Table 2.
Emerging therapies for SARS-CoV-2
| Proposed therapy | Mechanism of action | Published findings to date | Randomized controlled clinical trials in progress (selected from clinicaltrials.gov) |
|---|---|---|---|
| Antiviral therapies/strategies | |||
| 1. Remdesivir (GS-5734™) | Nucleoside-based RNA polymerase inhibitor |
Therapeutic in preclinical models of MERS-CoV and SARS-CoV and inhibits SARS-CoV-2 infection in vitro [60, 61] Remdesivir potentially beneficial in report of 61 patients with SARS-CoV-2 [62] Trend for enhanced recovery in a phase 3 study of 237 patients with COVID-19 [63] Remdesivir shortened the time to recovery in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection [64] |
1. Expanded Access Remdesivir (RDV; GS-5734™). NCT04302766 2. ACTT—Adaptive COVID-19 Treatment Trial. NCT04280705 3. Study of the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe Coronavirus Disease. NCT04292899 4. A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate COVID-19 Compared to Standard of Care Treatment. NCT04292730 5. The Efficacy of Different Anti-viral Drugs in COVID-19 Patients. NCT04321616 6. DISCOVERY—Trial of Treatments for COVID-19 in Hospitalized Adults. NCT04315948 7. The SOLIDARITY Trial. ISRCTN83971151 |
| 2. Favipiravir | Broad-spectrum RNA polymerase inhibitor |
Blocks viral replication and recently shown to improve chest opacities and reduce viral load in SARS-CoV-2 patients [66] No benefit over arbidol in open-label trial [70] |
1. THDMS-COVID-19—Various Combination of Protease Inhibitors, Oseltamivir, Favipiravir, and Chloroquin for Treatment of COVID-19. NCT04303299 2. Favipiravir Combined with Tocilizumab in the Treatment of Corona Virus Disease 2019. NCT04310228 3. Clinical Study to Evaluate the Performance and Safety of Favipiravir in COVID-19. NCT04336904 |
| 3. Lopinavir/ritonavir | HIV protease inhibitors |
Unsuccessful in a recent trial of 199 patients, infection was at advanced stage and very severe, however [67] Triple therapy with lopinavir/ritonavir, IFN-β1β, and ribavirin reduced viral shedding and hospital stays in a phase 2 study [68] |
1. ELACOI—The Efficacy of Lopinavir + Ritonavir and Arbidol Against Novel Coronavirus Infection. NCT04252885 2. The Efficacy and Safety of Lopinavir–Ritonavir in Hospitalized Patients with Novel Coronavirus Pneumonia. ChiCTR2000029308 3. Treatment of Moderate to Severe Coronavirus Disease in Hospitalized Patients. NCT04321993 4. REMAP-CAP—Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia. NCT02735707 5. DISCOVERY—Trial of Treatments for COVID-19 in Hospitalized Adults. NCT04315948 6. The SOLIDARITY Trial. ISRCTN83971151 |
| 4. Umifenovir (arbidol) | Inhibits viral interaction and binding with host cells via ACE2 |
Retrospective analysis showed that arbidol treatment (n = 16) in comparison with lopinavir/ritonavir treatment (n = 36) reduced viral load in SARS-CoV-2 patients [69] No benefit over favipiravir in open-label trial [70] |
1. UAIIC—Study of Umifenovir in COVID-19. NCT04350684 2. Study of Arbidol Hydrochloride Tablets in the Treatment of Pneumonia caused by Novel Coronavirus. NCT04260594 3. ELACOI—Efficacy of Lopinavir + Ritonavir & Arbidol Against Novel Coronavirus Infection. NCT04252885 |
|
5. Chloroquine 6. Hydroxychloroquine |
Antimalarial drugs |
Inhibits viral entry and SARS-CoV-2 infection in vitro [61] Hydroxychloroquine plus azithromycin reduced viral load in 20 COVID-19 patients [74] Concerns regarding cardiotoxicity and QT prolongation in COVID-19 [75, 76] A large observational study in 14,888 COVID-19 patients treated with either hydroxychloroquine or chloroquine reported that these drugs increased the risk of mortality and increased the risk of de novo ventricular arrhythmia [77] |
1. COPCOV—Chloroquine Prevention of Coronavirus Disease in the Healthcare Setting. NCT04303507 2. Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in Patients with Mild Coronavirus Disease. NCT04307693 3. HC-nCoV—Efficacy and Safety of Hydroxychloroquine for Treatment of Pneumonia Caused by 2019-nCoV. NCT04261517 4. HYDRA—Study of Hydroxychloroquine Treatment for Severe COVID-19 Pulmonary Infection. NCT04315896 5. THDMS-COVID-19—Various Combinations of Protease Inhibitors, Oseltamivir, Favipiravir, and Chloroquin for Treatment of COVID-19. NCT04303299 6. REMAP-CAP—Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia. NCT02735707 7. CLOCC—Combination Therapy With Camostat Mesilate + Hydroxychloroquine for COVID-19. NCT04338906 8. The Efficacy of Different Anti-viral Drugs in COVID-19 Patients. NCT04321616 9. DISCOVERY—Trial of Treatments for COVID-19 in Hospitalized Adults. NCT04315948 10. The SOLIDARITY Trial. ISRCTN83971151 |
| 7. TMPRSS2 inhibitor (camostat mesilate) | Protease Inhibitor | In vitro study showing SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by protease inhibitor [78] |
1. CamoCO-19—The Impact of Camostat Mesilate on SARS-CoV-2 Infection. NCT02735707 2. CLOCC—Combination Therapy with Camostat Mesilate + Hydroxychloroquine for COVID-19. NCT04338906 |
| 8. Baricitinib | JAK inhibitor |
Anti-inflammatory and inhibitor of ACE2-mediated viral entry may be promising for viral ARDS [79]. Identified using a drug discovery search engine platform Baricitinib well tolerated and potentially beneficial over standard care in small clinical study [80] |
1. Treatment of Moderate to Severe Coronavirus Disease (COVID-19) in Hospitalized Patients. NCT04321993 2. BARI-COVID—Pilot Study of Baricitinib in Symptomatic Patients Infected by SARS-CoV-2. NCT04320277 |
| 9. Inactivated convalescent plasma | IV immunoglobulins |
Enhanced viral clearance and clinical outcome in 5 patients in a case study of SARS-CoV-2 [82] Well tolerated in expanded access trial (un-reviewed preprint) [83] |
1. Anti-SARS-CoV-2 Inactivated Convalescent Plasma in the Treatment of COVID-19. NCT04292340 2. Anti-COVID-19 Convalescent Plasma Therapy. NCT04338360 |
| Immunomodulatory—pleiotropic effects | |||
| 1. Methylprednisolone | Steroid, anti-inflammatory | Retrospective studies of 46 and 201 patients with SARS-CoV-2 ARDS show that early and careful administration may have beneficial role [88, 89]. Steroid use may hinder viral clearance in MERS coronavirus infection [87] |
1. Steroids-SARI—Glucocorticoid Therapy for Novel Coronavirus Critically Ill Patients With Severe Acute Respiratory Failure. NCT04244591 2. Efficacy and Safety of Corticosteroids in COVID-19. NCT04273321 3. MP-C19—Efficacy of Methylprednisolone for Patients With COVID-19 Severe ARDS. NCT04323592 4. REMAP-CAP—Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia. NCT02735707 |
| 2. Thalidomide | Immunomodulator, anti-IL-6, pro-apoptotic | Therapeutic in preclinical model of viral ARDS [91] |
1. Efficacy and Safety of Thalidomide in the Adjuvant Treatment of Moderate COVID-19. NCT04273529 2. Efficacy and Safety of Thalidomide Combined With Low-dose Hormones in the Treatment of Severe COVID-19. NCT04273581 |
| 3. Type I and Type III interferons | Antiviral, anti-inflammatory, and anti-fibrotic |
Interferons affect SARS and MERS differentially, but SARS-CoV-2 is particularly sensitive to interferon treatment [92, 94] Triple therapy with IFN-β1β, lopinavir/ritonavir, and ribavirin reduced viral shedding and hospital stays in a phase 2 study [68] |
1. Study of IFN-α1β in the Treatment of Patients with Novel Coronavirus. NCT04293887 2. Study of Pegylated Interferon Lambda Treatment for COVID-19. NCT04343976 3. A Study of Interferon-β1α in COVID-19. NCT04350671 4. DIC—A Study of Interferon-β1α, Compared to Interferon-β1β and the Base Therapeutic Regiment in COVID-19. NCT04343768 5. Double Therapy With IFN-β1β and Hydroxychloroquine. NCT04350281 6. DISCOVERY—Trial of Treatments for COVID-19 in Hospitalized Adults. NCT04315948 7. REMAP-CAP—Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia. NCT02735707 |
| 4.MSCs | Immunomodulatory and pro-resolution effects |
Promising in preclinical and phase 1/2 ARDS studies [10, 11, 15] ACE2-/- MSCs were well tolerated, improved pulmonary function and immune response in a case series of 7 COVID-19 patients [95] |
1. REALIST—Study of MSC Repair in COVID-19-induced ARDS. NCT03042143 2. Study of UC-MSC Treatment for the 2019-Novel Coronavirus Pneumonia. NCT04269525 3. Mesenchymal Stem Cell Treatment for Pneumonia Patients Infected With COVID-19. NCT04252118 4. Study of Human Mesenchymal Stem Cells in the Treatment of COVID-19 Pneumonia. NCT04339660 5. Study of Mesenchymal Stem Cells for Severe Corona Virus Disease 2019. NCT04288102 6. Pilot Study of Inhale of MSC-Derived Exosomes for Treating Severe Novel Coronavirus Pneumonia. NCT04276987 7. MACOVIA—Study of MultiStem Administration for COVID-19-Induced ARDS |
| Immunomodulatory—pathway specific | |||
|
1. Tocilizumab 2. Sarilumab |
Human monoclonal antibody, IL6R antagonist | Improved chest CT, lung oxygenation and reduced immune cell counts in a retrospective study of 21 patients with SARS-CoV-2 [99] |
1. Favipiravir Combined With Tocilizumab in the Treatment of Coronavirus Disease 2019. NCT04310228 2. Efficacy and Safety of Tocilizumab in the treatment of New Coronavirus Pneumonia. ChiCTR2000029765 3. TOCIVID-19—Tocilizumab in COVID-19 Pneumonia. NCT04317092 4. TACOS—Tocilizumab vs CRRT in Management of Cytokine Release Syndrome in COVID-19. NCT04306705 5. Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19. NCT04315298 6. TOCIVID—Anti-IL-6 Treatment of Serious COVID-19 Disease With Threatening Respiratory Failure. NCT04322773 7. Treatment of Moderate to Severe Coronavirus Disease (COVID-19) in Hospitalized Patients. NCT04321993 |
| 3. Anakinra | Human monoclonal antibody, IL1-R antagonist | Post hoc analysis confirmed improved survival in a subgroup of sepsis patients [103] |
1. ESCAPE—Personalized Immunotherapy for SARS-CoV-2 Associated with Organ Dysfunction. NCT04339712 2. Study of Emapalumab and Anakinra in Reducing Hyperinflammation and Respiratory Distress in Patients with COVID-19. NCT04324021 3. CORIMUNO-ANA—Efficacy of Anakinra In Patients With SARS-CoV-2 Infection. NCT04341584 4. COV-AID—Treatment of COVID-19 Patients With Anti-interleukin Drugs. NCT04330638 5. REMAP-CAP—Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia. NCT02735707 |
| Other potential therapies | |||
| 1. Heparin | Anticoagulant | Low molecular weight heparin associated with better prognosis in severe COVID-19 patients with markedly elevated d-dimers [104] | 1. CHARTER study—Nebulized Heparin for patients with COVID-19 ARDS. ACTRN:1260000517976 |