Clinical trials: Top priority for long COVID


The Centers for Disease Control and Prevention and the U.S. Census Bureau estimate that 6.1% of the U.S. adult population is living with long COVID, with millions more debilitated worldwide. The demand for substantial treatment is enormous, but the urgency to fund and begin the necessary range of clinical trials has not met the severity of the problem.

While trials are slowly beginning to happen, the treatment choices and trial design require crucial nuances and understanding of viral-onset illnesses, and few research groups are creating strong trials that fully reflect the complexities of this landscape.

This article aims to share key considerations and best practices that are essential to the success of these trials. These recommendations recognize that roughly half of long COVID patients have new-onset myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia from COVID, which must be at the forefront of how trials are designed and conducted, and are additionally based on the current hypotheses about long COVID’s pathophysiologies.

1: Drugs proposed by experts in postviral fields should be prioritized

Upward of 50 drugs for viral-onset conditions like ME/CFS, dysautonomia, AIDS, and others have been waiting for years to go to trial, but have not had the funding to do so.

Treatments proposed by experts in viral-onset illnesses (such as ME/CFS and dysautonomia) should be prioritized (PM R. 2022 Oct;14[10]:1270-91), as outside researchers are not familiar with these fields and their potential treatment options.

2: Drugs targeting a wide range of mechanisms should be trialed

Treatments that should be trialed include anticoagulants/antiplatelets for clotting and vascular functioning, immunomodulators including JAK-STAT inhibitors, COVID-specific antivirals and antivirals against reactivated herpesviruses (Valcyte, Valacyclovir, EBV vaccine).

Other options include prescription mast cell stabilizers (ketotifen, cromolyn sodium), drugs that regulate microglial activation (low-dose naltrexone, low-dose aripiprazole), anti-CGRP medications, beta-blockers, and intravenous immunoglobulin.

Others include medications that target mitochondrial dysfunction; ivabradine; pyridostigmine;, DRP1 inhibitors; supplements showing success in patient communities including lactoferrin, ubiquinone, and nattokinase; and therapies targeting glymphatic/lymphatic dysfunction, microbiome therapies, and therapeutic peptides.

3: Use appropriate long COVID subtypes

Long COVID is an umbrella term that encompasses multiple new-onset and worsened conditions and symptoms after COVID. Roughly half of long COVID patients likely meet the criteria for ME/CFS and/or dysautonomia. Others may have new-onset diabetes, major clotting events, lung damage, neurological disorders, loss of smell or taste, and other manifestations.

Patients in different categories likely have different responses to treatments. It’s critical to identify appropriate subtypes for each trial, ideally performing detailed analyses to identify the treatments that work best, and don’t, for each subtype.

4: Behavioral treatments, especially those that have harmed similar populations, should not be trialed

Behavioral treatments including exercise, graded exercise therapy (GET), and cognitive-behavioral therapy (CBT) should not be trialed, let alone prioritized, for long COVID.

In patients with postexertional malaise (PEM), one of the most common long COVID symptoms, exercise is actively harmful and causes dysfunctional metabolic patterns, cardiac preload failure, impaired systemic oxygen extraction, and more. GET and CBT have failed similar populations , and exercise is explicitly contraindicated by the World Health Organization, the British National Institute for Health and Care Excellence, the CDC, and other organizations.

Resources should instead be put toward the wide range of medications that have not yet adequately undergone clinical trials.


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