Table 1.
Main clinical studies testing antiviral drugs for the treatment of COVID-19 disease
| Drugs | References | Study type (ST), population (P) and dosage (D) | Results | Adverse effects (AE) | Limitations/comments |
|---|---|---|---|---|---|
| Lopinavir/ritonavir (LPN/r) | Cao et al. NEJM 2020 [6] |
ST: randomized controlled open-label clinical trial P: 199 severe COVID-19 pneumonia patients D: 99 patients: LPN/r 400/100 mg twice daily for 14 days + supportive therapy vs. 100 patients: supportive therapy alone |
Treatment with LPV/r was not associated with a better survival rate or with faster clinical improvement (HR 1.24, 95% CI 0.90–1.72). 28-day mortality and time to negative swabs were similar in the two groups | Gastro-intestinal symptoms (nausea, vomiting and diarrhoea). 13 patients discontinued the treatment due to AE | All the recruited patients had severe pneumonia and started antiviral therapy very late after symptoms onset (12–14 days) |
| Liu and Xu. International Journal of Infectious Disease 2020 [7] |
ST: retrospective, observational, single-centre study P: 10 patients with moderate COVID-19 pneumonia D: LPV 400 mg twice a day + nebulized Interferon α2b 5 mln UI twice a day |
Positive effects on viral clearance, symptoms and imaging | Gastro-intestinal symptoms (nausea, vomiting, diarrhoea and hypokalemia). 3 patients discontinued the treatment |
Small sample size, no case–control, short term follow-up The drug seemed to be effective if administered early |
|
| Deng et al. Journal of Infection 2020 [8] |
ST: retrospective cohort study P: 33 patients with moderate COVID-19 pneumonia D: LPN/r 400/100 mg twice daily with or without Umifenovir (200 mg every 8 h) for 5–21 days |
Superiority of the combination therapy (LPN/r + Umifenovir) in decreasing viral load with negative nasopharyngeal swabs after 7 days of therapy (75% vs. 35%, p < 0.05) and in improving CT imaging (69% vs. 29%, p < 0.05) | Increased levels of bilirubin; gastro-intestinal symptoms (nausea, vomiting and diarrhoea). No treatment discontinuation due to AE | Small sample size, no randomization, possible selection bias. Variable additional treatments in the two groups | |
| Hung et al. Lancet 2020 [9] |
ST: multicentre, prospective, open-label, randomized phase 2 trial P: 127 moderate COVID-19 pneumonia patients D: 86 pts: LPN/r 400/100 mg for 14 days + ribavirin 400 mg twice daily for 14 days + Interferon β1b 8 mln UI on alternate days for 3 times maximum vs. 41 pts: LPN/r alone |
The combination therapy group had a significantly shorter time to negative nasopharyngeal swabs (7 vs. 12 days; HR 4.37, 95% CI 1.86–10.24, p = 0.001). The significant viral response was also associated with clinical improvement | Nausea and diarrhea (no differences between treatment groups); mild and self-limited liver dysfunction. 1 patient in the control group discontinued LPN/r because of biochemical hepatitis. No deaths |
Open-label trial without a placebo group; variable use of Interferon β1b according to time from symptoms onset Patients were treated early after symptoms onset (5 days) |
|
| Darunavir/cobicitstat (DAR/COB) | ClinicalTrials.gov Identifier: NCT04252274 |
ST: ranzomized interventional clinical trial P: 30 patients, still recruiting in China D: Dar/Cob 800/150 mg once/day for 5 days + standard therapy vs. standard therapy alone |
Outcomes: virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 7; adverse events and mortality at week 2 after end of treatment | Not available | Small sample size |
| Remdesivir | Wang et al. Lancet 2020 [11] |
ST: Multicentre, randomized controlled double-blind clinical trial (ClinicalTrials.gov NCT04257656) P: 237 patients with severe pneumonia D: 158 patients: Remdesivir 200 mg IV day 1 and 100 mg IV from day 2 to day 10 + supportive therapy vs. 79 patients: placebo + supportive therapy |
No significant differences in time to clinical improvement (HR 1.23, 95% CI 0.87–1.75) or 28-day mortality. Faster time to clinical improvement only among patients with symptoms duration of ten days or less (HR 1.52, 95% CI 0.95–2.43). No significant reduction of SARS-CoV2 RNA load or detectability in upper respiratory tract or sputum specimens | Treatment discontinuation because of AE (nausea, vomiting, increased liver enzymes, rash) more frequent in Remdesivir group (12% vs. 5%) | Target enrolment was not reached; patients were enrolled at late stages of disease |
| Grein et al. NEJM 2020 [15] |
ST: Case series on compassionate use of remdesivir P: 61 patients with severe COVID-19 pneumonia D: 200 mg IV day 1 and 100 mg IV from day 2 to day 10 |
Improvement in oxygen support class (in ventilated patients) and in general conditions (in all classes of enrolled patients) | Increased liver enzymes, diarrhoea, rash, renal impairment and hypotension. 4 patients discontinued the therapy because of major AE | Treatment was started 12 (9–15) days after symptoms onset; patients enrolled were severe/critical with an overall mortality of 13% | |
| Holshue NEJM 2020 [16] |
ST: Case report P: a 35 years old male patient D: Not available |
Fast improvement of symptoms and imaging | No AE | The drug was started 7 days after symptoms onset | |
| Beigel et al. NEJM 2020 [17] |
ST: adaptive, randomized, double-blind, placebo-controlled trial; ADAPTIVE COVID-19 TREATMENT TRIAL (ACTT) P: 1059 hospitalized patients affected by severe (88.7%) and moderate (11.3%) COVID-19 pneumonia D: 538 patients: Remdesivir: 200 mg on day 1, followed by 100 mg daily for up to 9 additional days + standard of care vs. 521 patients: placebo for 10 days + standard of care |
31% faster time to recovery (11 vs. 15 days; HR 1.32, 95% CI 1.12–1.55; p < 0.001) with remdesivir. The benefit was most apparent in patients requiring oxygen. Mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (HR 0.70, 95% CI 0.47–1.04) | No significant differences in serious AE. Anemia, acute kidney injury, hyperglycemia and increased liver enzymes were the most common AE. No deaths related to treatment |
Incomplete data: at the writing time 132 patients in the remdesivir group and 169 in the placebo group had not recovered and had not completed the day 29 follow-up visit Treatment was started 9 (6–12) days after symptoms onset |
|
| Goldman et al. NEJM 2020 [18] |
ST: randomized, open- label, phase 3 trial P: 397 hospitalized severe COVID-19 patients not requiring mechanical ventilation D: 200 patients: Remdesivir IV 200 mg on day 1, then 100 mg/day for 5 days vs. 197 patients: Remdesivir IV 200 mg on day 1, then 100 mg/day for 10 days |
Similar clinical status at day 14 in the two groups after adjustment for baseline features | Serious AE more common in 10-day group (21% Vs. 35%); acute respiratory failure was the most common serious AE. The most common AE were nausea, worsening of respiratory failure, elevation of liver enzymes and costipation | At baseline, patients assigned to the 10-day group had significantly worse clinical status than the 5-day group (p = 0.02). No placebo group; clinical heterogeneity of enrolled patients | |
| Favipiravir | Chen MedRxiv 2020 [19] |
ST: Prospective, multicentre, open-label, randomized clinical trial P: 236 patients; 116 pts: standard therapy + Favipiravir; 120 patients: standard therapy + umifenovir D: favipiravir: 1600 mg twice on day 1 and 600 mg twice daily from day 2 to day 14 for 7 days; Umifenovir: 200 mg 3 times daily for 7 days |
Favipiravir slightly more effective in improving clinical signs | The most frequent AE due to favipiravir were psychiatric and gastro-intestinal symptoms, increased uric acid and liver enzymes | Concerns have been raised because of the study design, the inclusion criteria and the distribution of the stages of disease severity in the different treatment groups |
| Quingxiang et al. Engineering 2020 [21] |
ST: Open-label control study P: 80 patients with mild/moderate COVID-19 pneumonia. 35 patients: favipiravir + nebulized interferon alfa + standard therapy vs. 45 patients: LPN/r + nebulized interferon alfa + standard therapy D: favipiravir 1600 mg twice on day 1 and 600 mg twice daily from day 2 to day 14; nebulized Interferon alfa 5 milions UI two times/day for 14 days; LPV/r 400/100 mg twice daily for 14 days |
Favipiravir more effective in improving CT imaging (91.4% vs 62.2%) and viral clearance at 14 days | AE less common in favipiravir group (diarrhoea, liver enzymes alterations and weight loss) |
Little sample size; not randomized and not double-blinded Antiviral drugs were administered in 7 days from symptoms onset |
|
| Umifenovir | Lian et al. Clinical Microbiology and Infection (2020) [23] |
ST: retrospective case–control study P: 81 patients with moderate and severe COVID-19 disease D: 45 patients: umifenovir + standard therapy vs. 36 patients: standard therapy alone |
Umifenovir treatment was not associated with a faster virus clearance after 7 days from admission (73% Umifenovir vs 78% Controls, p = 0.19) nor with a faster symptoms’ resolution (18 vs 16 days, p = 0.42). It was indeed associated with a longer hospital stay (13 vs 11 days, p = 0.04) | Digestive symptoms, including diarrhoea and nausea (not different from control group). No patients discontinued treatment because of AE. No severe impairment of liver and kidney function was observed | Little sample size; not randomized and not double-blinded |