Table 6 Summary of the ongoing trials investigating pharmacological agents targeting a cytokine storm and acute cardiac injury secondary to SARS-CoV-2 infection.
Pharmacological intervention Sample size and criteria Treatment protocol Reference
• TACTIC-E Trial
• Immunomodulatory agents • Multi-arm randomized trial
• Pre-intensive care unit (ICU) COVID-19 patients
• Immunomodulatory drug EDP1815 vs. dapagliflozin + ambrisentan vs. standard care
• Primary outcome includes need for cardiovascular organ support • EDP1815 as 2 capsules twice daily (1.6 × 1011 cells) for up to 7 days
• Dapagliflozin 10 mg + ambrisentan 5 mg once daily (NCT04393246, 2020)
• High dose IV Vitamin C to ameliorate cytokine storm and associated organ dysfunction • Prospective placebo controlled randomized controlled trial (RCT)
•  N = 308
• High dose i.v. vitamin C (HIVC) vs. placebo
• Primary outcome of ventilator-free days • 12 g/50 ml vitamin C infusion 12 ml/h twice daily for 7 days vs. 50 ml sterile water for injection infused at 12 ml/h (Liu, Zhu, Zhang, Li, & Peng, 2020)
• TOC-COVID Trial • Prospective placebo controlled RCT
• N = 100 tocilizumab + standard treatment
•  N = 100 placebo + standard treatment
• Primary outcome of ventilation-free days • Tocilizumab 8 mg/kg single i.v. dose (Rilinger et al., 2020)
• TACTIC-R Trial
• Immunomodulatory agents • Randomized parallel 3-arm open label trial
•  N = 125 Baricitinib
•  N = 125 Ravulizumab
• N = 125 standard of care
• Primary outcome includes need for cardiovascular organ support • Baricitinib 4 mg orally once daily on days 1–14
• Ravulizumab single i.v. weight-based dose regimen (Kulkarni et al., 2020)
• CytoResc Trial
• Cytokine storm in hyperinflammation and shock • Prospective, open-label, pilot study
• ‘CytoSorb’ polystyrene-based hemoadsorber to adsorb circulating cytokines
•  N = 40–50 ‘CytoSorb’
• N = 40–50 standard care
• Primary outcome is time to resolution of vasoplegic shock • ‘CytoSorb’ therapy administered via a shaldon catheter for 3–7 days (Stockmann et al., 2020)
• MelCOVID Trial • Double blind placebo controlled RCT
• ICU COVID-19 patients
• N = 12 melatonin + standard of care
•  N = 6 placebo control + standard care
• Secondary outcome includes CRP, IL-6 levels • Melatonin 5 mg/kg/day i.v. divided every 6 h for 7 days
• Placebo dose of 5 mg/kg/day i.v. divided every 6 h for 7 days (Rodriguez-Rubio et al., 2020)
• Siltuximab for patients diagnosed with severe respiratory complications due to COVID-19
• Anti-IL-6 mitigation of cytokine storm • Observational retrospective cohort study
• Cohort A: continuous positive airway pressure followed by siltuximab
• Cohort B: intubation followed by siltuximab
• Control group receiving continuous positive airway pressure or intubation only
•  N = 220
• Primary outcome of mortality over 30 days • Detailed siltuximab dosing regimen not specified.
• Treatment procedure was based on clinicians judgement
• Study completed May 8, 2020. Results pending (NCT04322188, 2020)
• COV-AID Trial
• Use of anti-interleukin agents for cytokine storm • Phase 3 prospective RCT
• Patients with signs of cytokine storm
• N = 38 Anakinra alone (anti-IL-1 receptor)
•  N = 76 Siltuximab alone (anti-IL-6)
•  N = 38 Anakinra + siltuximab
• N = 76 Tocilizumab alone (anti-IL-6 receptor)
• N = 38 Anakinra + tocilizumab
• N = 76 standard care alone
• Primary outcome as time to clinical improvement • Anakinra 100 mg s.c. daily for 28 days
• Siltuximab single i.v. infusion 11 mg/kg
• Tocilizumab single i.v. infusion 8 mg/kg max 800 mg (Maes et al., 2020)
• Sarilumab for hospitalized COVID-19 infections
• Cytokine storm syndrome • Phase 2/3 RCT
• Phase 2: Sarilumab in hospitalized patients regardless of disease severity vs. placebo
• Primary outcome of % change in CRP in patients with serum IL-6 > upper limit normal
• Phase 3 Cohort 1: Sarilumab in hospitalized critical infection receiving mechanical ventilation vs. placebo
• Cohort 2: Sarilumab in hospitalized infection receiving mechanical ventilation vs. placebo
•  N = 1912
• Primary outcome of at least 1 point improvement on 7 point clinical scale • Phase 2: Low dose sarilumab i.v.
• Phase 2: Mid-dose sarilumab i.v.
• Phase 3 Cohort 1: Low dose sarilumab i.v.
• Phase 3 Cohort 1: Mid-dose sarilumab i.v.
• Phase 3 Cohort 2: High dose sarilumab i.v.
• Placebo given to match sarilumab administration (NCT04315298, 2020)
• CORIMUNO-SARI Trial
• Sarilumab to mitigate enhanced IL-6 signalling • RCT
• Moderate, severe, or critical COVID-19 pneumonia
• Sarilumab vs. standard of care
•  N = 239 • Sarilumab 400 mg single i.v. infusion over 1 h on day 1 (NCT04324073, 2020)
• Barcitinib for hospitalized COVID-19 patients • Non-randomized clinical trial
• Any adult patient hospitalized with moderate/severe COVID-19
• Barcitinib + standard care vs. standard care alone
• Primary outcome of clinical status after 15 days • Barcitinib 2 mg orally daily for 10 days (NCT04321993, 2020)
• RUXCOVID Trial • Phase 3 placebo-controlled RCT
• Patients age ≥ 12 with cytokine storm
• Ruxolitinib + standard care vs. placebo + standard care
•  N = 402 randomized in 2:1 ratio
• treatment: placebo • Ruxolitinib 5 mg orally twice daily for 14 days
• May extend treatment to 28 days (NCT04362137, 2020)
• Losartan (ARB) in patients hospitalized for COVID-19 • Phase 2 RCT
• Losartan vs. placebo + standard care
•  N = 200
• Secondary outcome includes cardiovascular organ failure/dysfunction • Losartan 50 mg orally once daily (NCT04312009, 2020)
• Losartan (ARB) in patients not requiring hospitalization for COVID-19 • Phase 2 RCT
• Losartan vs. placebo + standard care
•  N = 500
• Primary outcome of patients admitted to hospital within 15 days of randomization • Losartan 25 mg orally once daily (NCT04311177, 2020)
• Eicosapentaenoic acid (EPA) free fatty acid for hospitalized COVID-19 patients • Phase 3 interventional trial
• Treatment with EPA gastro-resistant capsules vs. standard care
• 28-day treatment period
• Primary outcome of time to treatment failure i.e. need for additional therapy, intubation, transfer to ICU, or death
• Secondary outcome includes reduction of IL-6 levels • Eicosapentaenoic acid free fatty acid (EPA-FFA) 1 g gastro-resistant capsules twice daily (2 g total) (NCT04335032, 2020)
• COLCORONA Trial
• Colchicine and inflammatory cytokine storm • Phase 3 multi-centre placebo-controlled randomized controlled trial (RCT)
• Age 40 years or older
• Patients must have at least one high-risk factor i.e. uncontrolled hypertension, HF, coronary artery disease (CAD), diabetes, obesity, etc.
• Colchicine vs. placebo
• 30-day treatment
•  N = 6000
• Primary composite endpoint of need for hospitalization or death • Colchicine 0.5 mg orally twice daily for 3 days, then 0.5 mg once daily for 27 days
• Placebo will match colchicine administration (NCT04322682, 2020)