PCORI Biweekly COVID-19 Scan: C21 (VP01) for Severe COVID-19, Corneal Confocal Microscopy (September 2-15, 2021)
Briefing
The Briefing provides an at-a-glance view of some important developments in the information universe surrounding COVID-19. The views presented here are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders.

Recent studies by the Centers for Disease Control and Prevention (CDC) indicate that vaccines against COVID-19 have remained effective and that the risk of being hospitalized for COVID-19 is 4.5 times higher for adults who are not fully vaccinated. Patients requiring hospitalization might benefit from new treatments aimed to supplement standard of care for severe COVID-19 (see Topics to Watch).
Against this background, the science of booster shots is being debated and newer generations of vaccines continue to be tested, including the first ever DNA-based vaccine, recently approved in India.
A small study from the University of Arkansas for Medical Sciences hints that angiotensin-converting enzyme (ACE)-2 autoantibodies might be a promising target for future treatment of patients with long COVID, although other work is looking to objectively diagnose such patients (see Topics to Watch). A National Institutes of Health (NIH) project called the REsearching COVID to Enhance Recovery (RECOVER) Initiative is working to make future long-COVID studies stronger by creating a meta-cohort that brings together a national study population.
ECRI Horizon Scanning has selected the topics below as those with potential for impact relative to COVID-19 in the United States within the next 12 months. All views presented are preliminary and based on readily available information at the time of writing.
Because these topics are rapidly developing, we cannot guarantee the accuracy of this information after the date listed on this publication. In addition, all views expressed in the commentary section are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders. Topics are listed in alphabetical order.
C21 (VP01) to Treat Severe COVID-19
At a Glance
- C21 is an investigational oral small molecule angiotensin II type 2 receptor (AT2R) agonist added to standard of care for treating patients hospitalized with severe COVID-19.
- SARS-CoV-2 binding to ACE2 might cause a loss of function leading to an imbalance in and reduction of the protective effects of the renin-angiotensin-aldosterone system (RAAS). Treatment with C21 purportedly stimulates AT2R and restores the functionality of the RAAS, purportedly promoting antioxidant, anti-inflammatory, anticoagulative, and antifibrotic effects.
- Preprint data from a phase 2 randomized controlled clinical trial in 106 hospitalized patients found that at day 14, the proportion of patients in the C21 group still requiring supplemental oxygen was significantly reduced by 90%, compared with the placebo group.
- An ongoing phase 3 randomized trial comparing C21 with placebo in hospitalized adults with severe COVID-19 has a primary completion expected in February 2022.
Description
C21 (Vicore Pharm, Göteborg, Sweden) is an oral small molecule angiotensin II type 2 receptor (AT2R) agonist being investigated as an add-on to standard of care for treating patients hospitalized with severe COVID-19.
SARS-CoV-2 binds to and enters cells through angiotensin-converting enzyme (ACE)-2 receptors and is thought to inhibit normal ACE2 function, leading to overstimulation of the angiotensin II type 1 receptor (AT1R) and understimulation of the AT2R. This proposed imbalance in the renin-angiotensin-aldosterone system includes decreased production of the peptides angiotensin-1-7 and angiotensin-1-9, which are known to have a broad range of protective effects on the heart, lungs, and kidneys. Treatment with C21 might correct this imbalance and restore the functionality of the RAAS by stimulating the AT2R and promoting antioxidant, anti-inflammatory, anticoagulative, and antifibrotic effects.
Preprint data from a phase 2 randomized controlled clinical trial in 106 patients hospitalized with COVID-19, but not requiring mechanical ventilation, found that at the end of the 7-day treatment period, the proportion of patients who received C21 who required supplemental oxygen was 27.5% compared with 45.5% of patients given placebo. By day 14, the proportion of patients in the C21 group still requiring supplemental oxygen was significantly reduced by 90%, compared with the placebo group (1 patient vs. 11 patients). An ongoing phase 3 randomized controlled clinical trial is comparing C21 with placebo in hospitalized adults with severe COVID-19. Topline data are expected in the first quarter of 2022. The authors were unable to find information regarding the potential cost of C21.
Commentary
C21 is an investigational oral therapy to treat patients hospitalized with COVID-19 who require oxygen administration. Due to the surge in cases, the spread of variants, and those declining vaccination, additional effective treatments for severe COVID-19 are still needed.
Early feedback from ECRI internal stakeholders suggests that, if effective, C21 presents a promising treatment option that might reduce the need for respiratory support, shorten the length of hospitalizations, and free up hospital resources. C21 administration could increase short-term treatment costs, but it could also result in cost offsets from less care required and reduce the burden on the health care system.
Stakeholders thought that the mechanism behind C21 was theoretically sound because research suggests that AT1R promotes reparative and regenerative functions, but thought AT2R might make infections more severe. Preliminary safety and efficacy data for C21 are encouraging. However, larger published studies are needed to fully assess its effectiveness and disruptive potential.
- Category: Treatment
- Areas of potential impact: Patient outcomes, patient management, health care disparities, health care costs
Corneal Confocal Microscopy to Detect Long COVID
At a Glance
- Corneal confocal microscopy (CCM) is a noninvasive, ophthalmic imaging technology proposed as a method to identify patients with long COVID more objectively.
- CCM purportedly detects subtle changes in nerve fibers in the front of the eye that might be linked with other neurologic symptoms of long COVID.
- An early study found patients with post-COVID neurologic symptoms also had the largest reductions in several types of corneal nerve fibers. Reductions in these corneal nerve fibers were significantly correlated with patients’ scores on a standard long-COVID screening questionnaire.
- Further research is needed to definitively link corneal nerve changes with long COVID and differentiate it from other potentially preexisting neurologic conditions.
Description
Although the knowledge base of COVID-19 pathology has improved since the early days of the pandemic, gaps do remain, especially in identifying patients at greatest risk of developing long-term symptoms, known as long COVID.
A new study proposes a type of noninvasive, ophthalmic imaging called corneal confocal microscopy to more objectively identify patients with long COVID. Previously, CCM has been proposed as a noninvasive means for early detection of diabetic retinopathy, peripheral neuropathy, and other forms of nerve damage.
Researchers in Turkey found that CCM could detect loss of small nerve fibers in the corneas (the transparent front layer of the eye) and an increase in the density of dendritic cells, immune system cells key to initiating immune responses, in patients with neurologic symptoms 4 weeks after acute COVID-19 infection. Patients with neurologic symptoms also showed statistically significant reductions in corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length. Further, these reductions showed statistically significant correlations with the total score on the National Institute for Health and Care Excellence long-COVID screening questionnaire at 4 and 12 weeks.
Commentary
The recent surge in COVID-19 cases has raised interest in identifying individuals at risk of long-COVID symptoms. Having a noninvasive imaging technology capable of detecting signs of nerve damage could give physicians more information when developing treatment strategies for long COVID.
Early feedback from ECRI internal stakeholders suggested that CCM has potential as a novel and convenient method to help identify patients at greater risk of developing long–COVID-19 symptoms. However, CCM might require new infrastructure and might be available to relatively few trained ophthalmologists, potentially creating disparities in rural and low-resource areas.
The cost of implementing CCM in clinical practice might also be a barrier for adoption. If third-party payers do not reimburse CCM, most patients might not be able to afford it. Stakeholders also cited a need for more data to definitively differentiate COVID-linked nerve damage from other preexisting conditions such as diabetic retinopathy or peripheral neuropathy.
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Categories: Screening and diagnostics
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Areas of potential impact: Health care delivery and process, patient management, health care disparities
Horizon scanning is a systematic process that serves as an early warning system to inform decision makers about possible future opportunities and threats. Health care horizon scanning identifies technologies, innovations, and trends with potential to cause future shifts or disruptions—positive or negative—in areas such as access to care, care delivery processes, care setting, costs of care, current treatment models or paradigms, health disparities, health care infrastructure, public health, and patient health outcomes.
The PCORI Health Care Horizon Scanning System (HCHSS) conducts horizon scanning to better inform its patient-centered outcomes research investments. Initially, PCORI defined the HCHSS project scope to focus on interventions with high potential for disruption in the United States in 5 priority areas: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health conditions, and rare diseases. In addition, the system captures high-level disruptive trends across all clinical areas, which may lead PCORI to expand the project scope to include other priority areas in the future.
In early 2020, the COVID-19 pandemic created a fast-moving, widespread public health crisis. In May 2020, PCORI expanded its HCHSS to elucidate the landscape of potentially impactful applications for COVID-19. The HCHSS COVID-19 supplement scans for, identifies, monitors, and reports on emerging and available COVID-19-related treatments, diagnostics, preventive measures, management strategies, and systems changes with potential for high impact to patient outcomes—for individuals and populations—in the United States in the next 12 months.
The HCHSS COVID-19 supplement produces 3 main outputs:
- Biweekly COVID-19 Scans (eg, this document) provide ECRI Horizon Scanning with a vehicle to inform PCORI and the public in a timely manner of important topics of interest identified during ongoing scanning and topic identification or through the ECRI stakeholder survey process.
- Status Reports (quarterly) briefly list and describe all COVID-19-related topics identified, monitored, and recently archived.
- High Impact Reports (every 4 months) highlight those topics that ECRI internal stakeholders (eg, physicians, nurses, allied health professionals, public health professionals, first responders, health systems experts, clinical engineers, researchers, business and finance professionals, and information technology professionals) have identified as having potential for high impact relative to COVID-19 in the United States.
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Commentary in this COVID-19 Scan reflects preliminary views of ECRI Horizon Scanning and internal ECRI stakeholders.
The information contained in this document has not been vetted by other stakeholders.
We welcome your comments on this Scan. Send them by email to [email protected].
Posted: September 24, 2021
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