Table 1.
Clinical trials of potential therapeutic agents targeting immunothrombosis in COVID-19.
| Study | Design | Target sample size |
Population | Intervention | Control | Primary Outcome |
Established/postulated mechanisms for investigational agent |
|---|---|---|---|---|---|---|---|
| Systemic heparin/low molecular weight heparin | |||||||
| COVID-HEP NCT04345848 |
Randomised, open-label, multicentre, clinical trial | 200 | 1) Non-ICU patients with d-dimer >1000 μg/L or 2) ICU patients | Therapeutic LMWH or UFH | Prophylactic LMWH or UFH (augmented dose for ICU patients) | Composite outcome of arterial or venous thrombosis, DIC, and all-cause mortality (30 days) | Anticoagulant Anti-inflammatory Antiviral |
| HEP-COVID NCT04367831 |
Randomised, open-label, multicentre, clinical trial | 308 | Patients with d-dimer >4 × ULN or SIC score ≥4 stratified by ICU vs non- ICU stay | Therapeutic LMWH | Prophylactic or intermediate dose LWMH or UFH | Composite outcome of arterial thromboembolic events, venous thromboembolic events, and all-cause mortality (30 days) | Anticoagulant Anti-inflammatory Antiviral |
| IMPACT NCT04406389 |
Randomised, open-label, clinical trial | 186 | Non-ICU or ICU patients requiring supplemental oxygen and d-dimer >3× ULN | Therapeutic LMWH, UFH, fondaparinux, or argatroban | Intermediate dose LMWH, UFH, or fondaparinux |
Mortality (30 days) | Anticoagulant Anti-inflammatory Antiviral |
| X-Covid 19 NCT04366960 |
Randomised, open-label, multicentre, clinical trial |
2712 | Non-ICU patients | Intermediate-dose LMWH | Prophylactic LMWH | Objectively confirmed venous thromboembolism (30 days) |
Anticoagulant Anti-inflammatory Antiviral |
| IMPROVE-COVID NCT04367831 |
Cluster randomised, open-label, single-centre, adaptive trial |
100 | ICU patients | Intermediate-dose LMWH or UFH |
BMI- and weight-adjusted prophylactic dose LMWH |
Clinically relevant venous or arterial thrombotic events in ICU (30 days) |
Anticoagulant Anti-inflammatory Antiviral |
| ACTIV-4 NCT04505774 |
Randomized, open label, adaptive platform trial | 2000 | Hospitalised patients with confirmed COVID-19 | Therapeutic dose UFH or LMWH | Prophylactic dose UFH or LMWH | Organ Support (respiratory or vasopressor) Free Days | Anticoagulant Anti-inflammatory Antiviral |
| ATTACC NCT04372589 |
Randomized, open-label, multicentre, adaptive clinical trial |
Adaptive with maximum of 3000 | Patients with COVID-19 requiring hospitalisation or hospitalised not on mechanical ventilation | Therapeutic dose UFH or LMWH | Local standard care thromboprophylaxis | Mortality and days free of organ support | Anticoagulant Anti-inflammatory Antiviral |
| REMPA-CAP NCT02735707 |
Randomised, embedded, multifactorial, adaptive platform trial | Estimated enrolment 7100 | Patients admitted to an ICU for severe CAP within 48 h of hospital admission | Therapeutic dose UFH or LMWH | Local standard care thromboprophylaxis | Mortality and days free of organ support | Anticoagulant Anti-inflammatory Antiviral |
| RAPID COVID COAG NCT04362085 |
Randomised, pragmatic, open-label, multicentre, adaptive clinical trial | 462 | Hospitalised, Non-ICU patients with D Dimer ≥2 times ULN or above ULN and Oxygen saturation ≤93 % | Therapeutic dose UFH or LMWH | Local standard care thromboprophylaxis | Composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days | Anticoagulant Anti-inflammatory Antiviral |
| Nebulised heparin | |||||||
| NEBUHEPA NCT04530578 |
Randomised, open-label, clinical trial | 200 | Patients with suspected COVID-19 and severe acute respiratory syndrome | Nebulised unfractionated heparin and prophylactic dose LMWH | Prophylactic LMWH | Requirement for mechanical ventilation | Anticoagulant Anti-inflammatory Antiviral |
| CHARTER-MT NCT04545541 |
Randomised, open label and blinded placebo controlled, multicentre, clinical trials (Meta-trial) |
202 | Mechanically ventilated COVID-19 patients | Nebulised unfractionated heparin and prophylactic dose LMWH | Standard care and nnebulised 0.9 % sodium chloride (5 mL) in placebo-controlled studies | Alive and Ventilator Free Score | Anticoagulant Anti-inflammatory Antiviral |
| Fibrinolytic therapy | |||||||
| NCT04357730 | Randomised, open-label, multicentre, clinical trial (phase 2a) | 60 | Patients with known/suspected COVID-19 and ARDS | IV Alteplase 50 mg +/- re-bolus in patients who shown initial transient response | Standard care | PaO2/FiO2 improvement from pre-to-post intervention | Fibrinolytic |
| PACA NCT04356833 |
Non-randomised, open-label, single-centre clinical trial (phase 2) |
24 | Patients with COVID-19 and ARDS | Nebulised recombinant tissue-Plasminogen Activator (rt-PA) every 6 h for 66 h | Standard care | Percentage change in PaO2/FiO2 ratio from baseline and to day 5 (96 h ± 2 h) post treatment and day 7 (144 h ± 4 h) in the groups receiving rt-PA | Fibrinolytic |
| Dipyridamole | |||||||
| TOLD NCT04424901 |
Randomised, open-label, single-centre clinical trial |
100 | Hospitalized patients with moderate to severe COVID-19 | Dipyridamole 100 mg, 3 times daily for 7 days. | Standard care | D-dimer and platelet count | Anti-platelet Antiviral Inhibition of NETs |
| ATTAC-19 NCT04410328 |
Randomised, open-label, single-centre clinical trial |
132 | Patients with SARS-CoV-2 infection and symptoms consistent with COVID-19. | Dipyridamole ER 200 mg/ Aspirin 25 mg orally/enterally, 2 times daily starting on the day of enrolment for a total of 2 weeks. | Standard care | Change in composite COVID ordinal scale at day 15. | Anti-platelet Antiviral Inhibition of NETs |
| DICER NCT04391179 |
Randomised, Placebo-controlled, clinical trial |
160 | Non-severe hospitalised COVID-19 patients | Dipyridamole 100 mg 4 times a day for 14 days while in hospital | Placebo 4 times a day for 14 days while in hospital | Change in D Dimer | Anti-platelet Antiviral Inhibition of NETs |
| Complement inhibitors | |||||||
| CORIMUNO19-ECU NCT04346797 |
Randomised, open-label, clinical trial (cohort multiple RCT design) | 120 | 1) Non-ICU patients with moderate or severe COVID-19 pneumonia 2) ICU patients | Eculizumab | Standard care | 1) Survival without intubation at day 14 2) Change in organ failure at day 3, defined by the Sequential Organ Failure Assessment score |
C5a inhibition |
| NCT04570397 | Randomised, open-label, single-centre clinical trial |
120 | COVID-19 patients with acute kidney injury and clinical diagnosis of TMA (D dimer >100 % of upper limit and >25 % increase in Cr above normal range or baseline) | Ravulizumab | Standard care | 50 % improvement in eGFR compared to conventional therapy within 30 days of treatment | C5a inhibition |
| NCT04369469 | Randomised, open-label, multicentre, clinical trial (phase 3) | 270 | Patients With COVID-19 Severe Pneumonia, Acute Lung Injury, or ARDS | Ravulizumab | Standard Care | Survival (based on all-cause mortality) at Day 29 | C5a inhibition |
| TACTIC-R NCT04390464 |
Randomised, parallel arm, open-label platform trial | 1167 | Pre-ICU Patients admitted with Covid-19 who are at risk as defined by specific risk count criteria | Patients randomised in a 1:1:1 ratio to Ravulizumab, Baricrintinb or standard care | NA | Time to incidence of the composite endpoint of: Death, Mechanical ventilation, ECMO, Cardiovascular organ support, or Renal failure | C5a inhibition |
| SAVE NCT04395456 |
Randomized, placebo-controlled, single-blind clinical trial (phase 2) | 144 | Patients with ARDS due to COVID-19 | AMY-101 | Placebo | 1) Survival without evidence of ARDS. 2) COVID-19 ordinal scale |
C3 inhibition |
| NCT04402060 | Phase 1 Single arm, open label Phase 2 Randomized, Double-Blinded, Vehicle-Controlled, Multicentre, Parallel-Group Study | 66 | Adults with mild to moderate ARDS Due to COVID-19 | APL-9 | No comparator (phase 1) Vehicle control and standard of care (phase 2) |
Cumulative incidence of treatment-emergent serious adverse events and treatment-emergent adverse events | C3 inhibitor |
| ZILU-COV NCT04382755 |
Randomized controlled, open-label, multicentre clinical trial (phase 2) | 81 | Patients with suspected/confirmed COVID-19 with acute hypoxic respiratory Failure | Zilucoplan® for 14 days | Placebo and standard of care | Mean change in oxygen as defined by Pa02/FiO2 at room air, P(Aa)O2 gradient and a/A pO2 ratio |
C5 inhibitor |
Aa, alveolar-arterial; ARDS, acute respiratory distress syndrome; BMI, body-mass index; C, complement; CAP, Community Acquired Pneumonia; COVID-19, coronavirus disease 2019; Cr, creatinine; DIC, disseminated intravascular coagulation; ICU, intensive care unit; ECMO, extracorporeal membrane oxygenation; ER, extended release; IV, intravenous; eGFR, estimated glomerular filtration rate; FiO2, fraction of inspired oxygen; NET, neutrophil extracellular trap; LMWH, Low Molecular Weight Heparin; PaO2, partial pressure of oxygen; SARS-CoV2, severe acute respiratory syndrome coronavirus 2; SIC, sepsis-induced coagulopathy; TMA, thrombotic microangiopathy; UFH, unfractionated heparin, ULN; upper limit of normal.