REMDESIVIR SUCCESS AFTER CHLOROQUINE FAILURE?

Hospitalized patients who had advanced COVID-19 with lung involvement and who received the antiviral agent remdesivir (Gilead Sciences) recovered faster than similar patients who received placebo, according to a preliminary data analysis from a US-led randomized, controlled trial. On the basis of as yet unpublished data, remdesivir "will be the standard of care" for patients with COVID-19, said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), during a press conference at the White House today. The randomized, placebo-controlled international trial was sponsored by NIAID, which is part of the National Institutes of Health, and enrolled 1063 patients. It began on February 21. The interim results, discussed in the press conference and in a NIAID press release, show that time to recovery (ie, being well enough for hospital discharge or to return to normal activity level) was 31% faster for patients who received remdesivir than for those who received placebo (P < .001). The median time to recovery was 11 days for patients treated with remdesivir, compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir and 11.6% for the patients who received placebo (P = .059). The study, known as the Adaptive COVID-19 Treatment Trial (ACTT), is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19. It is being conducted at 68 sites ― 47 in the United States and 21 in countries in Europe and Asia. The data are being released after an interim review by the independent data safety monitoring board found significant benefit with the drug, Fauci said. "The reason we are making the announcement now is something that people don't fully appreciate: Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to let the people in the placebo group know so they could have access," he explained. "When I was looking at the data with our team the other night, it was reminiscent of 34 years ago in 1986 when we were struggling for drugs for HIV," said Fauci, who was a key figure in HIV/AIDS research. "We did the first randomized, placebo-controlled trial with AZT. It turned out to have an effect that was modest but that was not the endgame because, building on that, every year after, we did better and better." Similarly, new trials of drugs for COVID-19 will build on remdesivir, with other agents being added to block other pathways or viral enzymes, Fauci said. The study will be submitted to a journal for peer review, he noted, but the New York Times is reporting that the US Food and Drug Administration will approve remdesivir for emergency use later today. Chinese Trial Inconclusive In contrast to the positive results Fauci described from the NIAID-sponsored trial, a randomized, placebo-controlled clinical trial of remdesivir among hospitalized patients with severe COVID-19 in China was inconclusive.

Σελίδα 2 από 2 The study, published online in the Lancet today, showed some nonsignificant trends toward benefit but did not meet its primary endpoint. The study was stopped early after 237 of the intended 453 patients were enrolled, owing to a lack of additional patients who met the eligibility criteria. The trial was thus underpowered. Results showed that treatment with remdesivir did not significantly speed recovery or reduce deaths from COVID-19, but with regard to prespecified secondary outcomes, time to clinical improvement and duration of invasive mechanical ventilation were shorter among a subgroup of patients who began undergoing treatment with remdesivir within 10 days of showing symptoms, in comparison with patients who received standard care. "To me, the studies reported here in the Lancet appear to be less promising than some statements released today from the NIH, so the situation is a bit puzzling to me," commented Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, Texas, who was not involved in the study. "I would need to look more closely at the data which NIH is looking at to understand the differences." Trial Details The published trial was conducted at 10 hospitals in Hubei, China. Enrollment criteria included being admitted to hospital with laboratory-confirmed SARS-CoV-2 infection within 12 days of symptom onset, having oxygen saturation of 94% or less, and having radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (on that scale, 1 indicated that the patient was discharged, and 6 indicated death) or to the patient's being discharged alive from hospital, whichever came first. The trial was stopped early because stringent public health measures used in Wuhan led to marked reductions in new patient presentations and because lack of available hospital beds resulted in most patients being enrolled later in the course of disease. Between February 6, 2020, and March 12, 2020, 237 patients were enrolled and were randomly assigned to receive either remdesivir (n = 158) or placebo (n = 79). Results showed that use of remdesivir was not associated with a difference in time to clinical improvement (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.87 – 1.75). Although not statistically significant, time to clinical improvement was numerically faster for patients who received remdesivir than for those who received placebo among patients with symptom duration of 10 days or less (median, 18 days vs 23 days; HR, 1.52; 95% CI, 0.95 – 2.43). The mortality rates were similar for the two groups (14% of patients who received remdesivir died vs 13% of those who received placebo). There was no signal that viral load decreased differentially over time between the two groups. Adverse events were reported in 66% of remdesivir recipients, vs 64% of those who received placebo. Remdesivir was stopped early because of adverse events in 12% of patients; it was stopped early for 5% of those who received placebo. The authors, led by Yeming Wang, MD, China-Japan Friendship Hospital, Beijing, China, note that compared with a previous study of compassionate use of remdesivir, the population in the current study was less ill and was treated somewhat earlier in the disease course (median, 10 days vs 12 days). Because the study was terminated early, the researchers say they could not adequately assess whether earlier treatment with remdesivir might have provided clinical benefit. "However, among patients who were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement," they state. They add that remdesivir was adequately tolerated and that no new safety concerns were identified. In an accompanying comment in the Lancet, John David Norrie, MD, Edinburgh Clinical Trials Unit, United Kingdom, points out that this study "has not shown a statistically significant finding that confirms a remdesivir treatment benefit of at least the minimally clinically important difference, nor has it ruled such a benefit out." Norrie is cautious about the fact that the subgroup analysis suggested possible benefit for those treated within 10 days. Although he says it seems biologically plausible that treating patients earlier could be more effective, he adds that "as well as being vigilant against overinterpretation, we need to ensure that hypotheses generated in efficacy-based trials, even in subgroups, are confirmed or refuted in subsequent adequately powered trials or meta-analyses." Noting that several other trials of remdesivir are underway, he concludes: "With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like our best way to obtain robust insights into what works, safely, and on whom." Lancet. Published online April 29, 2020. Abstract, Comment For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Across the country, hospitals are incorporating Friday's warning from the US Food and Drug Administration (FDA) about the risks of prescribing hydroxychloroquine and chloroquine for COVID-19 into their treatment protocols.  For some hospitals, the message affirmed the cautious approach they were already taking with hydroxychloroquine. "From a New York state or Northwell perspective, there is no major change," said Onisis Stefas, PharmD, vice president of pharmacy at Northwell Health in New York. "We were not prescribing it out in the community very early on because of the concerns associated with the heart arrhythmias."  Brigham and Women's Hospital in Boston, Massachusetts, is currently in the process of updating its publicly available COVID-19 protocols website "to incorporate the FDA's updated safety assessment and ongoing clinical trials," a hospital spokesperson told Medscape Medical News. Prior to the updates, the treatment protocols indicated that hydroxychloroquine should only be considered after weighing the risks and benefits for patients who are not candidates for other clinical trials and meet a specific set of health criteria.  The warning is a timely and important synthesis of what physicians know about the drugs so far and how cautiously clinicians across the country should be using them, said Rajesh T. Gandhi, MD, infectious diseases physician at Massachusetts General Hospital (MGH), Boston, professor of medicine at Harvard Medical School, member of the Infectious Diseases Society of America (IDSA), and chair-elect of the HIV Medicine Association.  "I think to be honest it's a really important message to the public and clinicians across the country," said Gandhi. "Because we all know there is just a ton of discussion around this drug...and it came out fairly and said what we know right now." The two antimalarial drugs have been at the center of much political debate and scientific scrutiny in recent weeks, following President Trump's endorsement and the FDA's emergency use authorization for the two medications in March. Hospitals across the country had incorporated hydroxychloroquine and chloroquine into their constantly evolving treatment protocols for patients with COVID-19.  But the evidence that these drugs actually help treat COVID-19 remains scant. Some small studies suggest the therapies help patients with COVID-19, while others conclude the drugs have no effect or even harm patients. In the United States, medical societies including the American Heart Association have also warned about the serious cardiac issues that can accompany these drugs for some patients.  In the new warning, the FDA said it "cautions against use of hydroxychloroquine or chloroquine for COVID-19 patients outside of the hospital setting or a clinical trial" and urged "close supervision" of patients treated with these therapies, citing cardiac side effects.  The FDA also said it is aware that the outpatient prescription of these medications has increased since its March authorization, but the drugs still have not been shown to be safe or effective in treating or preventing COVID-19. 

Σελίδα 2 από 2 The FDA announcement is consistent with protocols established by the National Institutes of Health and IDSA earlier this month that recommend against using hydroxychloroquine or chloroquine, except when these drugs are administered as part of a clinical trial.  "We agree wholeheartedly with the FDA and have been hoping that the FDA would in fact issue that kind of clarification," said Samuel Brown, MD, study committee cochair of the ORCHID clinical trial, a multicenter, blinded study investigating the safety and efficacy of hydroxychloroquine. These medications need to be tested in clinical trials that are able to focus closely on safety monitoring, he said. Experts at Vanderbilt University, one of the medical centers participating in the ORCHID clinical trial, decided before Tennessee had any cases of COVID-19 that unproven therapies like hydroxychloroquine would only be available through clinical trials, said Wesley Self, MD, associate professor of emergency medicine at Vanderbilt University, Nashville, Tennessee, and chair of the ORCHID study committee. Northwell Health, like other hospitals in New York, has been following a March executive order issued by Governor Andrew Cuomo limiting the use of these drugs for COVID-19 outside of clinical trials, said Stefas. At Northwell Health, patients with COVID-19 only receive hydroxychloroquine or chloroquine when treated in hospital, where they can be closely monitored, or as part of a clinical trial. The hospital system's protocols currently do not recommend pairing hydroxychloroquine with azithromycin, said Stefas. The new FDA announcement is "very similar" to New York's existing executive order, he said. "Reading through this reinforces a lot of what we originally thought." At MGH in Boston, the FDA safety warning is in-line with and "solidifies" the hospital's evolving protocols, said Gandhi. Clinicians at MGH have been steadily moving away from prescribing hydroxychloroquine outside of clinical trials as the efficacy has remained murky, the serious side effects have become more evident, and clinical trials to assess the drug have gotten underway in recent weeks, he said. Given the conflicting evidence, Gandhi feels the use of these drugs needs to be focused in clinical trials, where scientists can truly evaluate how much they help or harm.  "We know fundamentally that's the way to do this," Gandhi said. "We also don't know that it doesn't work, so it is ethical and incumbent upon us to do a study," Gandhi said.  Other hospitals are already heeding the FDA's warning. At UW Medicine in Washington state, for example, hydroxychloroquine was considered a possible treatment for COVID-19 prior to the FDA's recent announcement. "Based on FDA guidance, hydroxychloroquine is no longer recommended as therapy for COVID-19 unless done through a clinical trial," said Tim Dellit, MD, chief medical officer for UW Medicine. Michigan Medicine stopped using hydroxychloroquine and azithromycin (both separately and in combination) about a month ago, said Daniel Kaul, MD, a professor of infectious disease at the University of Michigan. "When we reviewed the data that was available in more detail, we realized that it was essentially uninterpretable," he said. As of Monday, the only patients receiving this drug at Michigan Medicine are those enrolled in the ORCHID clinical trial.   But that does not seem to be the case everywhere. Most patients transferred to Michigan Medicine from other hospitals have received these drugs, indicating they are still being widely used, said Kaul. "I think this FDA guidance is appropriate and may reduce usage of this drug and make people more aware of the potential side effects both in inpatient and outpatient settings." Hopefully, the FDA guidance will help slow the use of these drugs outside the appropriate clinical trial setting, said Kaul. "I think that the kind of politicization of this drug, which is pretty much unprecedented in my experience, created a really harmful environment where calm decision-making and assessment of the relative risks and benefits became somewhat impossible," said Kaul.