, clinical effectiveness and safety of 
the first two licensed vaccines against Sars-CoV-2. The details of the intervention and control group will 
be described in a sub-protocol following the licensing of vaccines. Enrolment of patients is explained in 
figure 1.  Cohort data centres will identify eligible patients based on routinely collected cohort data and 
eligible patients will be contacted for consent for participation prior to randomisation. Randomisation will 
be performed through minimisation with respect to cohort (SHCS, STCS), center, age (<65, ≥65 years 
old), sex, immune-suppression (<200 CD4 cells/μl in SHCS and uninterrupted prednisone treatment of 
at least 6 months in addition to standard immunosuppression.in STCS) and a random element that 
reduces randomisation predictability. The trial platform allows to expand the pilot trial and to add further 
sub-study protocols to evaluate for example vaccine strategies in patients with a first vaccination but 
insufficient or lacking immune response (Figure 1). 
The COVID-19 pandemic has revealed a need for research infrastructure such as trial platforms, which 
allow for fast and efficient evaluation of multiple preventive and therapeutic interventions in case of 
infectious disease outbreaks. Ideally, trial platforms make use of already existing data infrastructures 
such as cohorts or registries. Once implemented, the present protocol is meant to provide orientation 
and guidance for other trial platforms.     
 
 

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Figure 1 Trial platform for immune compromised patients from the SHCS and STCS   
 
 
6.2 Methods of minimising bias  
6.2.1 
Randomisation  
Randomisation will be performed through minimisation with respect to centre, age (<65, ≥65 years old), 
sex, immune suppression and a random element. This will ensure that we control for imbalance in each 
treatment arm while reducing the predictability of the randomisation. The randomisation will be centrally 
implemented into the current electronic system which all cohort centres are using. In short, the 
“treatment preference” is written in Python and embedded in the Django framework (plus external 
Python script for STCS). With R, the random allocation scheme is generated. Depending on the 
preference, the treatment is then assign with the help of the allocation table. Randomisation will be 
conducted separately for each cohort. 
 
6.2.2 
Blinding procedures  
As we plan to embed the pilot trial as good as possible into the clinical routine and into the management 
of patient in clinical routine and within the cohort study infrastructure, we do not plan to blind treating 
physicians or patients. Further, also outcome assessors will not be actively blinded. Large part of the 
outcomes will be collected through routinely collected data (see “5. Study outcomes”). Analysis of 
immunological parameters will be blinded in regard to treatment groups. All the critical clinical endpoints 
of severe COVID-19, deaths and serious adverse events will be adjudicated by an infectiologist blinded 
to vaccine allocation.   
6.2.3 
Other methods of minimising bias  
Reasons for drop outs or loss to follow-up will be assessed and investigated with the routinely 
established processes endorsed by each cohort to minimize attrition bias. Loss to follow-up in both 
cohorts is small. In the SHCS in 2019 0.5 of patients died and 2.6 dropped out and in the STCS from 

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2008 to 2019 only 76 of 5672 patients were lost to follow-up (1.3%).  
 
6.3 Unblinding Procedures (Code break)  
Not applicable as the study has an open design.  
 

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7. STUDY POPULATION  
This is a multi-centre study recruiting patients from 4 of the 7 study centres of the SHCS and 2 of the  
the 6 study centres of the STCS.: 
 
SHCS study centres:  
 
Department of Infectious Diseases, Bern University Hospital, University of Bern 
 
Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel 
 
Division of Infectious Diseases, University Hospital Lausanne, University of Lausanne 
 
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University 
of Zurich 
 
 
STCS study centres: 
 
 
Klinik für Pneumologie, and Klinik für Nephrologie, Universitätsspital Zürich 
 
CHUV Lausanne, Service des maladies infectieuses, Clinique pour pneumologie et 
nephrologie 
 
Universitätsspital Basel, Pneumologie 
 
Universitätsspital Basel, Transplantationsimmunologie & Nephrologie,  
 
 
The cohorts are explained in more detail elsewhere (14, 15, 24, 25). The study will be explained to 
eligible patients during their visit at the cohort centre. These visits will not be scheduled specifically for 
the purpose of this study. 
7.1 Eligibility criteria  
 
Inclusion criteria: 
 
- All patients registered with informed consent from participating cohorts aged ≥18 years 
- Additional consent for participation in the specific sub-protocol 
 
Exclusion criteria: 
 
- Acute symptomatic SARS-CoV-2 infection, influenza or other acute respiratory tract infection 
- Known allergy or contra-indications for vaccines or any vaccine components 
- Any emergency condition requiring immediate hospitalization for any condition 
- Patients with previous PCR documented SARS-CoV-2 infection and, or documented antibodies in the 
last 3 months prior to screening visit (day 0).  
 
 
Inclusion and exclusion criteria will be specified further when eligible interventions are identified 
(i.e. in a separate sub-protocol). 
 
 
7.2 Recruitment and screening  
 

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Specific eligibility criteria can be defined and implemented by the trial platform data base which is based 
on all clinical and laboratory cohort data and managed by the cohort data centres (figure 2 and 
separately submitted electronic Case Report Form). Both cohorts have developed a clinical information 
system that summarizes all relevant clinical and laboratory information for patients and widely serves 
as a clinical management and decision support system. This system allows to flag all eligible patients 
by centre and centre physician and to make this information for the pilot trial available in the clinical 
information and data entry system. Thus, trial eligibility information will appear on the online cohort data 
entry form which is used by all participating cohort centres and physicians for data entry during cohort 
visits. When an eligible patient is coming to a planned cohort visit or in between consultation the treating 
physician will recognize the patient as eligible when open the patient specific data entry form and initiate 
the recruitment process. In case of logistic needs, patients may also be actively contacted and invited 
to come to the study centre for vaccination independent of the trial and will then be additionally informed 
about the purpose of this trial. This is line with the priority list established by the BAG for vaccination of 
high risk patients for Covid-19 infection (Details are defined in the first sub-study protocol). The eligibility 
checks, consent process and randomisation will be embedded into existing regular cohort or scheduled 
in between visits and done in a separated GCP conform clinical trials data collection system that is 
linked to both cohorts. The treating physician will explain the currently ongoing study to eligible patients 
and inform them about potential risks and benefits. According to the patients’ preferences, the 
randomisation can be done during the same visit or at a later appointment. 
7.3 Assignment to study groups  
For randomisation treating physicians will use a link function in the clinical information and data entry 
form and be linked to the web-based platform trial data entry and randomisation page. After rechecking 
all inclusion and exclusion criteria and after having the trial participation consent formed singed patients 
will be assigned to study groups using minimisation with a random element across a number of 
stratification factors to control for imbalance in each treatment arm ( stratification factors are cohort 
(STCS, SHCS), centre, age group, sex and presence of comorbidities). 
Patients not consenting to participate will be vaccinated according to clinicians’ judgement and be 
followed within the cohorts. 
The trial platform will allow for adaptive randomisation for future trials.  
 
 
 
 
Figure 2: Randomisation of cohort participants with informed consent for trial participation 
 

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7.4 Criteria for withdrawal / discontinuation of participants  
Enrolled patients have always the opportunity to withdraw from the trial without mentioning any specific 
reason at any time. In addition, patients can also state that they do not wish to be contacted for the 
study anymore and that also their physician shall not be contacted for outcome assessment. As the 
vaccines which will be assessed in this study (will be described in more detail in separate sub-protocol) 
will most likely be applied as a two-time injection, patients may withdraw from receiving a second vaccine 
shot. Eventual revaccination in patients with no immune response or loss of immune response will be 
handled by an additional sub-study protocol for these patient populations or will be conducted by 
individual clinicians’ decision according to best clinical management outside of a study protocol. In case 
a second sub-study protocol will be developed for patients with no or insufficient immune response at 
12 weeks follow-up, patients entering the second sub-study protocol will be censored within the firstsub-
study pilot trial.   
 
 

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8. STUDY INTERVENTION  
(SPIRIT #11) 
8.1 Identity of Investigational Products (treatment / medical device)  
 
8.1.1 
Experimental Intervention (treatment / medical device) 
The first SARS-CoV-2 vaccine receiving market authorisation is Switzerland. The specific intervention 
will be described in a separate sub-protocol as soon as the intervention is available. 
 
8.1.2 
Control Intervention (standard/routine/comparator treatment / medical device)  
The second SARS-CoV-2 vaccine receiving market authorisation is Switzerland. The specific 
intervention will be described in a separate sub-protocol as soon as the intervention is available. 
 
8.1.3 
Packaging, Labelling and Supply (re-supply)  
We plan to receive vaccines through hospital pharmacies or directly through available capacities from 
study centres. Original packaging and labelling (i.e. no re-packaging or re-labelling required) will be 
used. The usual vaccine bar code tags and batch number will be stored according to local clinical 
practice or patient vaccination cards as made available by local clinics or vaccine producers. Vaccine 
batch numbers will be entered into the trial platform database.  
 
8.1.4 
Storage Conditions  
Vaccines will be stored at necessary temperatures at cohort clinical centres according to 
recommendations provided by vaccine producers.  
 
8.2 Administration of experimental and control interventions  
8.2.1 
Experimental Intervention  
 
The one-time (or two time, if required) injection will be applied by the treating physician or designated 
clinic or study nurses from the participating study centres. The specific intervention will be described in 
a separate sub-protocol as soon as the intervention is available. 
 
8.2.2 
Control Intervention 
The one-time (or two time, if required) injection will be applied by the treating physician or designated 
clinic or study nurses from the participating study centres. The specific intervention will be described in 
a separate sub-protocol as soon as the intervention is available. 
 
8.3 Dose / Device modifications  
 
The vaccines which will be assessed in this study (will be described in more detail in separate sub-
protocol) will most likely be applied as a one-time injection. A modification of treatment is therefore not 
possible 
8.4 Compliance with study intervention  
The application of the one-time injection by the treating physician (or a delegated person) will be 
documented in the trial platform data entry form.   
 

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8.5 Data Collection and Follow-up for withdrawn participants  
Patients have the right to withdraw the planned follow-up visits. Clinical outcomes for those patients will 
be assessed from routinely collected cohort data.  
 
8.6 Trial specific preventive measures 
 
Trial specific permitted treatment as in usual care are based on the clinical judgment of the physician. If 
there are specific non permitted interventions (as indicated by the Swissmedic leaflet of the approved 
vaccine), this will be indicated in the separate sub-protocol. 
 
8.7 Concomitant Interventions (treatments)  
 
Concomitant interventions are allowed whenever necessary as in usual care based on the clinical 
judgement of the physician. If there are specific concomitant interventions that are not allowed (as 
indicated by the Swissmedic leaflet of the approved vaccine), this will be indicated in the separate sub-
protocol. 
 
8.8 Study Drug / Medical Device Accountability  
 
Vaccines will be delivered by the hospital pharmacies of participating cohort centres. 
8.9 Return or Destruction of Study Drug / Medical Device  
Since the vaccines will be a product which has received marked authorisation in Switzerland, unused 
products could be potentially used for other patients based on the clinical judgement of physicians. 
 
 
 
 

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9. STUDY ASSESSMENTS  
9.1 Study flow chart(s) / table of study procedures and assessments 
Eligible cohort patients will be informed about the study during their next visit (not study related) at one 
of the cohort centres. Patients willing to participate can decide to consent and be randomised during the 
same visit or at a separately planned visit (see study schedule). Planned study visits are at 12 and 48 
weeks after randomisation. Next to that, patients will be followed-up in the frame of the SHCS and the 
STCS.  
 
Data collection and patient assessment is based on trial platform which is nested into the routinely data 
collection of the two cohorts. All relevant baseline data will be gathered within the cohort infrastructure. 
All trial relevant endpoints will be collected within the trial platform infrastructure. Several endpoints like 
hospitalisations and death will continue to be collected in the cohort database as the assessment of 
theses outcomes is required by the cohort study protocols.  
 
The following trial baseline data will be used from the routinely collected cohort base database:  
SHCS:  
Age, sex, education, working status, co-morbities (diabetes mellitus, hypertension, dyslipidemia, 
coronary heart diseases and strokes, body mass index), depression, smoking, alcohol and illicit drug 
use, current antiretroviral therapy and any co-medication, first HIV antibody test or inclusion into cohort, 
CD4 cell nadir, latest CD4 cell count & HI viral load, glomerular filtration rate, SARS-CoV-2 PCR and 
antibodies (IgM & IgG), hepatitis C virus (HCV) and chronic hepatitis B virus (HBV) infection, contact 
with a person with a documented SARS-CoV-2 infection, documented SARS-CoV_2 infection, date of 
diagnosis, hospitalization due to SARS-CoV-2 infection.  
STCS: 
Routinely collected relevant baseline data from the STCS include age, sex, ethnicity, history of 
transplantation, organ-specific pre-transplant history, length of hospital stay due to actual transplantation, 
patient medical history (cardiopulmonary diseases, metabolic diseases, endocrine diseases, kidney 
diseases, history of cancer and other events and diseases), history of major infectious diseases, 
immunosuppressive treatment history, patient- and organ-specific lab assessment data, transplant 
immunologic assessments, pre-TX serologies (HBV, HCV, CMV, HIV, EBV, Toxo, Tpha, HSV, VZV), 
HLA tissue-typing, allograft biopsy (date and ID), drug prescription data (induction, mantenance 
immunosuppression, infectious diseases prophylaxis, other drugs), occurrence of any post-transplant 
infectious disease including SARS-Cov-2, STCS: education, profession, working capacity, medication 
adherence, smoking history, drug addiction). 
 
9.2 Assessments of outcomes  
 
9.2.1 
Assessment of feasibility outcomes 
 
 
Duration of RCT set up (i.e. time from deciding which interventions will be tested until the 
first patient is randomized). 
 
The date when the scientific committee/trial investigators decide which intervention will be tested will be 
documented. The date when the first patient is randomized will be capture in the centralised 
randomisation system. 
 
 
Time of patient recruitment (i.e. from activation of first study site until 40 patients are randomized) 
 
The date when the first study centre starts enrolling patients will be documented. The date when the 
first 40 patients and the last patient (number 380) are randomised will be captured in the centralised 
randomisation system. 
 

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 
Patient consent rate (i.e. proportion of patients giving informed consent out of approached 
eligible patients). 
 
Investigators will capture in the electronic system from the separate cohorts if a potential eligible patient 
was informed about the study and if the patient was actually included (i.e. randomised). 
 
 
 
Proportion of missing data for all baseline variables from routinely collected cohort data 
(baseline variables are listed under “Measurements and procedures”) 
 
For all baseline variables defined under 9.1 we will assess the proportion of missing data. 
 
 Proportion of missing data for all clinical outcomes from routinely collected cohort data and 
outcome data that is collected in the trial platform (clinical outcomes are listed below) 
 
For all defined clinical outcomes we will assess the proportion of missing data. 
 
9.2.2 
Assessment of immunological endpoints 
 
We will assess pan-IgG anti S (RBD) (quantitative) and anti- N antibodies (qualitative) with the 
commercial Elecsys® Anti-SARS-CoV-2 S and N tests at baseline and at 12 weeks following 
randomisation and vaccination. Patients will be invited to see their treating physician 12 weeks after 
randomisation (see Study schedule). During baseline and follow-up visits this visit a blood sample will 
be taken (EDTA blood (2 x  7.5 ml)) and assessed for the above listed antibodies: 
 
1ml for Elecsys® Anti-SARS-CoV-2  N and S tests (performed locally at each laboratory) 
 
2ml EDTA Plasma for ABCORA 2.0 test (performed at IMV, UZH) 
EDTA blood should be processed within 24h and EDTA plasma should be stored at -20°C. For ABCORA 
2.0 antibody measurements plasma samples will be collected at each center and a collective shipment 
will be sent after baseline and at 12 weeks after randomization and vaccination to the IMV, UZH. One 
sample will be stored according to SHCS and STCS protocols for later eventual analyses at the centers 
of University Hospital Zurich.  
 
9.2.3 
Assessment of clinical endpoints 
Patients are informed to contact center physicians in case an asymptomatic or symptomatic SARS-Cov-
2 infections was diagnosed outside the settings of participating cohort centers. Clinical endpoints will be 
assessed at 12 and 48 weeks, and during each cohort visits, that fall in between the trial specific visit 
dates.  
 
Newly PCR-confirmed asymptomatic Covid-19 infection (identified by the presence of anti–
SARS-CoV-2 nucleocapsid antibodies ,or PCR or rapid antigen test) and no related symptoms 
[(i.e. fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body 
aches, headache, new loss of taste or smell, sore throat, congestion or runny nose nausea or 
vomiting, and diarrhea]) at any time during the 48 weeks of follow-up   
During all visits at the trial centres (study specific at 12 and 48 weeks, as well as cohort visits) a PCR 
SARS-COV-2 test will only be conducted if the treating physician would also conduct such a test during 
clinical routine (e.g. exposure to infected individual). PCR tests done in between independently will be 
recorded with dates and results.  In case of a positive test result, physicians will check for symptoms 
and patients will be followed-up according to clinical routine and physicians’ judgement. 
 
 
Newly PCR-confirmed symptomatic Covid-19 infection with at least one of the following 
symptoms (i.e. fever or chills, cough, shortness of breath or difficulty breathing, fatigue, 
muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny 
nose nausea or vomiting, and diarrhea) at any time during the 48 weeks of follow-up 
During all visits at the trial centres (study specific at 12 and 48 weeks, as well as cohort visits) a PCR 
SARS-COV-2 test will only be conducted if the treating physician would also conduct such a test during 

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clinical routine (e.g. COVID-19 related symptoms; exposure to infected individual).  In case of a positive 
test result, physicians will check for symptoms and patients will be followed-up according to clinical 
routine and physicians’ judgement. 
 
 
 
Severe COVID-19 infection with respiratory failure, evidence of shock (as diagnosed by a 
treating physician), clinically significant acute renal, hepatic, or neurologic dysfunction; 
admission to an intensive care unit; or death at any time during the 48 weeks of follow-up. 
 
 
 
Covid-19 burden of diseases (BOD), a composite of the above endpoints. The BID is will be 
scored as by using 0 for no COVID-19, 1 for non-severe COVID-19, and 2 for severe COVID-
19. 
 
The burden of diseases endpoint will be assessed by combining the before listed outcomes (i.e. no 
COVID-infection, non-severe COVID-19 infection 
 
 
Patient reported asymptomatic or symptomatic infections of household members.  
Patients will be asked at the 12-week and 48-week visit if a household member was diagnosed with 
COVID-19. 
 
9.2.4 
Assessment of safety outcomes 
9.2.4.1 
Adverse events following vaccination 
 
Any local symptom (redness or swelling or prolonged pain at injection side) continuation of 
normal daily activities during the first 7 days after vaccination  
During the 12-week visit, patients will be asked if they had any local symptoms which limited 
their daily activities during the first 7 days after vaccination. 
 
 
Any systemic symptom (fever, generalized muscle or joint pain) limiting continuation of 
normal daily activities during the first 7 days after vaccination. 
 
During the 12-week visit, patients will be asked if they had any systemic symptoms after 
randomisation which limited their daily activities during the first 7 days after vaccination.  
  
 
Any vaccine related symptom leading to contacting a physician during the first 7 days after 
vaccination 
During the 12-week visit, patients will be asked if they had to contact a physician within 7 days 
after vaccination. 
 
9.2.4.2 
Serious adverse events  
For reporting of serious adverse events we will adhere to the ICH E2A guidelines (26) and define a 
serious adverse event (experience) or reaction ‘as any untoward medical occurrence that at any dose 
results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing 
hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth 
defect. Exemptions will be SARS-CoV-2 related deaths or SARS-CoV-2 related hospitalisations, which 
are among the assessed clinical outcomes. The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe’.  
 
 
 
9.2.4.3 
Laboratory parameters 
Specify laboratory parameters to be assessed; define when abnormal laboratory parameters will be 

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considered as adverse events, define time-points of assessment; describe sampling if deviating from 
hospital routine; specify tests to be used (e.g., for pregnancy: blood, urine; urinalysis); describe analysis 
of samples: local or abroad, if abroad, describe procedure for shipment, storage until shipment; if not 
yet known, refer to instruction to be written for the study team and to be part of the study manual. 
Laboratory parameters besides immune response parameters will be assessed at bi-annually cohort 
visits according to the cohort protocols.  
 
9.2.4.4 
Vital signs 
Not relevant for purpose of this trial.  
9.2.5 
Assessments in participants who prematurely stop the study 
All clinical outcomes will be assessed from routinely collected cohort data which will also be available if 
patients decide to prematurely stop participating in the clinical trial. 
 
9.3 Procedures at each visit 
9.3.1 
Eligibility (and eventual enrolment  randomisation) 
Visit 1; Day -90 – 0: All patients from the two cohorts (i.e. SHCS and STCS) will prospectively be 
assessed for eligibility based on the cohort study based trial platform. Eligible patients will be either 
contacted ahead by cohort centres and informed about the trial and availability of vaccines or directly 
informed during in between visits or cohort study visits. Based on the patients preferences they will have 
the option to start participating in the study (i.e. sign consent form, being randomised and eventually 
receiving the intervention or control) during the same visit or at a separate agreed on visit (see also 
“Study schedule”). Patients requiring vaccination without trial participation will be vaccinated.  
 
 
9.3.2 
Enrolment and randomisation 
Visit 2; Day 0: Patient will return the signed consent form which will also be signed by the treating 
physician. The patient will then be randomised by the treating physician and receive the intervention or 
control (applied by treating physician or delegated personnel). For patients who were already enrolled 
and randomised during visit 1, visit 2 will be skipped (see also “Study schedule”). For women in 
childbearing age it is required to make sure that they are not pregnant (i.e. conduct a pregnancy test) 
before they get vaccinated and a contraception is required for 12 weeks after the first vaccination dose. 
 
9.3.3 
Follow-up 1 week 12 
Patients will be asked with 3 questions in regard to side effects from vaccination during the first week 
following vaccination. Occurrence of asymptomatic or symptomatic COVID-19 infection, serious COVID-
19 infection and hospitalisation for any reason will be investigated, the dates of events will be requested 
and entered into the trial data collection form. All routine data and blood samples following protocols of 
the SHCS and STCS will be collected as usual and entered into the respective cohort database.  
A blood sample will be taken for investigating post- vaccination immune status at week 12 in all patients.  
9.3.4 
Follow-up 2 week 48 
Occurrence of asymptomatic or symptomatic COVID-19 infection, serious COVID-19 infection and 
hospitalisation for any reason will be investigated, the dates of events will be requested and entered into 
the trial data collection form. All routine data and blood samples following protocols of the SHCS and 
STCS will be collected as usual and electronically forwarded into the respective cohort databases.  
A blood sample will be taken for investigating post- vaccination immune status. 
 
 
 

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10. SAFETY  
10.1 Drug studies 
We follow the definition of the ICH E2A guidelines (26). An Adverse Event (AE) is any untoward medical 
occurrence in a patient or a clinical investigation participant administered a pharmaceutical product and 
which does not necessarily have a causal relationship with the study procedure. An AE can therefore 
be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. ICH E6 1.2 
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
 
results in death, 
 
is life-threatening, 
 
requires in-patient hospitalization or prolongation of existing hospitalisation, 
 
results in persistent or significant disability/incapacity, or 
 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in death, or 
require hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the 
other outcomes listed above should also usually be considered serious. ICH E2A 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at study 
termination (including safety visit) will be further followed up until recovery or until stabilisation of the 
disease after termination.  
 
Assessment of Causality 
Both Investigator and Sponsor-investigator make a causality assessment of the event to the study drug, 
based on the criteria listed in the ICH E2A guidelines: 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
Note that other categories can be used. However, a definition has to be provided in the protocol. 
 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator’s Brochure for drugs that are not yet 
approved and Product Information for approved drugs, respectively). ICH E2A 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, causality 
and expectedness. If the event is related to the investigational product and is both serious and 
unexpected, it is classified as a SUSAR. The information if the SAE is a potential SUSAR is a mandatory 

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field in our electronic case report form for SAEs (see separately submitted electronic case report form). 
 
Assessment of Severity 
The “Common Terminology Criteria for Adverse Events CTCAE Version 6.0” (27) terminology is going 
to be used to assess the severity of adverse events (i.e. 1 – Mild, 2 – Moderate, 3 – Severe, 4 – Life-
threatening, 5 – Death).  
 
10.1.1 Reporting of serious adverse events (SAE) and other safety related events  
All SAEs must be reported within 7 days to the Sponsor-Investigator of the study. The Sponsor-
Investigator will be averted in case a local investigator is reporting a SAE in the trial electronic data 
system by the cohort data centers. The Sponsor-Investigator will confirm or adapt the SAE and return 
the form to the site. 
SAEs resulting in death are reported to the Ethics Committee via BASEC within 7 days. 
The other in the trial involved Ethics Committees receive SAEs resulting in death in Switzerland via 
Sponsor-Investigator via BASEC within 7 days. 
Exemptions will be SARS-CoV-2 related deaths which are one of the assessed clinical outcomes. 
 
Reporting of SUSARs 
SUSARs will be reported to the Ethics Committee via BASEC within 7 days if the event is fatal, or within 
15 days (all other events). The Sponsor-Investigator must inform all Investigators participating in the 
clinical study of the occurrence of a SUSAR. All in the trial involved Ethics Committees will be informed 
about SUSARs in Switzerland via BASEC according to the same timelines. .  
 
Reporting of Safety Signals 
All suspected new risks and relevant new aspects of known adverse reactions that require safety-related 
measures, i.e. so called safety signals, must be reported to the Sponsor-Investigator within 24 hours. 
The Sponsor-Investigator must report the safety signals within 7 days to the Ethics Committee (local 
event via local Investigator) via BASEC. 
Closure of a sub-study protocol due to a negative benefit-risk ratio is reported to the Ethics Committee 
within 7 days.  
The Sponsor-Investigator must immediately inform all participating Investigators about all safety signals. 
The other in the trial involved Ethics Committees will be informed about safety signals in Switzerland via 
the Sponsor-Investigator. 
 
Reporting and Handling of Pregnancies 
Participation of pregnant women will be decided when vaccine related safety reports and 
recommendations are published by the producers. At present natural history data indicate no increased 
adverse pregnancy outcome of women with Sars-CoV-2 infection (28):   
Periodic reporting of safety 
No annual safety report will be submitted as this will be a Category A study. 
 
 
10.1.2 Follow up of (Serious) Adverse Events 
During the study every step is taken to ensure, that all (S)AEs are identified and documented. Treating 
doctors and study centres are responsible to treat the (S)AEs and follow-up (S)AEs. At the last follow-
up at week 48  it is ensured, that all (S)AEs are identified and well treated. If a (S)AE occurs, all efforts 
will be undertaken to treat these (S)AEs (i.e. antiallergic treatment in case of an allergic reaction) and 
follow-up until it is resolved is ensured. If patients are lost to follow-up at the last follow-up visit, at least 
3 attempts to contact them (by call and letter) should be made to contact them and assess why they 
were lost to follow-up.  
 

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10.2 Medical Device Category C studies 
Not applicable. 
 
10.3 Medical Device Category A studies 
Not applicable. 
 
10.4 Assessment, notification and reporting on the use of radiation sources 
Not applicable. 
 
 
 

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11. STATISTICAL METHODS  
 
11.1 Hypothesis 
The goals are 1) to assess the functionality of our trial platform that is nested in established national 
cohort (i.e. STCS and SHCS) and 2) to run a comparative effectiveness pilot trial of the first two licensed 
vaccines against SARS-CoV-2 infection with the aim to compare immunogeneity, safety and clinical 
efficacy of these vaccines in immunocompromised patients. We aim to power our trial to test for non-
inferiority of the immune response of the second licensed vaccine compared to the first licensed vaccine 
in randomised individuals from both cohorts. Formal hypothesis testing will be formulated in a separate 
sub-protocol.  
 
11.2 Determination of Sample Size  
This study is planned as a pilot study and aims to enrol patients for a period of 3 months. Sample size 
calculation will be provided in a separate sub-protocol, once relevant sub-group results of the phase III 
licensing vaccine trials pertinent to patients of this trial are published. We aim to power the pilot trial for 
non-inferiority of the immune response of the second licensed vaccine compared to the first licensed 
vaccine 
 
11.3 Statistical criteria of termination of trial  
For future sub-study protocols that may involve adding or dropping of study arms based on results from 
interim analyses a detailed action plan, an analysis plan with stopping rules for harm, benefit and futility 
will be established.  
No interim analysis is planned during the pilot trial and termination will not be based on any statistical 
criteria. 
 
11.4 Planned Analyses  
 
11.4.1 Datasets to be analysed, analysis populations 
Patients will be analysed according to their allocated randomisation group (intention to treat [ITT]). The 
pilot trial will inform us on the amount of missing variables. We will not have missing baseline information 
that define eligibility criteria or that are considered for the randomisation. The amount of missing values 
for the clinical outcomes will be assessed (see section 11.5. Handling of missing data and drop outs for 
more details).   
 
11.4.2 Feasibility analysis 
Actual time spans will be reported (i.e. how long it took to (i) set up the trial; and (ii) enrol patients 
(accrual time)). Proportion and number of consenting patients and missing data will be reported. 
 
11.4.3 Analyses of immunological and clinical outcomes 
 
Immunological outcomes at 12-week follow-up will be reported as frequency and percentage of positive 
serologic immune response for both vaccine arms and we will test for non-inferiority of the second 
licensed vaccine versus the first licensed vaccine.  
Clinical outcomes and patient-reported outcomes of household members will be described for both 
treatment arms. Detailed analysis will be provided in a separate sub-protocol.  

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11.4.4 Interim analyses 
No interim analyses will be done.  
 
11.4.5 Safety analysis 
Safety endpoints will be reported for each study arm using summary statistics (frequencies and 
percentages). We expect safety issue to be small and do not believe that we will have enough power to 
demonstrate any statistical difference between the treatment arms.  
 
11.4.6 Deviation(s) from the original statistical plan  
If there are any deviations from the pre-specified analysis planned, these will be clearly indicated and 
justified in the publication of the primary results. 
 
11.5 Handling of missing data and drop-outs  
We will report the number of drop-outs and reasons for drop-outs for each treatment arm separately. 
Reasons for drop-outs will be carefully explored for a deeper understanding of the drop-outs. In this pilot 
study, patients with missing outcomes will be dropped from the clinical outcome assessments. Patient 
characteristics of the dropped population will be compared to patient characteristics of the trial 
participants that have an outcome to avoid further bias.   
 
 

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12. QUALITY ASSURANCE AND CONTROL  
12.1 Data handling and record keeping / archiving  
 
12.1.1 Case Report Forms  
Data will be recorded with electronic Case Report Forms (eCRF) provided by the REDCap Software. 
For each enrolled study participant, a eCRF is maintained. A unique patient identifier will be used to 
identify patients (i.e., the same identifiers used in the respective cohorts, Swiss HIV Cohort Study 
(SHCS) and Swiss Transplant Cohort Study (STCS)). 
All participating physicians will be authorized to enter data in the eCRF. 
 
12.1.2 Specification of source documents  
Source data will include all study documents, like e.g. informed consent forms, online AE/SAE forms 
etc. Source data will be available at all sites and may be found in paper or electronic form. 
All source data is available at the local cohort centers via the routine cohort data collection and online 
display forms. 
Source data are the routinely collected and under 9.1 defined baseline data, all routinely within the 
cohort structure collected laboratory and the clinical endpoint and safety data and immunogeneity 
parameters which will be collected within the trial data collection infrastructure.  
 
12.1.3 Record keeping / archiving  
All study data will be archived for a minimum of 10 years after study termination or premature termination 
of the trial. Data will be extracted from REDCap and stored on the server of the University of Zurich. 
Any study relevant paper documents will be archived at each site for a minimum of 10 years. 
 
12.2 Data management  
Study data will be captured via REDCap, based at the data centre of the Swiss HIV Cohort study. The 
data collected is entered into the study eCRF. Baseline data available in the two participating cohorts 
(SHCS and STCS) is transferred directly from the cohorts into REDCap. The REDCap platform offers 
an audit trail to maintain a record of initial entries and any changes made, time and date of entry, user 
name of the person authorizing entry or change. The principal investigator at the study site will be 
responsible for assuring that the data entered into the eCRF is complete, accurate, and that the entry 
and updates are performed in timely manner. 
If a patient withdraws from the trial or is lost to follow up, the reason for drop-out will be reported on the 
corresponding eCRF. If the patient withdraws from the cohort, a cohort specific stop follow-up form is in 
place. 
 
12.2.1 Data Management System  
The eCRF will be implemented by the data centre of the SHCS at the University of Zurich using REDCap. 
REDCap is installed on the server of the University of Zurich and maintained by the IT department of 
the University of Zurich. Additional storage capacity can be added if needed. Data entry will be 
performed by participating clinicians. 
 
12.2.2 Data security, access and back-up  
The REDCap platform is accessible via a standard browser on devices with internet connection. 
Password protection ensures that only authorized study investigators, monitors and local authorities (if 
necessary) will have access to the data during and after the study. User administration is centrally done 
by the cohort data centers, and user training is performed online by the Principal investigator and local 
responsible investigator. REDCap offers an audit trail system maintaining a record of initial entries and 
changes made, time and date of entry, and user name of person authorizing entry or change. 

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Back-up of REDCap data is performed daily at the server of the University of Zurich. As the trial platform 
and sub-studies are nested into the existing data-bases of the SHCS and STCS patient IDs from the 
respective cohorts are taken when cohort participants are enrolled into a sub-study.  
 
12.2.3 Analysis and archiving 
The REDCap project will be locked after eCRF data entry is completed, all data has been monitored 
and raised queries have been resolved. The complete study data set is exported from the REDCap 
database and transferred to the study statistician as well as the principal investigator through a secure 
channel. The statistical analysis will be performed by the involved statistician at the University Hospital 
of Basel. The exported data will be archived for 10 years at the server of the Swiss HIV Cohort Study at 
the University of Zurich. 
 
Details and analysis and archiving are listed in the appendix documents 1 and 2.  
 
12.2.4 Electronic and central data validation  
Data entered into the REDCap platform will be validated for completeness and discrepancies 
automatically. In addition, the data will be reviewed by the responsible investigators . A regular download 
of the database will be performed and checked by the study statistician for missing values and 
correctness. All investigators have to respond to any resulting query and confirm or correct the 
corresponding data. Thereafter, the query can be closed. 
 
12.3 Monitoring  
Data monitoring will be exclusively done centrally within the infrastructure and processes established 
by each cohort. Weekly check-up of data entries into the clinical trial platform is done by the central data 
manager and the trial biostatistician.  
The following central data monitoring steps are planned. 
Patient recruitment will be centrally controlled and compared with the total number of eligible patients 
per center and cohort and the number of patients enrolled. 
Selection bias: Baseline characteristics of patients included into the trial and those vaccinated outside 
the trial can be compared to check whether the trial population is representative in respect to the cohort 
population.  
Trial inclusion: The responsible biostatistician/data manager will regularly check whether no patients 
violating an inclusion / exclusion criteria is recruited into the trial.  
Population description: The responsible biostatistician/data manager will check whether according to 
the baseline cohort data used for the pilot trial is complete and no data is missing (see also feasibility 
endpoints).  
Intervention: For each patient included into the trial local data managers and the central data managers 
will check whether patients received the same first and booster vaccines within a 3 weeks period. Co-
medication will be recorded within the cohort data base infrastructure. 
Primary endpoint: Site responsible investigators will regularly check that all samples are taken and 
stored at the site laboratories and shipped to the central laboratory. The trial data manager / 
biostatistician will control that all samples results are adequately entered into the trial platform data base. 
Secondary endpoints: Local and central cohort data managers will regularly check that all secondary 
endpoints are completely entered into the trial platform and into cohort data base. 
 
On-site monitoring visits are possible according to GCP 5.0.4, in case larger quality breaches are 
identified during the central data monitoring.  
 
12.4 Audits and Inspections  
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questions are answered during inspections. All involved parties must keep the patient data strictly 
confidential. 
Both cohorts have an annual local inspection at each center in place with random charts checks for 
consistency of all data entries.  
 
 
12.5 Confidentiality, Data Protection  
Direct access to source documents will be permitted for purposes of monitoring, audits and inspections. 
Study data entered into the eCRF is only accessible by authorized persons. Once all data is entered 
into the REDCap platform and monitoring is completed, the database will be locked and closed for 
further data entry. The complete dataset is then exported and transferred to the study statistician as well 
as the principal investigator through a secure channel. 
 
 
12.6 Storage of biological material and related health data  
 
Samples of serum and cells are collected in the SHCS biannually and in the STCS linked to the current 
transplantation and harvested at baseline, and the 6-month and 12-month visit. Procedures for data 
sampling and storage according to the cohorts’ standards are described in the appendix documents 1 
and 2. 
 

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13. PUBLICATION AND DISSEMINATION POLICY  
All trials that are set-up within the trial platform and results from sub-studies will be published (also 
negative results or if a trial has to be discontinued) open access in peer-reviewed journal publications. 
We intend to publish this master protocol together with the subsequent sub-protocols in a peer reviewed 
journal and on Open Science Framework (OSF). Authorship to publications will be granted according to 
the rules of the International Committee of Medical Journal Editors (ICMJE). 
 
 
 

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14. FUNDING AND SUPPORT  
 
14.1 Funding  
This study receives financial support from the Swiss National Science Foundation (grant # 
31CA30_196245). The Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) 
are funded by the Swiss National Science Foundation (grant #177499) and (grant 33CS30_177522), 
respectively. The funders have no role in designing, conducting, analysing and publishing trial results. 
 
14.2 Other Support  
Benjamin Speich is supported by an Advanced Postdoc.Mobility grant (P300PB_177933) and a return 
grant (P4P4PM_194496) from the Swiss National Science Foundation  
15. INSURANCE  
As the assessed intervention will be an approved SARS-CoV-2 vaccine (Category A study), no separate 
insurance is required.  
In case this study will receive another risk categorisation, an insurance will be provided by the sponsor 
which will be acquired after receiving ethical approval for the master protocol and the sub-protocol (proof 
will be submitted to the CEC before the first patient is enrolled).   
 
 
 
 
 

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16. REFERENCES  
 
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17. APPENDICES 
 
Appendix document 1 
 
Data Management Plan for the routinely collected cohort data SHCS 
Issues  
 
1 Data 
collection and 
documentatio
n 
 
1.1 What 
observational 
data is 
collected 
observed and 
generated? 
 
Data collection: 
SHCS questionnaires: Demographic, clinical, laboratory and risk 
behavior data is collected in biannual follow-up visits from all SHCS 
participants. All SHCS variables are listed in the publicly available 
code book www.shcs.ch/307-shcs-code-book. The data package is 
distributed in the form of csv-files, Access file and STATA dta-files. 
Volume: 62 tables, 800 MB 
 
SHCS bio bank: Plasma and cell samples are stored of every SHCS 
participant. The SHCS bio bank contains around 450’000 plasma and 
cell samples, and around 90’000 DNA samples. Information about the 
samples is distributed along with the SHCS questionnaire 
information. 
 
SHCS resistance data base: The SHCS drug resistance data base 
contains around 24’000 sequences of 12’000 patients in the format of 
FASTA files. 
1.2 How is 
routinely 
collected 
cohort data 
collected, 
observed or 
generated?  
- What 
standards, 
methodologie
s or quality 
assurance 
processes will 
you use?  
 
Standards and methodology: Data collection in the SHCS follows 
detailed 
standardized 
operating 
procedures 
(SOPs), 
see 
http://shcs.ch/238-handbooks. Details about every collected variable 
(data type, e.g. free text, choice, binary) is described in the publicly 
available code book, see www.shcs.ch/307-shcs-code-book  
 
Quality assurance processes: The SHCS data entry tool includes a 
three-step quality control. In a first step the physician/study nurse 
enters the data, in a second step a local data manager or research 
associate verifies the entries, in a third step, the entries undergo a final 
check at the datacenter. Integrated audit trails allow the tracking of 
changes at any time. Each registry includes the name of the person 
who collected the information and data of collection. Each time a 
follow-up visit has been registered, a graphical summary of the most 
relevant clinical data is sent to the physician. This feedback is a 
supplementary quality control and motivates the physician in 
reporting data of good quality. In addition, at least once a year, a 
collaborator of the data center visits each of the 7 collaborating 
centers. The quality of the information collected at the follow-up visits 

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is checked on a random sample of documents. The collaborator of the 
data center extracts the data from the patient chart and compares the 
result with the data previously reported. 
 
The database of the SHCS consists of more than 70 data tables, which 
are ordered by topic (eg demographic data, clinical data, treatment 
data, event data, laboratory data). The tables are available in 
different formats (including CSV, Access and STATA .dta files). 15 
Tables are descriptive and include metadata, which provide 
information on data interpretation (eg explanation of the codes used 
for diseases, medications, laboratory values etc.). Detailed metadata 
on SHCS variables is summarized in the SHCS code book, which is 
freely 
available 
on 
the 
open 
SHCS 
website 
http://www.shcs.ch/userfiles/file/code_book/SHCS_Variables_6.2.
pdf. (see also Section 3.1, Data export for research, in the grant 
application) 
 
HIV genotypic resistance tests are performed by four authorized 
laboratories in Switzerland. The sequences are stored in a central 
database (SmartGene; Integrated Database Network System version 
3.9.0). Record linkage is done and allows the SHCS to use these data 
for research. The SHCS has developed specifications, which allow an 
automated transfer of lab values between the university hospitals 
and the SHCS data center. This process is highly efficient and ensures 
a high data quality.  
2.1 How are 
ethical issues 
addressed and 
handled?  
 
The SHCS was approved by the local ethical committees of the participating 
centres: Ethikkommission beider Basel ("Die Ethikkommission beider Basel 
hat die Dokumente zur Studie zustimmend zur Kenntnis genommen und 
genehmigt."); Kantonale Ethikkommission Bern (21/88); Comité 
départemental d'éthique des spécialités médicales et de médecine 
communautaire et de premier recours, Hôpitaux Universitaires de Genève 
(01–142); Commission cantonale d'éthique de la recherche sur l'être humain, 
Canton de Vaud (131/01); Comitato etico cantonale, Repubblica e Cantone 
Ticino (CE 813); Ethikkommission des Kantons St. Gallen (EKSG 12/003); 
Kantonale Ethikkommission Zürich (KEK-ZH-NR: EK-793), and written 
informed consent was obtained from all participants. 
Open data statement: 
The individual level datasets generated or analyzed during the current 
study do not fulfill the requirements for open data access: 
1) The SHCS informed consent states that sharing data outside the SHCS 
network is only permitted for specific studies on HIV infection and its 
complications, and to researchers who have signed an agreement detailing 
the use of the data and biological samples; and 
2) the data is too dense and comprehensive to preserve patient privacy in 
persons living with HIV. 
According to the Swiss law, data cannot be shared if data subjects have not 
agreed or data is too sensitive to share. Investigators with a request for 
selected data should send a proposal to the respective SHCS address. The 

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provision of data will be considered by the Scientific Board of the SHCS and 
the study team and is subject to Swiss legal and ethical regulations, and is 
outlined in a material and data transfer agreement. 
2.2 How will 
data access 
and security 
be managed? 
The SHCS data remain encrypted (no names or addresses are 
collected); they are identified by a five-digit study number. Patients 
personal information is accessible only to individuals who are directly 
involved in the treatment (physicians, consulting staff, laboratory 
staff). Data for research is distributed via a secure drop-file system 
provided by the University of Zurich, the download links are sent to 
researcher who signed the Data transfer agreement. Some key 
variables potentially allowing identification of the patients are 
excluded from the data export for researchers, and are only available 
on request for specific research projects. These variables include the 
date of birth (data export only includes birth year), canton of 
residence, nationality, specific information about the route of HIV 
infection, details on education, etc. The column “access” in the SHCS 
code 
book 
(http://www.shcs.ch/userfiles/file/code_book/SHCS_Variables_6.2.p
df) indicates whether the variable is included in the download for all 
researchers. 
2.3 How will 
you handle 
copyright and 
Intellectual 
Property 
Rights issues? 
Use of SHCS data is regulated by the respective SOPs. Use of data is 
subject to approval of the respective projects by the SHCS scientific 
board. The guidelines for nested research projects are available at 
http://www.shcs.ch/130-guidelines-for-nested-research-projects .  
Data sharing with collaborators is regulated and data transfer 
agreements need to be signed before data is transferred. 
3.1 How will 
your data be 
stored and 
backed-up 
during the 
research? 
This SHCS data is stored centrally at the SHCS datacenter at the 
University of Zurich with standardized back-up protocols. An 
automatic back up is performed every night. 
3.2 What is 
your data 
preservation 
plan? 
SHCS data are stored permanently and are available for future studies 
provided that the respective projects are approved.  
4.1 How and 
where will the 
data be 
shared? 
 
All interested researchers can access SHCS data provided that a 
respective proposal is approved by the SHCS scientific board. The 
SOPs to submit research proposals for everybody are openly available 
on the website since many years and have further been clarified 
(http://www.shcs.ch/132-who-can-submit ). This solution ensures 
both access to data to all interested investigators as well as protection 
of sensitive data of all study participants.  
4.2 Are there 
any necessary 
limitations to 
protect 
sensitive data? 
Open access to all SHCS data is currently not possible, because this 
data is too dense and comprehensive to preserve patient privacy in 
patients with HIV-infection. Free access to all data would not be 
compatible with the SHCS informed consent and with preserving 
patient privacy. The open data statement is publicly available: 

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http://shcs.ch/294-open-data-statement-shcs  
 
Data Management Plan for the routinely collected cohort data STCS 
Issues  
 
1 Data 
collection and 
documentation 
 
1.1 What 
observational 
data is 
collected 
observed and 
generated? 
 
The core data structure of the STCS is the patient-case system: a 
framework that reflects the post-transplant patient process involving 
the collection of a multitude of data on patients, transplantations and 
allografts from transplantation until end of follow-up or death of the 
patient. The STCS data model reflects every transplant type and the 
monitoring of each whatsoever complex transplant scenario.  
The STCS patient-case system allows distinguishing data that accrue 
in relation to the patient from data related to the transplanted 
organ(s). We therefore define a ‘‘case’’ as any solid organ 
transplantation (SOT) of a given patient. A patient may have one or 
several cases, and one case can involve one, or simultaneously more 
than one allograft. Each case nested within a patient has its own time 
axis and follow-up. Patient-data, captures information which is of 
systemic nature and that relates to the patient, but not to the 
transplant itself. In contrast, case (transplant) data captures 
information restricted to the transplantation and to the allograft(s). 
Any SOT in Switzerland since May 2008 is captured in the STCS. 
Patients with any first, re- or second SOT, since May 2008, are 
enrolled in the STCS. A re-transplant is a repetition of the same SOT 
after failure of the previous transplant, e.g. a kidney re-transplanted 
after loss of function of the previous kidney allograft. A second or 
consecutive SOT refers to a subsequent SOT that differs from the 
previous type of allograft, e.g. a pancreas transplantation following a 
successful renal transplantation.  
The STCS’ data infrastructure consists of the following main layers: 
1. Non-genetic health related personal data from transplant 
recipients, donor-recipient matching data and donor-derived 
allograft data (short “clinical data”) 
2. Genomic data 
3. Bio banking of biological material 
4. Project-related “add-on” data  
5. External “third party” or linkage data.      
Non-genetic health related personal data from transplant recipients 
The STCS data model assigns unique patient and transplant 
identification numbers. Linkage of patient and transplant data allows 
reconstructing the entire transplantation process with longitudinal 
time updating of both patient and transplant information, as well as 

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the capture of intermediate events.  
On the patient-level, data collection involves, content wise: the 
psychosocial 
questionnaire 
(PSQ), 
medication-, 
comorbidity-, 
infectious disease-, cancer-, routine lab-, genetic- and causes-of-death 
data. Specific sections exist for medication data (including induction, 
maintenance immunosuppression, infectious disease prophylaxis and 
a selection of relevant “other” drugs). On the transplant and organ 
level, data collection focuses on the sampling of biological material 
(see 1.2.1 section Biological data (STCS Bio-banking) for further 
information), transplant-program specific data, organ function and 
survival, immunologic events, transplant-specific lab data and causes 
of graft failure. Moreover, biopsy samples that are taken during 
routine transplantation care, either at the time of transplantation 
(time zero biopsy) or during post-transplant follow-up, are important 
for the STCS and entered into the STCS database system. The STCS 
itself does not store biopsy material, but stores the biopsy’s 
identification numbers, which are assigned by the pathology institute 
of the respective center where the biopsy is stored. This means that 
the biopsy material can be made available for given questions within 
the framework of approved nested projects (NP). All non-genetic 
meta-data descriptions including the type, format and content of each 
variable and dataset (eCRF) is available via the electronic metadata 
codebook (ecodebook) of the STCS (https://www.stcs.ch/data-
portal/data-descriptions), in a version control manner.  
After transplantation, each patient remains associated with his or her 
transplant center, the center responsible for the care of the patient 
(“care center”). If two transplant centers simultaneously care for the 
same patient, both centers share and modify the same eCRFs. 
STCS plans to include in the data collection  information as to whether 
the patient has signed the "General Consent" of the transplant center. 
Donor-recipient matching data and donor-derived graft data  
In order to initiate the transplantation process, the transplant team 
needs specific data from the organ donor to test the suitability of an 
organ offer for a given transplant candidate. This pivotal routine data 
is shared with the transplant center by the SOAS or by direct 
communication between clinics prior to organ procurement. If the 
transplant team of the transplant center accepts the organ offer, the 
transplant procedure can be released. The STCS collects a limited set 
of donor-recipient matching data and of (donor-related) graft data to 
assess the matching (e.g. HLA-typing, DSA, blood groups) and the 
quality of the transplanted organ (e.g. donor age, gender, ischemic 
time). Donor-recipient data linkage is ensured via the unique Swiss 
Organ Allocation System IDentification numbers (SOAS-IDs), which 
are centrally generated by the SOAS (FOPH) and transferred to the 
STCS. 
Genetic data 
Individual’s genetic data are obtained from coded biological material 

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(DNA) by large-scale genotyping methods (e.g. genome-wide 
association studies (GWAS) or new generation sequencing (NGS) 
technologies which measures many hundreds of thousands to 
millions variants (e.g. single nucleotide polymorphisms (SNP), 
deletions, insertions, copy number variations (CNV)) at the same 
time. The collection of genetic data for further genetic screening is 
limited to very little personal information, including sex and ethnicity.  
“Add-on” data and biological material 
We refer to as "add-on" data as routine clinical care data or routinely 
collected biological material from transplant centers or closely 
related resources (e.g. related healthcare providers) that are collected 
upon enrolled STCS patients in addition to existing STCS data.  
“Add-on” data are collected in the context of Scientific Committee 
approved NPs and serve to enhance the granularity of the data for a 
specific NP. The NP  investigators are responsible to comply with the 
legislation and for meeting the regulatory requirements for the 
management of “add-on” data (see also Scientific Committee 
Guidelines, 
https://www.stcs.ch/research/information-for-
researchers). Such “add-on” data is collected separately from the STCS 
database system and stored by the investigators. “Add-on” routine 
biological material produced as part of standard treatment can, 
similarly as “add-on” data, be further used for research in compliance 
with regulations in the context of specific NPs. It is important to note 
that each NP is subject to competent EC review and approval, (see also 
Scientific 
Committee 
Guidelines, 
https://www.stcs.ch/research/information-for-researchers).      
External “third party” data sources and data linkage 
We refer to “third party” data as data sources that are independently 
collected and stored from the STCS. Third party data is of interest for 
data quality control or for re-use for research. The STCS and the 
corresponding third party are responsible for the proper 
management of third party data i.e. storage, archiving and further 
use for research according to regulatory requirements. Third party 
data may or may not be linked to STCS data. The STCS re-uses data 
from third parties and shares its data with third parties as part of its 
data governance structure and upon EC approval. Table 1 provides 
examples of third-party data, data sources and the purpose of use. 
However, it is important to note that this summary is not exhaustive 
and that in the future further sources may become available for 
linkage and use for research. 
1.2 How is 
routinely 
collected 
cohort data 
collected, 
observed or 
generated?  
The STCS uses a professional electronic data capture system (EDC) 
with web-based collection and management of clinical data and bio-
bank related data. The STCS IT system is currently hosted by SciCORE 
and maintained by SciCORE and SIMED and has been continuously 
developed over the last years in collaboration with the STCS DC and 
the users at the transplant centers (see section 2.2).  
 

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- What 
standards, 
methodologies 
or quality 
assurance 
processes will 
you use?  
 
What standards, methodologies or quality assurance processes will 
you use? 
1.2.1 Data processing  
Clinical data 
Data can be exported from the STCS DB system at any time. Raw 
encoded STCS data are initially stored within the landing zone of the 
STCS tenant at sciCORE (section 2.2). From there, only authorized 
members of the STCS DC exports the data and securely transfer them 
to the DC via upload to the ownCloud platform, a secure file sharing 
service that is provided by the Clinical Trial Unit Basel. From there, 
the properly formatted raw data tables are stored for further 
processing within the STCS DC within the USB IT secure framework. 
Processed data marts are stored in different user-friendly file formats 
and distributed to end users (researchers) twice a year via a 
password-protected 
web 
interface 
(https://www.stcs.ch/data-
portal/data-downloads) hosted within the STCS tenant on sciCORE. 
Two-factor authentication will soon be implemented to improve 
access control of research data (data and samples access policy).  
All further data steps are performed under the responsibility of the 
STCS DC, like the export validation and the data processing: 
● Export Validation (EVAT) procedure: cross-checking of the 
extracted STCS data versus the STCS electronic codebook 
(eCB) to assess conformity with STCS data definitions (e.g. 
formats, ranges, missing value definitions).  
● Data processing: Rearrangement of the STCS data for the 
purpose of data quality assessment, data quality reporting and 
data analysis (research and reporting).  
o The “Level 2” data processing refers to rearrangement 
of the STCS raw data for the purpose of data quality 
assessment and “hand” inspection of the data; 
o The “Entity Relationship      data” (ER data) and 
“analysis layer” data processing refers to the processing 
of the data ready for statistical analysis with an 
additional option to produce customized data for 
specific research projects. 
1.2.2 Data quality management 
Clinical data 
Data quality checks refer to the totality of automatic software 
processes that perform in depth testing of the accuracy of the STCS 
data. Complex checks that consider several content wise related 
database fields, potentially across different fs are performed on 
database exports based and on specific data processing steps. In 
principle, data are tested for consistency and completeness at the DC 
through the Data Quality management System. 
The STCS Data quality management system (DQMS) is a collection of 
scripts and folders used to assess, report back to the centers and store 

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checks performed about the completeness and consistency of a 
specific extraction of the STCS data.  
Consistencies checks are performed either on a regular      base or they 
are implemented ad hoc, usually for a given research project running 
on the cohort data. The data queries often involve clinical expertise 
and they precisely reflect the data collection processes that go 
alongside transplantation. The DQMS is constantly being expanded. 
Any time a research project finds a discrepancy or a new issue of data 
consistency, we include it in the DQMS and, whenever possible and of 
long-term use, we generalize it.   
Feedback loop and query resolution: identified issues are “queried” 
back to the transplant centers (STCS sites) for resolution. The 
resolution is monitored by direct communication with the study sites 
and by comparing current and previous data extractions. The 
repetitive loops of data checks, site feedback and query resolution, 
expor, data check and monitoring of resolution, etc… lead to an 
ongoing improvement of data quality. Data checks run according to 
defined priorities (Q1, Q2, Q3, project specific) and agreed-upon 
timelines for issues resolution (see table in the appendix A).  
● Q1: checks necessary for the processing of the STCS Annual 
Report 
● Q2: generic checks relevant for most research projects that 
reuse the STCS data (for example query of the drug repository 
(“drug query”), biopsies- and rejection data (“biops- and rj- 
query”), or infectious disease data (“ID query”)). Checks 
involve completeness and consistency. 
● Q3: any checks that have been included thanks to findings from 
a research project or that are carried out on request for a 
specific STCS project. 
 
The DQMS consists of the following objects/structures and it is 
completed by the internal SOP documents: 
● DQMS system directory, accessible from any member of the 
DC, where the scripts and files necessary to create the checks 
output are stored. 
● A structured folder where the output sent to the centers or the 
draft useful to the further assessment of the resolution status 
are stored together with the feedback from the centers. 
● The storage of additional documentation on a project 
management platform (Asana combined with google drives 
documents) where to keep track of the implemented checks 
and addressed issues on the last round. 
Outputs of the data quality system and feedback from the centers are 
stored by the STCS DC      and used to monitor and validate the resolved 
issues on the next extraction of the data. Centers-specific reports are 
distributed to the centers.  
On top of the DQMS a Data Quality Reporting (DQR) tool is being 
gradually implemented by the DC of the STCS. It involves the 

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generation of automatic data quality reports distributed to the STCS 
centers and the project investigators. DQR tools are currently under 
development but will involve the provision of regularly produced 
reports for the different transplant programs, for each transplant 
center and for STCS working groups. The focus is on consistency and 
data completeness. These tools are based entirely on the STCS 
metadata system (eCB).       
 
Quality control by cross-checking with other registries 
Follow-up of patients that return back on dialysis after renal allograft 
failure can be very demanding for the transplant centers. Mortality 
data of patients on dialysis after renal allograft failure is therefore 
cross-checked for data quality purposes with the Swiss Renal Registry 
and Quality Assessment Program (srrqap). 
The Federal Ordinance on Transplantation6 imposes that several 
post-transplant outcome parameters have to be monitored and 
reported to the Federal Office of Public Health (FOPH) on a yearly 
basis (Art. 20). This includes for example a yearly follow-up of all 
transplanted patients or that certain key transplant monitoring data 
recorded by the Swiss Organ Allocation System (SOAS) have to be 
cross-checked with the data from the transplant centers (i.e. the STCS) 
for consistency and accuracy (Art. 20a). Since the STCS is mandated 
by the centers to comply with the legal obligations of post-transplant 
monitoring, the STCS and FOPH cross-check key transplant 
monitoring data on a yearly basis. 
According to Art. 20a 6, the DC receives once per year (since 2017) an 
extraction of SOAS data, is provided by BAG, data since January 2008 
are included. We expect a 100% overlap of the SOAS numbers and of 
the data that are specified in Art. 20a. For each matching SOAS 
number the DC cross checks also the following information: age, 
gender, date of transplant and blood group. The comparison triggers  
a process of revision and feedback between the DC and      the centers 
until the overlap is complete.  
Genetic data 
Genetic data concerns heritable individual’s characteristics obtained 
from their genetic material (DNA) by genotyping or sequencing. 
Participation in genotyping and sequencing is evaluated based on 
STCS signed informed consent. Participants are informed about the 
nature of the research project, the way their genetic data is be 
collected, stored as well as which measures are be taken to protect 
their genetic data.  
Generated genetic data is tested for their quality by competent 
personnel in charge. Measure for quality control (QC) and accuracy of 
genetic data have been taken. It includes principal component 
analyses (PCs), sex determination, call rates, Hardy-Weinberg tests, 
homozygosity runs and imputation of measured SNPs to detect and 
exclude spurious effects of differential genotyping error. For 

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additional control, internal audits may be planned. 
Biological data (STCS Bio-banking) 
Specific management involves the STCS bio-bank where the DC 
collaborates closely with the head and the operational manager of the 
STCS Biobank. The STCS runs a decentralized bio-bank with bio-
banking of samples at each transplant center. Samples (plasma and 
viable cells at 0, 6 and 12 months follow-up, extracted DNA at time 0) 
are processed and stored according to the STCS bio-banking guideline 
and finally registered in the STCS DB by local site personnel.  
Upon SC and EC approval of a STCS NP that involves the STCS bio-
bank, sample lists are generated according to the project protocol by 
the STCS DC. Once the list has been approved by the head of the bio-
bank in collaboration with the operational bio-bank manager, it is 
sent to the local bio-bank (lab) at each involved center where the 
material can be retrieved and sent to the PIs under well-defined 
human material management, according to the ethical guidelines 
(www.stcs.ch).  
STCS LDMs check out the processed samples in the STCS DB by using 
the Sample Manager Tool. A copy of the requested sample list is stored 
at the DC for cross checking the      samples retrieval and for reporting 
purposes. 
Lab audits and sample quality checks are done according to the STCS 
EO’s and BOR’s directive, in collaboration with the head of the STCS 
bio-bank. 
Project-related data management 
According to the requirements specified by a given STCS NP, 
customized data quality management and data processing are often 
needed. The STCS DC, as the primary data requests entry point 
collaborates and specifies with the project investigators the 
requirements for project specific data processing and/or data quality 
management. The DC moreover helps with existing data definitions, 
versioning of the data, and with the definition and linkage of “add-on” 
data 
that 
is 
potentially 
needed 
for 
a 
certain 
project, 
(https://www.stcs.ch/research/information-for-researchers).  
1.2.3 Tools and Software 
● EVAT: Export validation tool 
● DQMS: preprocessed data are selected and merged to test and 
report specific issues that address questions that have been 
raised by an online daily usage of the STCS DB, by previous 
queries or by planned periodical ad-hoc checks. Each 
extraction of the data is checked for completeness and 
consistency of several entries defined over time by quality and 
reporting questions. The so called query system is a repository 
of all scripts of checks run      on each extraction and their 
outcomes. In addition the DC stores all issues addressed to the 

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centers in csv or excel format and their feedback to be able to 
cross check the resolution of the issues. 
● The ER Layer / analysis layer: is a tool that produced a set of 
tables based on preprocessed data with a relational data 
structure that contains all the data entered in the STCS 
application. The main difference to the data exported from the 
STCS application is the data structure and some additional 
variables (e.g. simult, resec, organ…) that can be derived. 
Introduced keys (unique identifier) will help that data can be 
safely merged in a flexible way. 
● Metadata (STCS electronic codebook, eCB, see appendix B). A 
comprehensive web-based repository of all (non-genetic) past, 
current and planned data definitions used in the STCS DB. The 
eCB represents a key query interface that provides full 
versioning of all STCS variables and associated values. The 
technical framework of the eCB allows export of the eCB and 
serves as a data matrix for the data extraction validation, data 
processing and data quality management. The STCS ecodebook 
is machine readable (.csv exports and json exports available) 
● Reporting tools for the STCS Annual Report and Data Quality 
Reports 
All analysis and data processing tools (EVAT, Analysis layer, Query 
tools) are implemented in SAS (Data Management and Advanced 
Analytics https://www.sas.com/de_ch/home.html) or R statistical 
software (The R Project for Statistical Computing, https://www.r-
project.org/). 
 
How will you organize your files and handle versioning? 
All study documents are properly organized and securely stored 
within the file system of the STCS stored within the secure network of 
the University Hospital Basel. An evolving repository of guidelines, 
SOPs, 
and 
STCS 
reports 
are 
publicly 
available 
via 
https://www.stcs.ch/documents 
or 
via 
the 
STCS 
DC 
(https://www.stcs.ch/requests/submit-request, login needed).   
A comprehensive metadata system is in place and provides detailed 
specification and versioning of all variables, eCRFs (collections of 
variables), and data consistency rules (see STCS electronic codebook, 
section 1.3).  
The information stored in the metadata system can be exported and 
is used to implement format and consistency checks, checks for 
completeness, and validation of database exports.  
1.3 
What 
documentation 
and metadata 
will you 
provide with 
the data? 
A comprehensive human and machine-readable metadata system 
(the STCS electronic codebook, eCB) is in place and represents the 
central repository of all non-genetic available data definitions that 
apply in the STCS. The eCB is an independent web-based platform 
hosted by SciCORE, that can be accessed after login. Users need to 
register via https://www.stcs.ch/contact/registration to receive 

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their login after their role in relation to the STCS is verified through 
STCS personnel. Currently access is restricted to STCS members or 
to nested project investigators, but can be set user by user, 
independently from the role. The eCB is a complete electronic 
repository of all current,      past and planned data definitions that 
apply in the STCS. All metadata content can be queried and exported 
(.csv or .json) and is thus fully machine-readable with the purpose to 
support data management, processing (see for example EVAT), and 
analysis. The eCB provides detailed specification of all non-genetic 
variables, formats, values, ranges, measures and units, used 
vocabularies, definitions and descriptions, eCRFs (collections of 
variables), and the mapping of variables into CRFs, dependencies of 
associated variables (records), and coherent classification of 
variables according to their content (e.g. all variables on renal 
transplant rejection, so called c     ategories). Each variable is fully 
version controlled with validity ranges specified by start- and stop-
dates for each version change. Naming conventions and version 
control are implemented for variables, CRFs, system releases, and 
export files (https://www.stcs.ch/data-portal/data-descriptions, 
requires a verified STCS account and login). 
 
What community standards (if any) will be used to annotate the 
(meta)data? 
FAIR speaks to the need to describe the conditions and processes for 
access and reuse after publication of discovered data. FAIR therefore 
requires to openly and richly describe the context within which 
those data were generated and to enable its evaluation of utility. 
FAIR is not equal to open. The concept of FAIR is superordinate to 
open data. As our cohort data are potentially sensitive (e.g. data 
sharing subject to consent, personal privacy of organ recipients and 
donors), they cannot be made freely open. The approach adopted in 
the STCS is to facilitate data reuse by making its metadata open, and 
by implementing a governance which allows distributing the actual 
data in a legally and ethically acceptable way. 
In the situation of the STCS, the FAIR approach can be applied to 
STCS nested projects (NP). The data of a NP corresponds to a 
snapshot i.e. a dataset of a given research project optionally enriched 
by “add-on” data. In this context, the FAIR principles can be applied.  
Findability: Register each NP at an open repository. Different 
repository 
choices 
must 
be 
carefully 
evaluated 
(e.g. 
dataverse@harvard.edu in line with the CTU Basel). Completion of 
the registration process by a research team will involve pushing the 
NP metadata to the repository and creation of a DOI persistent 
identifier for the metadata of the corresponding dataset. DOI 
reassures the long-term (at least 10 years) availability of the 
FAIRified dataset. The metadata are thus indexed in a searchable 
source.  
Accessibility: A user can openly access the metadata, will find the 
contact address and finds the requirements to request data for reuse 

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(e.g. access control in case of sensitive data). To decide upon such 
reuse requests, a Data Access Committee (DAC) must be installed. 
For example, the STCS Scientific Committee or a subgroup thereof 
could adopt the role of the DAC and the STCS DC the role of the 
contact point of entry and the unit to manage reuse requests.  
Interoperability: Semantic interoperability is the sine qua non 
condition for any compliance with FAIR principles. In concrete 
terms, this means the mapping of the values in a STCS NP dataset to 
a well-known semantic structure that is findable and accessible such 
as a commonly used controlled vocabularies or ontologies. To 
comply with FAIR, the semantics of a FAIRified dataset will need to 
be published on the repository. Moreover, for each dataset, the 
atomic elements together with their persistent identifiers must be 
described. For the situation of the STCS the atomic structure is 
complex due to several interrelated data layers.  
Reusability: For the biomedical data of the STCS, the question of the 
data usage license is actually addressed via the ethical consent 
covered in the accessibility part. 
2.1 How are 
ethical issues 
addressed and 
handled?  
 
The STCS stores only pseudonymized (de-indentified) data within the STCS 
IT system hosted at sciCORE. The STCS considers all data as sensitive and 
therefore enforces the use of secure IT. Contracts (SLA) are in place to 
prevent non-authorized access to the data hosted at sciCORE. 
The STCS is conducted according to the ethical principles laid down in 
the Human Research Act (HRA), its Ordinance (HRO), according to the 
Declaration of Helsinki and Swiss legislation. Guidelines for Good 
Clinical Practice (GCP) are closely followed and any issue that arises 
is discussed with the authorities and organization of the STCS. 
Informed consent (IC) procedures are fully implemented in the STCS 
since the beginning and they are regularly updated if required by new 
legislation or novel developments within the STCS.       
Before the start of the cohort in May 2008 each transplant center 
obtained local Ethics Committee (EC) approval for general 
participation in the STCS, i.e. patients provide general written 
informed consent for the collection and use of full STCS data including 
bio-banking of samples. By the end of 2019, 93% of the 5672 Swiss 
transplant recipients provided written informed consent to the full 
STCS datasets (the other 7% having the minimal dataset required by 
law), and 99% of consenting patients contributed to the bio-samples. 
The STCS processes and provides only encoded data for research.  
      
Since 2014, medical research has been regulated comprehensively in 
Switzerland through the HRA/HRO. In 2016, STCS EC application 
procedures were centralized, with the “Ethikkommission Nordwest- 
und Zentralschweiz (EKNZ)” acting as the leading EC for the cohort. 
In order to comply with the new legislation a substantial regulatory 
amendment was prepared, in close collaboration with the Clinical 
Trial Unit (CTU) Basel, the EKNZ, the Swiss Biobanking Platform (SBP) 
and the Data Protection Officer Basel-Stadt. Formally the amendment 

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was equivalent to a new project submission (research in persons, 
HRO Chapt. 2), with renewal of the complete study documentation. 
The STCS IC was updated and harmonized for all transplant centers. 
Where applicable, additional requirements for the consenting of 
particularly vulnerable patient groups were met, resulting in a total of 
seven population specific IC versions. After four years of preparation 
time the regulatory amendment was accepted on a national level in 
November 2019.  Re-consenting of already enrolled participants was 
not requested by the EKNZ. With its entry into force in all transplant 
centers on January 1, 2020, the STCS fully complies with the Swiss 
legislations on human research.       
Coverage of STCS IC: the IC is covering the collection and further use 
for research of a) study participants’ coded, health-related personal 
data and -samples, and of b) donor-derived data serving the donor-
recipient matching and the assessment of organ quality and function. 
Add-on data and -biological material, produced as part of standard 
treatment, can be collected and further used for research in the 
context of a specific research project, based on the STCS IC and in 
compliance with the relevant legislation. Not covered by the STCS IC 
is the collection and further use for research of un-coded or 
anonymized data/samples. Interventional trials require an additional, 
study specific informed consent. 
Every STCS nested scientific project (NP) is subject to STCS Scientific 
Committee review and approval (www.stcs.ch) on its own. In 
accordance with the Human Research Act (HRA) and its Ordinance 
(HRO) each NP principle investigator must obtain project approval 
from the competent EC prior to releasing data for a specific project. 
The STCS transmits only coded data of consenting patients to 
researchers. 
2.2 How will 
data access 
and security 
be managed? 
Clinical data 
In 2019 and 2020 the STCS has entirely re-established its IT 
governance structure. All STCS applications were migrated to 
sciCORE BioMedIT node. The environment of highly secured STCS 
virtual servers is referred to as the STCS tenant. All web services are 
relayed through a proxy server located on the jump host. Only the 
encrypted protocol HTTPS is allowed. Access to web services are only 
be allowed from explicitly white-listed domains, in principle 
restricted to the five Swiss University hospitals contributing to the 
STCS network and designated associated organizations (e.g. 
Kantonsspital St-Gallen). The STCS management approves any 
modification to the white list. Given the limited network accessibility 
of the tenant, two-factor authentication is not required. Command-
line access to the back-end systems is restricted to the developers of 
the STCS data management system and to the STCS management staff. 
The protocol to access the back-end is SSH.  
The physical infrastructure is located in an access-controlled data 
center managed by the central IT Services of the University of Basel 
(IT-S), the sciCORE/BioMedIT racks are locked and accessible only by 

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the sciCORE personal required for maintenance. sciCORE partially 
relies on an offsite backup infrastructure located in another access-
controlled data center at FHNW Muttenz, (under IT-S governance). 
Backups to this secondary site are encrypted at the source. 
The system hosted at SciCORE benefits from the following security 
framework: 
 All web services are relayed through a proxy server located 
on the jump host. Only the encrypted protocol HTTPS is 
allowed. 
 Access to web services is only be allowed from explicitly 
white-listed domains, in principle restricted to the 5 Swiss 
University hospitals contributing to the STCS network and 
designated associated organizations (e.g. Kantonsspital St-
Gallen). The STCS management approves any modification to 
the white list. 
 Given the limited network accessibility of the tenant, two-
factor authentication is not required. 
 Command-line access to the back-end systems is restricted to 
the developers of the STCS data management system and to 
the STCS management staff. The protocol to access the back-
end is SSH.      
Genetic data 
Individual’s genetic data is stored in the controlled-access database 
on HPC server or ACAD-NAS. The genetic data can be accessed with a 
personal login and password according to the Institutional rules. The 
service provides appropriate protection of the hosted data on its 
technical infrastructure including the confidentiality and integrity of 
the data. The Institution does not modify or transmit the data. 
Robust technical and administrative security measures are in place to 
protect against unauthorized access, accidental or illegal destruction 
or modification of genetic data in the central database. The access to 
genetic data is logged and protected by security password. Password 
enforcement rules apply for each user of genetic database at HPC or 
ACAD-NAS and the active directory requires the users to change their 
password regularly. 
 
2.3 How will 
you handle 
copyright and 
Intellectual 
Property 
Rights issues? 
Who will be the owner of the data? 
The STCS together with all participating centers own the data. 
Which licenses will be applied to the data? 
None.  
What restrictions apply to the reuse of third-party data? 
     The STCS Scientific committee and the competent Ethic Committee 
must revise and approve on all proposals for reuse of third party. 
Authorship and publication 
The procedure described      in the SWISS TRANSPLANT COHORT 
STUDY GUIDELINES AND OPERATIONAL RULES FOR SCIENTIFIC 

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PROJECTS applies (https://www.stcs.ch/research/information-for-
researchers). 
3.1 How will 
your data be 
stored and 
backed-up 
during the 
research? 
Clinical data 
The primary data storage is within the STCS database hosted at 
SciCORE.  
The secured tenant consists of: 
● 
A private virtual network 
● 
2 Linux virtual machines to host the development and 
production instances of the STCS data management system. 
● 
Associated storage system 
 
The following technical measures related to security are applied: 
● 
All web services are relayed through a proxy server located on 
the jump host. Only the encrypted protocol HTTPS is allowed. 
● 
Access to web services is allowed only from explicitly white-
listed domains, in principle restricted to the 5 Swiss University 
hospitals contributing to the STCS network and designated associated 
organizations (e.g. Kantonsspital St-Gallen). The STCS management 
approves any modification to the white list. 
● 
Given the limited network accessibility of the tenant, two-
factor authentication is not required. 
● 
Command-line access to the back-end systems is restricted to 
the developers of the STCS data management system and to the STCS 
management staff. The protocol to access the back-end is SSH. 
Backup procedures: 
● 
The VMs in the tenant undergo daily incremental backups to 
an NFS file share. Backups are then stored offsite using an encrypted 
tape infrastructure. Different versions of the backup can be recalled 
with a version history of up to 90 days.  
● 
The Gitlab service is backed up offsite, with a retention history 
of 90 days. 
 
Raw data exports are stored with the STCS DC as plain text files. 
Processed data are stored as sas-files, csv-files and text files within 
the STCS DC and distributed to end users (researcher) via a password-
protected web interface (www.stcs.ch). All files stored at DC are 
located within the host high performance computing (HPC) server at 
the USB (University Hospital of Basel) in a secured computer 
environment within dedicated space accessible only by authorized 
members of the STCS the DC. Sas-, csv-, text-, and specific program 
files together with the appropriate program code for projects and 
reports are preserved within the secured IT systems of USB (DC), 
SciCORE and regularly backed-up. 
Genetic data 
The genomic data is stored in the high-performance computing 

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cluster of the Lausanne University Hospital (CHUV), the genotype data 
are in plink and the imputed data are in bgen format.  
The cluster is located in the academic data center of the academic 
network of the CHUV (acad-net). The Academic Data Center (ACAD-
DC) and it is reachable only from ACAD-net, the CHUV clinical network 
and some users from the University of Lausanne (UNIL).  In order to 
use the HPC or ACAD-NAS resources, users must be authenticated by 
the Active Directory of the CHUV-IT. The allowed protocols to access 
HPC are http, https and SSH.  The active directory requires the users 
to change their password regularly. Other password enforcement 
rules are also applied.  Partners who signed an NDA (Non Discloser 
Agreement) may also access resources hosted in the ACAD-Net and 
ACAD-DC using VPN connection and each VPN connection is logged. 
Data is backed up on a NAS server on the same network. Only 
members of the group of Prof Kutalik have access to the data. 
3.2 What is 
your data 
preservation 
plan? 
What procedures would be used to select data to be preserved? 
The STCS is an open cohort study without a pre-specified end of study. 
Project specific data are stored by the investigator and the STCS Data 
Center together with the appropriate analysis code. The full data for 
the STCS Annual report is stored together with the report and the 
corresponding analysis code. 
What file formats will be used for preservation?  
Clinical data 
Sas-, csv-, text-, and specific program files together with the 
appropriate program code for projects and reports are preserved 
within the secured IT systems of USB (DC), SciCORE and regularly 
backed-up.  
Genetic data 
The entire individual’s genetic data is encrypted and stored either as 
PED/MAP files (PLINK format) and GEN files (IMPUTE format). This 
genetic data will be separated from sensitive data (e.g. health data). 
All files that need to be backed up will be stored at ACAD-NAS or NAS-
UNIL in a dedicated space accessible only by authorized members of 
the STCS genetic group. The ACAD-NAS will be backed up by 
snapshots, which are saved on different remote locations. In order to 
use genetic data from HPC or ACAD-NAS/NAS-UNIL resources, users 
must be authenticated by security staff (CHUV Active Directory). 
4.1 How and 
where will the 
data be 
shared? 
 
On which repository do you plan to share your data? 
SBP eCatalogue, other repositories are under evaluation. 
 
How will potential users find out about your data? 
The STCS is a nationally and internationally well-recognized tool for 
post-transplant outcome research. Investigators propagate the STCS 
as an open-access tool during conferences and meetings. The STCS 
website (www.stcs.ch) provides all information for researchers to 
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on national and international collaborations moreover propagate the 
STCS as an open tool for research.  
The transplant research community within Switzerland is closely 
linked to the STCS, therefore, new interested parties and young 
researchers are easily connected to the cohort via the transplant 
centers. The STCS applicants are also very active internationally, thus 
promoting the cohort beyond Switzerland, which leads to interest and 
requests for use of the data in international projects.  
In order to grant the correct and secure use of STCS data, all projects 
(national and international) undergo the review process of the STCS 
Scientific Committee and are registered as nested projects, regardless 
of whether they apply for STCS funding dedicated to STCS nested 
projects or not. 
Initial requests for information are handled through the website, 
which provides a detailed description of the data and samples 
available. For those researchers wishing to submit, the process is 
delineated in detail, with support from the Scientific Committee if 
necessary. Importantly, and to promote research and use of data, for 
MD and master thesis a simplified procedure is in place.  
Current STCS data access and publication policy: STCS data is open to 
external researchers as stated on the project website (www.stcs.ch). 
The publicly accessible section “Information for researchers” 
explicitly states that all types of research projects related to 
transplantation are welcome and that every scientist is invited to 
submit research projects. Projects are subject to review by the 
Scientific Committee (SC) of the STCS. The review process is 
transparent and follows defined guidelines. Since May 2016, all newly 
accepted STCS research projects must obtain EC approval.  The STCS 
is compliant with the Swiss National Science Foundation (SNSF) 
obligation for Open Access publishing and implemented the “Green 
road of Open Access” in 2017. PIs are working on data releases 
uploaded in the website and officially released by the DC. 
 
4.2 Are there 
any necessary 
limitations to 
protect 
sensitive data? 
 
 
The STCS is required to record and store the date of birth (DOB) of the 
recipient and the donor for the following reasons: 1. The DOB is of key 
importance for patient identification and quality assurance in the 
context of NPs that are in need of add-on data collection or data 
linkage 2. For studies on pediatric TX recipients. lt is important to note 
that, in order to comply with the guidelines of Swissethics on the 
encoding of a person-related health data, the STCS replaces each DOB 
by the year of birth and the age during the processing of research data. 
Hence, the date of birth is not passed on to researchers unless the 
competent ethics committee has explicitly approved this for a specific 
NP.