Table 1 Treatment regimens with drugs mentioned within the main text, which were used in clinical trials, and the results of these studies

Convalescent plasma

Five critically ill patients with PCR-confirmed SARS-CoV-2 infection and with acute respiratory distress syndrome. Shenzhen, China

Convalescent plasma was transfused to patients between 10 and 22 days after admission. IgG binding titter in plasma was greater than 1:1000, neutralization titer greater than 40

The results of this study show an improvement in the clinical condition of critically ill patients with COVID-19

[59]

334 hospitalized adult (32.4% female, 67.6% male) patients from Argentina (median age 62) with SARS-CoV-2 infection confirmed by PCR

Convalescent plasma from one or from a pool of two to five donors; transfused volume were 10–15 ml/kg of body weight

No significant difference between groups (convalescent plasma versus placebo) in clinical outcomes

[60], NCT04383535

103 adults (41.2% women and 58.3% men, median age 70 years) with PCR-confirmed COVID-19 (72 h prior randomization) with severe or life-threatening clinical symptoms. Wuhan, China

Transfusion dose of convalescent plasma 4–13 ml/kg of recipient body weight. Administration of plasma transfusion was 10 ml for the first 15 min, then increased to 100 ml per hour with constant monitoring. Time and units of plasma to transfuse was individually selected

No significant difference in the time to clinical improvement between groups; no significant difference in 28-day mortality or time to discharge

[61], ChiCTR2000029757

938 adults (≥ 16 years of age in Canada or ≥ 18 years of age in the USA and Brazil), median age 69 years (41% women. 59% men). Confirmed COVID-19 with required oxygen supply

Patients received approximately 500 ml of convalescent plasma from one or two donors. Time and units of plasma to transfuse was individually selected

No difference in the frequency of intubation or death at 30 days of treatment and nontreatment patients

[62], NCT04348656 (CONCOR-1)

11,558 patients with suspected or laboratory confirmed COVID-19 infection; median age 63.5 years. UK

Patients received two units of convalescent plasma (275 ml) right after randomization and second dose (from different donor) the next day

No significant improvement survival or clinical outcomes in patients hospitalized with COVID-19

[63], NCT04381936 (RECOVERY)

17 patients depleted of B cells and with prolonged COVID-19 symptoms; median age 58 years; 70% patients were men; SARS-CoV-2 infection confirmed by PCR

Two transfection of two plasma units (200–220 ml each) day after day. Clinical and biological parameters were collected at days 5 and 7 of the study

Convalescent plasma seems to be very promising solution for patients unable to maintain humoral response to SARS-CoV-2

[64]

Casirivimab (REGN10933) and imdevimab (REGN10987)

275 adults with confirmed COVID-19, non-hospitalized; median age 44 years; 51% female and 49% male patients

At day 1—REGN-COV2 on two doses (low dose or high dose) were administrated in 250 ml in 1 h

REGN-COV2 reduced viral load

[69], NCT04425629

Sarilumab

148 adults with moderate-to-severe pneumonia and confirmed COVID-19; France

400 mg of sarilumab was administrated intravenously on day 1; additional 400 mg dose was administrated on day 3 (depending on clinical status and oxygen demand)

Patients with moderate-to-severe COVID-19 pneumonia did not benefit from sarilumab treatment in early outcomes

[71], NCT04324073

Tocilizumab

Adults at the median age 63.3 ± 13.7 years, hospitalized, with viral pneumonia syndrome manifested by, among others, hypoxia and evidence of systemic inflammation

4116 adults of 21,550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. 2022 patients were allocated to tocilizumab and 2094 patients to usual care

Participants were eligible to usual standard of care alone versus usual standard of care plus tocilizumab as a single intravenous infusion over 60 min. The dose of tocilizumab was established by body weight (800 mg if weight was > 90 kg; 600 mg if > 65 and ≤ 90 kg; 400 mg if > 40 and ≤ 65 kg; and 8 mg/kg if weight ≤ 40 kg). A second dose could be given 12–24 h later if the patient’s condition had not improved

Outcomes were assessed at 28 days after randomization to tocilizumab versus usual care alone, with further analyses specified at 6 months

In hospitalized COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids

Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days. Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death

[72], NCT04381936 (RECOVERY)

Adults at the median age 60.9 ± 14.6 years, hospitalized with severe COVID-19 pneumonia confirmed by positive PCR, suffered from hypoxia

A total of 438 participants were included in the primary and secondary analyses: 294 in the tocilizumab group and 144 in the placebo group

Patients received a single intravenous infusion of tocilizumab at a dose of 8 mg/kg of body weight or placebo. Approximately one-quarter of the participants received a second dose of tocilizumab or placebo 8–24 h after the first dose

The primary analysis was performed at day 28, and the final trial visit occurred at day 60

Under this protocol, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days

[73], NCT04320615 (COVACTA)

GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2)

Adults between 18 and 80 years diagnosed with acute respiratory distress syndrome (ARDS) who had been mechanically ventilated for less than 72 h

A total of 44 participants were randomized for the study: 5 participants took part in part A and 39 in part B, of whom 19 participants received GSK2586881 and 20 participants received placebo

In part A, eligible participants received multiple single intravenous escalating doses of GSK2586881 (0.1 mg/kg, 0.2 mg/kg, 0.4 mg/kg, 0.8 mg/kg) as a slow infusion over 2 days to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Participants were followed for up to 7 days

Dose escalation in part A was well tolerated in patients without clinically significant hemodynamic changes

The rapid modulation of renin–angiotensin system (RAS) peptides observed in part B suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes

[77, 78], NCT01597635

Recombinant human angiotensin-converting enzyme 2 (RhACE2 APN01)

Adults at the median age 59 ± 11.9 years, hospitalized with confirmed SARS-CoV-2 infection. Patients whose clinical condition was deteriorating rapidly were not included to the study

A total of 178 participants were enrolled in the study: 88 assigned to RhACE2 APN01 and 90 to placebo

Patients were treated with APN01 intravenously twice daily for 7 days. Participants were followed for 28 days to assess safety, with assessments performed on days 3, 7, 10, 14, and 28

Fewer patients treated with APN01 died or received invasive ventilation compared with placebo. Also, reduction in viral load and a tendency to faster recovery in the group treated with APN01 was observed. Treatment with APN01 was safe and well tolerated, and no drug-related severe adverse events were observed during the study

NCT04335136; Apeiron Biologics media release 12 March 2021

Camostat mesylate

Adults with a median age of 62 years (51–75 years), hospitalized with COVID-19 infection defined as PCR-positive for SARS-CoV-2 in respiratory tract samples and hospital admission fo 48 h. Patients unable to understand or sign the informed consent form were not eligible

A total of 208 participants were enrolled in the study: 139 assigned to camostat mesylate and 69 to placebo

Two tablets 100 mg camostat mesylate or two placebo tablets were administered orally three times daily (every 8 h) for 5 days

Participants were clinically assessed daily until day 5, and at days 14 and 30

Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for COVID-19 and did not affect time to clinical improvement, progression to intensive care unit admission, or mortality

[95], NCT04321096

Hydroxychloroquine

Adults at the median age 57 years (44–68 years), hospitalized for less than 48 h with laboratory-confirmed SARS-CoV-2 infection and symptoms of respiratory illness for less than 10 days. The main exclusion criteria were more than one dose of hydroxychloroquine or chloroquine in the prior 10 days

A total of 479 participants were enrolled in the study: 242 assigned to hydroxychloroquine and 237 to placebo

400 mg of hydroxychloroquine sulfate in pill form twice a day for the first two doses and then 200 mg in pill form twice a day for the subsequent eight doses, for a total of ten doses over 5 days

Under this protocol, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults

[96], NCT04332991

Hydroxychloroquine + omega-3

A total of 30 adults diagnosed with COVID-19

Intervention group received hydroxychloroquine + 2 g of docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) for 2 weeks; control group received hydroxychloroquine

In comparison with control group, patients receiving omega-3 indicated favorable changes in all assessed clinical symptoms except for olfactory. Reducing effects of omega-3 supplementation compared with control group were also observed in the levels of ESR and CRP after treatment. No differences in the liver enzymes serum concentrations were observed between groups after supplementation

[102], IRCT20200511047399N1

Remdesivir

Adults at the median age 58.9 ± 15 years, hospitalized with illness of any duration, with laboratory-confirmed SARS-CoV-2 infection in sample collected for less than 72 h prior to randomization

A total of 1062 participants were enrolled in the study: 541 assigned to remdesivir and 521 to placebo

Remdesivir was administered intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death. A matching placebo was administered according to the same schedule and in the same volume as the active drug

Patients were assessed daily during their hospitalization, from day 1 through day 29

Under this protocol, treatment with remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection (median 10 days as compared with 15 days)

[114], NCT04280705

Molnupiravir

Adults at the median age 40.8 years (18–82 years), non-hospitalized, but with confirmed active SARS-CoV-2 infection in a sample collected ≤ 96 h prior to study entry. Study treatment was expected to begin within ≤ 7 days from first symptom onset. Participants who needed hospitalization or immediate medical attention or those who were vaccinated were excluded from the study

A total of 202 participants were enrolled in the study: 140 assigned to molnupiravir in three different doses and 62 to placebo

Molnupiravir was administered orally twice daily for 5 days at dose 200 mg, 400 mg, or 800 mg. A matching placebo was administered according to the same schedule

Participants were followed for 28 days to assess safety, with assessments performed on days 1, 3, 5, 7, 14, and 28

Time to viral RNA clearance was decreased in the 800 mg molnupiravir group (median 14 days) compared with the placebo group (median 15 days). Of participants receiving 800 mg of molnupiravir, 92.5% achieved viral RNA clearance compared with 80.3% of placebo recipients by study end. At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg of molnupiravir compared with 11.1% of placebo recipients. Molnupiravir was well tolerated across all doses

[117], NCT04405570

Paxlovid (PF-07321332 and ritonavir)

Adults at the median age 46 years (18–88 years), non-hospitalized, symptomatic, with at least one characteristic condition associated with high risk of progression to severe COVID-19 and with confirmed SARS-CoV-2 infection and symptoms for less than 5 days. The main exclusion criteria were previous confirmed SARS-CoV-2 infection or hospitalization for COVID-19, anticipated need for hospitalization within 48 h after randomization, and prior receipt of convalescent COVID-19 plasma or SARS-CoV-2 vaccine

A total of 2246 participants were enrolled in the study: 1120 assigned to PF-07321332 (nirmatrelvir) + ritonavir and 1126 to placebo

Either 300 mg of PF-07321332 (nirmatrelvir) plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo were administered orally every 12 h for 5 days (ten doses total)

Viral load was analyzed at days 1 (baseline), 3, 5, 10, and 14. Safety was also evaluated

Under this protocol, treatment reduced the risk of hospitalization or death of patients by 89%, compared with placebo, without evident safety concerns

The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, when treatment was initiated within 3 days after onset of symptoms

[120, 121], NCT 04960202

Lithium (data from retrospective cohort study)

Adults at the average age between 42 and 48 years, treated with lithium for borderline personality disorder (BPD). Patients were considered on lithium treatment if they had an order placed within 90 days prior to their first positive COVID-19 test (COVID-19 cases) or 90 days before their first negative COVID-19 test (COVID-19 controls). To capture long-term use of lithium, patients with two or more lithium orders placed within 12 months before their COVID-19 test were included

The data were obtained from three healthcare systems

Access to the data of 379,611 cases was obtained, of which 1245 cases were selected for meta-analysis

Patients were prescribed doses effective for the treatment of BPD. As a control, a group that did not use lithium was chosen

Patients were tested for COVID-19 via RT-PCR

The analysis of clinical data from over 300,000 patients in three major health systems demonstrates a 50% reduced risk of COVID-19 in patients taking lithium

[124]