May 1, 2020 | The clinical research community is continuing to gain momentum as it searches for solutions to COVID-19. This week brought several new insights to the table, including recent studies suggesting potential treatments for the virus and strategic plans for accelerating COVId-19 research.

Literature Updates

Leading cardiologists in China are recommending that proven cardiovascular anti-inflammatory therapies be used to treat COVID-19 patients that are at risk of, or have developed, cardiovascular problems. In the latest issue of Frontiers in Cardiovascular Medicine, they provide clinicians with guidance for the selection of specific cardiovascular anti-inflammatory therapies based on disease severity a patient's response to therapy. They also highlight known risks to the cardiovascular system of treatments currently being tested on patients with COVID-19. The focus is on promising COVID-19 treatments as well as cardiovascular anti-inflammatory therapies that have been verified in clinical trials with positive results. Some drugs currently in use for COVID-19 patients—including lopinavir/ritonavir, interferon-α, ribavirin, azithromycin and hydroxychloroquine—may increase the risk of cardiovascular impairment. DOI: 10.3389/fcvm.2020.00078

Cytokine storms may affect the severity of COVID-19 cases by lowering T cell counts, according to a study by researchers in China newly published in Frontiers in Immunology. Interestingly, they also found a high concentration of cytokines, which can trigger an excessive inflammatory response (aka cytokine storm) that causes the proteins to attack healthy cells. The study suggests that coronavirus does not attack T cells directly, but rather triggers the cytokine release that then drives the depletion and exhaustion of T cells. Researchers say more urgent, early intervention may be required in patients with low T lymphocyte counts. They examined 522 patients with coronavirus admitted to two hospitals in Wuhan between December 2019 and January 2020, along with 40 healthy controls. Of the 499 patients who had their lymphocytes recorded, 76% had significantly low total T cell counts. ICU patients had significantly lower T cell counts compared with non-ICU cases, and patients over the age of 60 had the lowest number of T cells. The T cells that did survive were exhausted and could not function at full capacity, which has implications for COVID-19 patient outcomes and leaves patients more vulnerable to secondary infection. All potential treatments require further study. DOI: 10.3389/fimmu.2020.00827

A new study in China, published in Frontiers in Public Health, is the first to examine gender differences in COVID-19 patients. The study finds that men and women are equally likely to contract the virus, but men are significantly more likely to suffer severe effects of the disease and die. Results suggest being male was a significant risk-factor for worse disease severity, regardless of age, but that additional care may be required for older men or those with underlying conditions. The study was based on an analysis of data on 43 patients treated by investigators and a publicly available dataset on 1,056 other COVID-19 patients. Strikingly, in the largest COVID-19 dataset men had almost 2.5 times the death rate of women. Researchers found a similar trend in a SARS dataset from 2003. DOI: 10.3389/fpubh.2020.00152

New research from Mayo Clinic indicates that people with obstructive hypertrophic cardiomyopathy (HCM) may be more susceptible to worse outcomes with COVID-19. HCM causes the heart to increase production of the ACE2 RNA transcript and the translated ACE2 protein. SARS-CoV-2 hijacks these ACE2 receptors on the membrane of cells and uses them to get inside the cells. The virus also takes ACE2 protein with it, removing a protective signaling pathway that normally counters the negative impact (increased blood pressure leading to fluid retention) of the hormone angiotensin II. Over the course of 20 years, researchers analyzed frozen samples of heart muscle tissue from 106 patients who had surgery for HCM; the control group used heart tissue from 39 healthy donor hearts. The next step is to look for other elevated ACE2 levels by analyzing available heart tissue from patients who have died from hypertension and other heart diseases. Lung tissue from COVID-19 victims also could be analyzed to see if ACE2 levels are higher than in normal lung tissue. Researchers say their discovery provides another reason for patients taking ACE inhibitors and angiotensin II receptor blockers to stay on their heart medications. The study was published in Mayo Clinic Proceedings. DOI: 10.1016/j.mayocp.2020.04.028

Researchers at UC San Diego Health report in International Forum of Allergy & Rhinology that when SARS-CoV-2 infection is signaled by olfactory impairment the resulting COVID-19 disease is more likely to be mild to moderate—making it a potential early indicator that could help healthcare providers determine which patients require hospitalization. In previous research, researchers found that loss of olfactory function is a common early symptom, following fever and fatigue. The latest retrospective analysis included 169 patients who tested positive for COVID-19; olfactory and gustatory data were obtained for 128 of them. The 26 patients requiring hospitalization were significantly less likely to report smell blindness. Patients who did report loss of smell (versus those who did not) were 10 times less likely to be admitted for COVID-19. Like the concept underlying live vaccinations, researchers hypothesize that the host can generate an immune response without severe infection because of where the virus initially concentrates and the lower viral burden. Loss of smell might also indicate a robust immune response that has been localized to the nasal passages, limiting effects elsewhere in the body. DOI: 10.1002/alr.22592

New research published in the Journal of Clinical Virology indicates that the vulnerability of neonates and children and their role in the spread of the SARS-CoV-2 virus should be included in preparedness and response plans. Scientists at Midwestern University say the COVID-19 pandemic poses substantial and underappreciated risks to pregnant women, and perinatal infections endanger pregnancy outcomes. Studies to date suggest the virus can be transmitted to the fetus in utero and the possible routes for infection are such that infection control measures are required to protect newborns. The researchers say vaccines targeting women of reproductive age, especially pregnant patients, should be evaluated in clinical trials that include the endpoints of neonatal infection and disease. DOI: 10.1016/j.jcv.2020.104372

A new clinical review published in The FASEB Journal casts doubt on use of chloroquine and hydroxychloroquine for treating the respiratory infection caused by COVID-19. Researchers looked at earlier anecdotal reports and poorly controlled clinical trials that raised considerable optimism about the widespread adoption of hydroxychloroquine. They point to late-breaking data that creates significant skepticism that either drug reduces viral uptake by cells in patients. Even more worrisome is the powerful immunosuppressive action of these drugs that have failed in previous respiratory virus outbreaks, including influenza. Current clinical trial results are leading to a rapidly diminishing view of the drugs’ utility for COVID-19. DOI: 10.1096/fj.202000919

The clinical benefits of remdesivir have also been thrown into question by the first randomized trial of the antiviral drug, as reported in The Lancet. Treatment with remdesivir did not speed recovery or reduce deaths from COVID-19 compared with placebo among 237 critically ill patients hospitalized in Wuhan, China. Researchers had hoped to enroll 453 patients. The study stopped early due to difficulty recruiting patients after the COVID-19 outbreak in the city was brought under control, so the true effectiveness of the antiviral drug remains unclear. Pre-specified secondary outcomes found that time to clinical improvement and duration of invasive mechanical ventilation were shorter in people treated with remdesivir within 10 days of showing symptoms, compared to standard care, but the finding was not statistically significant. Remdesivir remains one of a handful of experimental drugs undergoing clinical trials worldwide. DOI: 10.1016/S0140-6736(20)31022-9

Traditional medicine experts in India have published a well-referenced description of how the Ayurveda approach and yoga may help strengthen host immunity and provide an effective, accessible and affordable means of prophylaxis of COVID-19 infection. Their paper, published in JACM, The Journal of Alternative and Complementary Medicine, discusses the ability of Ayurveda practices such as consumption of hot water, hot food and herbal drinks, gargling with medicated water, and steam inhalation to help block virus entry to the body and passage to the lungs. Systemic prophylaxis focuses on overall health and includes factors such as diet, sleep, mental relaxation, lifestyle behaviors and yoga. Science supports Rasayana therapies, a specialty of Ayurveda, which deals with rejuvenation and can stimulate immunity. Botanicals also have been found effective in immunomodulation and restoration of immune homeostasis. DOI: 10.1089/acm.2020.0129

A new Boston University School of Public Health study published in the American Journal of Preventive Medicine finds discrimination and inequality have shaped the risk of severe illness and death from the coronavirus. Black, Native American and lower-income people are much more likely to have one or more of the risk factors for severe or deadly COVID-19 illness (e.g., asthma, diabetes, being pregnant or over 65 years old). Based on 2018 data on over 330,000 people from the Behavioral Risk Factor Surveillance System, 43% of American adults (97 million people) have at least one risk factor for COVID-19 and 18% (about 40 million people) have two or more. Among adults under 65 years old, a higher proportion of blacks (33%) and Native Americans (42%) have at least one risk factor versus whites (27%). The burden is similarly disproportionate when looking at those with multiple risk factors (respectively 11% and 18% vs. 8%). For those 65 or older with one or more additional risk factors beyond age, the figures are 69% for Native American, 61% for black and 54% for white respondents. At least 25 million people living in low-income households have at least one risk factor and, of those, the under-65 group are almost twice as likely to have one or more risk factors than high-income respondents and more than twice as likely to have multiple risk factors. Low-income respondents over 65 were also more likely to have multiple risk factors beyond age. The three identified groups are also more likely to be exposed to COVID-19 and develop severe illness if they contract the virus. DOI: 10.1016/j.amepre.2020.04.003

An international team of researchers, led by the University of Surrey, has identified a link between the COVID-19 cure rate and regional selenium status in China. Selenium, an essential trace element obtained from the diet (fish, meat and cereals), has been found to affect the severity of several other viral diseases, including HIV. China has both areas of high and low levels of selenium, depending on the soil. Examining data from provinces and municipalities with more than 200 cases and cities with more than 40 cases, researchers found that areas with high levels of selenium were more likely to recover from the virus. Most convincingly, they found that the COVID-19 cure rate was significantly associated with selenium status (as measured by the amount of selenium in hair) in 17 cities outside of Hubei, the province with the highest selenium intake in China. Result were reported in the American Journal of Clinical Nutrition. DOI: 10.1093/ajcn/nqaa095

Other News

xCures, a health technology company focused on the use of artificial intelligence, has released preliminary data from the company’s Behavior, Environment, And Treatments for COVID-19 (BEAT19) registry study, NCT04321811. The study is designed to enable everyday people, regardless of their health status, to contribute directly to the development of coronavirus treatments. Since the approval of the BEAT19 registry by the Genetic Alliance’s independent review board (IRB) and program launch on March 29, BEAT19 has collected more than 6,000 daily surveys representing people across all 50 US states and several countries. The preliminary data demonstrated that BEAT19 can collect data from patients who are infected with COVID-19 while they are undergoing quarantine and provide clinical researchers with important insights into disease progression. More information.

In Switzerland, a clinical trial was launched simultaneously in Geneva and Basel to assess the efficacy of two drugs in the treatment of people who were in close contact with newly confirmed COVID-19 cases (aka post-exposure ring chemoprophylaxis). The project—a collaboration between the University Hospitals Geneva, the University Hospital in Basel, and the Swiss Tropical and Public Health Institute, will assess the efficacy of two drugs by enrolling more than 400 people who were in close contact with newly diagnosed COVID-19 patients. Contact persons will be randomly allocated into a group administered a single dose of the antimalarial drug hydroxychloroquine or the anti-HIV drug lopinavir/ritonavir for five days, or a third group administered neither of the repurposed drugs. Three weeks post-enrollment, investigators will check if participants developed infection and, if so, how severe it is. Press release.

A research study by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) is evaluating the use of video counseling nationwide to help cancer patients who smoke to quit, because it puts them at even higher risk of severe respiratory illness if they contract COVID-19. The Smoke-Free Support Study 2.0 trial will randomly assign 308 current smokers (with any kind of cancer) into a group receiving 11 video counseling sessions with a tobacco treatment counselor from Massachusetts General Hospital (MGH) and the option to receive up to 12 weeks of standard nicotine replacement therapy at no cost, or stop-smoking advice and referral to the national smokers' quitting resource, smokefree.gov. The primary endpoint is abstinence at six months. Data will also be collected from participating oncology care providers to help identify barriers and facilitators of implementing tobacco treatment in community oncology settings. Colleagues from MGH and Memorial Sloan Kettering (MSK) Cancer Center collaboratively developed the program. Participating hospitals are all members of the National Cancer Institute’s Community Oncology Research Program and will join the trial on a rolling basis. Press release.

Researchers at the Icahn School of Medicine at Mount Sinai, in collaboration with GenScript, is developing a synthetic antibody to SARS-CoV-2 that is intended to block the virus from entering human lung cells and would be another potential treatment option for COVID-19. The antibody is targeting the peptide sequence of the virus’s spike protein and would stop the virus from infecting additional cells, much as doctors are already doing with convalescent plasma therapy. The goal is to have a targeted antibody for first human trials in under a year. Press release.

The National Institute of Allergy and Infectious Diseases (NIAID) has issue its strategic plan for accelerating research to diagnose, prevent and treat COVID-19. The four key priorities are to improve fundamental knowledge of SARS-CoV-2 and COVID-19; develop rapid and accurate diagnostics and assays to identify and isolate COVID-19 cases and track the spread of the virus; characterize and test potential treatments; and develop safe and effective vaccines to protect individuals from infection and prevent future SARS-CoV-2 outbreaks (NIAID recently launched a phase 1 clinical trial using a vaccine platform initially developed to target Middle East respiratory syndrome) The strategic plan aligns with priorities set by the White House Coronavirus Task Force and represents a comprehensive and coordinated effort to develop effective biomedical tools to combat COVID-19. Press release.

In Denmark, doctors and engineers have collaboratively developed an electric stocking to prevent loss of muscle mass in bedridden COVID-19 patients in intensive care units. Researchers from Aarhus University and the University of Copenhagen have developed a special biocompatible electrode that can be integrated and 3D-printed onto textiles. Production of the first 50 pairs of electric compression stockings has started and they’ll be ready for testing by patients in a month. If trials with COVID-19 patients show a reduction in muscle loss, the universities are ready to produce 500 extra pairs of the stockings by this fall when the next wave of the coronavirus is expected. Press release.

Boston Children's Hospital has launched a two-pronged study of COVID-19 disease among children and youth up to age 25 across the country. The Overcoming COVID-19 study will perform real-time surveillance at more than 35 U.S. children's hospitals to capture data on 800 patients hospitalized with COVID-19, reporting near real-time to the Centers for Disease Control and Prevention. It will also enroll up to 400 of these patients for detailed, prospective observation and periodic collection of respiratory and blood samples. Major goals are to understand why some children get very ill with COVID-19 and most aren't getting sick in the same numbers as adults, which may provide clues as to why older people are so susceptible. Selected study centers will also enroll positive but asymptomatic patients, as well as patients with influenza to serve as control groups. Among the parameters being investigated are patients' antibody levels and other indicators of immune response, markers of inflammation, viral shedding, and the various treatments used for COVID-19 and their effects. In a separate initiative at Boston Children’s, researchers will do whole-genome or whole-exome sequencing to look for variations in DNA that are protective or make people more susceptible to the virus. The hospital is also creating a biobank of samples from its own patients that investigators can submit applications to access. Press release.

In the United Kingdom, a new clinical trial has launched of bemcentinib as a potential treatment for COVID-19. The drug was developed by BerGenBio ASA as a potential treatment for certain cancers and targets a cell protein called AXL. Researchers at the University of Iowa Health Care and elsewhere have found it is also one of several cell surface receptors used by different lipid-encased viruses—including the Ebola and Zika viruses as well as SARS-CoV-2—to enter cells. Preclinical findings suggest bemcentinib profoundly inhibits virus entry into those cells. Based on work at the University of Bergen in Norway, BerGenBio has developed novel, selective AXL kinase inhibitors, including bemcentinib, which has been tested in clinical trials for certain cancers and shown to be safe and well-tolerated in hundreds of patients. Press release.

A global, phase 3 clinical trial is assessing whether tocilizumab (Actemra, made by Genentech/Roche), an immunosuppressive drug used to treat inflammatory disorders (primarily rheumatoid arthritis and systemic juvenile idiopathic arthritis), might also have therapeutic value for COVID-19 patients who have developed or at high risk of developing serious lung damage from SARS-CoV-2 infections. The monoclonal antibody-based therapy works by blocking cellular receptors for interleukin-6, which plays an important role in triggering inflammation as an early immune response to disease. The immune system of some COVID-19 patients overexpresses IL-6, generating a cytokine storm that can lead to potentially life-threatening damage to the lungs and other organs. In the early days of the novel coronavirus outbreak in Wuhan last year, Chinese physicians used tocilizumab to treat a small number of COVID-19 patients with serious lung damage and reported promising results. The Chinese National Health commission now includes tocilizumab in its guidelines for treating COVID-19-related pneumonia and other lung issues. The randomized, double-blind, placebo-controlled interventional trial will enroll approximately 330 participants at nearly 70 sites worldwide, with an estimated completion date of Sept. 30, 2020. Press release.

Another anti-inflammatory drug, developed at Scripps Research 25 years ago, will now be tested as a therapeutic to prevent acute respiratory distress in patients with COVID-19. The monoclonal antibody, known as IC14, is owned by Implicit Bioscience and will be used in a small clinical trial taking place at four sites in Italy, Spain, Australia and Singapore. The trial will test whether IC14 is safe in COVID-19 patients and whether it reduces the need for artificial ventilation and the risk of dying from the disease. The drug targets the immune system protein CD14, which scientists at Scripps Research first linked to innate immunity and inflammation in work started in the mid-1980s. CD14 helps immune cells recognize pathogens that alarm the immune system to danger, and exists on the surface of white blood cells as well as in the blood and lung fluids. This dual existence allows it to amplify the body's inflammatory responses in a variety of sites but can also prompt a cytokine storm in COVID-19 patients. ICI4 was tested in a phase 1 clinical trial in 2004 and determined to be safe in patients, and five years later Implicit Bioscience acquired the drug as a potential therapy to blunt the inflammation caused by amyotrophic lateral sclerosis. Press release.

Montefiore Health System, Albert Einstein College of Medicine and NYU Langone have launched a new clinical trial to study if convalescent plasma is effective in treating COVID-19. The randomized controlled trial will enroll 300 people with COVID-19 respiratory symptoms, half of whom will receive plasma that contains antibodies to the SARS-CoV-2 coronavirus and the remainder a placebo. Participants must have had respiratory symptoms for less than a week, require supplemental oxygen or have been in the hospital for less than four days. Previous studies suggest that convalescent plasma may be a helpful treatment for other coronaviruses, including SARS. The first Montefiore plasma donors came from Young Israel synagogue in New Rochelle, home to one of the largest clusters of COVID-19 cases in the country. Press release.