Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results
, NEJM, doi:10.1056/NEJMoa2023184, SOLIDARITY, NCT04315948, Oct 2020 (preprint)
HCQ for COVID-19
1st treatment shown to reduce risk in
March 2020, now with p < 0.00000000001 from 424 studies, used in 59 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
|
WHO SOLIDARITY open-label trial with 954 very late stage (64% on oxygen/ventilation) HCQ patients, mortality relative risk RR 1.19 [0.89-1.59], p=0.23.
HCQ dosage very high as in RECOVERY, 1.6g in the first 24 hours, 9.6g total over 10 days.
Authors state they do not know the weight or obesity status of patients to analyze toxicity (since they do not adjust dosage based on patient weight, toxicity may be higher in patients of lower weight).
KM curves show a spike in HCQ mortality days 5-7, corresponding to ~90% of the total excess seen at day 28 (a similar spike is seen in the RECOVERY trial).
Almost all excess mortality is from ventilated patients.
Authors refer to a lack of excess mortality in the first few days to suggest a lack of toxicity, but they are ignoring the very long half-life of HCQ and the dosing regimen - much higher levels of HCQ will be reached later. Increased mortality in Borba et al. occurred after 2 days.
An unspecified percentage used the more toxic CQ. No placebo used.
For more on the dosing problems see1, also noting that concentrations vary substantially in different tissues and lung concentration may be >30x plasma concentration.
This study is excluded in the after exclusion results of meta
analysis:
excessive dosage in late stage patients, results do not apply to typical dosages; very late stage, >50% on oxygen/ventilation at baseline.
Study covers lopinavir/ritonavir, remdesivir, and HCQ.
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risk of death, 19.0% higher, RR 1.19, p = 0.23, treatment 104 of 947 (11.0%), control 84 of 906 (9.3%).
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
SOLIDARITY Trial Consortium et al., 15 Oct 2020, Randomized Controlled Trial, multiple countries, peer-reviewed, baseline oxygen required 64.0%, 15 authors, study period 22 March, 2020 - 4 October, 2020, trial NCT04315948 (history) (SOLIDARITY).
Abstract: new england
journal of medicine
The
February 11, 2021
established in 1812
vol. 384
no. 6
Repurposed Antiviral Drugs for Covid-19 — Interim WHO
Solidarity Trial Results
WHO Solidarity Trial Consortium*
a bs t r ac t
BACKGROUND
World Health Organization expert groups recommended mortality trials of four
repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19).
METHODS
We randomly assigned inpatients with Covid-19 equally between one of the trial
drug regimens that was locally available and open control (up to five options, four
active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug
and its control (drug available but patient assigned to the same care without that
drug). Rate ratios for death were calculated with stratification according to age
and status regarding mechanical ventilation at trial entry.
RESULTS
At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750
were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir
(without interferon), 2063 to interferon (including 651 to interferon plus lopinavir),
and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment,
with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death,
day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8%
(39.0% if the patient was already receiving ventilation at randomization and 9.5%
otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303
of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to
1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of
906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of
1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio,
1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39;
P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.
CONCLUSIONS
These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little
or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World
Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov
number, NCT04315948.)
n engl j med 384;6
nejm.org
The members of the writing and steering
committees (H. Pan, R. Peto, A.-M.
Henao‑Restrepo, M.-P. Preziosi, V. Sathiyamoorthy, Q. Abdool Karim, M.M. Alejandria, C. Hernández García, M.-P. Kieny, R. Malekzadeh, S. Murthy, K.S.
Reddy, M. Roses Periago, P. Abi Hanna,
F. Ader, A.M. Al‑Bader, A. Alhasawi, E. Allum, A. Alotaibi, C.A. Alvarez‑Moreno, S.
Appadoo, A. Asiri, P. Aukrust, A. Barratt‑Due, S. Bellani, M. Branca, H.B.C.
Cappel‑Porter, N. Cerrato, T.S. Chow, N.
Como, J. Eustace, P.J. García, S. Godbole,
E. Gotuzzo, L. Griskevicius, R. Hamra, M.
Hassan, M. Hassany, D. Hutton, I. Irmansyah, L. Jancoriene, J. Kirwan, S. Kumar, P. Lennon, G. Lopardo, P. Lydon, N.
Magrini, T. Maguire, S. Manevska, O.
Manuel, S. McGinty, M.T. Medina, M.L.
Mesa..
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Late treatment
is less effective
is less effective
