Plain English Summary
Background and Study Aims:
COVID-19 has caused widespread disruption to people's lives. Clinicians have, during the course of their encounters, recognised some key features of this disease. It is a viral respiratory illness, and as such, can present with catastrophic destruction of the lining (the epithelium) of the lung, resulting in water in the lung. The disease can also precipitate the formation of clots in blood vessels, resulting in loss of blood supply to various organs, resulting in stroke, kidney failure, liver failure and cardiac arrest.
It is the hypothesis of this study that all these effects are due to the breakdown of what is known as the "epithelium" throughout the body. This would explain why water floods the lung in severe COVID-19, causing severe Acute Respiratory Distress Syndrome (ARDS) and why this disease predisposes to clot formation, since when the epithelium of blood vessels break down, clots naturally form.
Interleukin-18 (IL-18) plays a fundamental role in the breakdown of epithelium in the body. It is the end-product of a process known as "inflammasome" activation, and is part of the body's normal, healthy response to fighting off an infection like COVID-19. When, however, IL-18 is produced in unregulated amounts, due to the failure of IL-18 Binding Protein (IL-18BP), which mops up excess IL-18 and regulates its production, then widespread epithelium breakdown throughout the body, is the consequence.
This study therefore is investigating the levels of both IL-18 and its regulator, IL-18BP, in addition to Granzyme B, to see whether this hypothesis is borne out in the data. The hope is that, if IL-18BP is not being produced, resulting in unregulated high "free" IL-18, perhaps this study could lay the groundwork for seeing an interventional study, aimed at curbing "free" IL-18 by administering of IL-18BP in drug form, or other proteins that may act in a similar way.
Who can participate?
Patients over the age of 18 presenting with COVID-like symptoms.
What does the study involve?
The study involves the sampling of excess blood from blood samples that are already taken for clinical purposes from patients with and without COVID-19 disease. The study does not require patient participants to have further blood tests or additional interventions.
What are the possible benefits and risks of participating?
Since the study does not intervene in the patient's care, even to the extent of not taking further blood samples beyond what is already clinically necessary, there are no risks to participating in the study. The benefit is of course, in contributing to research. All patient data is pseudo-anonymised, and when published, will be presented in fully anonymised form.
Where is the study run from?
Redhill Hospital, Surrey and Sussex NHS Healthcare Trust (UK)
When is the study starting and how long is it expected to run for?
May 2020 to January 2021
Who is funding the study?
True Intelligence Limited (UK)
Who is the main contact?
Dr Syed Muhammad Tahir Nasser, sash.isaacstudy@nhs.net
Trial website
Contact information
Type
Scientific
Primary contact
Dr Syed Muhammad Tahir Nasser
ORCID ID
https://orcid.org/0000-0002-4700-862X
Contact details
East Surrey Hospital
Canada Avenue
Redhill
RH1 5RH
United Kingdom
+44 (0)7875603852
syed.nasser1@nhs.net
Type
Public
Additional contact
Dr Syed Muhammad Tahir Nasser
ORCID ID
https://orcid.org/0000-0002-4700-862X
Contact details
East Surrey Hospital
Canada Avenue
Redhill
RH1 5RH
United Kingdom
+44 (0)7875603852
syed.nasser1@nhs.net
Additional identifiers
EudraCT number
Nil known
ClinicalTrials.gov number
Nil known
Protocol/serial number
IRAS 285842
Study information
Scientific title
Levels of free IL-18, IL-18 binding protein and granzyme B according to disease severity of COVID-19
Acronym
ISAAC
Study hypothesis
Levels of free Interleukin-18 (IL-18) increase, while IL-18 Binding Protein (IL-18BP) and Granzyme B decrease, with increasing severity of COVID-19 disease.
It is the hypothesis of this study that the widespread features of COVID-19 disease, such as acute respiratory distress syndrome (ARDS), the development of diarrhoea, and the formation of widespread clots, are due to a multi-system breakdown of epithelium throughout the body.
Interleukin-18 (IL-18) plays a fundamental role in the breakdown of epithelium in the body. It is the end-product of a process known as "inflammasome" activation, and is part of the body's normal, healthy response to fighting off an infection like COVID-19. When, however, IL-18 is produced in unregulated amounts, due to the failure of IL-18 Binding Protein (IL-18BP), which mops up excess IL-18 and regulates its production, then widespread epithelium breakdown throughout the body, is the consequence.
This study therefore aims to investigate the levels of both IL-18 and its regulator, IL-18BP, in addition to Granzyme B, to see whether this hypothesis is borne out in the data. The hope is that, if IL-18BP is not being produced, resulting in unregulated high "free" IL-18, perhaps this study could lay the groundwork for seeing an interventional study, aimed at curbing "free" IL-18 by administering of IL-18BP in drug form, or other proteins that may act in a similar way.
Ethics approval
Approved 16/09/2020, Berkshire Research and Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 104 8224; berkshireb.rec@hra.nhs.uk), ref: 20/SC/0316
Study design
Observational trial comprising cross-sectional case-control and longitudinal cohort arms
Primary study design
Observational
Secondary study design
Two arms: a) cross-sectional case-control; b) longitudinal cohort
Trial setting
Hospitals
Trial type
Screening
Patient information sheet
See additional files
Condition
Investigation of inflammatory process in patients with COVID-19
Intervention
The approach is of a case-control and a cohort study, to accumulate data on Total IL-18, IL-18BP, IL-18/BP-Complex levels and Granzyme B levels (as a marker for NK cell and CD8 T-lymphocyte cytotoxicity) in a variety of different patients with and without COVID-19.
Case-Control: By comparing COVID19 positive and negative patients presenting with similar symptoms to hospital, we get information about how COVID-19 infection affects IL-18 related parameters generally as compared to other conditions.
Cohort Analyses: By comparing IL-18 related parameters between COVID-19 positive patients and correlating it to primary (degree of lymphopaenia) and secondary (oxygenation parameters/clinical features/disease course/biochemical parameters, neutrophil to lymphocyte ratio (NLR) outcomes, we can see whether IL-18 and Granzyme B levels correlate with disease severity. Given that high free IL-18 levels are seen in patients due to decreased IL-18BP levels in a condition known as macrophage activation syndrome (MAS), a condition with similarities to severe COVID-19, Granzyme B analysis may be useful in understanding the cause of high free IL-18.
The questions the study is asking, are as follows:
Q1: Is there an association between IL-18 parameters and COVID-19 diagnosis, at first presentation? (Case-Control)
Q2A: What is the relationship between free IL-18 levels and severity of COVID-19? (Cohort Study 1)
Q2B: How do free IL-18 levels change with change in disease severity? (Cohort Study 2)
Q3: What is the relationship between free IL-18 levels and activity of CD8+ T cells and NK cells, as measured by Granzyme B levels (Cohort Study 3)
Patients enrolled to this study have blood excess to clinical requirements, from samples taken solely for clinical purposes, stored and analysed for Inflammasome related parameters (Total IL-18, IL-18 Binding Protein (BP) and IL-18/BP complex levels) and Granzyme B levels. Primary and secondary outcome measures related in time to each blood sampling event are then correlated with the measured levels above, so as to build a picture of clinical disease progression, in tandem with changing levels of inflammasome parameters.
Intervention type
Other
Phase
Drug names
Primary outcome measure
Case-Control:
High free IL-18 measured at baseline (admission), obtainable through blood sampling analysis
Cohort Study 1
Lowest lymphopaenia level during attendance at hospital, obtainable through blood sampling analysis
Cohort Study 2:
Lymphopaenia percentage measured from baseline to the lowest level during the inpatient stay using patient records
Cohort Study 3:
Granzyme B levels measured by blood sampling when attending tertiary care centre for routine appointments
Secondary outcome measures
Case-Control
Measured at baseline using blood sample analysis:
1. High total IL-18
2. Low IL-18/BP Complex
3. Low IL-18 Binding Protein
4. Low Granzyme B levels
Cohort Study 1
Measured at the end of hospital stay using patient records:
1. Hospital length of stay
2. ITU admission
3. Mortality
4. Highest CRP level
5. Highest ferritin level
6. Oxygenation parameters
7. Neutrophil to lymphocyte ratio (NLR)
Cohort Study 2
Measured at the end of hospital stay using patient records:
1. Hospital length of stay
2. ITU admission
3. Mortality
4. Highest CRP level
5. Highest ferritin level
6. Oxygenation parameters
7. Neutrophil to lymphocyte ratio (NLR)
Cohort Study 3
There are no secondary outcome measures
Overall trial start date
07/05/2020
Overall trial end date
14/01/2021
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Criteria for Case/Control portion of study:
1. Above 18 years of age
2. Tested for COVID-19, positive or negative
Criteria for Cohort portions of study:
1. Above 18 years of age
2. COVID-19 positive swab test
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Initially 200 patients (100 for case/control and 100 cohort patients) however this is under review; end point being defined in terms of time (January 14th) rather than number of patients collected.
Participant exclusion criteria
Case-Control and Cohort:
1. Does not meet inclusion criteria
Cohort study only:
1. Not admitted to hospital after presentation to A&E (discharged without admission)
Recruitment start date
08/11/2020
Recruitment end date
14/01/2021
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Redhill Hospital
Surrey and Sussex Healthcare Trust
Canada Ave
Redhill
RH1 5RH
United Kingdom
Sponsor information
Organisation
Surrey and Sussex Healthcare NHS Trust
Sponsor details
East Surrey Hospital
Canada Avenue
Redhill
RH1 5RH
United Kingdom
+44 (0)1737768511 Ext.: 6843
sash.research.office@nhs.net
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Industry
Funder name
True Intelligence Limited
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Investigator initiated and funded
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal.
IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date
Intention to publish date
14/01/2022
Participant level data
To be made available at a later date
Basic results (scientific)
Publication list