3. Remdesivir

Hot topic alert! We’re unpacking the latest evidence around remdesivir – miracle drug, or overblown hype?

 

What is remdesivir?

Anti-viral that has been studied in vitro and in pre-clinical/animal models showing promising effects for COVID-19: Preventing symptoms occurrence if given early Improving symptoms during infection Decreasing viral load Acts as an adenosine nucleotide triphosphate analogue interfering with viral replication Many ongoing phase II and III trials are exploring the use of remdesivir compared to other anti-virals and/or standard of care Despite this early promise: the history of medicine is littered with therapies that looked promising in vitro/in preclinical models/in small non-randomized trials; only to end up having no benefit (or even causing harm!) when studied in robust RCTs

 

RCT: Wang et al1

Methods Double-blinded, placebo-controlled RCT at 10 hospitals in Wuhan, China Population 236 pts randomized in 2:1 fashion (158 REM, 78 placebo) Inclusion - all of: age > 18, COVID-19 confirmed with PCR, imaging evidence of pulmonary disease, hypoxemia (SpO2 < 94% on RA or P/F < 300), within 12d of Sx onset Exclusion: pregnancy/breastfeeding, severe CKD (GFR < 30), hepatic disease (transaminases > 5x ULN), transfer to non-study hospital, other clinical trial participation Treatment protocol REM: 200mg IV on day 1; followed by 100mg daily 10 day protocol (REM vs placebo infusions) Outcomes Primary outcome: time to clinical improvement up to day 28 OR hospital discharge (whichever came first) Defined as an improvement by 2 points on a 6 points scale (from 1= discharge to 6=death) Secondary outcomes: many; including 28d mortality, frequency of mechanical ventilation, duration of oxygen therapy, hospital LOS, etc. Also looked at viral load and viral PCR clearance Statistical analysis Intention to treat Power calculated with an estimated treatment effect of 1.4 for REM *trial stopped early due to low enrollment: only recruited 58% of their intended cohort (low numbers in China as virus was contained) Results Patient characteristics Median time from symptom onset was 10 days (IQR 9-12) REM groups appears slightly more comorbid/sicker (slightly higher incidence CAD, DM,HTN; higher RR) No difference in other treatments received About 30% got lopinavir-ritonavir; about 60% got steroids; about 90% got antibiotics *Most patients were not that sick: over 80% required only low-flow oxygen Question of the necessity of treatment for this group in the first place? Primary outcome No statistically significant difference Time to clinical improvement: median 21.0 days [IQR 13.0–28.0] in the REM group vs 23.0 days [15.0–28.0]; HR 1.23 [95% CI 0.87–1.75] Trend (not statistically significant) towards faster improvement in subgroup that received remdesivir within 10d of Sx onset (18d vs 23d) Secondary outcomes No difference in: 28d mortality (14% vs 13%), length of hospital stay, length of oxygen therapy Small difference in one secondary endpoint (time to clinical improvement by 6-point scale) à questionable significance *No difference in viral load Given that this is purported mechanism of action, this casts serious doubt on the in-vivo efficacy of this drug Adverse events Similar between groups (constipation, hypoalbuminemia, hypokalemia, anemia, thrombocytopenia, transaminitis and hyperbilirubinemia) Reported in about 2/3 of patients Overall no difference Major caveats Generally a well-done study Risk type 2 error? Underpowered to detect time to clinical improvement (under-recruitment) Definitely underpowered for outcomes like illness severity, mortality Not given early enough? About half of pts got drug 10d after Sx onset Previous animal models all involve drug administration within 24h of Sx onset Practically, administering the drug early would likely be challenging as most patients don’t present to hospital until 5-10d into their disease course Funding: Chinese Academy of Medicine Science, Beijing Science and Technology Project, National Key Research and Development Program of China NOT Gilead Bottom line NO statistically significant difference in time to clinical improvement for moderately ill patients treated with remdesivir vs placebo Remdesivir appears safe: no apparent increase in SEA

 

 

NIH study: prelim results

The US NIH (National Institute of Health) put out a press release on April 29 about promising preliminary data results from the ACTT trial (Adaptive COVID-19 Treatment Trial)2 Run at the University of Nebraska, sponsored by the NIAID Details of the study not reported other than in a media release3 Participants with confirmed SARS-CoV-2 with “evidence of lung involvement” Outcome: improvement on a 7 point scale? Interim analysis: reported a 31% faster recovery with REM vs placebo (11d vs 15d) “Results also suggested a mortality benefit” that didn’t reach significance Questionable validity: interim analysis, no details available, not peer-reviewed; also contrary to above well-conducted RCT

  

Coming down the pipeline

Two phase 3 randomized parallel group trial are underway, sponsored by Gilead sciences (NCT04292899 and NCT04292730) that seek to enroll 6000 patients with severe COVID-19, and 1600 patients with moderate COVID-19 respectively NCT04292730 aims to be completed in May of 2020 and the preliminary results should be available shortly.

  

Sources

Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, April 2020. doi: 10.1016/S0140-6736(20)31022-9

 

NIH press release, Apr 29 2020. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19

 

NIH press release, Feb 25 2020. https://www.niaid.nih.gov/news-events/nih-clinical-trial-remdesivir-treat-covid-19-begins