A three-day course of intravenous remdesivir reduced the risk of hospitalisation by 87% versus placebo, in COVID-19 outpatients at high risk of progression to severe disease, found an international phase III PINETREE study presented at the 2021 virtual IDWeek conference.
(IDWeek is the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medical Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP).)
In a MedPage Today video, study author Dr Joshua Hill, of the Fred Hutchinson Cancer Research Center in Seattle, discussed the study, its limitations, and the further potential of remdesivir in COVID-19 treatment.
Following is a transcript of his remarks:
I am a transplant infectious disease physician at the Fred Hutchinson Cancer Research Center at the University of Washington in Seattle, and we were one of the sites participating in a large international global trial, looking at remdesivir (Veklury) for treatment of patients with COVID-19 early in the course of their infection. These are patients who are outpatient, infected in the past seven days, and symptomatic due to COVID-19.
The high level findings from this study were that three days with intravenous remdesivir reduced the incidence of hospitalisation or death in the following month by 87%. So that was really a striking finding. This was placebo-controlled, randomised, double-blinded — about 550 patients or so total enrolled in the trial. Half of them got remdesivir, half got placebo.
It was a really exciting finding. It's basically on par with what we’re seeing with monoclonal antibodies. Granted, this is a three-day intravenous dose and compared to the monoclonals, which is a single day. So that’s one potential drawback of remdesivir.
The nice thing about remdesivir is that it’s readily available, it’s available internationally, which is nice, while the monoclonals aren’t. It targets the RNA polymerase as opposed to the spike protein, so theoretically it’s less likely to be affected by mutations in the spike protein like we're seeing with some of the new variants that are coming out. So that’s all really reassuring.
The safety looked fine. The safety profile was similar to placebo and is in line with what we’ve seen with other studies of remdesivir. So really quite well tolerated. So that was encouraging as well.
It certainly provides another tool in our tool belt for therapies that we can offer our patients. It will be challenging to implement for patients who aren’t established at a clinic that can offer outpatient infusions. That might be a challenge. But for patients at cancer centres and other areas of practice where patients are routinely getting infusions or have access to that, I think it’ll really offer another tool that we can use for patients. Ultimately we want an oral therapy: there are some new drugs in the pipeline there. We recently heard about fluvoxamine, and molnupiravir in a press release, but we haven’t seen data yet. So that’s exciting.
They have been able to generate an oral formulation of remdesivir which shows efficacy in a preclinical model, which is good. That’s going to continue to move through into human studies as well. So this is great proof-of-concept study that early intervention with a direct acting antiviral therapy, or along with the monoclonal antibody data, certainly can be effective and will help improve outcomes for our patients.
The trial was stopped early for administrative reasons. Basically there were fewer patients available to enroll because vaccinations were rolling out, and monoclonals, and rates were going down at the time. So we enrolled about half as many as patients as we initially proposed, but the data remained blinded and were unmanipulated in any way. So once the data were unlocked, we saw this large effect, which met statistical significance. I don’t think any additional studies are being done. This will move forward and has been submitted to the FDA for consideration.
Right now remdesivir is restricted to use in hospitalised patients. But hopefully this will get approved by the FDA for this indication. And I think we’ll make therapies more available for people globally at places where monoclonals aren’t available and where people are quite comfortable now using those drugs. So, that’s the goal.
Study details:
Three-day course of remdesivir may help stave off COVID-19–related hospitalization and death: results of the phase III PINETREE study.
Published in ContagionLive on 18 October 2021
Participants in this multinational, double-blind trial were 562 high-risk patients* (mean age ~50 years [30% aged ≥60 years], 52% male, median BMI 30.7 kg/m2) with confirmed COVID-19** who were not admitted to hospital. They were randomised 1:1 to receive intravenous remdesivir (200 mg on day 1, 100 mg on days 2–3) or placebo for 3 days.
The SARS-CoV-2 RNA nasopharyngeal viral load at baseline was a median 6.2 log10 copies/mL and patients had experienced symptoms for a median 5 days before the first dose of drug. The most common comorbidities in the population were diabetes, obesity, and hypertension, at 62, 56, and 48%, respectively.
At day 28, there was an 87% reduction in the risk of a composite of COVID-19–related hospitalisation or all-cause death with remdesivir vs placebo (0.7 percent vs 5.3 percent; hazard ratio [HR], 0.13, 95% confidence interval [CI], 0.03–0.59; p=0.008). [ID Week 2021, abstract LB1]. The between-group difference was evident from day 2, as noted by the separation of the curves, and was maintained to day 28.
The risk of COVID-19–related medically attended visits or all-cause death at day 28 was also reduced by 81% with remdesivir compared with placebo (1.6% vs 8.3%; HR, 0.19, 95% CI, 0.07–0.56; p=0.002).
The time-weighted average change in SARS-CoV-2 nasopharyngeal viral loads between baseline and day 7 did not differ between the remdesivir and placebo groups (median -1.15 vs -1.11 log10 copies/mL; least-squares mean difference, 0.07; p=0.43).
Treatment-emergent adverse event (TEAE) rates were similar between the remdesivir and placebo groups (42.3% vs 46.3%). Grade ≥3 TEAEs occurred in 3.6 and 7.1% of the remdesivir and placebo groups, respectively, and serious TEAEs in 1.8 and 6.7%, respectively. None of the serious AEs were deemed related to study drug and the higher number of serious AEs in the placebo group was reflective of the higher hospitalisation rate in this group. One remdesivir recipient experienced a grade ≥3 study drug-related TEAE (elevated transaminase levels).
The most frequently occurring AEs in remdesivir recipients were nausea, headache, and diarrhoea (11, 6, and 4 percent, respectively). There were no deaths in either the remdesivir or placebo group at day 28.
Study author Dr Joshua Hill said: “We still have very few treatment options to offer people who develop COVID-19, are at increased risk for progression, but are not yet hospitalized or not requiring hospitalisation. What we know from decades of experience in the field of virology [is that] early initiation of antiviral treatment may be the most effective way to prevent disease progression, particularly for those who are at highest risk.
“Remdesivir for three days provides a safe and highly effective treatment for non-hospitalized patients with COVID-19 at high risk for progression.” As there were no deaths, the benefits with remdesivir were specific to COVID-19–related hospitalisations or medically attended visits, he said. Hill also noted that the lack of difference between groups pertaining to SARS-CoV-2 nasopharyngeal viral load, despite the improvement in clinical outcomes, suggests that upper respiratory viral load is an inadequate surrogate for efficacy of remdesivir.
*age ≥12 years with risk factors or ≥60 years
**within 4 days of diagnosis, symptoms for ≤7 days
MedPage Today article – Remdesivir Appears Effective in COVID Outpatients, Too (Open access)
IDWEEK website: Restricted access
See more from MedicalBrief archives:
Interferon worse than placebo in severe COVID — US NIAID trial
Remdesivir did not affect COVID-19 outcomes or mortality — DisCoVeRy trial
Repurposed hep C drugs plus remdesivir highly effective at inhibiting SARS-Cov-2 — In vitro study
Remdesivir linked with clinical improvement and safety — Johns Hopkins hospital study