Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05514522 |
| Other study ID # |
21IC6978 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 18, 2021 |
| Est. completion date |
March 31, 2024 |
Study information
| Verified date |
November 2023 |
| Source |
Imperial College London |
| Contact |
mark weeks, Dr |
| Phone |
+44 (0)20 7594 7972 |
| Email |
m.weeks[@]imperial.ac.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Prospective observational study of hospitalised and non-hospitalised patients post- infection
with SARS-CoV-2. The study aims to recruit 2000 individuals, with proven COVID-19, who were
not hospitalised but presented to Long-COVID clinics with persistent respiratory symptoms
such as breathlessness or cough and are referred for cross-sectional imaging (computer
tomography, CT) at baseline (3 months weeks after their first COVID-19 symptoms). The study
will run for 18 months.
Description:
Given the large number of patients infected with SARS-CoV-2, it is vital that the extent of
PC-ILD is determined; its natural history defined particularly whether it is time-limited
inflammation and reversible, or develops into persistent, or even progressive, fibrosis.
Determining the natural history of PC-ILD, and risk factors as well as biomarkers related to
outcome such as disease progression, will enable a precise approach to treatments such as
immunomodulation or antifibrotic therapy [6], stratification into clinical trials,
prognostication and appropriate service provision. This will facilitate assessment and
prioritisation of both conventional and novel therapies used in the treatment of COVID-19
during the acute phase to mitigate the subsequent development of PC-ILD. By exploring the
long-term implications of SARS-CoV-2 infection across the full spectrum of COVID-19 disease
ranging from non-hospitalised patients managed in the community with mild symptoms to those
requiring mechanical ventilation, we will define the risk factors for PC-ILD including
disease severity, host genetic factors and the effects of antiviral and immunomodulatory
treatment administered during the acute phase of the illness. The UKILD Post COVID study is a
prospective multicentre observational cohort study that will be managed through the Imperial
College National Heart and Lung Institute and funded by the UKRI Medical Research Council and
an NIHR professorship (RGJ).
The PHOSP COVID study (ISRCTN10980107) is a national consortium that provides a platform to
study the long-term consequences of COVID19 hospitalisations [18]. An expected 10,000
individuals hospitalised by COVID-19 are to be included in baseline assessments after testing
positive on PCR for SARS-C0V-2 and will be recruited through the PHOSP platform. The study
described here will aim to recruit a further 2000 individuals, with proven COVID-19, who were
not hospitalised but presented to Long-COVID clinics with persistent respiratory symptoms
such as breathlessness or cough and are referred for cross-sectional imaging (computer
tomography, CT) at baseline (3 months weeks after their first COVID-19 symptoms) [19]. A
total of up to 12,000 people will be assessed for longitudinal follow up into the UKILD-Post
COVID study. Following assessment of Post COVID patients at baseline (~3-6 months post
infection as defined above), those with clinical and radiological features suggestive of ILD
will be included into the UKILD-Post COVID study population. Where there are
contraindications for CT and if clinically indicated, participants will be eligible for a
research-guided 3D ultrashort echo time (UTE) proton MRI as a surrogate for CT. Where
individuals meet criteria for initial study inclusion (COVID-19 and clinical indication for
CT scanning) but have no clinical, radiological or physiological features of ILD they will be
invited to enroll as part of the control cohort for follow up.
This protocol details the research partnership between Imperial (BREATHE Respiratory hub
partner), and partner organizations.
2 STUDY OBJECTIVES
2.1 Primary objective The primary objective of the study is to determine the prevalence of
ILD at 12 months following SARS-CoV-2 infection and whether clinical severity correlates with
severity of ILD in survivors.
2.2 Secondary objectives
1. to further define the PC-ILD population, in particular, to describe the emerging
phenotypes and risk factors of PC-ILD
2. to determine the natural history of PC-ILD phenotypes longitudinally
3. to explore pathomechanisms of PC-ILD for candidate prognostic and theranostic
biomarkers.
2.3 The primary endpoint
1. The primary endpoint of the study is as radiologically confirmed diagnosis of fibrotic or
non-fibrotic ILD in the 12 months following COVID-19. Sub-studies will have a co-primary
endpoint of change in the radiological extent of PC-ILD.
2.4 The secondary endpoints
1. progressive lung function impairment between 3 and 12 months, defined as ≥10% relative
decline in FVC, or ≥10% relative decline in DLco, or increasing radiological extent of
PC-ILD using image analysis [20].
2. Resolution of ILD, as defined by ≥10% relative improvement in FVC, DLco, or reduction of
radiological extent.
3. Persistence of ILD in those not meeting definition of progression or resolution
4. Presence of interstitial lung abnormalities (ILA) on radiological images that do not
meet definition of ILD.
5. A comprehensive series of clinical, molecular, MRI and biochemical parameters will be
assessed as biomarkers.
Pre-recruitment evaluations Screening and Eligibility Assessment Patients will be assessed by
the clinical teams for eligibility against the inclusion or exclusion criteria.
The clinical teams at the recruiting sites will confirm that patients have been infected with
SARS-CoV2 before approaching them. Participants must satisfy all the approved inclusion and
exclusion criteria of the protocol. Participants will then be invited to participate and
informed consent will be obtained at the start of visit 1. Pre-screening for eligibility will
take place prior to consent. It will be done by the direct care team using patient notes.
There will be no access to patient identifiable data outside of the direct care team prior to
consent.
Screening and eligibility for PHOSP COVID/C-MORE participants For PHOSP-COVID participants,
screening and eligibility assessment will occur as per the REC approved protocol (IRAS ID
285439).
All patients can be directed to other relevant post-COVID studies, including but not
restricted to POSTCODE and XMAS.
3 STUDY DESIGN Prospective observational study of hospitalised and non-hospitalised patients
post- infection with SARS-CoV-2. The study aims to recruit 2000 individuals, with proven
COVID-19, who were not hospitalised but presented to Long-COVID clinics with persistent
respiratory symptoms such as breathlessness or cough and are referred for cross-sectional
imaging (computer tomography, CT) at baseline (3 months weeks after their first COVID-19
symptoms). The study will run for 18 months.
Description of study procedure(s) History and Examination (10 mins) : Medical history,
allergies, medications and anthropometric measurements including height, weight, and body
mass index will be recorded during the study visit (or taken from the hospital notes. Or
PHOPS data)
Blood sample collection (10 mins) :
Samples will be taken for plasma/ serum for epithelial and endothelial damage biomarkers,
coagulation and genetics Questionnaires (45 mins) Participants will be provided with seven
questionnaires; 36 Short-Form Survey (SF-36), Clinical Frailty Scale (CFS), Patient Health
Questionnaire 9 (PHQ9), Montreal Cognition Assessment (MOCA), Dyspnoea-12 score, EQ5D-5L,
FACIT-F at the end of each study visit.
There are no investigations required for participants co-enrolled in the PHOSP-COVID study.
3.3 Baseline and follow up assessments Initial patient approach Eligibility assessment by
clinical team Study information and invitation letter provided to eligible patients
Visit 1 (~3 months) (Post COVID-19 infection patients)
1. Review of eligibility with participant
2. Obtain written informed consent
3. History and anthropometric measurements, e.g. height, weight, body mass index (BMI)
4. Blood sample (6-10 ml) collection
5. Pulmonary function test (20 minutes)
6. Optional 6-minute walk test (6MWT) (10 minutes)
7. Quality of Life questionnaire (SF-36) (10 minutes)
8. Clinical Frailty Scale (CFS) (5 minutes)
9. Personal health questionnaire (PHQ) (10 minutes)
10. Montreal Cognitive Assessment MOCA (10 minutes)
11. Dyspnea 12 score (10 minutes)
12. EQ5D-5L (10 minutes)
13. FACIT-F questionnaire (10 minutes)
Optional Visit 2 (~6 months) (Post COVID-19 infection patients and matched controls) All
visit 1 assessments will be repeated.
Visit 3 (~12 months) (Post COVID-19 infection patients) All visit 1 assessments will be
repeated. Visits will be scheduled to take place over 1 day. Visit 2 is optional, Visits 1
and 3 are obligatory.
3.3 Monitoring of clinical events and re-analysis of previous scans (clinically indicated)
Clinical outcome data and images from clinical scans for all COVID-19 patients will also be
collected from around the time of infection and hospitalisation and follow up. Laboratory
analyses and chest imaging results undertaken for clinical reasons will also be collected.
Access to participant medical records and any relevant hospital data that is recorded as part
of routine standard of care; i.e., CT-Scans, blood results and disease progression data etc.
will be obtained with patient consent from hospital electronic patient records and NHS
digital
3.4 Sample Handling Blood samples for the analysis of serum inflammatory markers, serum
biomarkers of endothelial and epithelial injury and coagulation studies, viral serology,
viral PCR, and whole genome sequencing, ribonucleic acid sequencing and flow cytometry in
blood will be collected. Analysis of venous blood samples will be performed in local NHS
laboratories. If the Participant consents approximately 10 ml of blood will be stored in the
Division of Cardiovascular Medicine for further analysis as part of collaborations with other
groups. Samples will not be collected from participants who are also participating in
PHOSP-COVID
Withdrawal Criteria
Early Discontinuation/Withdrawal of Participants : During the course of the study a
participant may choose to withdraw early from the study treatment at any time. This may
happen for several reasons, including but not limited to:
- The occurrence of what the participant perceives asintolerable AE.
- Inability to comply with study procedures
- Participant decision
According to the design of the study, participants may have the following three options for
withdrawal;
1. Participants may withdraw from active follow-up and further communication but allow the
study team to continue to access their medical records and any relevant hospital data
that is recorded as part of routine standard of care; i.e., CT-Scans, blood results and
disease progression data etc.
2. Participants can withdraw from the study but data and samples obtained up until the
point of withdrawal to be retained for use in the study analysis. No further data or
samples would be collected after withdrawal.
3. Participants can withdraw completely from the study and withdraw samples collected up
until the point of withdrawal. The samples already collected would not be used in the
final study analysis.
4. In addition, the Investigator may discontinue a participant from the study at any time
if the Investigator considers it necessary for any reason including, but not limited to:
- Ineligibility (either arising during the study or retrospectively having been
overlooked at screening)
Participants that choose to withdraw from the study will not be replaced. The type of
withdrawal and reason for withdrawal will be recorded in the CRF. If the participant is
withdrawn due to an adverse event, the Investigator will arrange for follow-up visits or
telephone calls until the adverse event has resolved or .
ASSESMENT AND FOLLOW UP Optional follow up and assessment
As previously detailed in section 3.3 above, participants will agree to a final follow up
assessment and an optional interim assessment
Optional Visit 2 (~6 months) (Post COVID-19 infection patients and matched controls) All
visit 1 assessments will be repeated. All visit 1 assessments will be repeated.
Visits will be scheduled to take place over 1 day. Visit 2 is optional, visits 1 and 3 are
obligatory. For research specific visits, participants will be offered reimbursement for
travel expenses. This includes reimbursement for petrol, car parking, taxis.
Clinical outcome data and images from clinical scans for all COVID-19 patients will also be
collected from around the time of infection and hospitalisation and follow up. Laboratory
analyses and chest imaging results undertaken for clinical reasons will also be collected.
Access to participant medical records and any relevant hospital data that is recorded as part
of routine standard of care; i.e., CT-Scans, blood results and disease progression data etc.
will be obtained with patient consent from hospital electronic patient records and NHS
digital. The end of the study will be the point at which the final patient follow-up and
assessment have been completed.
A detailed Image Management protocol for the UKILD-Post COVID Study provides a comprehensive
outline of the purpose, operation, methods, policies, and governance of Image collection for
UKILD. It describes the procedures used to collect and store images. (appendix 1)
STATISTICS AND DATA ANALYSIS
The prevalence of MDT-confirmed PC-ILD at both early (up to 6 months) and again at late
(10-15 month) time-points and will be assessed within the total study population. The
prevalence of broader radiological abnormalities and phenotypic patterns will also be
assessed in a descriptive analysis, together with demographics, haematological and
biochemical profiles, physiological performance, and patient-reported outcome measures.
Analyses will be performed overall and stratified according to hospitalised and
non-hospitalised, as well as severity of infection in hospitalised patients defined above.
Baseline and longitudinal changes in biomarkers reflecting PC-ILD evolution, including
circulating factors and cell-types from detailed serological and cellular analysis, will be
assessed in multilevel models for repeated measures to test associations according to the
presence or absence of PC-ILD at late time points (10-15 months), and according to
progression, resolution, or persistence of radiological patterns over follow up time points.
Analyses will be performed using standard epidemiological and statistical genetics
methodology. This will include cross-sectional and longitudinal studies, and analyses of
disease prevalence and incidence.
Analysis design and choice of controls will be dependent upon the precise nature of the
research question. Identification of risk factors for a specific COVID-19 sequela would
involve controls both from within UKILD-Long COVID (without the sequela) and
serology-positive controls with prospective questionnaire and healthcare record linkage from
Longitudinal Population Studies (for example, UK Biobank, Coronagenes, EXCEED) and
pre-existing disease cohorts. Analyses aiming to characterise and understand the clinical
features, subtypes and trajectories of sequelae (for example, sarcopaenia) would evaluate the
cross-sectional and longitudinal clinical data and biomarkers of UKILD-Long COVID
participants who are presenting with the sequelae being studied.
The participant organisations making uo the UKILD-long COVID study group have extensive
experience of development of, and collaborative use of, disease-specific and general
population cohort studies both nationally and internationally enabling access to control
populations and alignment of research strategies for rapid validation and replication of
findings.
Statistical significance thresholds will be defined in advance of each analysis and will take
into account issues of multiple testing and a priori evidence.
Data and all appropriate documentation will be stored for a minimum of 10 years after the
completion of the study, including the follow-up period.
Project statistician: Dr Iain Stewart email:
iain.stewart@imperial.ac.uk National Heart and Lung Institute Guy Scadding Building, Cale
Street, London, SW3 6LY
