The University of Tennessee, Knoxville.
The Status of Therapeutic Trials for COVID-19

A Policy Brief by the Howard H. Baker Jr. Center for Public Policy

in Partnership with the Coronavirus-19 Outbreak Response Experts (CORE-19)

April 30, 2020
Tennessee State Capitol and Flag
Using publicly available data from emerging research on COVID-19, this brief was written and reviewed by the Coronavirus-19 Outbreak Response Experts (CORE-19) at the University of Tennessee, Knoxville.  It provides an update on the status of therapeutic trials for COVID-19. 

Introduction

COVID-19 is a viral disease affecting primarily the respiratory system in humans, caused by an RNA virus of the coronavirus family, known as SARS COV-2.
In contrast with bacteria, viruses are obligatory intracellular microorganisms and rely on host biosynthetic machinery to reproduce. This makes drug therapy for bacteria and viruses very different from each other. Most effective antivirals have been developed and approved in the last 25 years, thanks to the identification of biochemical targets in viruses allowing for selective toxicity. Effective drugs target virus-directed rather than host-cell directed nucleic acid or protein synthesis.

Are there any drugs approved to treatment ofCOVID-19?

Currently there are no Food and Drug Administration (FDA)-approved drugs for COVID-19. The FDA is announcing today support for the emergency use of a virus treatment after an ongoing trial with the drug remdesivir showed shortened recovery time. Early results indicate that time to recovery in the treatment group was 11 days, compared to 15 days in the control group. The difference was statistically significant, with p value: 0.001. Mortality in the treatment group was 8%, vs 11% in the control group. While the difference in mortality was not statistically significant, it represents a trend that might be statistically confirmed as additional data are obtained. Remdesivir blocks RNA-polymerase, a key enzyme for viral replication.
An array of drugs approved for other indications, as well as multiple investigational agents, are being studied for the treatment of COVID-19 around the globe. In addition, providers can access and prescribe investigational drugs or agents approved or licensed for other indications through various mechanisms, including Emergency Use Authorizations (EUA), Emergency Investigational New Drug (EIND) applications, compassionate use or expanded access programs with drug manufacturers, and/or off-label use
In order to formulate recommendations, multiagency working groups critically review and synthesize the available data. Aspects of the data that are considered include, but are not limited to, the type of study (e.g., case series, prospective cohort, randomized controlled trial), the quality and suitability of the methods, the number of participants, and the effect sizes observed.
Each recommendation is assigned two ratings according to the scheme presented in the following table:

Strengh of Recommendation and Quality of Evidence for Recommendation table.

What therapeutic strategies are currently being explored for COVID-19?

Potential therapeutic targets include those related to different steps in the viral replication process, as well as those related to the body’s inflammatory/immunitary response, which may often result in acute respiratory distress and insufficiency. Finally, secondary bacterial infections in the lungs as well as sepsis can occur, requiring proper antibiotic therapy.
Stages of Viral Replication and Possible Targets of Antiviral Agents:
  1. Cell Entry: Refers to attachment and penetration into cells in the human body
  2. Uncoating: Release of viral genome after cell entry
  3. Transcription of viral genome: Making copies of genetic material
  4. Translation of viral proteins: Formation of regulatory and structural proteins
  5. Post-translational modifications: Proteolytic cleavage
  6. Assembly of viral components: Making of the new viral particle
  7. Release: Cell lysis and virus release.
Stages of Body Response and Possible Targets for Supporting Therapy:
  1. Initial inflammatory response: Characterized by fever and flu-like symptoms.
  2. Cytokine-storm: Evidence is suggesting patients with severe COVID-19 can suffer from ‘cytokine storm syndrome’, which is an overreaction of the immune system to the virus.  That is, when COVID-19 enters the lungs, it triggers the body’s immune response to attack the virus, resulting in localized inflammation. This localized inflammatory response can go into overdrive, resulting in hyper-inflammation, which can seriously harm or kill the patient. Acute respiratory distress pneumonia occurs as a response to exaggerated and sustained cytokine storm.
  3. Organ failure: respiratory, renal, cardiovascular.

What types of drugs are being explored to treat COVID-19 and why?

Antivirals: Drugs that specifically inhibit virus-specific replicative events. Replicative events include those processes that are necessary for effective virus replication, as described above. Some examples include
  • Remdesivir
  • Ritonavir
  • Danoprevir
  • Hydroxychloroquine
  • Chloroquine
  • Isotretinoin
  • Others
Anti-inflammatories: Drugs and biologicals aimed at reducing the excessive inflammatory response, often referred to as a cytokine-storm, which results in the acute respiratory distress and pneumonia in some of the most severely affected patients.
  • Tocilizumab
  • Ruxolitinib
  • Baricitinib (also antiviral penetration)
  • Glucocorticoids
  • Allogeneic Cardiosphere-Derived Cells (CDCs): Potential to modify the immune system’s activity to encourage cellular regeneration.
  • Mesenchymal Stromal Cells (MSCs): Umbilical Cord Tissue-derived MSCs have the potential to dampen the hyper-inflammatory reactions in COVID-19 patients, and therefore assist in returning the activity of the immune system back to normal.
  • Others
Interferons: Naturally-occurring proteins that are made and secreted by cells of the immune system (for example, white blood cells, natural killer cells, fibroblasts, and epithelial cells). The theory is that interferon may be able to make the immune system stronger by turning on dormant parts and directing them toward the defense against SARS-nCoV-2's assault.
Antibiotics: To prevent or treat the emergence of bacterial secondary infections, as well as, in some cases to take advantage of a double antiviral/antibacterial effect.
  • Azythromycin
  • Polymyxin-B
  • Others
Convalescent Plasma: Antibodies from patients that suffered COVID-19 and recovered, may have a therapeutic effect in new patients by neutralizing viral particles.

How many trials are currently underway and when are they expected to yield results?

The clinicaltrials.gov webpage reports 1050 ongoing clinical trials related to COVID-19. Out of these, 259 trials are classified as Phase-2. These studies gather preliminary data on whether a drug works in people who have a certain condition/disease.
Another 224 studies are classified as Phase-3 or Phase-4 studies. Phase 3 studies involve relatively large numbers of patients and seek to gather information about a drug's safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase-4 studies take place for drugs already approved by FDA for marketing, even if for a different indication. These trials gather additional information about a drug's safety, efficacy, or optimal use.
Additionally, there are 15 expanded access trials. These trials represent a way for patients with serious diseases or conditions who cannot participate in a clinical trial to gain access to a medical product that has not been approved by the U.S. Food and Drug Administration (FDA). This is also called compassionate use. Drugs currently part of expanded access trials include:
  • Remdesivir: antiviral
  • CDCs: anti cytokine storm
  • Ruxolitinib: anti cytokine storm
  • Convalescent Plasma: SARS COV-2 antibodies, antiviral
  • MSCs: anti cytokine storm
  • nhaled Nitric Oxide: antiviral, improving arterial oxygenation
  • Eculizumab: anti cytokine storm
  • Polymixin-B: antibiotic, septic patients
  • Anti CD14 antibodies: anti cytokine storm

What are the results of studies completed thus far?

Recently, the results of a study with hydroxychloroquine were reported in the press. In this study, veterans with COVID-19 given hydroxychloroquine showed no benefits. This was described as a retrospective study, not yet peer-reviewed, where doctors examined patient outcomes for U.S. military veterans with COVID-19 who were given hydroxychloroquine and compared them to patients who did not receive that treatment; the researchers concluded there was no overall benefits and that there were more deaths among patients treated with the drug than in the untreated group.
About 28% of patients given hydroxychloroquine plus usual care died, compared to 22% who received the drug plus azithromycin. About 11% of those who received neither drug passed away, but when the researchers controlled for other factors, they concluded this represented a similar risk to the group that received the combination of the two drugs, but that “the risk of death from any cause was higher” among those who took hydroxychloroquine alone.
Hydroxychloroquine made no difference in patients’ needs for ventilators, in combination or alone, according to the study. Authors concluded that the findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.
The following two Phase-2 studies have been reported as completed, although results have not been published yet on the website.
Phase-2 studies that have been reported as completed, although results have not been published yet on the website.
The following five Phase-3 or Phase-4 studies have been reported as completed, although results have not been published yet on the website.
Table of phase 3 and 4 studies that have been reported as completed.

Are there any drugs that represent a risk factor for COVID-19?

Given that SARS COV-2 targets ACE2 proteins in type II pulmonary cells and other cells throughout the body (brain, cardiac) and the fact that the concentration of this protein increases with the use of ACE inhibitors (commonly used in the treatment of hypertension), theoretical concerns have been raised about their use, as well as that of angiotensin receptor blockers. However, as of 29 April 2020, these are not sufficient to justify stopping these medications.
Send additional questions regarding drug therapy to Dr. Tomás Martín-Jiménez or to the CORE-19 research team. 
tmartinj@utk.edu | core19@utk.edu | 865-321-1299

Coronavirus-19 Outbreak Response Experts (CORE-19) 

Dr. Tomas Martin-Jimenez

Dr. Tomás Martín-Jiménez, DVM, PhD, DACVCP, DECVPT

Dr. Kathleen Brown

Dr. Kathleen C. Brown, PhD, MPH

Brown is an Associate Professor of Practice in the Department of Public Health and the Program Director for the Master's in Public Health (MPH) degree. Her research focuses on the health and well-being of individuals and communities. She has experience in local public health in epidemiology, risk reduction and health promotion.
Dr. Katie Cahill

Dr. Katie A. Cahill, PhD

Cahill is the Associate Director of the Howard H. Baker Jr. Center for Public Policy. She also is the Director of the Center's Leadership & Governance program and holds a courtesy faculty position in the Department of Political Science. Her area of expertise is public health policy. She leads the Healthy Appalachia project. 
Dr. Kristina Kintziger

Dr. Kristina W. Kintziger, PhD, MPH

Kintziger is an Assistant Professor in the Department of Public Health and the co-Director of the Doctoral Program. She has worked in academia and public health practice. Prior to coming to Tennessee, she served as an epidemiologist and biostatistician at the Florida Department of Health. She is an environmental and infectious disease epidemiologist.
Dr. Matthew Murray

Dr. Matthew N. Murray, PhD

Murray is the Director of the Howard H. Baker Jr. Center for Public Policy. He also is the Associate Director of the Boyd Center for Business and Economic Research and is a professor in the Department of Economics in the Haslam College of Business. He has led the team producing Tennessee's annual economic report to the governor since 1995. 
Dr. Agricola Odoi

Dr. Agricola Odoi, BVM, MSc, PhD

Odoi is a professor of epidemiology at the University of Tennessee College of Veterinary Medicine. He teaches quantitative and geographical epidemiology and his research interests are in population health and impact of place on health and access to health services. He was a public health epidemiologist before joining academia.
Dr. Marcy Souza

Dr. Marcy J. Souza, DVM, MPH

Souza is an associate professor and Director of Veterinary Public Health in the UT College of Veterinary Medicine.  Her teaching and research focuses on zoonotic diseases and food safety issues. 
Disclaimer: the information in this policy brief was produced by researchers, not medical or public health professionals, and is based on their best assessment of the existing knowledge and data available on the topic. It does not constitute medical advice and is subject to change as additional information becomes available. The information contained in this brief is for informational purposes only. No material in this brief is intended to be a substitute for professional medical advice, diagnosis or treatment, and the University of Tennessee makes no warranties, expressed or implied, regarding errors or omissions and assumes no legal liability or responsibility whatsoever for loss or damage resulting from the use of information provided.
Howard H. Baker Jr Center for Public Policy
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Phone: 865-974-0931
Email: bakercenter@utk.edu
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