Condition category
Infections and Infestations
Date applied
30/12/2020
Date assigned
12/01/2021
Last edited
07/01/2021
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

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

https://surreyandsussex.nhs.uk/

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

Publication citations

Additional files

Editorial Notes

07/01/2021: Trial’s existence confirmed by NHS HRA.