Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05097677 |
| Other study ID # |
ORCHESTRA WP2 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
April 16, 2021 |
| Est. completion date |
July 16, 2023 |
Study information
| Verified date |
December 2021 |
| Source |
Azienda Ospedaliera Universitaria Integrata Verona |
| Contact |
Evelina Tacconelli, Professor |
| Phone |
+390458128283 |
| Email |
evelina.tacconelli[@]univr.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
The protocol, in accordance with the objectives of ORCHESTRA project - Work Package 2, aims
at investigating the characteristics and determinants of COVID-19 long-term sequelae. This
goal will be reached through the harmonization of follow-up strategies across the
participating cohorts to allow a standardized collection of data on COVID-19 long-term
sequelae. The result will be a platform including a set of data and biomaterials from large
scale international cohorts, that will be uniformly recorded, prospectively tracked and
analysed. The ultimate goal will be that of providing evidence to contribute to the
optimization and improvement of the management and prevention of COVID-19 sequelae.
The follow-up will be organized in multiple levels of tests, according to the capability of
each cohort, and will include questionnaires to collect demographic, epidemiological and
clinical data, physical examination, radiological exams and biological sampling. The
long-term follow-up will also allow the assessment of long-term immunological response to
SARS-CoV-2 infection and its association to the vaccination and to different treatment
strategies, including monoclonal antibodies.
Description:
Study design
This is a multicenter, observational, concurrent cohort study investigating COVID-19 sequelae
in hospitalised and non-hospitalised patients up to 18 months after the diagnosis of
SARS-CoV-2 infection.
Patients will be recruited in multiple European and non-European countries, accounting for
the participation of approximately 7500 individuals in the prospective follow-up data
collection.
Collection of clinical data, administration of questionnaires, collection of biological
samples and imaging will take place at fixed time-points to allow a comprehensive follow-up
of COVID-19 patients. The follow-up will include two levels of assessments: the first one is
mandatory, the second one will be customized according to the feasibility of each cohort. An
ad hoc database will be provided to each COVID-19 cohort involved to allow homogeneous and
standardized data collection.
ORCHESTRA has received funding from the European Union's Horizon 2020 research and innovation
programme under grant agreement No 101016167.
The Main objectives of the study are:
- To describe characteristics of COVID-19 sequelae, including type, rate, and length,
through clinical, laboratory, and radiological assessments;
- To investigate valuable, confounder-adjusted, associations between COVID-19 sequelae and
COVID-19 severity, comorbidities, aetiology (SARS-CoV-2 variants), treatment (including
monoclonal antibodies), and trends in SARS-CoV-2 antibodies;
- To describe the rate, the aetiology (SARS-CoV-2 variants), severity, and clinical
determinants of COVID-19 re-infections.
Furthermore, data retrieved from COVID-19 cohorts will allow the following:
- To compare the time course of the immunological response of the population with sequelae
with the immunological response of the population without sequelae;
- To investigate immunological patterns related to specific long-term sequelae;
- To investigate possible associations of SARS-CoV-2 variants with COVID-19 severity, time
course of the immunological response, and long-term sequelae;
- To describe the rate and severity of sequelae and immunological trends of COVID-19 in
patients vaccinated against SARS-CoV-2;
- To describe the time course of intestinal and pulmonary microbiome after SARS-CoV-2
infection;
- To investigate possible associations of long-term sequelae with hypercoagulability;
- To describe the relationship between risk perception of reinfection and the adherence to
preventative measures over time after the SARS-CoV-2 infection, including vaccine
acceptance;
- To describe the use of health care services among patients recovered from SARS-CoV-2;
- To identify human and viral genetic markers indicative of disease severity using WGS or
WES followed by functional analysis of the most promising variants.
Recruitment strategy
Inpatients will be recruited by the study team at the treating hospital. Outpatients will be
recruited by the study team in the emergency rooms, outpatient clinics, and through the
coordination with regional primary care networks.
Patients will be followed up for up to 18 months after the SARS-CoV-2 infection diagnosis.
The recruitment can take place at any time between the SARS-CoV-2 infection diagnosis and the
end of the 18-month follow-up, provided that the patient ensures at least one follow-up
visit. Discharged inpatients as well as recovered outpatients will be invited to participate
by a phone call (which will be repeated once in case of no reply). The screening/baseline
data collection (including the informed consent process) can be carried out on the same day
of a follow-up visit.
Before the first patient is recruited at a location, the responsible investigator will ensure
that all legal and regulatory requirements are met. Patients can revoke their consent to
participate in the study without restriction at any time and at their own request, without
giving reasons and without any consequences for their future treatment.
Patients will be recruited by the cohort of University of Verona (UNIVR), the cohort of
University of Bologna (UNIBO), the French Covid-19 cohort (INSERM), COVID-HOME study from
University Medical Center Groningen (UMCG), Fondation Congolaise pour la Recherche Médicale
(FCRM) cohort - Republic of The Congo, Servicio Andaluz de Salud (SAS) cohort, the cohort of
the Hospital Universitario Virgen Macarena (HUVM), the cohort of Universidade Federal de São
Paulo (UNIFESP)
Study procedures
This study aims to improve the COVID-19 patient care in the context of routine clinical care.
Considering the lack of standardized follow-up pathways for COVID-19 patients, the selection
of assessments has been based on available evidence and according to the definition of good
clinical practice.
The organization of follow-up visits will be up to each center, according to the facilities
and logistics of outpatient monitoring.
The follow-up will last 18 months. Day 0 corresponds to the time of the first positive
SARS-CoV-2 test. The screening/baseline data collection (including the informed consent
process,) can be carried out on the same day of a follow-up visit. Procedures conducted as
part of the participant's routine clinical management at the time of SARS-CoV-2 active
infection and obtained before the signature of the informed consent form may be recorded,
provided that the procedures meet the criteria specified in the protocol.
Follow-up visits will occur at the following time-points: 3, 6, 12, 18 months. During each
time-point, epidemiological data collection (SARS-CoV-2 vaccination status), treatment data
collection (comorbidity management), clinical assessments (relevant medical new events,
COVID-19 symptom assessment, physical examination, vital signs, 6-minute walking test), and
the administration of questionnaires on functional status, respiratory impairment, and mental
health will be performed as part of level I (mandatory) assessments, as well as the
assessment of the SARS-CoV-2 immunological status (SARS-CoV-2 antibodies). A SARS-CoV-2
molecular test will be repeated only if positive at the previous follow-up visit.
Self-administered questionnaires on symptoms, will be completed daily by the participant to
provide timely data on the symptom length.
Level II (imaging, biochemistry, pulmonary function tests, electrocardiography) will be
performed according to the capability of each cohort and will be based on the clinical
evaluation, according to the participant's healthcare status. Imaging and biochemistry tests
will be reassessed only if outside the normal ranges at the previous follow-up visit or if
clinically indicated.
COVID-19 biological samples (including blood, naso-pharingeal swabs, urine, and stool) will
be collected and stored in the biobank of each participating center (according to local ethic
commission recommendations). Test to be performed in a centralised laboratory (genomic,
transcriptomic, cytokine, viral analyses, PBMCs and genetic and epigenetic) will be sent,
following international regulation, to the University of Antwerp, INSERM, University of
Bologna or HMGU. Stool sample for microbiological analysis will be sent to the University of
Bologna. Whole blood samples for epigenetic and genetic analysis will be sent out to UNIBO,
INSERM and Helmholtz Zentrum Munchen (HMGU). In-depth human genetic analysis will be
conducted using WGS or whole exome sequencing (WES) followed by functional analyses of the
most promising variants. Genome-wide methylation analyses of COVID-19-positive patients in
addition to a small number of control patients will enable differentiation of inherited and
acquired genomic regulatory features through COVID-19 infection, which result in severe
disease or an efficient clearing of infection through immune responses.
Sample size calculation
The number of inclusions will depend on the progress of the SARS-CoV-2 pandemic, which is
unknown, at this time. Therefore, the number of patients who will be included cannot be
determined in advance. However, depending on the timing of the project and the included
cohorts, the expected enrollment is around 10000 subjects.
Statistical analysis
A comprehensive descriptive analyses taking into account sociodemographic factors and
clinical courses will be carried out. The frequency distributions of the characteristics will
be given in absolute and relative numbers, median plus interquartile range (IQR) or mean
values plus 95% confidence interval (CIs). Associations with specific treatment strategies,
disease severity patterns and laboratory results will be analysed using chi-square tests,
t-tests or Mann-Whitney tests, depending on the data. To evaluate potential risk factors,
multivariate regression models will be carried out. Outcome time analyses using Cox
proportional-hazards regression models with time-dependent covariates will be performed to
examine factors associated with each endpoint (including death). In addition, cumulative
incidence functions, such as the Fine-Gray subdistribution hazard regression model, will be
used to account for competing events (i.e., relocation, discharge against medical advice,
etc.). For missing values, a different strategy to understand the causes and the significance
for the analysis will be developed and a graduated procedure for dealing with censorship and
imputations via linked regressions will be developed. The significance level is defined with
a p-value <0.05. All statistical analyses will be carried out with STATA, Python and/or R
statistics software by trained staff (epidemiologists, statisticians) using the latest
analysis methods.
Data collection
Patient data will be collected through a specific eCRF created for the study, which will not
contain personal data suitable for identifying the patient. The clinical and outcome
information collected in relation to the study will be limited to the objectives of the
study, taking care to reduce as much as possible the burden for the patient and for the
enrolling clinical center. Only the enrolling clinical center will have access to the
patient's identity and will be able to contact him if the coordinating center needs to have
further information or for follow-up appointments during or after the closure of the study.
For each patient, a special unique digital identification code (barcode) will be provided.
The code will consist of a three-character part to identify the recruiting center and a
second part consisting of 5 digits to identify the enlisted person. The code will be
associated with the patient by the clinical center, which will keep a copy of it in the
patient file and in the medical record. Each patient enrolled will have a specific study file
with all ethical and clinical documentation. The manual for compiling the eCRF will be
provided in the Trial Master File.
The data will be entered directly into the patients' eCRF and the related clinical and
outcome information will be digitized in a specific database that will be developed using the
RedCap® data capturing platform.
Data quality assurance
All participant data related to the study will be recorded on printed or eCRF, unless
transmitted to the Sponsor or designed electronically (eg, laboratory data). The Investigator
is responsible for verifying that data entries are accurate and correct by physically or
electronically signing the eCRF or paper CRF. The Investigator must maintain accurate
documentation (source data) that supports the information entered in the eCRF or paper CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory
agency inspections and provide direct access to source data documents. The Promotor is
responsible for the data management of this study including quality checking of the data. All
source documents must be accurate, clear, unambiguous, permanent, and capable of being
audited. All source documents should be made using some permanent form of recording (typing,
printing, optical disc). All source documents should not be obscured by correction fluid or
have temporary attachments (such as removable self-stick notes). Source documents are
original records in which raw data are first recorded. These may include
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results,
pharmacy records, care records, ECG or other printouts, questionnaires, or video, for
example. Source documents should be kept in a secure, limited access area.
