What is the FY21 TBIHRP Clinical Trial Award Focus Area? This proposal addresses the focus area of “Treat,” utilizing a “Novel Treatment.” The specific Focus Areas addressed include “Interventions that promote sustained functional recovery,” “Rapid assessments and treatments for psychological health conditions (PTSD),” “Treatments that promote recovery and improve long-term outcomes,” and “Novel therapeutic candidates based on evolving changes in pathophysiology or theoretical mechanisms of psychological health.”

What Is the Problem or Question to Be Addressed? Posttraumatic stress disorder (PTSD) is a mental health problem that some people develop after experiencing traumatic events such as combat, accidents, natural disasters, or assault. Even long after these events, people with PTSD may experience upsetting memories of their trauma, feel “on edge,” and have trouble sleeping—all of which can lead to difficulty carrying out daily activities. It is estimated that about 8% of people worldwide and up to 30% of Veterans experience PTSD. Currently available treatments for PTSD include talk therapy and antidepressant medications. Many people with PTSD have trouble accessing talk therapy, and antidepressants only lead to modest improvements of PTSD symptoms.

By analyzing the electronic health records of patients receiving care in the Veterans Affairs health system, we identified a medication that may be able to improve PTSD symptoms. We found that patients with PTSD who were prescribed an antiviral medication called Mavyret (glecaprevir/pibrentasvir) for their hepatitis C experienced strong improvement of their PTSD symptoms. To properly test whether Mavyret causes PTSD improvement, we are proposing a clinical trial to randomly assign (like the flip of a coin) patients with PTSD (but, in this case, without hepatitis C) to receive Mavyret or placebo.

Research Questions: Do patients receiving Mavyret have better PTSD improvements than patients receiving placebo? Do patients receiving Mavyret have better improvements in carrying out daily activities than patients receiving placebo? Do patients with PTSD, but without hepatitis C, tolerate Mavyret well, and is it safe to take?

How Does the Research Improve the Understanding and/or Treatment of PTSD? There is currently no consensus among researchers on what causes PTSD. Much of PTSD research focuses on symptoms that occur after a traumatic event. Current PTSD medications target brain activity related to depression, anxiety, and stress. However, some researchers believe that PTSD could be the result of a genetically determined overactive immune response to stress. Since Mavyret is an antiviral medication that treats an infection by activating the body’s immune system, it is possible that this study could help researchers better understand the relationship between the immune system and the development of PTSD. If our study shows that Mavyret improves PTSD in patients without hepatitis C, we will also have discovered a new treatment option.

Clinical Applications: Mavyret is already approved by the Food and Drug Administration. This means that it has already been tested for safety and possible side effects. Mavyret is better tolerated than antidepressants; the most common side effects include headache and nausea. The most serious risks include recurrence of hepatitis B infection and possible worsening of preexisting liver problems. Therefore, we will not include people with past hepatitis B infection, nor will we include people with liver problems. Many primary care providers

prescribe Mavyret for hepatitis C, so it is already available for widespread prescribing in clinical practice. The benefit of discovering a new medication for PTSD treatment would improve the lives of many civilians, Veterans, and Service Members.

Benefit to Service Members, Veterans, and/or Military Beneficiaries: While civilians can experience PTSD, current and former Service Members experience PTSD at higher rates, possibly due to frequent exposures to traumatic events. Service Members with PTSD are often placed on medical leave due to an inability to perform. Those who develop PTSD after experiencing combat trauma often suffer long after deployment, and these effects can have a negative impact on their loved ones. Because this medication does not have sedating effects, it could possibly be used in the military zone. For those already suffering the debilitating effects of PTSD from past combat trauma, this medication could help to finally bring some relief. If this medication can help alleviate PTSD symptoms, it would address a common health problem among current and former Service Members and greatly improve quality of life.