inDemic Perspectives

As part of an ongoing series of “Expert Perspectives”, Dr. Leon Henderson-MacLennan, Medical Advisor to inDemic Foundation and inThought Research, discusses the role of thromboembolic disease in COVID-19, and its implications for developmental therapeutics. Dr. Leon Henderson-MacLennan describes the rationale for conducting randomized, placebo-controlled trials on anticoagulants and anticomplement agents for COVID-19 associated thromboembolic disease, and highlights several agents and mechanisms of action to watch closely.

In the first of an ongoing series of “Expert Perspectives” with members of inDemic Foundation’s scientific advisory board, we discuss data from EMPACTA, a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of Roche’s Actemra (tocilizumab) in hospitalized patients with COVID-19 pneumonia (NCT04372186). Actemra is one of several IL-6 inhibitors that’s been evaluated for patients with COVID-19.  At the time of this writing, data from EMPACTA has not been published in a peer-reviewed journal, but some of its key findings have been released by Roche/Genentech.  

This Q&A is with Bob Dickson, MD, associate professor of pulmonary and critical care medicine at University of Michigan, and Hrishikesh Kulkarni, MD, MSCI, assistant professor of pulmonary and critical care medicine at Washington University in St. Louis.  

In the midst of growing public and scientific concern regarding the integrity of clinical trials for COVID-19 vaccines, Moderna publicly released its 135-page clinical study protocol. Of biopharma companies with a COVID-19 vaccine candidate in phase 3 trials, Moderna is the first to publicly release its study protocol. The overall goal or primary endpoint of the Moderna’s phase 3 trial is to show that mRNA-1273 has a vaccine efficacy (VE) of 60% in preventing COVID-19. In biostatistics parlance, the VE is [1-HR], or 1 minus the hazard ratio. That is, the goal is to show that healthy participants who receive Moderna’s vaccine are 40% as likely to develop COVID-19, compared to participants that receive placebo. In the trial, a case of COVID-19 is defined as:

• At least TWO of the systemic symptoms: fever (at least 100.4 degrees), chills, muscle aches, headache, sore throat, loss of taste or smell;
• At least ONE of the respiratory symptoms: cough, shortness of breath, difficulty breathing, or pneumonia; AND, 
• At least ONE nasopharyngeal, nasal, saliva, or respiratory test that’s positive for SARS-CoV-2

“It was the best of times; It was the worst of times”

COVID-19 has forced a re-think of clinical trial design, enrollment, and execution. Among the challenges of clinical trial investigators are the ethical principles of compassionate (“off-label”) use of investigational therapies vs. randomized, placebo-controlled trials [1-2], as well as the logistical challenges of manufacture and distribution of investigational therapies [2].

Here, we discuss a peculiar and paradoxical challenge of clinical trials accrual in a pandemic. For any clinical trial – whether it be for cancer, Alzheimer’s disease, or diabetes – identifying and enrolling patients is a well-known challenge. For example, targeted therapies for cancers may enroll patients with rare mutations, who may be difficult to identify and to enroll onto a clinical trial at a limited number of cancer centers [3]. It is peculiar that, as millions of patients are infected by SARS-CoV-2, that there are insufficient patients for clinical trials, whose accrual goals are typically a few hundreds of patients.

The COVID-19 pandemic has often been compared with prior infectious disease outbreaks, such as those caused by SARS, Ebola, MERS, H1N1, and the 1918 influenza virus. In the past, the spread of a virus could often be contained with public health tools alone (e.g. SARS outbreak in 2002-2004). These tools have become familiar to the public and include “containment” strategies such as testing, contact tracing, & quarantine, and “mitigation” strategies such as hand hygiene, masking, & social distancing [1].