3. Summary of characteristics of ongoing studies.
| Study | Country | Design | Experimental intervention | Comparator intervention | Primary outcomes | Estimated number of participants | Estimated primary completion date |
| ACTRN12620000517976 | Australia | RCT | Nebulised heparin (UFH) | Standard care (without anticoagulants) | Time to separation from invasive ventilation | 172 | 25 July 2021 |
| Busani 2020 | Italy | RCT | Enoxaparin | UFH | All‐cause mortality at day 28, defined as the comparison of proportions of patients' deaths for any cause at day 28 from randomisation | 210 | 6 May 2021 |
| Chambers 2020 | USA | RCT | Intermediate‐dose enoxaparin | Standard prophylactic dose enoxaparin | Risk of all‐cause mortality (time frame: 30 days post‐intervention) | 170 | 16 April 2021 |
| ChiCTR2000030700 | China | RCT | Enoxaparin | Standard care (without anticoagulants) | Time to virus eradication | 60 | 30 September 2020 |
| ChiCTR2000030701 | China | RCT | Enoxaparin | Standard care (without anticoagulants) | Time to virus eradication | 60 | 30 September 2020 |
| ChiCTR2000030946 | China | Prospective cohort | LMWH | Mechanical prevention | Biochemical indicators | 120 | 24 April 2020 |
| CTRI/2020/06/026220 | India | RCT | Nafamostat (synthetic serine proteinase inhibitor) | Standard care (without anticoagulants) | Proportion of patients showing clinical improvement | 40 | 27 January 2021 |
| CTRI/2020/08/027033 | India | RCT | Enoxaparin | Standard care (without anticoagulants) | Reduction in clinical symptoms and RT‐PCR test negative | 100 | 27 January 2021 |
| CTRI/2020/11/029175 | India | RCT | Nebulised heparin | Standard care (without anticoagulants) | Time to separation from mechanical ventilation (duration of mechanical ventilation) up to day 28 | 58 | 27 January 2021 |
| CTRI/2020/11/029345 | India | RCT | Higher‐dose enoxaparin | Lower‐dose enoxaparin; apixaban | Time to first event rate within 30 days of randomisation of the composite of all‐cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism (including PE) confirmed by imaging or requiring surgical intervention or ischaemic stroke confirmed by imaging | 3600 | 27 January 2021 |
| EUCTR2020‐001302‐30‐AT | Austria | RCT | Rivaroxaban | Standard care (without anticoagulants) | Time to sustained improvement of one category from admission | 500 | 11 January 2021 |
| EUCTR2020‐001708‐41‐IT | Italy | RCT | Higher‐dose enoxaparin | Lower‐dose enoxaparin | Incidence of VTE (a composite of incident asymptomatic and symptomatic proximal DVT diagnosed by serial compression ultrasonography, and symptomatic PE diagnosed by CT scan), in patients with SARS‐CoV‐2 infection | 2000 | 30 October 2020 |
| EUCTR2020‐001709‐21‐FR | France | RCT | Higher‐dose LMWH | Lower‐dose LMWH | VTE (causing death or not) | 230 | 11 May 2020 |
| EUCTR2020‐001891‐14‐ES | Spain | RCT | Enoxaparin | Standard care (without anticoagulants) | Need for oxygen therapy escalation due to oxygen saturation (Sat O2) = 92% with FiO2 = 0.5 and respiratory rate = 30 (IROX index = SatO2/FiO2)/FR < 5.5) or invasive mechanical ventilation or mortality during admission | 140 | 16 November 2020 |
| EUCTR2020‐002234‐32‐IT | Switzerland | RCT | Higher‐dose edoxaban | Lower‐dose edoxaban | Major vascular thrombotic events at 25 (+/‐3) days defined as a composite of:
|
420 | 11 January 2021 |
| EUCTR2020‐002504‐39‐DE | Germany | RCT | Edoxaban | Fondaparinux | Composite of all‐cause mortality and/or VTE and/or arterial thromboembolism within 42 days | 172 | 5 January 2021 |
| EUCTR2020‐003349‐12‐IE | Ireland | RCT | Heparin | Standard care (without anticoagulants) | D‐dimer profile, with data collected on days 1, 3, 5 and 10 | 40 | 19 October 2020 |
| Goldin 2020 | USA | RCT | Higher‐dose LMWH | Lower‐dose LMWH | Composite outcome of arterial thromboembolic events, venous thromboembolic events and all‐cause mortality at day 30 ± 2 days (time frame: day 30 ± 2 days). Risk of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), VTE (including symptomatic DVT of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non‐fatal PE), and all‐cause mortality at day 30 ± 2 days | 308 | 26 April 2021 |
| IRCT20200515047456N1 | Iran | RCT | UFH | Standard care (without anticoagulants) | Decrease D‐dimer level Improve compliance Improve of oxygenation Improve SOFA score |
15 | 13 July 2020 |
| ISRCTN14212905 | UK | RCT | Nafamostat (synthetic serine proteinase inhibitor) | Standard care (without anticoagulants) | Safety of candidate agents as add‐on therapy to standard care in patients with COVID‐19 measured at 30, 60 and 90 days post‐treatment | 100 | 3 August 2020 |
| Kharma 2020 | Qatar | RCT | Bivalirudin (DOAC) | LMWH or UFH | PaO2/FiO2 ratio (time frame: 3 days of intervention) | 100 | 24 June 2020 |
| Lasky 2021 | USA | RCT | Dociparstat (heparinoid) | Placebo | Proportion of participants who are alive and free of invasive mechanical ventilation | 525 | 17 February 2021 |
| Lins 2020 | Brazil | RCT | UFH | Standard care (without UFH) | The percentage of clotted dialysers within 72 h in each of the studied groups | 90 | 27 July 2020 |
| Marietta 2020 | Italy | RCT | Higher‐dose LMWH | Lower‐dose LMWH | Clinical worsening (includes death and necessity for additional respiratory support) | 300 | June 2021 |
| NCT04333407 | UK | RCT | Rivaroxaban | Standard care (without anticoagulants) | All‐cause mortality at 30 days after admission | 3170 | 30 March 2021 |
| NCT04344756 | France | RCT | Higher‐dose LMWH or UFH | Lower‐dose LMWH or UFH | Survival without ventilation | 808 | 31 July 2020 |
| NCT04345848 | Switzerland | RCT | Higher‐dose LMWH or UFH | Lower‐dose LMWH or UFH | Composite outcome of arterial or venous thrombosis, disseminated intravascular coagulation and all‐cause mortality | 200 | 30 November 2020 |
| NCT04352400 | Italy | RCT | Nafamostat (synthetic serine proteinase inhibitor) | Placebo | Time to clinical improvement | 256 | December 2021 |
| NCT04366960 | Italy | RCT | Higher‐dose enoxaparin | Lower‐dose enoxaparin | Incidence of VTE detected by imaging | 2712 | August 2020 |
| NCT04367831 | USA | RCT | Higher‐dose enoxaparin | Lower‐dose enoxaparin | Total number of patients with clinically relevant venous or arterial thrombotic events in ICU | 100 | November 2020 |
| NCT04373707 | France | RCT | Higher‐dose enoxaparin | Lower‐dose enoxaparin | VTE | 602 | September 2020 |
| NCT04377997 | USA | RCT | Higher‐dose LMWH or UFH | Lower‐dose LMWH or UFH | Risk of composite efficacy endpoint of death, cardiac arrest, symptomatic DVT, PE, arterial thromboembolism, myocardial infarction, or haemodynamic shock Risk of major bleeding event according to the ISTH definition |
300 | 1 January 2021 |
| NCT04397510 | USA | RCT | Nebulised heparin | Placebo | Mean daily PaO2/FiO2 | 50 | 31 December 2020 |
| NCT04406389 | USA | RCT | Higher‐dose heparinoid or fondaparinux | Lower‐dose heparinoid or fondaparinux | 30‐day mortality | 186 | December 2021 |
| NCT04409834 | USA | RCT | Higher‐dose heparinoid plus antiplatelet agent | Lower‐dose heparinoid without antiplatelet agent | Venous or arterial thrombotic events | 750 | May 2021 |
| NCT04416048 | Germany | RCT | Higher‐dose DOAC (rivaroxaban) | Lower‐dose heparinoid | Composite endpoint of VTE (DVT and/or fatal or non‐fatal PE), arterial thromboembolism, new myocardial infarction, non‐haemorrhagic stroke, all‐cause mortality or progression to intubation and invasive ventilation (time frame: 35 days post‐randomisation) | 400 | 30 May 2021 |
| NCT04420299 | Spain | RCT | Higher‐dose heparin | Lower‐dose heparin | Combined worsening variable. Presence of any of the following will be considered worsening
|
120 | 31 March 2021 |
| NCT04444700 | Brazil | RCT | Higher‐dose enoxaparin | Lower‐dose enoxaparin | Composite outcome of ICU admission (yes/no), non‐invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all‐cause death (yes/no) up to 28 days | 462 | 31 December 2020 |
| NCT04485429 | Brazil | RCT | Higher‐dose heparin | Lower‐dose heparin | Rate of invasive mechanical ventilation | 268 | 31 December 2020 |
| NCT04508439 | Mexico | RCT | Higher‐dose enoxaparin | Lower‐dose enoxaparin | Ventilatory support time Thrombotic complications Length of hospital stay Mortality rate |
130 | 30 December 2020 |
| NCT04511923 | Ireland | RCT | Nebulised heparin | Standard care (without anticoagulants) | D‐dimer profile up to day 10 Frequency of severe adverse outcomes up to day 60 |
40 | January 2022 |
| NCT04512079 | USA | RCT | Apixaban (DOAC) | Lower‐dose enoxaparin; higher‐dose enoxaparin | Time to first event (time frame: 30 days) Number of in‐hospital rate of BARC 3 or 5 (time frame: 30 days) Number of in‐hospital rate of BARC 3 or 5 bleeding (binary). BARC Type 3: a. Overt bleeding plus haemoglobin drop of 3 to < 5 g/dL (provided haemoglobin drop is related to bleed); transfusion with overt bleeding b. Overt bleeding plus haemoglobin drop < 5 g/dL (provided haemoglobin drop is related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents c. Intracranial haemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision |
3600 | March 2022 |
| NCT04530578 | Argentina | RCT | Nebulised heparin | Enoxaparin | Percentage of patients requiring mechanical ventilation (time frame: 15 days) | 200 | 1 June 2021 |
| NCT04542408 | Germany | RCT | Higher‐dose LMWH | Lower‐dose LMWH | Combined endpoint: all‐cause mortality and/or VTE and/or arterial thromboembolism (time frame: 42 days)
|
172 | 30 September 2021 |
| NCT04545541 | USA | RCT | Nebulised heparin | Placebo | Alive and Ventilator‐Free Score (time frame: day 28) | 300 | June 2022 |
| NCT04584580 | Egypt | RCT | Higher‐dose LMWH | Lower‐dose LMWH | Mortality (time frame: until patient is discharged or up to 4 weeks whichever comes first) Occurrence of venous and/or arterial thrombosis (time frame: until patient is discharged or up to 4 weeks whichever comes first) |
50 | 31 December 2020 |
| NCT04600141 | Brazil | RCT | Higher‐dose LMWH or UFH | Lower‐dose LMWH or UFH | Proportion of patients with clinical improvement (time frame: 30 days)
|
308 | 31 December 2020 |
| NCT04604327 | Spain | RCT | Higher‐dose LMWH | Lower‐dose LMWH | Clinical deterioration (time frame: 10 days) Combined outcome that includes number of patients who suffer any of the following: death, ICU admission, mechanical ventilatory support, progression to moderate or severe ARDS (according to Berlin criteria) or arterial or venous thrombosis |
164 | 31 July 2021 |
| NCT04623177 | Spain | Prospective cohort | Higher‐dose LMWH | Lower‐dose LMWH; no anticoagulation | ICU mortality rate (time frame: from admission to ICU discharge, an average of 1 month) | 950 | 30 September 2020 |
| NCT04640181 | USA | RCT | Rivaroxaban at low, intermediate or therapeutic dose | Enoxaparin at low, intermediate or therapeutic dose | Death or 30‐day all‐cause mortality (time frame: 30 days) Mechanical ventilation, intubation (time frame: 30 days) Transfer to an ICU setting (time frame: 30 days) |
150 | 31 July 2021 |
| NCT04646655 | Italy | RCT | Higher‐dose enoxaparin | Lower‐dose enoxaparin | Mortality rate (time frame: 30 days from enrolment ) Progression of respiratory failure (time frame: 30 days from enrolment) Progression of respiratory failure (time frame: 30 days from enrolment) Progression of respiratory failure (time frame: 30 days from enrolment) Number of major bleeding episodes (time frame: up to 6 months from randomisation) |
300 | 31 July 2021 |
| NCT04655586 | USA | RCT | Higher‐dose heparin | Lower‐dose heparin | Change in D‐dimer level from baseline to day 8, or day of discharge if prior to day 8 Number of major or non‐major clinically relevant bleeding events within 8 days of randomisation Time to recovery within 30 days of randomisation |
100 | 31 May 2021 |
| NCT04723563 | USA | RCT | Nebulised heparin | Placebo | Need for mechanical ventilation at day 28 | 50 | 29 May 2021 |
| NCT04730856 | Spain | RCT | Higher‐dose heparin | Lower‐dose heparin | Reduction of suspicion of systemic thrombotic symptomatic events (time frame: 30 days) Use of mechanical ventilation (time frame: 30 days) Progression on the WHO Progression Scale during follow‐up (time frame: 30 days) Overall survival at 30 days (time frame: 30 days) Length of hospital stay (days) (time frame: 30 days) Length of ICU stay (days) (time frame: 30 days) |
600 | 31 July 2021 |
| NCT04743011 | Brazil | RCT | Nebulised heparin | Placebo | Change in aPTT > 1.5 (time frame: immediately or up to 8 days after starting treatment) Viral load in nasal swab RT‐PCR (time frame: immediately or up to 8 days after starting treatment) |
50 | 31 December 2021 |
| NCT04745442 | Spain | RCT | Heparin | No anticoagulant | Combined variable: mortality or worsening rate with need for non‐invasive mechanical ventilation or with need for invasive mechanical ventilation (time frame: at day 31 after randomisation or hospital discharge (whichever occurs first) | 48 | 15 January 2021 |
| PACTR202007606032743 | Egypt | RCT | Nebulised heparin | No anticoagulant | The average daily ratio of partial pressure of oxygen to FiO2 (PaO2/FiO2) while the patient is on room air for 7 days | 100 | 22 February 2021 |
| RBR‐7y8j2bs | Brazil | RCT | Nebulised heparin | Placebo | Efficacy: relative to the proposed treatment, through the analysis of the viral load of the SARS‐CoV‐2 virus in the participants treated by the sequential evaluation of the viral load in RT‐PCR of nasal swab. Safety: related to the use of inhalational high‐molecular‐weight heparin in patients with SARS‐CoV‐2 through the assessment of haemorrhagic events of any nature, alteration of the coagulogram that indicates an increase in aPTT > 1.5 and HIT |
40 | 11 October 2021 |
| Sholzberg 2021a | Canada | RCT | Higher‐dose heparinoids | Lower‐dose heparinoids | Composite outcome of ICU admission (yes/no), non‐invasive positive pressure ventilation (yes/no), invasive mechanical ventilation (yes/no), or all‐cause death (yes/no) up to 28 days | 462 | April 2022 |
| Vanassche 2020 | Belgium | RCT | LMWH | DOAC plus aprotinin | The overall objective of the study is to evaluate the clinical efficacy and safety of different investigational therapeutics relative to standard care in patients hospitalised with COVID‐19 | 210 | 18 August 2020 |
| Van Haren 2020 | Argentina | RCT | Nebulised heparin | No anticoagulant | Intubation rate (time frame: day 28) Proportion of patients requiring invasive mechanical ventilation |
712 | 1 June 2021 |
| Wilkinson 2020 | UK | RCT | Anticoagulants (no details) | NA | Time to clinical improvement of at least 2 points (from randomisation) on a 9‐point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by day 29 (this will also define the 'responder' for the response rate analyses) | 1800 | 04 September 2021 |
| Total number of studies | Argentina: 2 Australia: 1 Austria: 1 Belgium: 1 Brazil: 6 Canada: 1 China: 3 Egypt: 2 France: 3 Germany: 3 India: 4 Iran: 1 Ireland: 2 Italy: 6 Mexico: 1 Qatar: 1 Spain: 6 Switzerland: 2 UK: 3 USA: 13 |
Prospective cohort: 2 RCT: 60 |
35 studies considered mortality 26 studies considered additional respiratory support |
35,470 participants (120 from NRS; 35,350 from RCTs) | 58 studies to December 2021 Four studies to July 2022 |
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| aPTT: activated partial thromboplastin time; ARDS: acute respiratory distress syndrome; BARC: Bleeding Academic Research Consortium; CNS: central nervous system; DOACs: direct oral anticoagulants; DVT: deep vein thrombosis; ECMO: extracorporeal membrane oxygenation; FiO2: fraction of inspired oxygen; HIT: heparin‐induced thrombocytopenia; ICU: intensive care unit; ISTH: International Society on Thrombosis and Haemostasis; LMWH: low‐molecular‐weight heparin; NA: not available; NRS: non‐randomised studies; PaO2: arterial oxygen pressure;PE: pulmonary embolism; RCT: randomised controlled trial; RT‐PCR: reverse transcription polymerase chain reaction; SOFA: sequential organ failure assessment; UFH: unfractionated heparin; VKA: vitamin K antagonist; VTE: venous thromboembolism; WHO: World Health Organization | |||||||