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Great news from coronavirus vaccine clinical trials have earned a deserved spotlight over the last couple of weeks. For good reason, too: The Pfizer and Moderna, and other COVID-19 vaccines, will do much to douse the COVID-19 pandemic.
Meanwhile, though, the number of people infected with the virus that causes COVID-19 skyrockets during the holiday season, and we enter a pandemic phase that looks to be taking cues from the disastrous autumn of 1918. The hard truth is that months will pass before the slow drip of vaccines finally put out this fire. In the meantime, the fruits of a different variety of clinical trials – those that test therapies to help those who have already caught the coronavirus – hold the most medical promise in limiting the worst damage.
UCHealth has been hosting coronavirus therapy trials since spring. They have come in three varieties: those for outpatients, those for inpatients, and those for inpatients sick enough to be in intensive-care units.
Success, discovery from coronavirus drug trials
Dr. Adit Ginde, a UCHealth emergency physician and vice chair for research in the Department of Emergency Medicine at CU School of Medicine, has been leading coronavirus drug trials at UCHealth even as he has been a leader in the design and conduct of clinical trials on the international stage.
“We UCHealth investigators are doing work across the spectrum – prophylaxis, outpatient, and inpatient – to prevent the disease from getting worse and improve recovery,” Ginde said. “Over one-third of patients have prolonged symptoms for weeks and months even if not hospitalized.”
Sometimes, the results aren’t promising. Ginde and Dr. Marc Moss, head of the Division of Pulmonary Sciences and Critical Care Medicine at the CU School of Medicine, led UCHealth efforts on a national trial studying the impact of hydroxychloroquine on hospital inpatients. The medical community had, despite heavy political support for the drug, already recognized that COVID-19 shrugs off the repurposed antimalarial; the ORCHID study’s results, published on Nov. 9, nailed the coffin shut.
“The number of articles in the peer-reviewed literature over the last several months that have consistently and convincingly demonstrated the lack of efficacy of a highly hyped ‘cure’ for COVID-19 represent the consequence of the irresponsible infusion of politics into the world of scientific evidence and discourse,” wrote Dr. Michael Saag of the University of Alabama School of Medicine. “For other potential therapies or interventions for COVID-19 (or any other diseases), this should not happen again.”
Ginde says the study’s an example of a null result doing some good.
“It is very clear that hydroxychloroquine does not work,” Ginde said. “Given all the publicity over the spring and summer, it’s also important to provide definitive proof when treatments don’t work.”
Mixed bag from COVID-19 drug trials
Ginde’s study on Eli Lilly’s bamlanivimab monoclonal antibody – synthetic proteins designed to whip the immune system into action against a virus that’s already invaded the body – didn’t fare any better with inpatients. UCHealth participated in that study’s international trial. That trial was stopped on Oct. 26 because the drug didn’t seem to work. That wasn’t the end of the story, though: based on data from a concurrent trial with outpatients, the U.S. Food and Drug Administration granted emergency use authorization (EUA) to the drug on Nov. 9 – but only for high-risk outpatients whose disease has yet to progress far enough to be admitted to a hospital. UCHealth has received doses of the drug and provided it to patients at UCHealth Memorial Hospital.
Lilly’s coronavirus drug joins Regeneron’s monoclonal antibody – also trialed at UCHealth, in what Ginde and others hope will be a growing pool of such drugs available to coronavirus patients. Ginde is a leader of the international Operation Warp Speed ACTIV-3 trial, which will test another two monoclonal antibodies in early December.
Convalescent plasma – blood plasma from recovered COVID-19 patients – is another study focus at UCHealth. Convalescent plasma has already received emergency-use authorization from the FDA, but it has yet to prove itself in a major clinical trial. That’s happening now in two national trials, one with Emergency Department outpatients, one inpatient. UCHealth is participating in both, with Ginde leading these efforts locally. The inpatient trial expected to wrap up in January and the ED outpatient trial soon thereafter.
Ginde is the national lead investigator of the TREAT NOW trial enrolling outpatients at UCHealth and five other hospitals across the country. The trial is testing the antiviral drugs lopinavir and ritonavir. These drugs appear to be ineffective with inpatients with severe COVID-19, but there’s hope that it might work better with patients who aren’t sick enough to be hospitalized.
It’s tempting to believe that, the earlier in the course of COVID-19 disease a drug is taken, the more effective the drug should be. In medicine, early intervention and better outcomes usually go hand-in-hand (think cancer). But from its confounding and hijacking of the immune system to its tendency to induce blood clotting to its strange neurological impacts, the coronavirus has vexed medical intuition. Dr. Ellen Burnham, a CU School of Medicine pulmonary sciences and critical care medicine specialist and medical director of the medical intensive care unit at UCHealth University of Colorado Hospital on the Anschutz Medical Campus, says all that makes doing coronavirus clinical trials for inpatients as well as outpatients all the more important.
Burnham is leading the UCHealth site of a national trial testing a rolling list of therapies for effectiveness on those sick enough to land in the ICU. Called I-SPY COVID-19, the UCHealth patients in the trial – 30 so far – are given one of four drugs on top of a standard of care including the antiviral remdesivir and the steroid dexamethasone.
The drugs include the anti-inflammatory apremilast (used for psoriasis), the anti-inflammatory and antifibrotic cenicriviroc (HIV and liver fibrosis), icatibant (hereditary angioedema), and razuprotafib (inflammation and reduced capillary leakage).
“They’re all quite different from each other,” Burnham said. But, she added, they all have been shown to target mechanisms implicated in acute respiratory distress syndrome (ARDS), COVID-19’s most lethal manifestation.
The coronavirus drug trial is built for speed: as soon as its leaders have enough data to see if a drug seems to be helping, the candidate will graduate from I-SPY COVID-19 for closer examination in a traditional, larger trial. If a drug doesn’t seem to work, it will roll back to where it came from. Burnham says the trial has five additional candidates, each vetted by national ARDS experts, waiting in the wings to backfill departures.
Patients who would like to participate but don’t qualify for the I-SPY COVID-19 trial’s drugs still contribute to science. They may participate in an observational study where their clinical data, outcomes, and specimens are collected during inpatient hospitalization. This project will help investigators better understand the relationships between demographic and clinical factors on outcomes in COVID-19-related respiratory failure.
Burnham’s is one of several observational studies that have happened or are underway at UCHealth. These have considered antibodies in health care workers, the general course of disease, and the impacts on COVID-19 and other viral diseases we may see as the winter progresses, among others.
Neither Burnham nor Ginde nor anyone else expects a silver bullet therapy to emerge before coronavirus vaccines end the pandemic. But then, nobody quite expected the vaccines to be the silver bullets they look to be. Either way, medical researchers at UCHealth and around the world will press on with their studies of coronavirus therapies. The drugs may work, and they may not. Certain is this: when it’s over, their efforts will have left homesteads of empirical proof where only empty expanses of conjecture and hope had been.