Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04903834 |
| Other study ID # |
RHM MED1717 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 30, 2020 |
| Est. completion date |
June 24, 2024 |
Study information
| Verified date |
May 2021 |
| Source |
University Hospital Southampton NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This project aims to undertake a high-resolution analysis of previous cases of COVID19
infection to determine from all available clinical data recorded over the timeline of
admission, who might benefit best from specific interventions designed to target a hyper
inflammatory response in this condition. This approach offers a timely contribution to the
field where the first phase of unselected clinical trials is already underway, and the second
phase will require a more targeted approach. Southampton offers a unique opportunity to
undertake this work, as it is widely accepted that the investigators lead the UK in clinical
data informatics. This project links the investigators research efforts at the clinical level
to current understanding of disease pathways, for which the investigators have effective
interventions and the problem the investigators aim to solve is, who will benefit from the
available novel anti-inflammatory approaches and when should this treatment be given?
Description:
Purpose:
The primary purpose of this research is to identify an early warning for hyperinflammation in
COVID19 so that interventional trials of anti-inflammatory agents can target this sub-group.
Background Mortality from SARS-CoV-2 infection causing COVID-19 is estimated to be 3.7%
globally. The principal cause of death due to COVID-19 is respiratory failure due to acute
respiratory distress syndrome. Early reports have suggested that a subgroup of individuals
suffer a hyperinflammatory state with a high mortality which is associated with high levels
of IL-6 and CRP. Recent randomised controlled trial data has shown that the anti-inflammatory
agent dexamethasone can reduce mortality in severe COVID-19 in an unselected COVID-19 cohort.
Whilst impressive, these results suggest that if the anti-inflammatory interventions could be
targeted early to individuals with hyperinflammation, even greater benefit in mortality may
be seen, and this approach may additionally reduce the morbidity of COVID-19 by preventing
escalation to high dependency and intensive care. The purpose of our study is to identify
hyperinflammation early because there are specific therapies which are in clinical use which
treat hyperinflammation.
Hyperinflammation has been previously described secondary to acute infection and termed
cytokine release syndrome / cytokine storm (CRS / CS), macrophage activation syndrome (MAS),
macrophage-cytokine self-amplifying loop (MCSAL) and secondary haemophagocytic
lymphohistiocytosis (sHLH). Viral infections are the commonest cause of sHLH, and symptoms of
hyperinflammation resemble those of general sepsis, therefore hyperinflammation has generally
been under-recognised at an early stage leading to a high mortality. Blockade of the key
pathways in hyperinflammation such as IL-1 have been shown to be effective in sepsis
triggered cases without increased adverse events . Early data in a single arm open label
study of 21 severely ill COVID-19 patients with increased IL-6 expression, showed that
inhibition of IL-6 signaling with tocilizumab caused rapid clinical improvement in 75% of
cases, with some improvement in all cases .
During COVID19 infection, the initial viral invasion of epithelial tissues causes direct
cytotoxic damage but subsequently progresses to an inflammatory response at 7-10 days. While
an inflammatory response is likely to be needed to eliminate virus, there is a risk of
ongoing activation with inflammatory mediators causing end organ damage. Therefore, it seems
that targeting hyperinflammation (e.g. IL-6) during acute SARS-CoV-2 infection requires the
timing of blockade to be finely balanced to avoid early on impairment of host antiviral
responses. Similarly, intervening too late is likely to show minimal benefit. Due to the
urgency, despite this uncertainty, clinical trials to address the effectiveness of anti-IL-6
are already underway with Tocilizumab (ClinicalTrials.gov Identifier: NCT04317092, REMAP-CAP,
RECOVERY) and Sarilumab (ClinicalTrials.gov Identifier: NCT04315298). The entry criteria for
the UK trials of such interventions have largely been unselected, ie not specifically
targeting individuals who have hyperinflammation.
However, it is not yet clear how to identify those COVID-19 cases in whom
anti-hyperinflammation strategies are required. Retrospective examination of IL-6 expression
in 150 cases of COVID-19, estimated that in survivors median IL-6 level was approximately
6.9ng/ml (5-8.8 ng/ml), whereas in those who died was 11.25 ng/ml (7.75-16.25) (p<0.001) .
Overall, 46 cases with IL-6 >7.75 ng/ml 63% died whereas 47 cases IL-6 <7.75ng/ml showed only
23% mortality. Similar data were identified in a second study to examine IL-6 levels, but
only showed these to be elevated in 6 out of 48 cases (mortality 50% in IL-6 high) . This
suggests that IL-6 expression levels may provide a useful biomarker of outcome, but IL-6
measurement alone is not sufficient and additionally this is not widely available. Although
dexamethasone has been reported to reduce mortality in unselected cases with severe COVID-19,
dexamethasone has a well-known side effect profile and risk of complications. Indeed, it is
not surprising that for those patients with less severe COVID the non-significant trend was
that dexamethasone caused harm (death compared to controls, OR 1.22, [0.86 to 1.75]).
Therefore, it is likely that strategies to identify hyperinflammation and targeted
intervention will offer the most effective approach to management of COVID-HI. Indeed, as
well as anti-IL-6 other cytokines released in hyperinflammation for which existing biologic
therapies are available are also potential targets for intervention including TNF-α
(Infliximab), IL-1 (Anakinra), and JAK-inhibitors (e.g. Ruxolitinib). In addition, secondary
events may prove potential check-points in hyperinflammation for blockade and IL-6 is also
known to regulate Th17 differentiation and induction of CD8 cytotoxic T cells which are
important in anti-viral responses.
To facilitate diagnosis of hyperinflammation, the 'HScore' which is a validated score and was
developed in the context of secondary sHLH because of evidence that early recognition and
intervention is beneficial. Some authors have recommended using the HScore in COVID-19 to
identify hyperinflammation. However, very few COVID patients fulfil the current HScore
criteria. So, it is unclear whether COVID hyperinflammation (COVID-HI) is an attenuated form
of sHLH but with a similar mechanism or whether it is a distinct entity. Indeed, there are
unique aspects to SARS-CoV-2 infection such as the unusual coagulopathy that arises in up to
67% of cases which suggests that perhaps COVID-HI is a unique entity.
This proposal aims to examine the HScore parameters in NHS clinical and laboratory records of
patients admitted to Southampton with confirmed SARS-CoV-2 infection, with an aim to
determine the relevance to COVID19, and will explore whether other routine NHS parameters
could be incorporated to enhance the sensitivity of hyperinflammation diagnosis. To
facilitate a validation of this scoring approach, the study will confirm how such a scoring
system differentiates between the COVID-19 cohort and control cohort of hospitalised patients
stratified for key parameters. This analysis primary objective is to develop a clear
algorithm (COVID-HI score) for identification of the COVID19 subset with COVID-HI, and expect
these results will inform the next phase of COVID19 interventional clinical trial design in
anti-hyperinflammation therapy, such as the ACCORD study (CI, Prof T Wilkinson, Southampton)
. To identify hyperinflammation, the investigators will specifically examine the data for
trajectory changes in individual patients that reflect a hyperinflammatory response.
Hypothesis Our primary hypothesis is that it is possible to develop a scoring system from
existing NHS clinical and laboratory parameters to facilitate early identification of
COVID-HI. Our secondary hypothesis, for examination in a subsequent study, is that this score
will offer an important pre-screening tool for COVID19 cases for entry to clinical trials of
anti-hyperinflammation therapies.
To address the primary hypothesis, the aims are:
1. Correlate the existing HScore with outcomes in our dataset.
2. Examine in granular detail those cases who meet or partially meet the HScore threshold
for hyperinflammation.
3. Utilise non-hypothesis driven approaches to determine other clinical or laboratory data
which would improve the sensitivity of the identification of hyperinflammation in
COVID19 to identify a Soton HI score.
