Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19

COVID-19 CADTH HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19

This report is current as of December 23, 2020. To produce this report, CADTH used a modified approach to the selection of the evidence to meet decision-making needs during the COVID-19 pandemic. Care has been taken to ensure the information is accurate and complete, but it should be noted that international scientific evidence about COVID-19 is changing and growing rapidly.

Version: 15.0 Publication Date: December 2020 Report Length: 38 Pages

Authors: Sirjana Pant, Christine Perras

Cite As: Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19. Ottawa: CADTH; 2020 December. (CADTH Health Technology Review).

ISSN: 1922-8147 (online)

Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.

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About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.

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Questions or requests for information about this report can be directed to [email protected].

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 2

The following version table will be updated as changes are made to the report.

Version Date of publication Summary of revisions 1.0 June 9, 2020 Information current as of May 28, 2020 2.0 July 2, 2020 Addition of phase IV trials. Addition of new trials. Information current as of June 19, 2020 3.0 July 8, 2020 Addition of Health Canada’s Clinical Trial Database’s identifier Addition of new trials. Information current as of July 3, 2020 4.0 July 21, 2020 Addition of new trials. Information current as of July 17, 2020 5.0 August 6, 2020 Addition of new trials (to February 28, 2021). Information current as of July 31, 2020. Removal of all trials of chloroquine/hydroxychloroquine. 6.0 August 18, 2020 Addition of new trials. Information current as of August 14, 2020. 7.0 September 1, 2020 Addition of new trials. Information current as of August 28, 2020. 8.0 September 16, 2020 Addition of new trials (to March 31, 2021). Information current as of September 11, 2020. 9.0 September 29, 2020 Addition of new trials. Information current as of September 25, 2020. 10.0 October 16, 2020 Addition of new trials (to April 30, 2021). Information current as of October 9, 2020. 11.0 October 28, 2020 Addition of new trials (to May 31, 2021). Information current as of October 23, 2020. 12.0 November 13, 2020 Addition of new trials (to June 30, 2021). Information current as of November 6, 2020. 13.0 November 26, 2020 Addition of new trials (to July 31, 2021). Information current as of November 20, 2020. 14.0 December 8, 2020 Addition of new trials (to August 31, 2021). Information current as of December 4, 2020. 15.0 December 23, 2020 Addition of new trials (to September 30, 2021). Information current as of December 18, 2020.

About This Document

This report provides information on the ongoing phase II/III, phase III, and phase IV randomized controlled trials (RCTs) of drugs intended to prevent or treat COVID-19. The goal is to provide an evergreen document that is regularly updated. It is important to note that this report is not a systematic review and does not include a critical appraisal of studies. It is not intended to provide any recommendations.

Objective

To describe the trial characteristics and estimated primary completion dates of the ongoing phase II/III, phase III, and phase IV RCTs evaluating drugs to prevent or treat COVID-19.

Selection Criteria and Methods

The phase II/III, phase III, and phase IV RCTs were identified from the ClinicalTrials.gov website1 using the inclusion criteria in Table 1.

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 3

Table 1: Selection Criteria

Population Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) or at risk (pre-/post-exposure prophylaxis or prevention) Intervention Drugs for treatment and prevention Comparator No restriction Outcomes No restriction Study designs Phase III (including phase II/III) and phase IV RCTs that are: recruiting; not yet recruiting; enrolling by invitation; or active, but not recruiting Estimated primary completion date By September 30, 2021

Exclusion Criteria

Non-drugs (e.g., devices), natural products, nutraceuticals, plasma products, stem cell therapies, and vaccines were excluded from this report. Trials on plasma products and vaccines are provided in separate reports. Non-randomized studies and single-arm trials were excluded. All trials of chloroquine, hydroxychloroquine, and remdesivir were also excluded from this review, as their trial information is available in published CADTH reports.2

The results were tabulated according to indication (prevention and treatment) and phase of clinical development and are presented in order of estimated primary trial completion dates (with the earliest first). Health Canada’s Clinical Trial Database’s identifier is also noted in the tables (Health Canada [HC] Control No.).3

The tables will be updated bi-weekly or if key trial data or results become available. When a trial’s status changes to “Completed,” “Withdrawn,” “Terminated,” or “Suspended” in ClinicalTrials.gov, the information will be moved to an appendix. A separate report may be initiated to evaluate and critically appraise the evidence once results are published.

Results

As of December 18, 2020, 68 phase II/III, 116 phase III, and 38 phase IV treatment trials; one phase II/III, four phase III and one phase IV pre-exposure trials; and one phase II/II and 11 phase III post-exposure trials met the inclusion criteria (Tables 2 and 3). The sample sizes of the included trials ranged from 20 to 16,500 patients.

Trial populations for most of the trials included hospitalized adult patients; few treatment trials included outpatients (22 trials) or children younger than 16 years (15 trials). Based on dates included in the tables, 101 trials have estimated primary completion dates by the end of December 2020. Twenty trials with Canadian study sites were identified (as highlighted in the tables).

Trials for which the status was changed to “Completed,” “Withdrawn,” “Terminated,” or “Suspended” in ClinicalTrials.gov are depicted in Appendix 1, Table 4.

Limitations

The information provided in this report relies on the information posted on the ClinicalTrials.gov registry. There may be reporting errors in the study records posted on ClinicalTrials.gov. Furthermore, given the rapid changes occurring with the scientific evidence related to COVID-19, the reporting of amendments to the included trial protocols

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may be delayed. While some trials have reached their primary completion dates, their status are still showing as “recruiting” and results have not yet been posted. Finally, not all ongoing trials are posted to the website and, as such, ClinicalTrials.gov may provide an incomplete picture of the ongoing clinical trials related to COVID-19.

We have chosen to show the earliest trial completion date, that is the “estimated primary trial completion date” (the date on which the data collection was completed for all the primary outcome measures) and not the “estimated trial completion date” (the date on which the last patient was examined or received a treatment) to be able to quickly flag trials that may have results available ahead of the completion of a trial. We have limited our search date from March 1, 2020 to September 30, 2021, as these trials address the immediate needs for evidence.

Summary

A total of 240 ongoing phase II/III, phase III, or phase IV drug trials on COVID-19 met the inclusion criteria as of December 18, 2020.1 Their sample sizes range from 20 to 16,500 patients. Most of the trials are being conducted in hospitalized adult patients, with few trials evaluating children or outpatients. By the end of December 2020, 101 trials will have reached their estimated primary completion dates. Twenty trials have Canadian study sites (as highlighted in the tables).

The ClinicalTrials.gov registry will be monitored regularly, and tables will be updated bi-weekly or when key trial data or results become available. A separate report may be initiated to evaluate and critically appraise the evidence once results are published.

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Table 2: Drugs to Treat COVID-19: Ongoing Randomized Controlled Trials — September 2021 Estimated Primary Completion Date

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Phase IV Tocilizumab NA MC, OL April 29, 2020 Hospitalized adult NCT04377750 Israel patients with severe N = 500 COVID-19 with suspected pulmonary hyperinflammation Spironolactone NA DB, PC July 21, 2020 Hospitalized adult NCT04345887 Turkey patients with ARDS due N = 60 to COVID-19 Budesonide NA OL August 31, 2020 Hospitalized adult NCT04355637 Spain patients with COVID-19 N = 300 Cholecalciferol COVID-VIT-D DB September 14, 2020 Adult patients with NCT04552951 Spain COVID-19 N = 80

Bivalirudin ANTI-CO DB September 28, 2020 Hospitalized adult NCT04445935 Qatar patients with COVID-19 N = 100 Desferal NA OL September 30, 2020 Hospitalized children and NCT04389801 Egypt adult patients with N = 200 moderate COVID-19 Telmisartan NA OL October 1, 2020 Hospitalized adult NCT04355936 Argentina patients with N = 400 COVID-19 Losartan NA MC, OL October 6, 2020 Adult patients with mild- NCT04340557 US to-moderate respiratory N = 200 symptoms of COVID-19 Nebulized heparin with or NEBUHEPA OL October 30, 2020 Adult patients with NCT04530578 without enoxaparin Argentina COVID-19 N = 200

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Low-molecular-weight heparin NA OL October 31, 2020 Hospitalized adult NCT04584580 Egypt patients with COVID-19 N = 50 pneumonia Enoxaparin prophylactic dose IMPROVE-COVID OL November 2020 Hospitalized adult NCT04367831 and heparin SC, or enoxaparin US patients with intermediate dose and heparin N = 100 COVID-19 infusion

Povidone iodine, NA DB November 2020 Hospitalized adult NCT04603794 chlorhexidine gluconate, US patients with hydrogen peroxide, or normal N = 60 COVID-19 saline Early or late dexamethasone NA OL November 30, 2020 Adult patients with mild- NCT04528329 Egypt to-moderate COVID-19 N = 300 Intermediate dose prophylaxis IMPACT OL December 2020 Critically ill adult patients NCT04406389 (enoxaparin sodium or US with COVID-19 unfractionated heparin or N = 186 fondaparinux) or therapeutic dose anticoagulation (enoxaparin sodium or unfractionated heparin or fondaparinux or argatroban) Valsartan PRAETORIAN-COVID DB, PC December 2020 Hospitalized adult NCT04335786 Netherlands patients with COVID-19 N = 651 Rivaroxaban followed by ACTION OL December 2020 Hospitalized adult NCT04394377 enoxaparin or unfractionated Brazil patients with COVID-19 heparin N = 600 Cyclosporine NA OL December 2020 Hospitalized adult NCT04392531 Spain patients with COVID-19 N = 120 Aerosolized NA OL December 2020 Hospitalized adult NCT04623385 13-cis-retinoic acid Egypt patients with COVID-19 (isotretinoin) with inhaled N = 1,000 testosterone

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Early or late dexamethasone NA OL December 1, 2020 Adult patients with mild NCT04530409 Egypt and moderate COVID-19 N = 450 Vitamin D (cholecalciferol) CARED DB, PC December 15, 2020 Hospitalized adult NCT04411446 Argentina patients with COVID-19 N = 1,264 Heparin NA DB, PC December 31, 2020 Hospitalized adult NCT04397510 US patients with COVID-19 N = 50

Sodium bicarbonate NA OL January 2021 Hospitalized adult NCT04530448 US patients with COVID-19 N = 40 Angiotensin receptor blocker CLARITY SB January 30, 2021 Adult patients with NCT04394117 (candesartan, eprosartan, Australia SARS-CoV-2 infection irbesartan, losartan, N = 605 olmesartan, telmisartan, or valsartan)

Sargramostim SARPAC OL January 31, 2021 Adult patients with acute NCT04326920 Belgium hypoxic respiratory N = 80 failure due to COVID-19

N-acetylcysteine NA OL January 31, 2021 Adult patients with mild- NCT04419025 US to-moderate COVID-19 N = 200 Vitamin D NA DB, PC January 31, 2021 Hospitalized adult NCT04636086 Belgium patients with COVID-19 N = 100

Heparin (prophylactic dose ACTIV-4 OL, MC March 2021 Hospitalized adult NCT04505774 and therapeutic dose) US patients with COVID-19 N = 2,000 Enoxaparin prophylactic dose FREEDOM COVID OL March 2021 Hospitalized adult NCT04512079 or full dose, or apixaban US patients with COVID-19 N = 3,600

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Tetrandrine TT-NPC OL March 1, 2021 Adult patients with mild NCT04308317 China and severe N = 60 SARS-CoV-2 pneumonia Pioglitazone NA OL March 10, 2021 Adult patients with type 2 NCT04535700 Spain diabetes mellitus and N = 76 COVID-19

NA MC, OL April 16, 2021 Hospitalized adult NCT04360824 Prophylactic or intermediate US patients with COVID-19 dose enoxaparin N = 170 Ibuprofen LIBERATE MC, DB May 25, 2021 Hospitalized adult NCT04334629 UK patients with confirmed N = 230 or suspected SARS- CoV-2 and acute hypoxemic respiratory failure Pioglitazone PIOQ8 DB, PC June 29, 2021 Diabetic adult patients NCT04604223 Kuwait (Type 2) with COVID-19 N = 1,506 Famotidine with vitamin C and CDFCOV19 OL June 30, 2021 Adult patients with NCT04565392 vitamin D US probable COVID-19 N = 216 based on symptoms Linagliptin NA OL June 30, 2021 Diabetic adult patients NCT04341935 US (Type 2) with COVID-19 N = 20

Nintedanib ENDCOV-I DB, PC July 2021 Adult patients with NCT04619680 US COVID-19 and findings N = 120 consistent of lung fibrosis Vitamin D or zinc NA DB, PC August 31, 2021 Adult patients with NCT04641195 India COVID-19 N = 700

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Lenalidomide GETAFE DB, PC August 31, 2021 Adult patients NCT04361643 (low-dose) Spain (≥ 60-years-old) with N = 120 mild-to- moderate signs of COVID-19 Phase III Azithromycin AMBU-COVID OL June 2020 Adult outpatients with NCT04371107 France non-severe symptoms of N = 64 COVID-19 Tacrolimus and TACROVID OL June 1, 2020 Patients with severe lung NCT04341038 methylprednisolone Spain injury secondary to N = 84 COVID-19 Favipiravir NA MC, DB, PC July 2020 Adult patients with NCT04336904 Italy moderate COVID-19 N = 100 Neurokinin 1 receptor NA DB July 15, 2020 Hospitalized adult NCT04468646 antagonist Pakistan patients with severe or N = 100 critical COVID-19 infection Bromhexine and BISCUIT OL July 18, 2020 Hospitalized adult NCT04424134 spironolactone Russian Federation patients with mild and N = 80 severe COVID-19 Favipiravir NA OL, MC July 29, 2020 Adult patients with mild- NCT04501783 Russian Federation to-moderate COVID-19 N = 168 without respiratory failure Azithromycin with or without AziA MC, OL July 30, 2020 Hospitalized adult NCT04363060 amoxicillin-clavulanate France patients with COVID-19 N = 104 pneumonia in a non- intensive care unit Sarilumab NA Adaptive, MC, DB, PC July 30, 2020 Hospitalized adult NCT04327388 Multi-countryb patients with severe or N = 420 critical COVID-19

Favipiravir NA MC, DB, PC August 2020 Adult patients with NCT04425460 Multi-country moderate COVID-19 N = 256

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Enoxaparin low dose or high X-COVID 19 MC, OL August 2020 Hospitalized adult NCT04366960 dose Italy patients with N = 2,712 SARS-CoV-2 infection Vitamin D (ergocalciferol) low NA DB August 2020 Adult inpatients and NCT04385940 dose or high dose Canada outpatients with N = 64 COVID-19 HC Control No. 240943

Tradipitant ODYSSEY DB, PC August 1, 2020 Adult patients with NCT04326426 US severe or critical COVID- N = 300 19

Tocilizumab EMPACTA MC, DB, PC August 18, 2020 Hospitalized adult NCT04372186 Multi-country patients with COVID-19 N = 379 pneumonia related article

Chlorpromazine ReCoVery MC, SB August 30, 2020 Hospitalized adult NCT04366739 France patients with moderate N = 40 COVID-19

Lenzilumab NA MC, DB, PC September 2020 Hospitalized adult NCT04351152 US patients with severe and N = 300 critical COVID-19 pneumonia

Imatinib mesylate NA OL September 2020 Hospitalized adult NCT04422678 Egypt patients with moderate- N = 30 to-severe COVID-19‒ induced pneumonia

Ciclesonide NA MC, DB, PC September 1, 2020 Outpatient patients NCT04377711 US (≥ 12-years-old) with N = 400 symptomatic COVID-19

Tocilizumab or deferoxamine TRONCHER MC, OL September 4, 2020 Hospitalized adult NCT04361032 Tunisia patients in intensive care N = 260 unit

Azithromycin ATOMIC2 MC, OL September 13, 2020 Adult outpatients with NCT04381962 UK COVID-19 N = 800

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Canakinumab CAN-COVID MC, DB, PC September 16, 2020 Hospitalized patients NCT04362813 Multi-country (≥ 12-years-old) with N = 451 COVID-19‒induced pneumonia and cytokine release syndrome Linagliptin with or without COVID19DPP4i DB September 30, 2020 Hospitalized adult NCT04542213 insulin Mexico patients with COVID-19 N = 28 and hyperglycemia

Favipiravir or oseltamivir NA OL September 30, 2020 Adult patients with NCT04558463 Indonesia COVID-19 N = 100

Dapagliflozin DARE-19 MC, DB, PC October 2020 Hospitalized adult NCT04350593 Multi-countryb patients with mild-to- N = 900 moderate COVID-19 HC Control No. 240352 Prasugrel hydrochloride PARTISAN MC, DB, PC October 2020 Hospitalized adult NCT04445623 Italy patients with severe N = 128 COVID-19 pneumonia Colchicine COL-COVID OL October 20, 2020 Hospitalized adult NCT04350320 Spain patients with N = 102 SARS-CoV-2 infection confirmed within the first 48 hours after hospital admission Anakinra ANACONDA MC, OL October 20, 2020 Hospitalized adult NCT04364009 France patients with COVID-19 N = 71 CD24Fc SAC-COVID MC, DB, PC October 20, 2020 Adult patients with NCT04317040 US severe N = 243 COVID-19 Famotidine NA OL October 30, 2020 Patients (16- to 80- NCT04504240 Bangladesh years-old) with COVID- N = 200 19 Tocilizumab or NA OL October 31, 2020 Hospitalized adult NCT04345445 methylprednisolone Malaysia patients with moderate N = 310 COVID-19 at risk for complications

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Heparin RAPID COVID COAG MC, OL November 2020 Hospitalized adult NCT04362085 Canada patients with COVID-19 N = 462 HC Control No. 238510 Losmapimod LOSVID STUDY DB, PC November 2020 Hospitalized adult NCT04511819 Multi-country patients (≥ 50-years-old) N = 410 with COVID-19 Lidocaine LidoCovid DB, November 4, 2020 Hospitalized adult NCT04609865 France patients with ARDS due N = 100 to COVID-19 pneumonia Dexamethasone or NA OL November 5, 2020 Hospitalized adult NCT04499313 methylprednisolone Bangladesh patients (20- to N = 60 80-years-old) with moderate-to-severe COVID-19 Intermediate dose enoxaparin/ INSPIRATION MC, OL, PC November 19, 2020 Critically ill hospitalized NCT04486508 unfractionated heparin or Iran adult patients with standard prophylactic dose N = 600 COVID-19 admitted enoxaparin/ unfractionated to ICU heparin or atorvastatin Dornase alpha COVIDORNASE MC, OL November 21, 2020 Hospitalized adult NCT04355364 France patients with ARDS due N = 100 to COVID-19 Budesonide COVIDORL MC, SB, PC November 24, 2020 Adult patients with NCT04361474 France persistent hyposmia N = 120 related to SARS-CoV-2 infection Enoxaparin RAPID- BRAZIL OL November 30, 2020 Hospitalized adult NCT04444700 Brazil patients with COVID-19 N = 462 and with low oxygen saturation Prednisone PREDCOVID SB November 30, 2020 Non-critical adult NCT04451174 Chile patients with COVID-19 N = 184 pneumonia Favipiravir with or without FVR OL November 30, 2020 Adult patients with NCT04613271 azithromycin Indonesia COVID-19 N = 210

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Vitamin D NA DB, PC November 30, 2020 Hospitalized children or NCT04621058 Spain adult patients with N = 108 COVID-19 pneumonia and vitamin D deficiency Prednisone or hydrocortisone CORTICOVIDHUGO SB December 2020 Hospitalized adult NCT04359511 hemisuccinate France patients with COVID-19 N = 210 pneumonia on oxygen therapy Methylprednisolone CORTIVID DB December 2020 Hospitalized adult NCT04438980 Spain patients with COVID-19 N = 72 Almitrine AIRVM-COVID DB, PC December 2020 Hospitalized adult NCT04357457 France patients with N = 212 COVID-19 Colchicine COLCORONA MC, DB, PC December 2020 Adult patients NCT04322682 Multi-countryb (≥ 40-years-old) with N = 6,000 COVID-19 and have at HC Control No: 237317 least one high-risk criterion Doxycycline DYNAMIC MC, DB, PC December 1, 2020 Adult patients NCT04371952 France (> 45-years-old) with N = 330 SARS-CoV-2 infection Nitazoxanide and NA DB, PC December 30, 2020 Patients (12- to NCT04486313 vitamin B US 120-years-old) with N = 800 mild-to-moderate COVID-19 Colchicine or interferon-beta ACTCOVID-19 OL December 31, 2020 Adult patients with NCT04324463 or Aspirin or rivaroxaban Multi-countryb COVID-19 N = 4,000 HC Control No. 238157

Methylprednisolone or heparin NA OL December 31, 2020 Adult patients with NCT04485429 or both in combination Brazil COVID-19 N = 268 Dexamethasone NA MC, OL December 31, 2020 Adult patients with ARDS NCT04395105 (high dose) Argentina due to COVID-19 N = 284

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Favipiravir NA MC, DB, PC December 31, 2020 Adult patients (21- to NCT04529499 Kuwait 80-years-old) with N = 780 moderate-to-severe COVID-19 hospitalized or quarantined in an institutional quarantine facility Enoxaparin ETHIC OL, MC January 2021 Adult patients NCT04492254 Country NR (≥ 55-years-old) with N = 1,370 COVID-19 symptoms Anakinra NA DB January 2021 Hospitalized adult NCT04362111 US patients with N = 30 SARS-CoV-2 infection with markers of cytokine storm syndrome Anakinra or siltuximab or COV-AID MC, OL January 2021 Adult patients with acute NCT04330638 tocilizumab or in combination Belgium hypoxic respiratory N = 342 failure and systemic cytokine release syndrome due to COVID-19 Tissue plasminogen activator AtTAC MC, DB January 15, 2021 Hospitalized adult NCT04453371 Russia patients with severe N = 50 COVID-19 Niclosamide NICLONEX DB, PC January 30, 2021 Hospitalized adult NCT04558021 Turkey patients with COVID-19 N = 200 Vitamin D (cholecalciferol) NA OL February 2021 Pediatric patients NCT04502667 Mexico (1-month to 17- years- N = 40 old) hospitalized with COVID-19 Pulsed inhaled nitric oxide COViNOX DB, PC February 2021 Hospitalized adult NCT04421508 (INOpulse) US patients with mild to N = 500 moderate COVID-19

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Bucillamine NA MC, DB, PC February 1, 2021 Adult patients with mild- NCT04504734 US to-moderate COVID-19 N = 1,000 Azithromycin, NA OL February 2, 2021 Adult patients with NCT04673214 paracetamol, and Mexico COVID-19, with type 2 ribaroxaban with or N = 62 diabetes mellitus, without ivermectin systemic arterial NEW hypertension, obesity, or who are overweight

Nintedanib NINTECOR DB, PC March 2021 Adult patients with NCT04541680 France SARS-CoV-2‒induced N = 250 pulmonary fibrosis and a history of hospitalization due to COVID-19 Colchicine COLCOVID19 OL March 2021 Hospitalized adult NCT04539873 Colombia patients with COVID-19 N = 128 Vitamin D3 VIVID DB, PC March 1, 2021 Adult patients NCT04536298 US (≥ 30-years-old) with N = 2,700 COVID-19 Rivaroxaban PREVENT-HD MC, DB, PC March 3, 2021 Adults outpatients with NCT04508023 US COVID-19 N = 4,000 Enoxaparin NA MC, OL March 14, 2021 Adult outpatients NCT04400799 Switzerland (≥ 50-years-old) with N = 1,000 COVID-19 Sitagliptin SIDIACO OL March 30, 2021 Hospitalized adult NCT04365517 Italy patients with COVID-19 N = 170 and type 2 diabetes Colchicine ECLA PHRI COLCOVID OL March 30, 2021 Hospitalized adult NCT04328480 Argentina patients with moderate- N = 2,500 to-severe COVID-19 Favipiravir PIONEER OL March 31, 2021 Hospitalized adult NCT04373733 UK patients with suspected N = 450 or confirmed COVID-19

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Lopinavir-ritonavir CORIPREV-LR OL March 31, 2021 Patients (≥ 6-months- NCT04321174 Canada old) with COVID-19 N = 1,220 symptoms HC Control No. 237350 Sevoflurane SevCov MC, DB March 31, 2021 Hospitalized adult NCT04355962 Switzerland patients with COVID-19 N = 64 ARDS Enoxaparin high dose COVID-HEP OL, SB March 31, 2021 Hospitalized adult NCT04345848 or low dose Switzerland patients with severe N = 200 COVID-19 Methylprednisolone or MEDEAS OL March 31, 2021 Hospitalized adult NCT04636671 dexamethasone Rome patients with COVID-19 N = 680 pneumonia Dipyridamole and Aspirin ATTAC-19 OL March 15, 2021 Hospitalized adult NCT04410328 US patients with COVID-19 N = 132 Nitazoxanide NA MC, DB, PC April 2021 Hospitalized adult NCT04423861 Brazil patients with COVID-19 N = 380 EQ001 (Itolizumab) EQUINOX DB, PC April 2021 Hospitalized adult NCT04605926 Colombia patients with COVID-19 N = 800 Methylprednisolone NA MC, DB April 2021 Hospitalized adult NCT04673162

Italy patients with COVID-19

N = 260 pneumonia NEW

Fenofibrate FENOC OL April 01, 2021 Hospitalized adult NCT04661930

Israel patients with COVID-19

N = 50 NEW

Enoxaparin HEP-COVID MC, DB April 26, 2021 Hospitalized adult NCT04401293 US patients with COVID-19 N = 308

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Rivaroxaban COVID-PREVENT MC, OL April 30,2021 Hospitalized adult NCT04416048 Germany patients with moderate- N = 400 to-severe COVID-19 Ruxolitinib RUXCOVID-DEVENT MC, DB, PC April 30, 2021 Patients (≥ 2-years-old) NCT04377620 US with COVID-19 who N = 500 require mechanical ventilation DAS 181 NA DB, PC April 30, 2021 Hospitalized adult NCT03808922 Multi-country patients with severe N = 250 COVID-19 Rivaroxaban MICHELLE OL April 30, 2021 Adult patients with NCT04662684

Brazil COVID-19 and at an N = 320 increased risk of VTE,

NEW and discharged from the hospital

Ravulizumab NA OL May 2021 Hospitalized adult NCT04369469 Multi-country patients with severe N = 270 COVID-19 pneumonia Colchicine NA OL May 09, 2021 Hospitalized adult NCT04667780

Pakistan patients with COVID-19

N = 102 NEW

Baricitinib COV-BARRIER MC, DB, PC May 19, 2021 Hospitalized adult NCT04421027 Multi-country patients with COVID-19 N = 1,400 Edoxaban (or high- dose HERO-19 DB May 31, 2021 Hospitalized adult NCT04542408 LMWH) and low-dose LMWH Germany patients COVID-19 N = 172 Bemiparin BEMICOP OL May 31, 2021 Hospitalized adult NCT04604327 Spain patients with mild or N = 164 moderate COVID-19 pneumonia

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Enoxaparin EMOS-COVID OL May 31, 2021 Hospitalized adult NCT04646655 Italy patients with COVID-19- N = 300 related pneumonia with moderate-to-severe respiratory failure FOY-305 NA MC, DB, PC May 31, 2021 Adult patients with NCT04657497

Japan COVID-19

N = 110 NEW

Enoxaparin (high and low COVID-19 HD MC, OL June 2021 Hospitalized adult NCT04408235 dose) Italy patients with severe N = 300 COVID-19 pneumonia and coagulopathy Favipiravir NA OL June 2021 Hospitalized adult NCT04600999 Hungary patients with COVID-19 N = 150 pneumonia Azvudine NA DB, PC June 2021 Hospitalized adult NCT04668235

Brazil patients with COVID-19

N = 342 NEW

Losartan ARBs CORONA II MC, OL June 30, 2021 Hospitalized adults with NCT04606563 Multi-countryb COVID-19 N = 1,372 HC Control No: 243532 STAUNCH -19 MC, OL June 30, 2021 Hospitalized adults with NCT04528888 Enoxaparin with or without Italy critically ill pneumonia methylprednisolone N = 210 from COVID-19 Ivermectin NA DB, PC June 30, 2021 Adult outpatients with NCT04530474 US highly suspicious N = 200 symptoms of COVID-19 Linagliptin NA OL June 30, 2021 Diabetic adult patients NCT04371978 Israel (Type 2) with COVID-19 N = 100

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 19

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Carrimycin NA MC, DB, PC June 30, 2021 Hospitalized patients NCT04672564

Countries NR with severe COVID-19

N = 300 NEW

Angiotensin-converting COVID-RASi OL July 2021 Older adult patients NCT04591210 enzyme inhibitors or Canada (≥ 65-years-old) with angiotensin II receptor N = 1,155 COVID-19 and at high HC Control No. 244591 blockers risk for cardiovascular diseases Fluvoxamine Stop Covid 2 DB, PC July 2021 Adult outpatients with NCT04668950 b Multi-country COVID-19 HC Control No. 246471

N = 1100 NEW

BACTEK-R (MV130) NA OL July 1, 2021 Hospitalized patients NCT04363814 Dominican Republic with non-severe N = 100 pneumonia due to COVID-19

Eicosapentaenoic acid NA DB, PC July 13, 2021 Hospitalized patients NCT04335032 Switzerland with non-severe N = 284 pneumonia due to COVID-19 Pacritinib NA MC, DB, PC July 31, 2021 Hospitalized patients NCT04404361 US with severe COVID-19 N = 364 with or without cancer

Apixaban NA MC, DB, PC August 2021 Hospitalized adult NCT04650087 US patients with COVID-19 N = 5,320

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 20

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Favipiravir PRESECO DB, PC August 2021 Adult outpatients with NCT04600895 US mild-to-moderate N = 826 COVID-19

Fostamatinib NA MC, DB, PC August 2021 Hospitalized patients NCT04629703 Countries NR with COVID-19, and N = 308 without respiratory failure

Sphenopalatine ganglion NA DB, PC August 2021 Adult patients with NCT04636034 block with local anaesthetic Denmark moderate-to-severe (lidocaine and ropivacaine) N = 60 headache during or maximum 4 weeks after COVID-19 diagnosis Novaferon (aerosolized) NOVATION-1 DB, PC August 2021 Hospitalized patients NCT04669015 Countries NR with COVID-19 HC Control No. 246575

N = 914 NEW

Colchicine and rosuvastatin COLSTAT OL August 1, 2021 Hospitalized patients NCT04472611 US with COVID-19 N = 466

Apremilast NA DB August 15, 2021 Hospitalized patients NCT04590586 Countries NR with COVID-19 HC Control No. 242568 N = 700 Colchicine COLCHI-COVID OL August 25, 2021 Adult outpatients NCT04416334 Spain (≥ 60-years-old) with N = 954 COVID-19 and at high risk of pulmonary complication due to COVID-19

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 21

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference N-Acetyl cysteine INFECT-19 DB, PC August 30, 2021 Hospitalized patients NCT04455243 Saudi Arabia with COVID-19 who are N = 1,180 on oxygen supplement

TY027 NA MC, DB, PC August 31, 2021 Hospitalized adult NCT04649515 Singapore patients (≥ 21-years-old) N = 1,305 with symptomatic COVID-19 infection Apixiban or Aspirin NA MC, DB, PC September 2021 Adult (40-to 79-years- NCT04498273

US old) with COVID-19

N = 7000 NEW

Montelukast COSMO DB, PC September 2021 Adult (≥ 40-years-old) NCT04389411

Canada with COVID-19

N = 600 NEW

Nicotine patch NICOVID-REA DB, PC September 2021 Hospitalized adult NCT04598594

France patients with COVID-19

N = 220 in intensive care unit NEW

Dexamethasone COVIDSTEROID2 DB September 17, 2021 Hospitalized adult NCT04509973

Multi-country patients with COVID-19

N = 1000 NEW

Azithromycin ACTION DB, PC September 30, 2021 Adult outpatients with NCT04332107

US COVID-19

N = 2271 NEW

PHASE II/III

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 22

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Favipiravir NA DB, PC July 2020 Adult patients with novel NCT04402203 Bangladesh coronavirus N = 50 Ivermectin NA OL July 30, 2020 Adult patients with NCT04445311 Egypt COVID-19 N = 100 Nitazoxanide NA DB, PC September 2020 Adult outpatients NCT04441398 Brazil (≥ 50-years-old) with N = 300 symptomatic SARS-CoV-2 infection Vidofludimus calcium NA MC, DB, PC September 2020 Hospitalized adult NCT04379271 (IMU-838) Multi-country patients with COVID-19 N = 230 LY3819253 and BLAZE -1 DB, PC September 20, 2020 Child and adult NCT04427501 LY3832479 Multi-country outpatients (≥ 12-years- Related article N = 1300 old) with mild to

NEW moderate COVID-19

Pyridostigmine PISCO DB, PC September 30, 2020 Hospitalized adult NCT04343963 Mexico patients with pneumonia N = 436 secondary to SARS-CoV-2 infection Chlorpromazine NA SC, SB, OL October 2020 Adult patients with NCT04354805 Egypt COVID-19 N = 100 Ivermectin and nitazoxanide NA DB October 2020 Adult patients with NCT04360356 Egypt SARS-CoV-2 infection N = 100 Metenkefalin-tridecactide NA OL October 31, 2020 Hospitalized adult NCT04374032 Bosnia and Herzegovina patients with moderate- N = 120 to-severe COVID-19

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 23

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Vitamin D NA MC, DB, PC November 15, 2020 Treatment: Adult patients NCT04386850 (25-hydroxyvitamin D3) Iran with COVID-19 N = 1,500 Prevention: See Table 3 Nitazoxanide NA SB, PC November 15, 2020 Adult patients with mild NCT04463264 Argentina COVID-19 N = 135 Cannabidiol CANDIDATE SC, DB, PC November 16, 2020 Adult patients with mild NCT04467918 Brazil or moderate COVID-19 N = 104 Olokizumab NA MC, DB, PC November 16, 2020 Hospitalized adult NCT04452474 US patients with severe N = 376 SARS-CoV-2 infection Emtricitabine and tenofovir or NA OL November 30, 2020 Hospitalized adult NCT04359095 colchicine or rosuvastatin Colombia patients with COVID-19 N = 1,200 Favipiravir Avi-Mild MC, DB, PC December 2020 Adult patients with mild NCT04464408 Saudi Arabia COVID-19 N = 576 Anakinra ANA-COVID-GEAS MC, OL December 2020 Hospitalized adult NCT04443881 Spain patients with severe N = 180 pneumonia due to SARS-CoV-2 CT-P59 NA DB, PC December 2020 Adult patients with mild NCT04602000 Republic of Korea to moderate COVID-19 N = 1,020

Favipiravir NA OL, PC December 1, 2020 Children, adults, and NCT04351295 Egypt older adult patients with N = 90 COVID-19 Ivermectin NA DB, PC December 21, 2020 Adult patients with mild NCT04405843 Columbia SARS-CoV-2 infection N = 476 within 7 days of symptoms ABX464 MiR-AGE DB, PC December 30, 2020 Adult inpatients or NCT04393038 Multi-country outpatients with N = 1,034 SARS-CoV-2 infection

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 24

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Angiotensin-(1,7) ATCO Adaptive, DB, PC December 30, 2020 Adult patients with NCT04332666 Belgium COVID-19 requiring N = 60 mechanical ventilation Ivermectin IVERCORCOVID19 DB, PC December 31, 2021 Adult patients with NCT04529525 Argentina COVID-19 N = 500 NA-831 alone or in NATADEX DB December 31, 2020 Hospitalized adult NCT04452565 combination with atazanavir US patients with or dexamethasone, and N = 525 SARS-CoV-2 atazanavir with dexamethasone Heparin NA OL, MC January 2021 Hospitalized adult NCT04372589 Multi-countryb patients with COVID-19 N = 3,000 HC Control No. 238691

VIR-7831 COMET-ICE MC, DB, PC January 2021 Adult outpatients with NCT04545060 Multi-countryb COVID-19 N = 1,360 HC Control No. 244708

Lopinavir-ritonavir or losartan COVIDMED MC, DB, PC January 1, 2021 Hospitalized adult NCT04328012 US patients with COVID-19 N = 4,000 RESP301 (nitric oxide) NA MC, OL January 27, 2021 Hospitalized adult NCT04460183 UK patients with COVID-19 N = 300 Bardoxolone methyl BARCONA MC, DB, PC January 30, 2021 Hospitalized adult NCT04494646 US patients with COVID-19 N = 440 PTC299 FITE19 DB, PC, MC January 30, 2021 Hospitalized adult NCT04439071 Multi-country patients with COVID-19 N = 380 EB05 NA DB, PC February 2021 Hospitalized adult NCT04401475 Canada patients with moderate- N = 865 to-severe COVID-19 HC Control No. 239462

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Mavrilimumab NA DB, PC February 2021 Hospitalized adult NCT04447469 Multi-country patients with severe N = 573 COVID-19 pneumonia and hyperinflammation Dociparstat NA DB, PC February 2021 Hospitalized adult NCT04389840 US patients with severe N = 524 COVID-19 and at high risk of respiratory failure INB03 NA MC, DB, PC February 2021 Adult patients with NCT04370236 US severe N = 366 COVID-19 who have high-risk factors for complication LY3819253 (bamlanivimab; ACTIV-2 DB, PC February 2021 Adult patients with NCT04518410 LY-CoV555) US COVID-19 in an N = 2,000 outpatient setting Opaganib NA DB, PC February 2021 Adult patients with NCT04467840 Multi-country COVID-19 pneumonia N = 270 EDP1815 or dapagliflozin and TACTIC-E OL February 15, 2021 Hospitalized adult NCT04393246 ambrisentan UK patients (pre-ICU) with N = 1,407 COVID-19

Ruxolitinib RUXO-COVID DB, PC February 17, 2021 Hospitalized adult NCT04477993 Brazil patients with COVID-19 N = 200 pneumonia Ciclesonide CONTAIN DB, PC February 25, 2021 Symptomatic adult NCT04435795 Canada patients with mild N = 454 COVID-19 HC Control No. 239123 Atazanavir or daclatasvir with REVOLUTIOn MC, DB, PC MAMS February 28, 2021 Hospitalized adult NCT04468087 or without sofosbuvir Brazil patients with COVID-19 N = 1,005 Amiodarone or verapamil ReCOVery-SIRIO OL March 2, 2021 Hospitalized adult NCT04351763 Poland patients with COVID-19 N = 804

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 26

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Lopinavir-ritonavir alone or in INTENSE-COV MC, OL March 26, 2021 Adult patients with NCT04466241 combination with telmisartan Cote D’Ivoire SARS-CoV-2 infection or atorvastatin N = 294 Sarilumab CORIMUNO-SARI MC, OL March 27, 2021 Hospitalized adult NCT04324073 France patients with moderate N = 239 or severe COVID-19 pneumonia Nafamostat mesylate NA OL March 30, 2021 Hospitalized adult NCT04418128 China patients with COVID-19 N = 84 pneumonia Zavegepant NA DB, PC April 2021 Hospitalized adult NCT04346615 (BHV-3500) US patients with COVID-19 N = 120

Azoximer bromide NA MC, DB, PC April 2021 Hospitalized adult NCT04381377 Russian Federation patients with COVID-19 N = 394 Nitazoxanide C3-RCT PC, DB April 2021 Adult outpatients with NCT04523090 South Africa COVID-19 N = 960 Unfractionated heparin INHALE-HEP DB April 1, 2021 Hospitalized adult NCT04635241 Multi-country patients with COVID-19 N = 712

Sofosbuvir or daclatasvir NA DB April 1, 2021 Adult patients with NCT04497649 Egypt COVID-19 N = 100

REGN10933 and NA DB, PC April 10, 2021 Child, adult, and older NCT04425629 REGN10987 US adult patients with

N = 6420 COVID-19 NEW

Meplazumab NA MC, DB, PC April 28, 2021 Hospitalized adult NCT04586153 China patients with COVID-19 N = 456

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Sargramostim NA MC, DB, PC April 30, 2021 Hospitalized adult NCT04642950 Japan patients (≥ 20-years-old N = 60 to 80-years-old) with COVID-19 pneumonia Anakinra NA OL April 30, 2021 Hospitalized adult NCT04643678 Qatar patients with COVID-19, N = 80 and presence of respiratory distress and pneumonia rNAPc2 (AB201) or ASPEN-COVID-19 MC, DB April 30, 2021 Hospitalized adult NCT04655586 heparin US patients with COVID-19 N = 100 and elevated D-dimer

NEW levels

SCTA01 NA MC, DB, PC May 10, 2021 Hospitalized adult NCT04644185 Multi-country patients with severe N = 795 COVID-19

Molnupiravir MK-4482-002 PC, DB May 28, 2021 Adult outpatients with NCT04575597 Multi-countryb COVID-19 N = 1,450 HC Control No. 244315 Molnupiravir MK-4482-001 PC, DB May 30, 2021 Hospitalized adult NCT04575584 Multi-countryb patients with COVID-19 N = 1,300 HC Control No. 244159

IFX-1 NA MC, DB, PC May 31, 2021 Adult patients with NCT04333420 Multi-country severe COVID-19 N = 390 pneumonia

Niclosamide NA DB, PC June 2021 Adult patients with NCT04603924 US moderate COVID-19 N = 436 infection

Aviptadil AVICOVID-2 MC, DB, PC July 1, 2021 Patients (≥ 12-years-old) NCT04360096 US with moderate and N = 288 severe COVID-19 who have not yet developed respiratory failure

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Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference BIO101 COVA DB, PC July 2021 Hospitalized adult NCT04472728 Multi-country patients (≥ 55-years-old) N = 310 with COVID-19 Nafamostat mesylate or TD139 DEFINE OL July 3, 2021 Children and adult NCT04473053 UK patients (≥ 16-years-old) N = 60 with COVID-19

Sofosbuvir and daclatasvir or NA OL August 1, 2021 Children and adult NCT04460443 ledipsavir Egypt patients with COVID-19 N = 60

BDB-001 NA MC, OL August 7, 2021 Adult patients with NCT04449588 Multi-Country severe COVID-19 with N = 368 severe pneumonia, or acute lung injury/acute respiratory distress syndrome Telmisartan or vitamins or COVERAGE MC, OL, MAMS August 15, 2021 Outpatient elderly NCT04356495 ciclesonide France patients (≥ 50-years-old) N = 615 with symptomatic SARS-CoV-2 infection Camostat NA OL August 31, 2021 Adult outpatients NCT04455815 UK (≥ 50-years-old) N = 389 with symptomatic SARS-CoV-2 infection

Cannabidiol NA DB, PC September 2021 Hospitalized adult NCT04615949 US patients with COVID-19, N = 422 with a history of or at risk

NEW of cardiovascular diseases Metformin MET-Covid DB, PC September 2021 Adult outpatients (30- to NCT04510194 US 85-years-old) with

N = 70 COVID-19 NEW

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 29

Experimental arm Trial name Study design, country, Estimated trial primary Population ClinicalTrials.gov sample size completion datea reference Colchicine COLHEART-19 OL September 01, 2021 Hospitalized adult NCT04510038 US patients with COVID-19

N = 75 NEW

ARDS = acute respiratory distress syndrome; DB = double blind; HC = Health Canada; LMWH = low molecular weight heparin; hsCRP = high-sensitivity C-reactive protein; MC = multi-centre; OL = open label; MAMS = multi-arm multi-stage; NA = not applicable; NR = not reported; PC = placebo controlled; SARS-CoV2 = severe acute respiratory syndrome coronavirus 2; SB = single blind; SC = subcutaneous. a The date on which data collection is completed for all the primary outcome measures. b Includes Canada.

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Table 3: Drugs to Prevent COVID-19: Ongoing Randomized Controlled Trials — September 2021 Estimated Primary Completion Date

Experimental arm Trial name Study design, Estimated trial primary Population ClinicalTrials.gov country, completion datea reference sample size Pre-exposure prophylaxis or prevention Phase IV Icosapent ethyl MITIGATE OL August 7, 2021 Adults (≥ 50-years-old) with no NCT04505098 US prior history of COVID-19, and N = 16,500 established atherosclerotic cardiovascular disease Phase III Levamisole or isoprinosine NA OL November 1, 2020 Healthy health care workers NCT04360122 or in combination Egypt testing negative for COVID-19 N = 100 Emtricitabine-tenofovir CoviPrep DB, PC November 15, 2020 Healthy health care workers NCT04405271 alafenamide Argentina having a high transmission risk for N = 1,378 COVID-19 and no prior diagnosis of SARS-CoV-2 infection Doxycycline and zinc NA MC, DB, PC December 31, 2020 Military health care workers NCT04584567 Tunisia N = 1,100 High and low dose vitamin D CORONAVIT OL June 30, 2021 Children and adults NCT04579640 UK (≥ 16-years-old) N = 6,200 Phase II/III Vitamin D NA MC, DB, PC November 15, 2020 Prevention: Hospital health NCT04386850 (25-hydroxyvitamin D3) Iran providers with a negative N = 1,500 COVID-19 test Prevention: Close relative of a patient with COVID-19 Treatment: See Table 3

Post-exposure prophylaxis Phase III

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Experimental arm Trial name Study design, Estimated trial primary Population ClinicalTrials.gov country, completion datea reference sample size Ivermectin IverprofCovid19 MC, DB, PC November 30, 2020 Health care workers at all levels of NCT04527211 Colombia care N = 550

Nitazoxanide NA MC, DB, PC December 31, 2020 Residents (≥ 55-years-old) of NCT04343248 US long-term care facilities N = 800

Icosapent ethyl PREPARE-IT DB, PC January 2021 Health care providers at risk NCT04460651 Argentina of occupational exposure to N = 2,000 COVID-19

Lopinavir-ritonavir COPEP OL March 2021 Children and adults (≥ 16-years- NCT04364022 Switzerland old) exposed to N = 300 SARS-CoV-2

Bamlanivimab (LY3819253; BLAZE-2 DB, PC March 8, 2021 Residents and facility staff in NCT04497987 LY-CoV555) US a skilled nursing or assisted living N = 2,400 facility with at least one confirmed case of SARS-CoV-2 Peginterferon beta-1a ConCorD-19 OL April 2021 Adults with no previous history of NCT04552379 Chile confirmed SARS-CoV-2 diagnosis, N = 1,240 living in a household with a confirmed SARS-CoV-2 case (first known diagnosis in the household). Nitazoxanide NA MC, DB, PC April 30, 2021 Health care workers at increased NCT04359680 US risk for direct occupational N = 4,000 exposure to COVID-19 Vitamin D3 PROTECT DB, PC May 1, 2021 Health care workers at high risk of NCT04483635 Canada COVID-19 infection (working at N = 2,414 COVID-designated or infected HC Control No. 243196 installations)

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Experimental arm Trial name Study design, Estimated trial primary Population ClinicalTrials.gov country, completion datea reference sample size REGN10933 and REGN10987 NA DB, PC June 15, 2021 Children and adults (≥ 12- years- NCT04452318 Multi-country old) with household contact with N = 2,000 exposure to an individual with a diagnosis of SARS-CoV-2

Phase II/III Tenofovir and emtricitabine NA MC, DB, PC December 31, 2020 Health care professionals in direct NCT04519125 Colombia care of patients in emergency N = 950 rooms, general COVID-wards, or intensive care units

ARDS = acute respiratory distress syndrome; DB = double blind; MC = multi-centre; OL = open label; MAMS = multi-arm multi-stage trial; NA = not applicable; NR = not reported; PC = placebo controlled; SARS-CoV2 = severe acute respiratory syndrome coronavirus 2. a The date on which data collection is completed for all the primary outcome measures.

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References 1. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2020: https://clinicaltrials.gov/. Accessed 2020 Dec 18. 2. CADTH COVID-19 evidence portal. CADTH report archives. Ottawa (ON): CADTH; 2020: https://covid.cadth.ca/tag/cadth-report/. Accessed 2020 Dec 18. 3. Government of Canada. Clinical trial search. 2020; https://health-products.canada.ca/ctdb-bdec/index-eng.jsp. Accessed 2020 Dec 18.

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Appendix 1: Trials That Are No Longer Active Table 4: Drugs to Treat COVID-19: Completed, Withdrawn, Terminated, or Suspended Randomized Controlled Trials

Treatment groups Trial name Study design, Trial end datea Population ClinicalTrials.gov Publication country, reference and status sample size Phase IV Bromhexine NA OL August 31, 2020 Medical personnel at risk NCT04405999 Not yet published Russian of contracting COVID-19 Federation (assisting patients with Completed N = 50 COVID-19) Famotidine NA MC, DB September 7, Hospitalized adult patients NCT04370262 Not yet published US 2020 with COVID-19 Completed N = 233 Dexamethasone DEXA-COVID19 MC, OL October 30, 2020 Adult patients with NCT04325061 NA Spain moderate-to-severe N = 200 ARDS due to COVID-19 Suspended and who are mechanically ventilated Sofosbuvir and ledipasvir NA OL October 30, 2020 Hospitalized patients NCT04498936 Not yet published or nitazoxanide Egypt (12- to 65-years-old) with N=240 COVID-19 Completed

Thiazide or thiazide-like CORONACION OL July 31, 2021 Adult patients (≥ 60-years- NCT04330300 NA diuretics, calcium channel Ireland old) with a diagnosis of blockers, angiotensin- N = 2,414 hypertension and Suspended converting enzyme currently using ACEi or inhibitors, or angiotensin ARB, and not yet infected receptor blockers with COVID-19 Phase III Tocilizumab COVACTA MC, DB, PC June 24, 2020 Hospitalized adult patients NCT04320615 Not yet published Multi-countryb with severe COVID-19 N = 450 pneumonia HC Control No. related article 237397 related article Completed Levilimab CORONA MC, PC, DB July 03, 2021 Hospitalized adult patients NCT04397562 Not yet published with severe COVID-19

HEALTH TECHNOLOGY REVIEW Ongoing Trials for Drugs in the Prevention and Treatment of COVID-19 35

Treatment groups Trial name Study design, Trial end datea Population ClinicalTrials.gov Publication country, reference and status sample size Russian Completed Federation N = 206 Tocilizumab TOCIBRAS OL July 8, 2020 Adult patients with NCT04403685 NA Brazil moderate-to-severe N = 129 COVID-19 Terminated Tocilizumab NA MC, DB, PC July 13, 2020 Hospitalized adult and NCT04356937 Published US older adult patients with Completed N = 243 severe COVID-19 Dornase alfa (Tigerase) NA OL July 20, 2020 Adult patients with NCT04459325 NA Russian moderate Federation COVID-19 Completed N = 100 Dexamethasone CoDEX MC, OL July 22, 2020 Adult patients with NCT04327401 Published Brazil moderate and severe N = 299 ARDS due to Terminated SARS-CoV2 Favipiravir NA OL August 10, 2020 Hospitalized adult patients NCT04542694 Not yet published Russian with moderate COVID-19 Federation Completed Results posted on N = 200 ClinicalTrials.gov

Ivermectin and NA DB, PC August 22, 2020 Adult patients with mid NCT04523831 Not yet published doxycycline Bangladesh and moderate COVID-19 N = 400 Completed Results posted on ClinicalTrials.gov

Ivermectin NA OL September 2, Hospitalized adult patients NCT04646109 Not yet published Turkey 2020 with severe COVID-19 N = 60 pneumonia Completed Results posted on ClinicalTrials.gov

Ruxolitinib RUXCOVID MC, DB, PC October 17, 2020 Hospitalized patients NCT04362137 Not yet published Multi-country (≥ 12-years-old) with N = 432 COVID-19 — associated HC Control No. cytokine storm 240395

Completed

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Treatment groups Trial name Study design, Trial end datea Population ClinicalTrials.gov Publication country, reference and status sample size Mometasone furoate NA OL October 25, 2020 Adult patients with NCT04484493 Not yet published Egypt COVID-19 and recent N = 100 onset of anosmia or Completed hyposmia XC221 NA MC, DB, PC October 29, 2020 Adult patients with NCT04487574 Not yet published Russian COVID-19 Federation Completed N = 118 Emapalumab or anakinra NA MC, OL November 13, Adult patients with SARS- NCT04324021 NA Multi-country 2020 CoV-2 infection Terminated N = 16

Aspirin, losartan, or CRASH-19 OL April 2021 Hospitalized adult patients NCT04343001 NA simvastatin, each alone or Multi-country (≥ 40- years-old) with combined with another N = 0 COVID-19 Withdrawn

Colchicine NA OL May 14, 2021 Hospitalized adult patients NCT04603690 NA Spain SARS-CoV-2 infection Withdrawn N = 0

Phase II/III Methylprednisolone NA MC, OL April 13, 2020 Hospitalized adult patients NCT04244591 Not yet published China with COVID-19 N = 80 Completed RPH-104 or olokizumab NA Adaptive, MC, July 10, 2020 Adult patients with severe NCT04380519 Not yet published DB, PC SARS-CoV-2 infection Russia Completed Federation N = 372 Ivermectin NA OL July 14, 2020 Asymptomatic family NCT04422561 Not yet published Egypt contact (≥ 6-years-old) N = 304 with patients with Completed Results posted on confirmed COVID-19 ClinicalTrials.gov

Sarilumab NA DB, PC July 24, 2020 Hospitalized adult patients NCT04315298 Not yet published US with SARS-CoV-2 N = 1,912

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Treatment groups Trial name Study design, Trial end datea Population ClinicalTrials.gov Publication country, reference and status sample size HC Control No. 237332

Completed Sulodexide SuIES-COVID OL, PC September 7, Adult patients (40- to NCT04483830 Not yet published Mexico 2020 80-years-old) with N = 243 COVID-19 symptoms Completed DAS181 STOP MC, DB, PC September 30, Adult patients with NCT04354389 NA COVID-19 Italy 2020 SARS-CoV-2 infection N = 0 with lower respiratory tract Withdrawn infection who require supplemental oxygen Lopinavir-ritonavir TRASCOV OL December 31, Outpatients (≥ 12-years- NCT04409483 NA Nigeria 2020 old) with COVID-19 N = 928 Withdrawn ACEi= angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blockers; ARDS = acute respiratory distress syndrome; MC = multi-centre; NA = not applicable, OL = open label; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. a Actual trial completion, withdrawal, termination, or suspension date as indicated in ClinicalTrials.gov. b Includes Canada.

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