Clinical trial NCT04351646: Diagnostics of COVID-19/DARTS (Development and Assessment of Rapid Testing for SARS-CoV-2 Outbreak)
Official title: Development and Assessment of Rapid Testing for SARS-CoV-2 Outbreak (DARTS)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: COVID-19
Keywords: SARS-CoV-2
COVID-19
coronavirus
Lead sponsor: St George's, University of London
Sponsor class: OTHER
First posted: 2020-04-17
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients population will include inpatients ad St George Hospital Foundation Trust (SGHFT) requiring SARS-CoV-2 test.

Health Care Professionals population will encompass staff working at St George Hospital Foundation Trust (SGHFT) during the SARS-CoV-2 outbreak who are suspected or confirmed cases of SARS-CoV-2.

Brief summary: This project will evaluate point-of-care / point-of-need (POC/PON) tests for the detection of the novel strain of coronavirus (2019 nCoV). We are working with Mologic Ltd, who have been funded by DFID/Wellcome Trust to develop a rapid, accurate and low cost, lateral flow assay (LFA) to detect viral circulating antigens and IgM/G against SARS-CoV-2 in less than 15 minutes.

These POC/PON tests are intended for the rapid triage of patients with fever and/or cough and to identify patients likely to be immune from previous infections. In addition to this the POC/PON tests will be designed as self-tests, offering the additional benefit of enabling wide deployment in the home and community settings. In addition, we will evaluate ELISA assays, also produced by Mologic to detect IgG and IgM (and possibly IgA) against SARS-CoV-2. Comparison of antibody and antigen dynamics over time will compare with ELISA and quantitative RT-PCR.

Detailed description: On 12 January 2020, a novel coronavirus was identified as the cause of an outbreak of unexplained pneumonia in Wuhan City, Hubei Province, China. This coronavirus was later named SARS-CoV-2, and the disease it causes COVID-19.

SARS-CoV-2 is a non-segmented, positive sense RNA virus and part of the family of coronaviruses. Similar to the Systemic Acute Respiratory Syndrome (SARS) virus, it binds to the angiotensin-converting enzyme 2 (ACE2) receptor located on type II alveolar cells and intestinal epithelia. SARS-CoV-2 can result in a severe Acute Respiratory Distress Syndrome (ARDS) which is characterised by diffuse alveolar damage and direct viral cytopathic effect on pneumocytes. Some patients who develop COVID19 may respond with a fulminant "cytokine storm" reaction.

As of 23 March 2020, a total of 374,921 COVID-19 cases have been reported in 168 countries with a total of over 16,411 deaths (case fatality amongst confirmed cases of 4.4%) (John Hopkins's Coronavirus Resource centre). Over 293,425 cases and 13,258 deaths have been reported from countries outside mainland China. The World Health Organisation (WHO) declared on the 12th of March the SARS-CoV-2 outbreak a pandemic in the context of a Public Health Emergency of International Concern (PHEIC) \[4\]. Europe has rapidly become the epicentre of the pandemic and in the UK, cases are increasing daily. There have been 6,724 confirmed cases in the UK as of 23 March 2020, including 190 confirmed inpatients at St George's Hospital NHS Trust (23 March 2020 , Dr. Breathnach, personal communication).

Because of the lack of a validated serological test, the actual number, and therefore the proportion, of people that develop asymptomatic infection remains unknown. This means that an accurate case fatality estimate remains elusive. Due to the rise in the number of diagnostic samples, tests are taking longer than expected. Among the foremost priorities to facilitate public health interventions is a reliable laboratory diagnosis. Prompt case ascertainment is necessary to ensure rapid and effective contact tracing, implementation of infection prevention and control measures according to WHO recommendations, and collection of relevant epidemiological and clinical information.

Because of the lack of a validated serological test, the actual number, and therefore the proportion, of people that develop asymptomatic infections remains unknown. This means that an accurate case fatality estimate remains elusive. Due to the rise of the number of samples to diagnose, tests are taking longer than expected. Among the foremost priorities to facilitate public health interventions is a reliable laboratory diagnosis. Prompt case confirmation is necessary to ensure rapid and effective contact tracing, implementation of infection prevention and control measures according to WHO recommendations, and collection of relevant epidemiological and clinical information.

The experience in China has been that around 15% of patients with confirmed infection develop severe disease and around 5% become critically ill. In the UK, a modelling analysis by the Imperial College COVID-19 Response Team suggests that even with the implementation of self-isolation measures (household quarantine and social distancing) the surge limits for both general wards and ICU beds will be exceeded 8-fold. Furthermore, a relaxation of these mitigation measures is likely to lead to a rebound of cases until there is an effective vaccine - which is not expected for some 12-18 months. We can therefore clearly expect a significant number of inpatients with COVID-19 infection in the UK in the coming months.

The SARS-CoV-2 antigen and antibody lateral flow assay (LFA) development has been led by Mologic, a company based in Bedford. We will use prototype LFA and ELISA that are ready for preliminary evaluation, and subsequently use these tests on-site to evaluate the test at POC. LFA have been developed for SARS-CoV-2 antigen detection in throat/ nose swabs and detection of IgG and IgM in blood/serum and SARS-CoV-2 antigen detection, IgG, IgM and IgA in saliva. Saliva is an exciting sample to use as it is far easier to use than blood or throat / nose swabs for potential self-testing.

Additionally, it is currently unknown why some patients develop severe COVID-19, while others affected by the same SARS-CoV-2 infection display only mild symptoms. Co-morbidities such as hypertension, kidney disease and diabetes have been linked to poorer prognosis and clinical outcomes. However, a proportion of patients of younger age and without comorbidities also develop severe disease- and there is a need for greater understanding of the immunopathogenesis of severe COVID-19 infection is important.

The use of diagnostics developed within this study will improve the management of cases of COVID-19. The LFA are rapid, easy to use and designed to be affordable globally. The rapid diagnosis of SARS-CoV-2 with antigen detection will allow patients to be rapidly triaged in hospital, GP surgeries and other places such as immigration areas. They are sufficiently cheap to be appropriate for use in low- and middle-income countries. The use of antibody detection will allow both for diagnosis of immunological response to acute infections as well as after patients have recovered later . To utilise these tests appropriately an understanding of dynamic immunopathological changes over time is necessary.

Characterisation of immune response and susceptibility and its association with viral clearance and disease progression on in large cohorts with varied disease severity is important to assist clinical risk prediction outcomes and evaluate the potential for novel immunotherapeutic interventions. Immune response characteristics may have predictive and prognostic value, with early adaptive immune responses possibly correlated with improved clinical outcomes.

Eligibility criteria: ==INCLUSION CRITERIA =========

Negative SARS-CoV-2:

* Aged 18 years of age or over
* Negative SARS-CoV-2 result from specimen received at SWLP laboratory in SGHFT

Positive SARS-CoV-2:

* Aged 18 years of age or over
* Positive SARS-CoV-2 result from specimen received at SWLP laboratory in SGHFT
* Requires hospitalisation in SGHFT

HCP with suspected or confirmed SARS-CoV-2:

* Aged 18 years of age
* Staff member with positive SARS-CoV-2 result from specimen received at SWLP laboratory in SGHFT or suspected diagnosis of COVID-19

==EXCLUSION CRITERIA =========

Negative SARS-CoV-2:

* Aged less than 18 years
* Outpatients
* History of known immune suppression

Positive SARS-CoV-2:

* Aged less than 18 years
* Patients unlikely to survive \>28 days in view of attending medical team
* Outpatients
* Anticipated transfer to another hospital within 72 hours
* History of known immune suppression

HCP with suspected or confirmed SARS-CoV-2:

* Aged less than 18 years
* History of known immune suppression

Primary outcomes:
measure: Antibody titres to SARS-CoV-2
timeFrame: Day 3 post baseline samples
measure: Antibody titres to SARS-CoV-2
timeFrame: Day 5 post baseline samples
measure: Antibody titres to SARS-CoV-2
timeFrame: Day 7 post baseline samples
measure: Antibody titres to SARS-CoV-2
timeFrame: Day 10 post baseline samples
measure: Antibody titres to SARS-CoV-2
timeFrame: Days 14 post baseline samples
measure: Antibody titres to SARS-CoV-2
timeFrame: Day 28 baseline samples
measure: Antibody titres to SARS-CoV-2
timeFrame: Day 56 post baseline samples
Secondary outcomes:
Other outcomes:
measure: Antigen dynamics
timeFrame: Days 3, 5, 7,10 14 and 28 and 56 post baseline samples
measure: HLA-KIR interactions
timeFrame: Days 3, 5, 7,10 14 and 28 and 56 post baseline samples
measure: Plasma cytokine levels
timeFrame: Day 7, day 14 and optionally day 28.
measure: Transcriptome
timeFrame: Day 7, day 14 and optionally day 28.
Locations:
city: London
country: United Kingdom
facility: St. Georges Hospital Foundation Trust
Study officials:
References:
citation: Staines HM, Kirwan DE, Clark DJ, Adams ER, Augustin Y, Byrne RL, Cocozza M, Cubas-Atienzar AI, Cuevas LE, Cusinato M, Davies BMO, Davis M, Davis P, Duvoix A, Eckersley NM, Forton D, Fraser AJ, Garrod G, Hadcocks L, Hu Q, Johnson M, Kay GA, Klekotko K, Lewis Z, Macallan DC, Mensah-Kane J, Menzies S, Monahan I, Moore CM, Nebe-von-Caron G, Owen SI, Sainter C, Sall AA, Schouten J, Williams CT, Wilkins J, Woolston K, Fitchett JRA, Krishna S, Planche T. IgG Seroconversion and Pathophysiology in Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Emerg Infect Dis. 2021 Jan;27(1):85-91. doi: 10.3201/eid2701.203074. Epub 2020 Nov 30.