CMAAO CORONA FACTS and MYTH BUSTER 84 Remdesivir Game Changer
CMAAO CORONA FACTS and MYTH BUSTER 84 Remdesivir Game Changer
Dr K K Aggarwal
President Confederation of Medical Associations of Asia and Oceania, HCFI, Past National President IMA, Chief Editor Medtalks
With inputs from dr Monica Vasudeva
792: What is Remdesivir
Remdesivir is an investigational antiviral under evaluation for COVID-19.
793: What are the preliminary reports
Emerging data from randomized trials are limited and mixed. Interim analysis of an unpublished trial of >1000 patients with confirmed COVID-19 and pulmonary involvement suggested that remdesivir resulted in faster time to recovery (median 11 versus 15 days with placebo); a trend towards lower mortality was noted though not statistically significant (8 versus 11.6 percent) .
In contrast, in a randomized trial in China of 237 patients with severe COVID-19, remdesivir and placebo had similar times to clinical improvement (median 21 versus 23 days) and mortality rates (14 versus 13 percent); however, confidence in the finding of no effect was reduced by use of concomitant therapies, differences in baseline comorbidities between the groups, and failure to meet the target enrollment . Overall, if the preliminary results of the larger trial are confirmed, remdesivir likely has some clinical benefit, although the patient population most likely to benefit is uncertain.
1.World Health Organization. Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 (Accessed on February 12, 2020).
2.Centers for Disease Control and Prevention. 2019 Novel coronavirus, Wuhan, China. Information for Healthcare Professionals. https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html (Accessed on February 14, 2020).
In the US, FDA has issued an emergency use authorization for remdesivir for hospitalized children and adults with severe COVID-19 (SpO2 ≤94 percent on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation [ECMO]) [US FDA. Remdesivir letter of EUA. https://www.fda.gov/media/137564/download (Accessed on May 01, 2020).
796: What is the dose
The suggested adult dose is 200 mg intravenously on day 1 followed by 100 mg daily for 10 days total in patients on mechanical ventilation or ECMO and 5 days total in other patients (with extension to 10 days if there is no clinical improvement).
797: What about in raised liver enzyme patients
Remdesivir is not recommended in patients with an alanine aminotransferase ≥5 times the upper limit of normal (and should be discontinued if it rises above this level during treatment or if there are other signs of liver injury).
780: What about in kidney patients
The pharmacokinetics of remdesivir in the setting of renal impairment are uncertain, and it is prepared in a cyclodextrin vehicle that accumulates in renal impairment and may be toxic; thus, remdesivir is not recommended in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m2 unless the potential benefit outweighs the potential risk.
781: What about results in US
The United States National Institute of Allergy and Infectious Diseases announced preliminary results of a multinational, randomized, placebo-controlled trial of remdesivir among 1063 patients with confirmed COVID-19 and evidence of lung involvement. On interim analysis, remdesivir resulted in a faster time to recovery, defined as being discharged from the hospital or no longer requiring supplemental oxygen (median 11 versus 15 days with placebo, p<0.001). There was also a trend towards lower mortality that was not statistically significant (8 versus 11.6 percent with placebo, p = 0.059). Final analysis and peer review of these data are pending. [https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19 (Accessed on April 29, 2020).]
Clinical improvement was defined as discharge from the hospital or a two-point improvement on a six-point clinical score that ranges from death to mechanical ventilation to lower levels of oxygen support to discharge. This study only included one patient who was on mechanical ventilation at baseline. Mortality at 28 days was also similar with remdesivir or placebo (14 versus 13 percent); there was also no difference in time to viral clearance. Among patients who had received treatment within 10 days of symptom onset, there were trends towards lower mortality and more rapid clinical improvement with remdesivir, but these differences were not statistically significant. Remdesivir was stopped early because of adverse events (including gastrointestinal symptoms, aminotransferase or bilirubin elevations, and worsened cardiopulmonary status) in 12 percent, compared with 5 percent in the placebo group. Several limitations reduce confidence in the finding of no effect; concomitant therapies (lopinavir-ritonavir, interferon alpha-2b, and/or corticosteroids) were used by most study participants, patients in the remdesivir group had a higher proportion of comorbidities (hypertension, diabetes mellitus, and coronary heart disease), and the study was stopped early for poor enrollment (the target enrollment pre-determined to demonstrate effect was 435 patients).
783: How long to give
Early data suggest that 5 days of remdesivir result in similar outcomes as 10. In a preliminary report from the manufacturer of a randomized, open-label trial among nearly 400 patients with severe COVID-19 who were not on mechanical ventilation, the rates of clinical recovery and discharge by day 14 were not statistically different when remdesivir was given for 5 days (65 and 60 percent, respectively) versus 10 days (54 and 52 percent, respectively). Mortality rates at day 14 were 8 and 11 percent with 5 and 10 days of treatment, respectively, and varied by geographic location. [Gilead Announces Results From Phase 3 Trial of Investigational Antiviral Remdesivir in Patients With Severe COVID-19. https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19 (Accessed on April 29, 2020)
784: Case reports
Use of remdesivir 92) has also been described in several case series [3,4,5]. In one multicenter, multinational series, 53 patients with severe COVID-19 and hypoxia received compassionate-use remdesivir for up to 10 days and had a median of 18 days of follow-up; 68 percent had clinical improvement (decreased requirement for oxygen support or hospital discharge), and 13 percent died . Of the 30 patients who were mechanically ventilated at baseline, 17 (57 percent) were extubated, and three of four patients on extracorporeal membrane oxygenation (ECMO) were taken off it.
Reported side effects include nausea, vomiting, and transaminase elevations. In a preliminary report from a trial of remdesivir among patients with severe COVID-19, grade 3 aminotransferase elevations occurred in 7 percent and led to drug discontinuation in 3 percent . Other adverse events described in patients who received remdesivir include worsening kidney injury, multiple organ failure, and worsened cardiopulmonary status [1,5 ].
1.Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020.
2.Gilead Announces Results From Phase 3 Trial of Investigational Antiviral Remdesivir in Patients With Severe COVID-19. https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19 (Accessed on April 29, 2020).
Remdesivir is not suitable for oral delivery as its poor hepatic stability would likely result in almost complete first-pass clearance.
786: Can it be given IM
IM route is also suboptimal for the administration of remdesivir. Studies assessing IM administration did shown a slow and variable release from muscle, evidence for IM metabolism, and delayed appearance of the pharmacologically active triphosphate GS443902 in PBMCs. IV administration delivers GS-443902 more rapidly and consistently into target cells
787: What is the risk vs benefit
In severe cases, COVID-19 can cause pneumonia, severe acute respiratory syndrome, kidney failure, and death. The drug is used in patients who require invasive mechanical ventilation. Such patients have been reported to have a mortality at and above 50%. There are no specific therapies with established efficacy and safety for the treatment of COVID-19. Thus, the target condition fulfils criteria for the compassionate use insofar as there is life-threatening illness which cannot be treated satisfactorily with any currently authorised medicine.
The assumption that RDV may be efficacious is mainly based on efficacy in animal models of SARS-Cov and MERS-Cov, in which RDV, when given prior to or one day after experimental infection, had better clinical and virological efficacy than vehicle alone or lopinavir/ritonavir with or without interferon beta1b. These results are bridged from SARS-CoV or MER-CoV to SARS-Cov2 via in vitro data indicating that all these viruses are susceptible to RDV with EC50 values below 1 uM (=approximately 0.6 ug/mL). Furthermore, plasma exposure to RDV, as well as PBMC exposure to triphosphate metabolite GS443902, appear to support the assumption that the efficacy seen in Rhesus monkeys might also be seen in humans.
Major uncertainties include the relevance of the animal models for human COVID-19, as well as the fact that RDV was administered latest one day after viral challenge in the animal models. Furthermore, prophylactic administration appeared more effective that administration after challenge, indicating that, similar to other acute viral diseases, the benefit of remdesivir treatment may be greater the earlier treatment is started in relation to the onset of symptoms. From this point of view, treating patients that already have respiratory failure, and presumably in most cases would have been symptomatic for a while, may not represent the optimal use of RDV.
With regards to the Paediatric indication, based on the limited data, no safety or efficacy issue in children below 12 years of age can be predicted.
787: How costly is the salt
App 10 million rupees for one Kg of the salt
787: During Pandemics can countries make and copy the salts on compassion grounds
Countries do have such powers
788: Will India get this salt
All likely, either will get it or make it.
789: Can the drug be given sub lingually
There is no data
790: Can the drug be potentised and given sub lingually