By Clinical Research News Staff 

May 8, 2020 | Data emerges from the US and France exploring the safety issues of hydroxychloroquine, and research looks at how cancer patients are faring COVID-19. Arizona State University tracks SARS-CoV-2 mutations, and new data is released on anticoagulants. Clinical trials look at how the disease impacts the kidneys and who is most likely to be infected. We round up the week’s research and industry news for COVID-19.  

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Literature Updates  

Mount Sinai researchers report that treating hospitalized COVID-19 patients with anticoagulants may improve their chances of survival. The study, published in the Journal of the American College of Cardiology, found that taking anticoagulants—orally, subcutaneously, or intravenously—improved outcomes both in and out of the intensive care unit setting. The difference in bleeding events among patients treated with and without anticoagulants was not significant. Anticoagulants may play a major role in caring for COVID-19 patients, preventing possible deadly events associated with the novel coronavirus, including heart attack, stroke and pulmonary embolism. Previous research from Mount Sinai showed many patients hospitalized with COVID-19 have developed high levels of life-threatening blood clots, leading to potentially deadly thromboembolic events. The latest study looked at 2,773 confirmed COVID-19-positive patients admitted to five hospitals in the Mount Sinai Health System between March 14 and April 11, 2020 and compared survival rates for those who were and were not placed on blood thinners. Improved hospital survival was noted among the 28% of patients received a full-treatment dose of anticoagulant. Among those who did not survive, those taking anticoagulants lasted a week longer in the hospital than those who did not. The effect of anticoagulation had a more pronounced effect on ventilated patients, with 62.7% of intubated patients in the non-anticoagulant group dying versus 29.1% of those on anticoagulants. Patients receiving anticoagulants also had higher inflammatory markers, suggesting patients with more severe illness may benefit from anticoagulants early on, and fewer bleeding events. DOI: 10.1016/j.jacc.2020.05.001 

A study led by clinician scientists at RCSI University of Medicine and Health Sciences has found that Irish patients admitted to hospital with severe COVID-19 infection are experiencing abnormal blood clotting that causes micro-clots within the lungs, contributing to death in some patients. This scenario is not seen with other types of lung infection and explains why blood oxygen levels can fall dramatically in COVID-19 patients. An additional finding was that patients with higher levels of blood clotting activity had a significantly worse prognosis and were more likely to require ICU admission. How the micro-clots are being formed remains a mystery, and further studies will be required to investigate whether different blood thinning treatments may have a role in selected high-risk patients. Emerging evidence shows that the abnormal blood-clotting problem in COVID-19 results in a significantly increased risk of heart attacks and strokes. Results published in the British Journal of Haematology. DOI: 10.1111/bjh.16749 

In a cohort study of 90 hospitalized patients with COVID-19, use of hydroxychloroquine for treatment of COVID-19 was associated with frequent QTc prolongation, and the risk was even greater if azithromycin was also taken. The retrospective observational study was conducted at Beth Israel Deaconess Medical Center and enrolled COVID-19 patients with pneumonia who received at least one day of hydroxychloroquine between March 1 and April 7 of this year. More than half of these patients also had high blood pressure, and more than 30% had diabetes. One participant taking the drug combination experienced a potentially lethal tachycardia (torsades de pointes), believed to be the first such report in the peer-reviewed COVID-19 literature. Researchers say hydroxychloroquine for the treatment of COVID-19 should probably be limited to clinical trials .The study published in JAMA Cardiology. DOI: 10.1001/jamacardio.2020.1834 

Simultaneously, researchers in France report in JAMA Cardiology that similar safety concerns were raised in a retrospective study of 40 COVID-19 patients admitted to the ICU and treated with hydroxychloroquine with or without azithromycin, but particularly when both drugs are administered together. The finding that QTc intervals increased in more than 90% of patients provides evidence against widespread use of hydroxychloroquine to treat COVID-19 in settings where patients cannot be adequately monitored. DOI: 10.1001/jamacardio.2020.1787 

Researchers in China, in a study published in Cell Metabolism, have added to the evidence that people with type 2 diabetes (T2D) are at greater risk of a poor outcome from COVID-19 but controlling blood glucose well may act as an effective auxiliary approach to improve their prognosis. The retrospective, longitudinal study included 7,337 confirmed COVID-19 cases enrolled across 19 hospitals in Hubei Province, China. Of those, 952 people had T2D; blood glucose was well-controlled for 282 of them. The data showed that people admitted to the hospital with COVID-19 and T2D had significantly higher mortality (7.8% vs. 2.7%) as well as a greater incidence of multiple organ injury despite having more medical interventions. However, those with well-controlled blood sugar were less likely to die. They also received fewer medical interventions, including supplemental oxygen and/or ventilation, and had fewer health complications. DOI: 10.1016/j.cmet.2020.04.021 

Despite concerns expressed by some experts, common high blood pressure drugs did not increase the risk of contracting COVID-19, or of developing severe disease, in a study of 12,594 patients led by researchers from NYU Grossman School of Medicine. The study focused on four drug classes—angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta blockers and calcium channel blockers. It also found no substantial increase in risk for more severe illness (intensive care, use of a ventilator or death) with any of the treatments in patients with the pandemic virus. Patients for the study were identified in the NYU Langone Health electronic health record. Next, researchers plan to use similar approaches to investigate other medications and their relationship to COVID-19 illness. Findings published in the New England Journal of Medicine. DOI: 10.1056/NEJMoa2008975 

People with cancer who develop COVID-19 are much more likely to die from the disease than those without cancer, according to physician-researchers at Montefiore Health System and Albert Einstein College of Medicine. The study, published in Cancer Discovery, is the largest of its kind to address the question. It involved 218 cancer patients who tested positive for COVID-19 from March 18 to April 8, 2020 at Montefiore Medical Center in a region of New York City hit hard by the pandemic. Sixty-one cancer patients died from COVID-19, a dramatically high case-fatality rate of 28% (the World Health Organization puts the overall COVID-19 mortality rate in the U.S. at 5.8%). Among those with hematologic cancers, such as leukemia and lymphoma, the mortality rate was especially high at 37%. But mortality appears to be more closely related to frailty, age and comorbidities than to active therapy for cancer. At the time of their COVID-19 diagnosis, widespread social distancing had not yet been implemented. As a result of the study findings, Montefiore started using telemedicine and early and aggressive social distancing for its cancer patients has opened a dedicated cancer outpatient and inpatient clinical service. DOI: 10.1158/2159-8290.CD-20-0516 

Most newly discharged patients who recently recovered from COVID-19 produce virus-specific antibodies and T cells, suggests a 14-patient study in Immunity, but for unknown reasons the responses of different patients are not all the same. Antibodies were maintained for at least two weeks, based on results from six patients assessed at two weeks after discharge. Researchers in China report that both B and T cells participate in immune-mediated protection against the viral infection. Compared to six healthy donors, the newly discharged and follow-up COVID-19 patients showed higher levels of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies that bind to the SARS-CoV-2 nucleocapsid protein, which encapsulates the viral genomic RNA, as well as the S protein's receptor-binding domain (S-RBD) that binds to receptors on host cells during the process of viral entry. In addition, five newly discharged patients had high concentrations of neutralizing antibodies that bind to a pseudovirus expressing the SARS-CoV-2 S protein and five of the six follow-up patients had detectable neutralizing antibodies against the pseudovirus. Researchers say study results suggest that the S-RBD is a promising target for SARS-CoV-2 vaccines, based on the finding that neutralizing antibodies were positively associated with IgG antibodies against S-RBD, but not with those that bind to the nucleocapsid protein. Moreover, S-RBD induced both antibody and T cell responses. DOI: 10.1016/j.immuni.2020.04.023 

Researchers at Arizona State University (ASU) have identified a new mutation where 81 of the chemical letters have been permanently deleted from the SARS-CoV-2 genome. Finding were based on a pool of 382 nasal swab samples obtained from possible COVID-19 cases in Arizona. The 81-base pair mutation had never been found before in GISAID’s EpiCoVTM Database and could provide a clue into how the virus makes people sick. Genetic sequences deposited in the database indicate that SARS-CoV-2 originated at a single source in Wuhan, China, while many of the first cases in Arizona identified travel from Europe as the most likely source. The discovered mutation is of interest because it mirrors a large deletion that arose in the 2003 SARS outbreak. Scientists believe that a weakened virus that causes less severe disease may have a selective advantage if it is able to spread efficiently through populations by people who are infected unknowingly. The study published in the Journal of Virology. ASU researchers have teamed up with TGen, the University of Arizona and Northern Arizona University to form the Arizona COVID-19 Genomics Union and continue tracking different genetic strains of the new coronavirus. DOI: 10.1128/JVI.00711-20 

Researchers from the Cleveland Clinic, in a study published in JAMA Cardiology, offer data supporting various society guidelines to continue current treatment of chronic disease conditions with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) during the COVID-19 pandemic. Their cohort study looked at 18,472 patients, 7.2% of whom were taking ACEIs and 5.3% of whom were taking ARBs. A positive COVID-19 test result was observed in 9.4% of tested patients and, of those, 6.7% were taking ACEIs and 5.6% were taking ARBs. No association was found between ACEI/ARB use and testing positive for COVID-19. DOI: 10.1001/jamacardio.2020.1855 

In a Policy Forum published in Science, scholars from Northwestern University outlined an ethical framework for conducting controlled human infection (CHI) studies in response to the COVID-19 pandemic. In CHI studies, a small number of willing participants are deliberately exposed to infection to rapidly gather data on the efficacy of experimental vaccine candidates or treatments. Many such studies have a safe and successful track record, but they can be wrought with ethical concerns. The framework outlines the conditions under which CHI studies with SARS-CoV-2 would be ethically acceptable and provide guidance for the research community and participants considering them. The authors argue that potential CHI studies must have sufficient social value to warrant their use and maintain reasonable risks to participants. DOI: 10.1126/science.abc1076  

A study in Italy found that men who were being treated for prostate cancer with androgen-deprivation therapies (ADT) were four times less likely to develop COVID-19 and, if they were infected, the disease was less severe. Researchers found that 430 (9.5%) of 4,532 men in the Veneto region of Italy infected with COVID-19 had cancer and 118 (2.6%) had prostate cancer. Male cancer patients, compared to the whole male population, had a 1.8-fold increased risk of COVID-19 infection and developed more severe disease. However, when they looked at all prostate cancer patients in the Veneto region, they found that only four out of 5,273 men on ADT developed COVID-19 infection and none of them died. This compared to 37,161 men with prostate cancer who were not receiving ADT, of whom 114 developed COVID-19 and 18 died. Among 79,661 patients with other types of cancer, 312 developed COVID-19 and 57 died. The findings may suggest that even in the absence of prostate cancer those at high risk of developing COVID-19 could take ADT for a limited period to prevent infection, while those who become infected could take ADT to reduce the severity of symptoms. Researchers note that prostate cancer patients have high levels of the protein TMPRSS2 and its action is regulated by the androgen receptor targeted by ADT. The androgen receptor also regulates TMPRSS2 levels in non-prostate tissues, including the lungs. Results published in Annals of Oncology. DOI: 10.1016/j.annonc.2020.04.479 

Researchers at the University of Pennsylvania School of Medicine have discovered a key mechanism of cytokine storm in Castleman disease (a relatively uncommon group of inflammatory disorders) that could have implications for COVID-19 patients experiencing the same symptoms. With idiopathic multicentric Castleman disease (iMCD, the most severe subtype of Castleman disease), just as with COVID-19, it is the body's hyper-response that's deadly rather than the disease itself. When looking at the immune cells of iMCD patients, they found a group of cytokines called Type-I Interferons are highly active when patients are in flare and a pathway called JAK that seems to be a critical mediator of the cytokine storm. Previous research has shown cytokine storms are tied to interleukin-6, which in turn is connected to another pathway called mTOR. The latest findings, published in the Journal of Clinical Investigation Insight, strengthens the link between mTOR activation and cytokine storms and suggests new treatment approaches for the patients in flare. A provisional patent has been filed for a new treatment approach involving inhibition of JAK based on this work. DOI: 10.1172/jci.insight.135031. 

Industry News 

Investigators from the Icahn School of Medicine at Mount Sinai will use the KidneyIntelX platform from Renalytix AI to assess the risk of adverse kidney events in patients diagnosed with COVID-19. Acute and chronic kidney disease is strongly associated with severity of disease and fatal outcomes in COVID-19 patients. Evaluation of a patient's kidney risk status at the time of COVID-19 diagnosis, through recovery and during follow-on monitoring, can be of potentially high clinical value. The KidneyIntelX platform will be used in a large study of COVID-19 admitted patients at Mount Sinai called "Pred-MAKER" (Prediction of Major Adverse Kidney Events and Recovery). Pred-MAKER will study clinical features and biomarkers, including multiple plasma biomarkers and urine proteomics and RNA sequences, as predictors of major adverse kidney events in patients hospitalized with COVID-19. The study has been submitted for Institutional Review Board (IRB) review and approval. Press release.  

Researchers at University of California San Diego (UCSD) School of Medicine have launched a clinical trial to investigate whether ACE inhibitors (approved for treating high blood pressure, heart failure and diabetic kidney disease) might reduce the severity of COVID-19 infections, lowering rates for intensive care unit admissions, the use of mechanical ventilators and all-cause mortality. The trial will be randomized, double-blind and placebo-controlled, and involve up to 560 participants either presenting with COVID-19 symptoms at emergency departments or currently hospitalized with the disease. It is expected to last one year. ACE inhibitors boost the expression and abundance of ACE2 receptors, potentially increasing the number of portals for SARS-CoV-2 to enter cells throughout the body. Some scientists posit that patients taking these drugs may be at greater risk for COVID-19 infection and worse outcomes, pointing to findings of a Chinese study early in the Wuhan outbreak. But compelling evidence exists suggesting ACE inhibitors would likely help reduce COVID-19 mortality by reducing disease severity. UCSD researchers hypothesize that ACE inhibitor drugs help keep the renin-angiotensin-aldosterone system (which regulates blood pressure) in balance and functioning optimally. The trial is expected to involve sites in multiple states. Press release. 

The global academic community is being given complimentary access to the research communications platform Kudos Pro for 60 days if they sign up during the month of May. Over 2,000 researchers have already signed up for access following an exclusive pre-launch. Kudos Pro serves is a means for academics in all fields to ensure continued communication of critical research insights and to rapidly communicate results and recommendations. Researchers can also explain, share and showcase their work within the academic community as well as to government, journalists, educators, practitioners, industry and the general public. Distributed teams working remotely can additionally use Kudos Pro to collaborate for impact and extend their networks. Press release. 

Simon Fraser University spinoff company Lungpacer Medical has received Emergency Use Authorization clearance from the U.S. Food and Drug Administration (FDA) for its Diaphragmatic Pacing Therapy SysteInc. m (DPTS) to help wean COVID-19 patients from ventilators—specifically, those at a high risk of weaning failure. About 30% of ventilated patients typically fail to wean and die in hospitals, but the death rate appears to be much higher for ventilated COVID-19 patients in the U.S. DPTS is temporary, non-surgical, minimally invasive technology that distributes breathed oxygen more evenly throughout the lungs, helping to protect tissue from mechanical injury. Pacing the diaphragm also helps maintain or restore its size, strength and endurance, which is key to successful weaning. The diaphragm stimulation therapy is delivered through a central venous catheter along with fluids and medications and incorporates electrodes that activate the diaphragm muscle via transvenous phrenic-nerve stimulation. The FDA granted the Lungpacer DPTS an expedited access pathway designation in 2016 and the company has since completed two clinical trials. A pivotal trial to support FDA approval is currently enrolling patients. Press release. 

The COVIDENCE UK study, led by Queen Mary University of London, opened on May 1 and aims to recruit at least 12,000 people (ages 16 and up) from across the country to help identify who is most at risk of contracting COVID-19 and why some people become more ill than others with the disease. The number of cases and deaths from COVID-19 include a high proportion of people from black, Asian and minority ethnic backgrounds. Research partners include King's College London, the London School of Hygiene & Tropical Medicine, the University of Edinburgh, Queen's University Belfast and Swansea University. A diverse group of volunteers will be recruited, including those who have already had proven or suspected COVID-19 and those who have not as well as people with and without underlying conditions. Participants will fill in a detailed questionnaire and monthly updates will then track any new symptoms. The study will automatically draw on patients' National Health Service records, including information on test results and hospitalizations. Researchers also hope to see how the COVID-19 outbreak is affecting people's mental well-being and vice versa. The study will run up to five years and create a platform to fast-track future trials of preventive treatments. Press release. 

A multi-site study led by the University of Washington is investigating whether hydroxychloroquine can prevent infection with COVID-19. Enrollment is now underway for 2,000 participants who are close contacts of persons confirmed or suspected to be infected with COVID-19. The FDA has issued a warning against the use of hydroxychloroquine outside of clinical trials or hospital settings where patients can be closely monitored. The eight-week, placebo-controlled trial is part of the COVID-19 Therapeutics Accelerator initiative launched by the Bill & Melinda Gates Foundation, Wellcome and Mastercard, and one of many approaches being funded. Sandoz, a Novartis division, has donated the hydroxychloroquine doses for the study. Researchers expect to have answers by summer. Press release. 

Preliminary evidence published in the Journal of Allergy and Clinical Immunology suggests that having an allergic condition paradoxically may reduce susceptibility to SARS-CoV-2 infection and severe COVID-19 disease in both children and adults (DOI: 10.1016/j.jaci.2020.04.009). A new Human Epidemiology and Response to SARS-CoV-2 (HEROS) study will now further clarify whether reduced ACE2 gene expression in the airway cells of children with allergic diseases correlates with a lower rate of COVID-19. It will also help determine the percentage of children infected with SARS-CoV-2 who develop symptoms of the disease. The study will be conducted completely remotely and require a caretaker to collect nasal swabs from the primary study participant and all other family members every two weeks, as well as complete online questionnaires about each participant's current symptoms, social distancing practices, recent activities outside the home and recent exposure to people who are sick. If any member of the household develops symptoms of a viral illness, the caregiver will fill out another online questionnaire and, if COVID-19 is determined to be likely, collect nasal swabs from all study participants and a stool sample from the symptomatic participant within 24 hours. Lab analyses of nasal swabs will test for SARS-CoV-2 and assess gene expression in the collected airway-surface cells. Additionally, caregivers will collect a blood sample (using a new, nearly painless device) from each study participant two weeks, 18 weeks and 24 weeks after enrollment as well as three weeks after the family's first likely case of COVID-19, if there is one. The blood will be analyzed for antibodies to SARS-CoV-2 once an appropriate antibody test becomes available. The HEROS study team will rapidly enroll 6,000 people from 2,000 U.S. families already participating in NIH-funded pediatric research studies in 11 cities and follow them for six months. Press release. 

The Paris Institute for Advanced Study has spearheaded the launch of the World Pandemic Research Network (WPRN), the first global, real-time directory of research and research resources on the societal and human impacts of the Covid-19 pandemic. WPRN differs from other initiatives by the priority given to the human and social sciences, the robustness of its infrastructure anchored in the cloud and because it mobilizes an international and interdisciplinary network of "referents" who sort the projects. It allows the sharing of data, questionnaires and hypotheses in real time, while maintaining the intellectual property system of tracking and accountability. Fourteen leading personalities in the field serve on its scientific board. Press release. 

Grant funding from the Melinda Gates Foundation will allow the Murdoch Children's Research Institute's clinical trial of the BCG vaccine against COVID-19 to extend from 4,000 to 10,000 healthcare workers across Australia, Spain and The Netherlands. The BRACE trial started at the end of March and has already enrolled more than 2,500 healthcare workers in hospitals across Australia. Half of enrollees in the randomized, controlled trial are being given the BCG vaccine (originally developed against tuberculosis) to test whether it can protect those exposed to SARS-CoV-2 from developing severe symptoms by boosting their innate immunity. Previous research has shown that BCG can provide some protection against respiratory viral infections and reduce virus levels and enhance immunity to a virus with a similar structure. Press release. 

Replacing the usual filter in a kidney dialysis machine with one known to trap the tiny proteins wreaking havoc on COVID-9 patients during a cytokine storm may prevent devastation caused by immune hyper-response, says nephrologists at the Medical College of Georgia and Augusta University (AU) Health System. They made the discovery while working with COVID-19 patients who, like many critically ill patients, need dialysis when their kidneys are failing. Medical products company Baxter International Inc. provided the Oxiris filter sets for the machines that work like a sponge to capture and absorb cytokines along with toxins released by cytokine-inducing endotoxins and uremic toxins, after securing emergency use authorization from the FDA for their use in the U.S. for COVID-19. The filters have been used in Europe and Asia for more than a decade to treat sepsis, which also produces a cytokine storm. Doctors at AU Health System are now using the blood filter for up to 72 hours when patients show signs of significant respiratory problems and are headed to intensive care. Cytokine levels are being assessed before the new therapy, then at 24 and 48 hours to look at trends and determine how the patients are doing clinically. A documented allergy to heparin (found in this and all standard kidney dialysis filters) is the only absolute contraindication for using the new therapy. Steps are also being taken to enable a traditional clinical trial. Press release. 

Pfizer Inc. and BioNTech have announced the U.S. rollout of a randomized phase 1/2 clinical trial testing whether four of their experimental mRNA vaccine candidates can prevent infection with SARS-CoV-2. NYU Grossman School of Medicine and the University of Maryland will be the first centers to enroll patients. Healthy patients will receive either one or two doses of one of the vaccines or a placebo. The companies recently launched a similar, first-in-human trial in Germany. Other trial centers include the University of Rochester and Cincinnati Children's Hospital. Two of the study vaccines contain viral RNA encoding the spike proteins used by SARS-CoV-2 to attach to proteins on human cell surfaces, the first step in invading cells. The other two feature receptor-binding domains, the specific region of the spikes that enables their attachment to cells and may generate antibodies even better able to disable the virus. The study’s initial dose escalation phase will by mid-summer gather evidence on safety, best dose, and number of doses in 360 subjects in the 18-55 and 65-85 age groups, beginning with younger, healthier adults. Press release.  

University of Idaho researchers will work with colleagues at the University of Rochester in New York to test whether the milk of women who test positive for novel coronavirus might contain the virus. The $315,000 project, funded by the Bill and Melinda Gates Foundation, will provide the most comprehensive testing of human milk for the SARS-CoV-2 virus. Currently, the American Academy of Pediatrics and the U.S. Centers for Disease Control and Prevention recommend considering separating mothers and infants after a positive test, while the World Health Organization recommends mothers continue breastfeeding as normal while practicing heightened hygiene. The unknown is whether the novel coronavirus is in mothers' milk, and whether it can infect infants. Medela is donating the breast pumps that will be used in the study. The U of I team will oversee obtaining samples from 50 women nationwide within 48 hours of receiving a positive COVID-19 test result, and the University of Rochester will be validating the test to determine if the virus is present in milk. The researchers also plan to work with colleagues from other major cities, including New Orleans, New York City, Seattle, Spokane, Boston and Chicago. Press release.