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Prognostication of Oxygen Requirement in Non-severe SARS-CoV-2 Infection (PRIORITISE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04441372
Recruitment Status : Not yet recruiting
First Posted : June 22, 2020
Last Update Posted : August 14, 2020
Sponsor:
Collaborators:
Mahidol Oxford Tropical Medicine Research Unit (MORU)
International Centre for Diarrhoeal Disease Research, Bangladesh
Foundation for Innovative New Diagnostics, Switzerland
Information provided by (Responsible Party):
Medecins Sans Frontieres, Spain

Tracking Information
First Submitted Date June 17, 2020
First Posted Date June 22, 2020
Last Update Posted Date August 14, 2020
Estimated Study Start Date October 1, 2020
Estimated Primary Completion Date March 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 30, 2020)
Clinical and biochemical prognostic markers [ Time Frame: 14 days ]
Identify clinical and biochemical prognostic markers in adults with non-severe COVID-19. This is assessed through the ability of the markers to predict progression to subsequent supplemental oxygen requirement - sensitivity, specificity, NPV, PPV and AUROC, and discrimination (c-index) and calibration (plots of observed probabilities against predicted probabilities) of a prognostic model combining up to four markers.
Original Primary Outcome Measures
 (submitted: June 17, 2020)
Clinical and biochemical prognostic markers [ Time Frame: 6 months ]
Identify clinical and biochemical prognostic markers in adults with non-severe COVID-19. This is measured through the ability of the markers to predict progression to subsequent oxygen requirement - sensitivity, specificity, NPV, PPV and AUROC, and discrimination (c-index) and calibration (plots of observed probabilities against predicted probabilities) of a prognostic model combining up to four markers
Change History
Current Secondary Outcome Measures
 (submitted: August 10, 2020)
Evaluate field-based performance of POC [ Time Frame: 14 days ]
To evaluate the field-based performance of near-patient lateral flow assays for suPAR and IL-6 in adults with non-severe SARS-CoV-2 infection. This is assessed through looking at correlation of the near-patient lateral flow assays and the instrumented multi-analyte immunoassaygold standard.
Original Secondary Outcome Measures
 (submitted: June 17, 2020)
  • Performance of LMIC-friendly POC [ Time Frame: 6 months ]
    Determine the performance of LMIC-friendly POC or near-patient prognostic tests in adults with non-severe COVID-19. Measured through the ability of test to predict progression to subsequent oxygen requirement -sensitivity, specificity, NPV, PPV and AUROC
  • Safe and ethical operational research [ Time Frame: 6 months ]
    To demonstrate that operational research can be conducted ethically and effectively in the context of a pandemic in a resource-limited setting without detracting from the emergency response. This is achieved via survey to explore the challenges and experiences of staff interacting with the research.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Prognostication of Oxygen Requirement in Non-severe SARS-CoV-2 Infection
Official Title Prognostication of Oxygen Requirement in Non-severe SARS-CoV-2 Infection
Brief Summary

Note that this is a study that is co-sponsored by Medecins Sans Frontieres, Spain, and the University of Oxford.

The primary objective of this study is to identify clinical and biochemical prognostic markers in adults with virologically confirmed COVID-19 who do not require oxygen supplementation, with a focus on: aiding safe discharge from a healthcare facility (i.e. a high NPV); near-term impact on COVID-19 interventions in resource-limited settings (i.e. simple clinico-demographic variables and biochemical markers for which near-patient / POCTs are commercially available or in late-stage development).

The secondary objective of this study is to evaluate the field-based performance of near-patient lateral flow assays for suPAR and IL-6 in adults with non-severe SARS-CoV-2 infection

Detailed Description

Background

At the time of writing the novel betacoronavirus SARS-CoV-2 has infected more than 11 million individuals and killed more than 500,000. The most recent epidemiological surveillance curve shows that the number of new infections continues to rise, with over 230,000 new cases reported in the last 24 hours.

Whilst the absolute number of deaths attributable to COVID-19 is substantial, effectively managing high patient volumes is also a major challenge facing health systems, particularly in under-resourced settings. With an estimated case-fatality rate amongst symptomatic patients of between 1-2%, it is vitally important that health workers are able to accurately identify the majority of patients at low risk for progression to severe disease. These patients can be safely discharged away from the health facility ensuring the available resources are allocated to patients most likely to benefit. If low-risk patients cannot be readily identified, there is a real risk that health facilities in these regions will be overrun, with consequent substantial avoidable mortality.

COVID-19 has already started to hit extremely vulnerable populations in refugee camps and conflict areas. In Bangladesh, cases within the Rohingya refugee megacamps have already been reported, and local transmission is ongoing. Such contexts already suffer from a lack of medical facilities and even a moderate number of COVID-19 cases will overburden existing, and proposed, capacity. Having the ability to prognosticate the need for supplemental oxygen (the main treatment available in these settings) through measurement of parameters available at the time of arrival at a healthcare facility would strengthen the capability to identify those patients presenting with moderate symptoms that can be safely discharged away from the facility. Based on recent estimates, only 20% of all symptomatic patients with COVID-19 develop a requirement for supplemental oxygen.

Although existing prognostic scores have yielded disappointing results in patients with SARS-CoV-2 infection a number of demographic, clinical and laboratory parameters are associated with a more severe disease course and worse patient outcomes. However, to our knowledge, few studies have examined the performance of prognostic markers in patients who do not require supplemental oxygen at presentation. Only one of these studies included outpatient or ambulatory care settings and none were conducted in resource-limited settings. Hence, whether measurement of these parameters can inform the decision to safely discharge a patient away from a health facility is as yet unclear.

Main research question

In adults presenting to care with non-severe COVID-19, can subsequent need for oxygen be predicted from parameters measured at the time of arrival at a healthcare facility?

This study will evaluate several clinical and biochemical biomarkers that have been identified as possible predictors of deterioration in patients with COVID-19. The primary objective is to develop a prognostic tool combining up to four markers (including a maximum of two biochemical markers) with a high negative predictive value (NPV) for subsequent supplemental oxygen requirement (WHO Grade ≥ 5). Clinical biomarkers will be limited to simple clinico-demographic variables (for example, age, sex and duration of symptoms) in order to ensure the tool remains as simple as possible. Biochemical biomarkers for which point-of-care (POC) and/or near-patient tests are either already commercially available or in late-stage development have been prioritised, in order to maximise the chance of translation on to the field within a time period that is useful for the current global pandemic response.

The requirement for supplemental oxygen has been selected as the primary outcome: it is a relatively objective endpoint (based either on the measurement of peripheral oxygen saturation [sO2 ≤ 93%] or a respiratory rate > 30 breaths per minute or a clinical decision to give supplemental oxygen) and from a practical perspective is the main evidence-based therapeutic intervention available in such settings, but in very limited supply in the majority of low- and middle-income countries (LMICs).

We have identified near-patient tests for two of the priority biochemical biomarkers that have not yet been field-evaluated in LMICs (IL-6 and suPAR). We will evaluate the performance of these tests under field conditions. We have selected these tests for evaluation because unlike the other potential markers for which near-patient tests also exist, there is a relative paucity of field experience in tropical settings. As all biochemical markers (including suPAR and IL-6) will be measured using a validated multi-analyte quantitative immunoassay (using the Ella platform), this study will provide an opportunity to evaluate the field performance of these tests. If either of the markers is found to be useful prognosticators for patients with non-severe SARS-CoV-2 infection, this may facilitate a more rapid translation of the results of this study into practice.

Assumptions, limitations, and generalisability

The main assumption that underlies this work is that a validated, rapid, low-cost antigen-based test for SARS-CoV-2 will become available in the near future. There is reason to believe that this will be the case.Availability of such a test would allow the prognostic tool developed in this study to be applied to the appropriate patient population at the point of arrival at a health facility. Whilst the absence of such a test would undoubtedly limit the utility of the tool, it is likely that when local incidence of patients presenting with confirmed SARS-CoV-2 infection exceeds a threshold, use of the tool could be justified based upon a clinical case definition alone. Furthermore, in order to mitigate this risk, we plan to use the data collected in this study (specifically the baseline and outcome data collected from participants who are subsequently confirmed to be SARS-CoV-2 negative by RT-PCR) to inform exploratory simulation analyses, with the aim of customizing of the tool for use in different prevalence settings, thereby extending utility to different phases of the pandemic.

An additional limitation of this study is that due to its single-site nature we will not be able to explore whether the performance of the prognostic markers is impacted by different host populations, or perform an external geographic validation of the prognostic model. To mitigate this risk we have designed a pragmatic study that could be implemented in other sites. We are actively exploring options for conducting the study at other sites if sufficient additional funding can be identified. We will inform and seek approval from all relevant regulatory bodies (international and local) prior to the inclusion of any additional study sites.

Study Type Observational [Patient Registry]
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration 14 Days
Biospecimen Retention:   Samples With DNA
Description:
Blood will be taken for biomarker assessment from all participants and may include pathogen identification
Sampling Method Non-Probability Sample
Study Population The study will be conducted at two MSF-OCBA COVID-19 treatment facilities in Cox Bazar, Bangladesh, both located in the southern Upazilla of Teknaf (Nayapara and Unchiparang treatment centres). Both have the capacity for screening and admission of patients, and cater to host and refugee populations. Both sites are recognised by the government and Health Clusters as COVID-19 management facilities.
Condition
  • SARS-CoV2
  • COVID
Intervention Not Provided
Study Groups/Cohorts Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Not yet recruiting
Estimated Enrollment
 (submitted: June 30, 2020)
1200
Original Estimated Enrollment
 (submitted: June 17, 2020)
850
Estimated Study Completion Date April 1, 2021
Estimated Primary Completion Date March 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

The participant may enter the study if ALL of the following apply:

  1. Willing and able to give informed consent and comply with study procedures;
  2. Aged ≥ 18 years;
  3. Axillary temperature at presentation ≥ 37.5°C OR history of fever in last 24h;
  4. Cough OR shortness of breath OR difficulty breathing.

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:

  1. No limitation of daily activities (WHO COVID-19 Clinical Progression Scale Grade ≤ 2);
  2. Requires supplemental oxygen at presentation (WHO COVID-19 Clinical Progression Scale Grade ≥ 5);
  3. Currently enrolled in study and under follow-up (not yet reached D14);
  4. Previous laboratory-confirmed SARS-CoV-2 infection (virological or serological).
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Mikhael Yosia, MD +6281378778784 msfe-jakarta-med@barcelona.msf.org
Contact: Arjun Chandna, MD +85585712586 arjun@tropmedres.ac
Listed Location Countries Bangladesh
Removed Location Countries  
 
Administrative Information
NCT Number NCT04441372
Other Study ID Numbers MSF0001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Medecins Sans Frontieres, Spain
Study Sponsor Medecins Sans Frontieres, Spain
Collaborators
  • Mahidol Oxford Tropical Medicine Research Unit (MORU)
  • International Centre for Diarrhoeal Disease Research, Bangladesh
  • Foundation for Innovative New Diagnostics, Switzerland
Investigators
Principal Investigator: Arjun Chandna, MD Cambodia Oxford Medical Research Unit
Principal Investigator: Sakib Burza, PhD Medecins Sans Frontieres, Spain
PRS Account Medecins Sans Frontieres, Spain
Verification Date August 2020