Remdesivir, hydroxychloroquine, lopinavir/ritonavir, and Interferon used for treating COVID-19 not quite effective: Solidarity Trial
USA: Four re-purposed antiviral drugs including remdesivir, hydroxychloroquine, lopinavir/ritonavir, and Interferon-β1a used for the treatment of the COVID-19 virus are not quite effective, reveals Solidarity Therapeutics Trial coordinated by the World Health Organisation (WHO). Solidarity is an international clinical trial to help find an effective treatment for COVID-19, launched by the World Health Organization and partners.
The regimens appeared to have little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients.
The world's largest randomized control trial on COVID-19 therapeutics has generated conclusive evidence on the effectiveness of repurposed drugs for the treatment of COVID-19 in just six months.
WHO expert groups recommended mortality trials in hospitalized COVID-19 of the four re-purposed antiviral drugs which include Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-β1a.
WHO accepted the recommendation from the Solidarity Trial's International Steering Committee to discontinue the trial's hydroxychloroquine and lopinavir/ritonavir arms on 4 July 2020.
The International Steering Committee formulated the recommendation in light of the evidence for hydroxychloroquine vs standard-of-care and for lopinavir/ritonavir vs standard-of-care from the Solidarity trial interim results, and from a review of the evidence from all trials presented at the 1-2 July WHO Summit on COVID-19 research and innovation.
These interim trial results showed that hydroxychloroquine and lopinavir/ritonavir produce little or no reduction in the mortality of hospitalized COVID-19 patients when compared to standard of care. Solidarity trial investigators will interrupt the trials with immediate effect.
For each of the drugs, the interim results did not provide solid evidence of increased mortality. There were, however, some associated safety signals in the clinical laboratory findings of the add-on Discovery trial, a participant in the Solidarity trial.
The study, which spans more than 30 countries, looked at the effects of these treatments on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized patients. Other uses of the drugs, for example in the treatment of patients in the community or for prevention, would have to be examined using different trials.
In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug.
Key findings of the trial include:
- Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8).
- Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise).
- Death rate ratios were: Remdesivir RR=0.95 (301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (104/947 vs 84/906), Lopinavir RR=1.00 (148/1399 vs 146/1372) and Interferon RR=1.16 (243/2050 vs 216/2050).
- No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalization duration.
"These Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials," concluded the authors.
Newer antiviral drugs, immunomodulators and anti-SARS COV-2 monoclonal antibodies are now being considered for evaluation.
The results of the trial are under review for publication in a medical journal and have been uploaded as a preprint at medRxiv available at this link: https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1
