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Factors Tied to Clinical Improvement or
Death in Phase 3 Remdesivir Trial
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IAS COVID-19 Conference, July 10-11, 2020.
Mark Mascolini
Black or white versus Asian race, no or low-flow oxygen support, and no comedication all independently predicted clinical improvement in a phase 3 trial of the nucleotide analog remdesivir for COVID-19 [1]. The 397-person trial linked more intensive breathing support, chronic obstructive pulmonary disease (COPD), and age 65 or older to a higher risk of death.
An international phase 3 open-label trial that randomized 397 people with severe COVID-19 to 5 or 10 days of intravenous remdesivir [2]. In an analysis adjusted for baseline clinical variables, clinical status at day 14 on a 7-point ordinal scale* did not differ significantly between the 5-day group and the 10-day group (P = 0.14) [2].
Trial participants had confirmed SARS-CoV-2 infection, oxygen saturation at or below 94%, and x-ray evidence of pneumonia. Researchers randomized them evenly to intravenous remdesivir for 5 days or 10 days. Everyone took 200 mg of remdesivir on day 1, then 100 mg daily on the following days. The investigators combined treatment arms for this analysis.
The 397 participants enrolled from March 6 through March 26, 2020 at 55 sites in 8 countries, including 229 people in the United States, 77 in Italy, 61 in Spain, 12 in Korea, and smaller numbers in Singapore, Germany, Hong Kong, and Taiwan.
Most participants entered the trial on low-flow oxygen (55%), while 27% used noninvasive ventilation (NIPPV) or high-flow oxygen (HFNC), 14% breathed room air, and 3% used invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). The primary endpoint was time to improvement of at least 2 points on an ordinal scale* at treatment day 14. Statisticians analyzed that result with a competing risk analysis that counted death as a competing risk. A Cox proportional hazards model assessed time to all-cause mortality on day 14.
The 397 trial participants averaged 60 years in age and 42% were 65 or older. Proportions by race were 70% white, 12% Asian, and 11% black. One third of participants (36%) were women, and median body mass index stood at 28.7 kg/m2 (within the overweight range). Half of participants had hypertension, 22% diabetes, 22% hyperlipidemia, 12% asthma, and 4% COPD. Before starting remdesivir the group spent a median of 2 days in the hospital and a median of 8 days with symptoms.
Six factors independently predicted improvement in clinical status (defined as a 2-point or greater gain on the ordinal scale* by day 14) at the following adjusted hazard ratios (HR) (and 95% confidence intervals):
-- Low-flow oxygen or room air vs IMV or HFNC/NIPPV: HR 2.16 (1.50 to 3.10), P < 0.0001
-- Age under 65 vs 65+: HR 1.93 (1.46 to 2.55), P < 0.0001
-- Black vs Asian: HR 3.80 (2.28 to 6.35), P < 0.0001
-- White vs Asian: HR 2.45 (1.60 to 3.76), P < 0.0001
-- Outside Italy vs Italy: HR 1.59 (1.07 to 2.37), P = 0.0225
-- No concomitant medication: HR 2.70, (1.49 to 4.88), P = 0.0010
Three factors independently predicted increased risk of all-cause mortality:
-- IMV or HFNC/NIPPV vs low-flow oxygen or room air: HR 5.47 (2.74 to 10.9), P < 0.0001
-- COPD vs no COPD: HR 3.41 (1.30 to 8.94), P = 0.0125
-- Age 65 or older vs younger: HR 2.30 (1.18 to 4.47), P = 0.0139
The researchers speculated that clinical improvement looked worse in Italy than other countries because Italy was the center of the pandemic at the time of this study, when its healthcare system was severely taxed.
Findings support the opinion of experts who reviewed remdesivir studies and concluded that this medication offers the greatest benefit to in-hospital COVID-19 patients who require low-flow oxygen or no respiratory support versus high-flow oxygen, noninvasive ventilation, or invasive mechanical ventilation [3].
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*The ordinal scale included (1) death, (2) invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), (3) noninvasive ventilation or high-flow oxygen, (4) low-flow oxygen, (5) room air and ongoing medical care, (6) room air and no ongoing medical care, (7) not hospitalized.
Slides
COVID Congress: Baseline Characteristics Associated With Clinical Improvement and Mortality in Hospitalized Patients With Severe COVID-19 Treated With Remdesivir
References
1. Marks K, Hojat L, Huhn G, et al. Baseline characteristics associated with clinical improvement and mortality in hospitalized patients with severe COVID-19 treated with remdesivir. IAS COVID-19 Conference, July 10-11, 2020. Track B. https://cattendee.abstractsonline.com/meeting/9307/presentation/4287
2. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020 May 27. doi: 10.1056/NEJMoa2015301. https://www.nejm.org/doi/10.1056/NEJMoa2015301
3. Davis MR, McCreary EK, Pogue JM, et al. That escalated quickly: remdesivir's place in therapy for COVID-19. Infect Dis Ther. 2020 Jul 10. https://doi.org/10.1007/s40121-020-00318-1
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