June 26, 2020 | New research indicates that COVID-19 disproportionately affects those of lower socioeconomic status and greater household crowding. Meanwhile, companies are forming a crowd-sourcing initiative to jump start COVID-19 data collection. This, plus more, are included in this week’s announcements and updates from the clinical research industry.

Literature Updates

A population-based, cross-sectional study published in JAMA Cardiology found that out-of-hospital cardiac arrests and deaths during the COVID-19 pandemic significantly increased compared with the same period the previous year and were associated with older age, nonwhite race/ethnicity, hypertension, diabetes, physical limitations, and nonshockable presenting rhythms. The authors concluded that identifying patients at greatest risk should allow for early, targeted interventions in the outpatient setting and improve the situation. A total of 5,325 patients, including 3,989 in the COVID-19 period and the remainder from the same March 1 to April 25 period a year prior were included in the main analysis. DOI: 10.1001/jamacardio.2020.2488

Patients with COVID-19 who were admitted to an intensive care unit (ICU) were 10 times more likely than other hospitalized COVID-19 patients to suffer cardiac arrest or heart rhythm disorders, according to a new study from researchers in the Perelman School of Medicine at the University of Pennsylvania that published in Heart Rhythm. Results suggest cardiac arrests and arrhythmias suffered by some patients are likely triggered by a severe, systemic form of the disease and are not the sole consequence of the viral infection—findings that differ significantly from early reports showing a high incidence of arrhythmias among all COVID-19 patients. The Penn team evaluated cardiac telemetry and clinical records of 700 patients with COVID-19 who were admitted to the Hospital of the University of Pennsylvania between early March and mid-May. The cohort of patients had a mean age of 50 years, with black patients accounting for more than 70% of the population. A total of 53 arrhythmic events were identified, including cardiac arrest, atrial fibrillation that required treatment, clinically significant bradyarrhythmias, and non-sustained ventricular tachycardia events but no cases of heart block, sustained ventricular tachycardia or ventricular fibrillation; 11% were admitted to the ICU. DOI: 10.1016/j.hrthm.2020.06.016

Mayo Clinic researchers and collaborators have found investigational convalescent plasma to be safe following transfusion in a diverse group of 20,000 patients. The findings, from the FDA’s Expanded Access Program for COVID-19, are reported in Mayo Clinic Proceedings. The safety report assessed the seven days following transfusion for hospitalized patients between April 3 and June 11 who were deemed at risk of progressing to a severe or life-threatening condition. Nearly 40% of the patients were women; 20% African Americans; nearly 35% Hispanic and 5% Asian. Seven-day mortality rates declined to 8.6 % compared to 12% in a previous safety study of the first 5,000 transfused patients. Serious adverse events continued to be less than one percent. The authors caution that this alone does not provide any evidence on effectiveness of convalescent plasma, which is currently the only antibody-based therapy for treating COVID-19. Journal Pre-Proof

A study of nearly 400 pregnant women in New York City is among the first to show that lower neighborhood socioeconomic status and greater household crowding increase the risk of becoming infected with SARS-CoV-2, and this may explain why black and Hispanic people are disproportionately at risk for contracting the virus. Women in the study gave birth at either NewYork-Presbyterian/Columbia University Irving Medical Center or NewYork-Presbyterian Allen Hospital during the peak of the COVID-19 outbreak. There was no association between infection and population density. Findings published in JAMA. DOI: 10.1001/jama.2020.11370

The first known case of a potentially deadly heart rhythm disturbance induced by chloroquine therapy for COVID-19 was reported by Israeli researchers in Heart Rhythm. The 84-year-old female patient, who had a history of breast cancer and controlled hypertension and was taking the medications letrozole (for breast cancer) and memantine (for Alzheimer's disease), met many of the published safety guidelines for chloroquine therapy. But she was observed to have a very abnormal ECG pattern after treatment began, leading to multiple episodes of torsade de pointes (a life-threatening arrhythmia in which the lower chambers of the heart beat out of sync with the upper chambers). Her condition was resolved after chloroquine was discontinued. The authors note that memantine likely contributed to the proarrhythmic effects of chloroquine, but that the patient’s QTc interval spiked only after chloroquine was introduced. Chloroquine and hydroxychloroquine are known to cause prolongation of the QT interval but there is no evidence of sudden, unexplained death when they are used to treat malaria. Also, neither the American nor the European rheumatology societies recommend ECG surveillance for patients who receive long-term treatment with hydroxychloroquine. DOI: 10.1016/j.hrthm.2020.04.046

A Danish review of 43 scientific articles (most from Asia and performed as online questionnaires) indicates that the COVID-19 pandemic has negative consequences for the mental health of the people being infected, healthcare professionals and the overall population, according to a study that published in Brain, Behavior and Immunity. The review was produced by researchers from the University of Copenhagen and the Mental Health Centre Copenhagen, Mental Health Services in the Capitol Region of Denmark. The same phenomenon was seen during the previous SARS epidemic in 2002-2003. Only two studies have so far examined mental symptoms among COVID-19 patients, and these showed that 96% of those who were seriously ill exhibited symptoms of post-traumatic stress and that the risk of developing depression increased after hospitalization. One contributing factor might be that the infection has affected the brain and caused the symptoms, either directly or through the induced immune response. DOI: 10.1016/j.bbi.2020.05.048

Researchers from Queen Mary University of London, in collaboration with the Medical Research Council Lifecourse Epidemiology Unit at the University of Southampton, has found that higher rates of severe COVID-19 infections in black, Asian and minority ethnic (BAME) populations are not explained by socioeconomic or behavioral factors, cardiovascular disease risk, or by vitamin D status. The findings, published in the Journal of Public Health, suggest that the relationship between COVID-19 infection and ethnicity is complex, and requires more dedicated research to explain the factors driving these patterns. Investigators used a dataset that included 4,510 people in the UK Biobank who were tested for COVID-19 in a hospital setting, of whom 1,326 had a positive test result. Results demonstrate that BAME ethnicity, male sex, higher body mass index, greater material deprivation, and household overcrowding are independent risk factors for COVID-19. DOI: 10.1093/pubmed/fdaa095

A report from Ann & Robert H. Lurie Children's Hospital of Chicago shows that infants under 90 days of age who tested positive for COVID-19 tend to be well, with little or no respiratory involvement. Fever was often found to be the primary or only symptom. The study included 18 infants, none with a significant medical history, 50% of whom were admitted to the hospital's general inpatient service without ever requiring oxygen, respiratory support or intensive care. Researchers say there may be opportunities to utilize rapid SARS-CoV-2 testing to determine disposition of clinically well infants with fever. An overrepresentation of Latinx ethnicity among their sample of infants with COVID-19 (78 percent) was also observed. The journal pre-proof is with the The Journal of Pediatrics. DOI: 10.1016/j.jpeds.2020.06.047

Early approvals of new drug applications for preventing and treating COVID-19 could get delayed by the standards the FDA used for older drugs, according to an associate management professor at the McCombs School of Business at The University of Texas at Austin. A review of 291 drugs approved over 35 years found that the more information the FDA had about existing drugs, the longer it took to OK new ones for the same conditions. When there was more information about older drugs, more than half the newer drugs in the study took more than 20 months to win approval. By contrast, only 20% of new drugs took that long to get approved when less information was available about older drugs. A lesson for COVID-19 therapies is that regulators should be thinking ahead about new standards by which to judge them, since different drugs might require different criteria to measure their effectiveness. The forthcoming paper published online in advance by the Strategic Management Journal. DOI: 10.1002/smj.3196

In an open-label, randomized clinical trial (GRECCO-19), an international team of researchers has found that patients with COVID-19 who received colchicine had statistically significantly improved time to clinical deterioration compared to a control group receiving standard medical care alone. However, the observed difference was based on a narrow margin of clinical significance; therefore, the observations should be considered hypothesis generating. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. The study enrolled a total of 105 patients admitted to one of 16 hospitals in Greece April 3-27, 2020. Findings published in JAMA Network Open. DOI: :10.1001/jamanetworkopen.2020.13136

An article in the American Journal of Respiratory and Critical Care Medicine provides an exhaustive, evidence-based review of how COVID-19 droplets from infected patients spread through the air and describes how healthcare professionals can protect themselves. Scientists from the University of Tennessee and Rush University cover the various types and sizes of virus-containing droplets present in sneezes and coughs, the locations in the respiratory systems where they deposit, and how certain medical procedures and devices may spread these droplets and the risks for healthcare professionals. The authors note that the evidence linking aerosol-generating procedures (e.g., suctioning and tracheal intubations) to spread of viral infections is limited by the low quality of studies on the topic and that aerosols produced by medical aerosol generators do not contain pathogens unless the aerosol device is contaminated. They also make recommendations for reducing the transmission of respiratory tract infections, which are consistent with guidelines from the Centers for Disease Control and Prevention. DOI: /10.1164/rccm.202004-1263PP

A cancer drug (ruxolitinib) cured a COVID-19 patient with acute respiratory distress at Marburg University Hospital (Germany). As reported in Leukemia, the patient is a 65-year-old woman without pre-existing conditions who was admitted to the hospital for progressive shortness of breath and fever who had to be intubated to receive artificial ventilation three hours after admission. A standard molecular genetic test confirmed she was infected with SARS-CoV-2. Her overall prognosis was assessed as very poor due to extensive organ damage. After receiving the drug, the patient stabilized and her respiration and heart function rapidly improved; viral replication was also reduced during the administration of the cancer drug. She was gradually weaned from the ventilator starting on the tenth day of her hospital stay. It was not an isolated case. The treatment team also administered ruxolitinib to several other patients to control a severe course of the disease and those who received the drug for longer than one week improved. Their counterparts at Schwarzwald-Baar Hospital have also reported successful use of the immune inhibitor, although in less severe cases. The German Federal Institute for Drugs and Medical Devices has approved a clinical trial that will now test the effect of the administration of ruxolitinib in additional COVID-19 patients. DOI: 10.1038/s41375-020-0907-9

A patient study coming out of China finds that both symptomatic and asymptomatic COVID-19 patients can contaminate their surroundings, demonstrating the importance of environmental cleaning in areas they have occupied. Researchers sampled the surroundings and air of six negative pressure non-intensive care unit rooms with 13 laboratory-confirmed COVID-19 patients (two asymptomatic) who had returned from overseas in a designated isolation ward in Chengdu, China. Sampled sites included bedrails, room and toilet door handles, light switches, foot flush buttons, sink rims, sink and toilet bowls and drains, bedside tables, bedsheets, pillows, equipment belts on wall, floor, air exhaust outlets and air. Among the sampled surfaces, 39.3% were positive for SARS-Cov-2 and all the air samples were negative. Isolation of asymptomatic COVID-19 patients at home impose risks to family members, making shelter hospitals a potentially better option. The study published in mSphere. DOI: 10.1128/mSphere.00442-20

Researchers at the University of Cambridge and the Cambridge Centre for AI in Medicine have found striking differences in COVID-19 deaths between intensive care units (ICUs) of NHS trusts across England and are calling for comparative effectiveness research to understand why. Where a patient ends up is just as important as the strongest patient-specific risk factors such as older age, immunosuppression or chronic heart/kidney disease. In the worst case, COVID-19 patients in the ICU of an NHS trust were over four times as likely to die than COVID-19 patients in an average trust's ICU. The analysis was carried out on anonymized data from the COVID-19 Hospitalization in England Surveillance System (CHESS) dataset, supplied by Public Health England. The data covered the Feb. 8 through May 22 period, when there were 5,062 ICU cases in 94 NHS trusts across England, with 1,547 patient deaths and 1,618 ICU discharges. DOI: 10.1007/s00134-020-06150-y

In Scientific Reports, Ben-Gurion University of the Negev (Israel) published results of a study showing that a one-time, hour-long session with a plush, seal-like Japanese social robot named PARO can reduce pain and oxytocin levels and increase happiness—making it a potential fill-in for human-to-human contact during the pandemic. The robot emits seal-like sounds and moves its head and flippers in response to being spoken to and touched. Outside of close romantic relationships, the researchers point out, oxytocin production is a stress indicator and a reduction could therefore indicate relaxation. DOI: 10.1038/s41598-020-66982-y

One-third of U.K. pediatricians report seeing emergency “delayed presentations” during the COVID-19 pandemic lockdown, based on results of a snapshot survey published online in Archives of Disease in Childhood. Children with diabetes were most often involved, but with life-threatening sepsis and cancer also featured prominently. The survey, conducted by British Paediatric Surveillance Unit in late April, was completed by 2,433 senior pediatricians working in the U.K. and Ireland. DOI: 10.1136/archdischild-2020-319848

Bacteriophages that prey on the main species of bacteria known to cause respiratory failure could help decrease the mortality of patients affected by COVID-19, according to an article by a researcher in Norway that published in PHAGE: Therapy, Applications, and Research. Decreasing bacterial growth would also give the body more time to produce protective antibodies against the disease-causing coronavirus. Unlike antibiotics, bacteriophage treatments are far less susceptible to developing resistances, as the bacteriophage itself can also adapt to overcome any resistance that the bacteria develop, she points out. The comprehensive article touches on the possible significance of bacteria in symptoms for COVID-19, the history of phage therapy and how phage can serve as a direct weapon against secondary infections. DOI: /10.1089/phage.2020.0014

A team of researchers at Memorial Sloan Kettering (MSK) Cancer Center has found that common cancer treatments don't worsen coronavirus infection. Results were based on their experience with 423 MSK patients diagnosed with COVID-19 between March 10 and April 7 during the height of the pandemic in New York City. Notably, metastatic disease, recent chemotherapy, or major surgery within the previous 30 days did not show a significant association with either hospitalization or severe respiratory illness due to COVID-19. Overall, 40% were hospitalized for COVID-19, 20% developed severe respiratory illness, about 9% had to be placed on a mechanical ventilator, and 12% died. Researchers say their findings suggest that no one should delay cancer treatment because of concerns about the virus. The study published in Nature Medicine. DOI: 10.1038/s41591-020-0979-0

Statin use has been linked to a lower death rate and incidence of mechanical ventilation in patients hospitalized with COVID-19, an international team of researchers report in Cell Metabolism. The large-scale retrospective study also showed that mortality risk and other negative outcomes were not increased by combination therapy consisting of statins and angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Statins have been shown to slow the progression of lung injury in animals, improve immune cell responses, and strongly reduce inflammation, they point out. The study looked at 13,981 COVID-19 patients admitted to 21 hospitals in Hubei Province, China. Among these patients, 1,219 used statins—319 in combination with ACE inhibitors or ARBs and 603 in combination with other antihypertensive drugs. DOI: 10.1016/j.cmet.2020.06.015

Updates from Industry

The Department of Energy's Oak Ridge National Laboratory (ORNL) has launched a COVID-19 Rapid Access Licensing Program allowing companies to license select technologies at no cost for one year. In collaboration with researchers, ORNL's Technology Transfer Office is creating a growing portfolio of inventions available to license through the program. The licenses are nonexclusive and interested licensees must demonstrate intent to use ORNL's innovations to address COVID-19 and commit to disseminating resulting products as widely and quickly as possible. Only U.S. entities, companies and universities are eligible. Alternative licenses will be available for companies creating products that require exclusivity to support large development investments, such as for diagnostic platforms, drug delivery systems, therapies and vaccines. Press release.

The FDA issued guidance in June that suggests one or more statistical analysis strategies that can be used to mitigate the effect of missing data in clinical trials underway during the COVID-19 pandemic. The recommended options include collecting information on discontinuation of treatment, withdrawal of a patient from the trial, use of alternative or rescue treatments, and missed or alternative endpoint assessments to incorporate into the statistical analysis plan. Trials stopped early may perform a blinded power assessment to determine what possible effect the smaller data pool on the validity of statistical conclusions. Trials may also gather additional data by enrolling more participants and extending the study period or patient follow-up period. Guidance.

Canakinumab, an interleukin-1 blocker approved for the treatment of juvenile rheumatoid arthritis, is now being studied for its effectiveness in treating cytokine release syndrome (aka cytokine storm) in COVID-19 patients with pneumonia. Researchers at The University of Texas Health Science Center at Houston are enrolling patients into the phase III, randomized, double-blind, placebo-controlled clinical study at Harris Health System's Lyndon B. Johnson Hospital. The study is investigating if canakinumab combined with standard-of-care treatment can increase the chances of survival without ever requiring invasive mechanical ventilation. Over a two-hour period, enrolled patients will receive either a 450 mg, 600 mg or 750 mg IV dose of canakinumab (based on their body weight) or placebo. Participants will be monitored for up to 29 days, or until they are discharged from the hospital. A follow-up will occur at 127 days. Press release.

Delve Health has announced that it is joining xCures and Cancer Commons to support Beat19—a crowd-sourcing initiative to jump start COVID-19 data collection from around the world. Its role is to create a user-friendly and secure mobile app for the Beat19 project, which will allow volunteers to participate in sharing their data. Beat19 is a patient-led initiative that is looking for patterns between things like types of cancers, types of treatments, behaviors, and exposure and/or symptoms of COVID-19. The people-powered study is registered on clinicaltrials.gov, and the goal of the partnership is to engage 100,000 volunteers to use the app. Press release.

The Critical Path Institute has announced the launch of the FDA-funded CURE Drug Repurposing Collaboratory (CDRC) in collaboration with the National Center for Advancing Translational Sciences (NCATS) as a crowdsourced central repository for clinician experiences. The public-private partnership will provide a forum for the exchange of clinical practice data to inform potential new uses of existing drugs for areas of high unmet medical need, advancing research in these areas. CDRC will also create a network connecting major treatment centers, academic institutions and researchers, private practitioners, government facilities and healthcare professionals around the world. The FDA-NCATS CURE ID platform, available on the web and as a mobile app, serves as a centralized source of reliable, curated, clinician-submitted information. In a pilot project focused on COVID-19, CDRC will use data collected via CURE ID to identify existing drugs that demonstrate possible treatment approaches that should be studied further in randomized trials. Critical updates have been made to the CURE ID case report form for capturing relevant details related to COVID-19. More than 5,500 healthcare professionals have already registered on the CURE ID platform. Press release.

Members of Vivli, the Center for Clinical Research Data, which have committed to sharing data from their COVID-19 trials include Eli Lilly & Company, Regeneron, Roche and Takeda. Cochrane, Covid Collaboration Platform, UCB, and the Wellcome Trust have expressed their support of these efforts. The means for data-sharing is the COVID-19 portal, a dedicated search function within the Vivli platform. Non-members are also invited to share their data, and Vivli has partnered with vendors who are waiving their normal fees to anonymize datasets. Wellcome Trust Independent Review Panel will provide an accelerated review process within three business days of receiving a request. Vivli has also waived all member and user fees. Press release.

Scientists in the U.S. are launching a research project this summer into whether the public health impacts of extreme heat will be amplified by the COVID-19 pandemic. They’ll be conducting three national surveys, querying a total of 3,000 residents about COVID-19 and extreme heat. The surveys will ask about symptoms and potential household coping mechanisms as well as perceptions of the risks from both the pandemic and heat waves and the effectiveness of taking protective actions against them. Researchers will share preliminary results via a web-based mapping tool to help guide efforts by public health officials to better protect at-risk populations. The project brings together an interdisciplinary team of researchers at National Center for Atmospheric Research, the University of Colorado and Utah State University. It is being funded by the National Science Foundation through a special RAPID (Grants for Rapid Response Research) award. Press release.

The first clinical trial in South Africa and on the African continent for a COVID-19 vaccine has launched. At least 80,000 people have already been diagnosed with COVID-19 in South Africa, and more than 1,674 have died, since March. South Africa also accounts for 30% of all COVID-19 cases and 23% of all COVID-19 deaths across Africa. The South African Ox1Cov-19 Vaccine VIDA-Trial is being led by a researcher at the University of Witwatersrand, in collaboration with colleagues at the University of Oxford and the Oxford Jenner Institute. The vaccine is already being evaluated in a large clinical trial in the U.K. and similar and related studies are about to start in Brazil. An even larger study of the same vaccine is planned in the U.S. that will have up to 30,000 participants. The vaccine’s technical name is ChAdOx1 nCoV-19, made from a weakened and non-replicating version of a common cold virus and engineered to express the SARS-CoV-2 spike protein. Press release.

The Patient-Centered Outcomes Research Institute (PCORI) is allocating up to $50 million in additional funding for new COVID-19 projects and to enhance existing PCORI-funded studies. Research is aimed at providing answers to difficult COVID-19-related questions faced by patients, providers and health systems. Existing studies being enhanced include one examining telehealth as a viable option to increasing care access and improving health outcomes for people with sickle cell disease and another that will examine the clinical presentation, treatments, and outcomes of children with a new multisystem inflammatory condition (MIS-C) that has emerged in communities heavily impacted by COVID-19. The announcement also provides details about multiple other projects receiving a fresh infusion of funds from PCORI. Press release.

PPD, Inc. has expanded its laboratory test portfolio by adding five new molecular, serology and functional assays designed expressly for COVID-19 vaccine and therapy development programs. The new additions include two molecular assays (qualitative and quantitative) that utilize reverse transcriptase, polymerase chain reaction and target spike proteins that are specific to SARS-CoV-2 and nucleocapsid proteins that are more general to the coronavirus family, for disease detection. Two enzyme-linked immunosorbent assays have also been developed specifically for vaccine trials that detect immunoglobulin G to full-length recombinant protein, one for spike and the other for nucleocapsid. The fifth test is a plate-based functional assay to detect anti-spike antibodies in human serum that can prevent infection by disrupting the binding of angiotensin converting enzyme 2 to SARS-CoV-2 spike protein. The PPD Laboratories central lab also is validating molecular and serology in vitro diagnostic assays that are released for commercial use by regulatory agencies to support clinical trials. Press release.