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Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
Published: Efficacy of Hydroxychloroquine in Patients With COVID-19: Results of a Randomized Clinical Trial (not yet peer-reviewed) - RCT; 62 hospitalized pts w/ confirmed COVID-19 randomized to HCQ 200 mg bid x5 days or placebo, in addition to standard of care
- HCQ-treated pts had shorter duration of cough (2.0 days vs 3.1 days) and fever (2.2 days vs 3.2 days), and higher rates of pneumonia improvement (80.6% vs 54.8%); 4 pts progressed to severe dz, all in placebo arm; 2 pts in HCQ arm developed mild ADRs
- Study limitations: small size
- Access medRxiv article
Published: Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-label Non-randomized Clinical Trial
- Single-arm protocol; 26 hospitalized pts (6 asymptomatic; 22 w/ URTI sx; 8 w/ LRTI sx) treated w/ HCQ 200 mg tid x10 days; 6 pts also received azithromycin (500 mg x1dose, then 250 mg daily x4 days) to prevent bacterial superinfxn: ECG was monitored daily due to higher QT prolongation risk w/ this combo
- Treated pts had significant reduction in viral carriage at day 6 and much lower carriage duration vs controls; addition of azithromycin resulted in significantly more efficient virus elimination
- Study limitations: small sample size, limited f/u, drop-out of 6 pts
- Access free full-text Int J Antimicrob Agents article
Published: A Pilot Study of Hydroxychloroquine in Treatment of Patients With Common Coronavirus Disease-19 (COVID-19) - Randomized, controlled trial: 30 tx-naïve, hospitalized pts w/ confirmed COVID-19 randomized to HCQ 400 mg daily x5 days or placebo, in addition to conventional tx
- On day 7, viral nucleic acid in throat swab (primary endpoint) was negative in 86.7% of HCQ group vs 93.3% of control group; median time from hospitalization to negative conversion was 4 (1-9) days in HCQ group vs 2 (1-4) days in control group; median time to temp normalization was 1 (0-2) day after hospitalization in HCQ group vs 1 (0-3) day in control group; radiological progression on CT seen in 33% of HCQ group vs 46.7% of controls, all showed improvement at f/u
- Study limitations: small sample size, questionable endpoints
- Access J Zhejiang Univ article (abstract in English)
Active U.S. trials: - Post-exposure Prophylaxis and Preemptive Therapy for SARS-Coronavirus-2: A Pragmatic Randomized Clinical Trial, NCT04308668
- Randomized Study to Evaluate the Safety and Antiviral Efficacy of Hydroxychloroquine in Patients With Newly Diagnosed COVID-19 Compared to Standard of Care Treatment, NCT04334967
- A Phase 1b, Randomized, Double-blinded, Placebo-controlled Study of Hydroxychloroquine in Outpatient Adults With COVID-19, NCT04333654
- A Prospective Clinical Study of Hydroxychloroquine in the Prevention of SARS-CoV-2 (COVID-19) Infection in Healthcare Workers After High-risk Exposures, NCT04333225
Upcoming U.S. trials: - Pre-exposure Prophylaxis for SARS-Coronavirus-2, NCT04328467
- Hydroxychloroquine Post-exposure Prophylaxis for Coronavirus Disease (COVID-19), NCT04318444
- Hydroxychlorioquine vs Azithromycin for Hospitalized Patients With Suspected of Confirmed COVID-10 (HAHPS); NCT04329832
- The PATCH Trial (Prevention and Treatment of COVID-19 With Hydroxychloroquine); NCT04329923
- Comparison of Therapeutics for Hospitalized Patients Infected With SARS-CoV-2 in a Pragmatic aDaptive Randomized Clinical Trial During the COVID-19 Pandemic (COVID MED Trial), NCT04328012
- Efficacy of Hydroxychloroquine for Post-exposure Prophylaxis (PEP) to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Among Adults Exposed to Coronavirus Disease (COVID-19): A Blinded, Randomized Study, NCT04328961
- Pre-exposure Prophylaxis for SARS-Coronavirus-2: A Pragmatic Randomized Clinical Trial, NCT04328467
- Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease, NCT04332991
- A Phase II Pilot Study of Quintuple Therapy to Treat COVID-19 Infection, NCT04334512
- Hydroxychloroquine vs Azithromycin for Outpatients in Utah With COVID-19 (HyAzOUT): A Prospective Pragmatic Trial, NCT04334382
- An Open Label Phase II Pilot Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection, NCT04335084
- Phase 2 Pragmatic Factorial Trial of Hydroxychloroquine, Azithromycin, or Both for Treatment of Severe SARS-CoV-2 Infection, NCT04335552
- Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine Trial (HERO-HCQ Trial), NCT04334148
- Randomized Comparison of Combination Azithromycin and Hydroxychloroquine vs Hydroxychlorquine Alone for the Treatment of Confirmed COVID-19, NCT04336332
Emergency Use Authorization: - Fact Sheet for Health Care Providers, FDA EUA
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Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
Upcoming U.S. trials: - A Phase 2, International Multi-site, Bayesian Adaptive, Randomized, Double-blinded, Placebo-controlled Trial Assessing the Effectiveness of Varied Doses of Oral Chloroquine in Preventing or Reducing the Severity of COVID-19 Disease in Healthcare Workers, NCT04333732
Emergency Use Authorization:
- Fact Sheet for Health Care Providers, FDA EUA
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Pharmacology/Background - Proposed mechanism: no direct antiviral activity; indirect immunomodulatory effects
Published: Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-label Non-randomized Clinical Trial - Single-arm protocol; 26 hospitalized pts (6 asymptomatic; 22 w/ URTI sx; 8 w/ LRTI sx) treated w/ HCQ 200 mg tid x10 days; 6 pts also received azithromycin (500 mg x1dose, then 250 mg daily x4 days) to prevent bacterial superinfxn: ECG was monitored daily due to higher QT prolongation risk w/ this combo
- Treated pts had significant reduction in viral carriage at day 6 and much lower carriage duration vs controls; addition of azithromycin resulted in significantly more efficient virus elimination
- Study limitations: small sample size, limited f/u, drop-out of 6 pts
- Access free full-text Int J Antimicrob Agents article
Upcoming U.S. trials:
- Hydroxychloroquine vs Azithromycin for Hospitalized Patients With Suspected of Confirmed COVID-10 (HAHPS); NCT04329832
- Azithromycin for Prevention of Disease Progression in Patients With Mild or Moderate COVID-19, NCT04332107
- Hydroxychloroquine vs Azithromycin for Outpatients in Utah With COVID-19 (HyAzOUT): A Prospective Pragmatic Trial, NCT04334382
- Phase 2 Pragmatic Factorial Trial of Hydroxychloroquine, Azithromycin, or Both for Treatment of Severe SARS-CoV-2 Infection, NCT04335552
- Randomized Comparison of Combination Azithromycin and Hydroxychloroquine vs Hydroxychlorquine Alone for the Treatment of Confirmed COVID-19, NCT04336332
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Pharmacology/Background: - Proposed mechanism: terminates viral replication by binding to RNA-dependent RNA polymerase; circumvents proofreading activity by exonucleases
Active U.S. trials - A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults, NCT04280705
- A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe COVID-19, NCT04292899
- 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
Expanded Access/Compassionate Use - Intermediate-Size Patient Population Expanded Access Treatment Protocol for Coronavirus Disease 2019 (COVID-19) Remdesivir (RDV; GS-5734™), NCT04302766
- Manufacturer not currently accepting new compassionate use requests; more info available at manufacturer website; Expanded Access Treatment Protocol: Remdesivir (RDV; GS-5734) for the Treatment of SARS-CoV2 (CoV) Infection (NCT04323761)
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Pharmacology/Backgound: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
Published: Effective Treatment of Severe COVID-19 Patients With Tocilizumab - Retrospective study; 21 severely ill, hospitalized pts (4 pts critically ill) w/ confirmed COVID-19 treated w/ tocilizumab 400 mg x1 (3 pts received 2nd dose w/in 12h); study pts also received lopinavir/ritonavir, in addition to other standard-of-care measures
- Treated pts had significant clinical improvement w/in a few days; all pts had normalized temp on Day 1; 15/20 pts had lower O2 intake, 1 needed no O2; CT lesions “absorbed” in 10/19 on 5th day after tx; CRP decreased significantly in 16/19 pts; no obvious ADRs, incl subsequent infections; 90.5% of pts d/c home on avg 13.5 days after tx
- Study limitations: non-comparative, small size
- Access chinaXiv abstract
Upcoming U.S. trials: - A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia, NCT04320615
- Early Institution of Tocilizumab Titration in Non-Critical Hospitalized COVID-19 Pneumonitis, NCT04331795
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Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
Active U.S.trials: - An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients With COVID-19, NCT04315298
Expanded Access/Compassionate Use: - For info on compassionate use access or investigator-sponsored clinical studies, contact manufacturer (Sanofi Genzyme): 1-800-633-1610
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Pharmacology/Background: - Proposed mechanism: interferes w/ maturation of viral particles by inhibiting protease enzymes
Published: A Trial of Lopinavir–Ritonavir in Adults Hospitalized w/ Severe Covid-19 - Randomized, controlled, open-label trial; N=199 hospitalized adult pts w/ confirmed SARS-CoV-2, O2 sat ≤94%
- No benefit in time to clinical improvement; mortality at 28 days numerically lower w/ lopinavir/ritonavir but difference not statistically significant
- Access the free full-text N Engl J Med article
Upcoming U.S. trials: - Comparison of Therapeutics for Hospitalized Patients Infected With SARS-CoV-2 in a Pragmatic aDaptive Randomized Clinical Trial During the COVID-19 Pandemic (COVID MED Trial), NCT04328012
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Pharmacology/Background: - Proposed mechanism: blocks viral entry by inhibiting ACE2 receptors
Active U.S. trials: - An Open Label Phase 1 Trial of Losartan for Worsening Respiratory Illness in COVID-19, NCT04335123
Upcoming U.S. trials: - Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization, NCT04312009
- Randomized Trial of Losartan for Patients With COVID-19 Not Requiring Hospitalization, NCT04311177
- Comparison of Therapeutics for Hospitalized Patients Infected With SARS-CoV-2 in a Pragmatic aDaptive Randomized Clinical Trial During the COVID-19 Pandemic (COVID MED Trial), NCT04328012
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Pharmacology/Background: - Proposed mechanism: disrupts cytokine pathways by inhibiting janus-associated kinases (JAK)
Expanded Access/Compassionate Use - Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very Severe COVID-19 Illness, NCT04337359
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Pharmacology/Background: - Proposed mechanism: selectively dilates pulmonary vasculature, leading to vasodilation and increased oxygenation; reports of antiviral activity against other coronaviruses (eg, SARS-CoV)
Active U.S. trials: - Nitric Oxide Gas Inhalation Therapy in Spontaneous Breathing Patients With Mild/Moderate COVID-19: A Randomized Clinical Trial, NCT04305457
- Nitric Oxide Gas Inhalation Therapy for Mechanically Ventilated Patients With Severe Acute Respiratory Syndrome Caused by SARS-CoV2: A Randomized Clinical Trial, NCT04306393
Upcoming U.S. trials: - Nitric Oxide Gas Inhalation for Prevention of COVID-19 in Healthcare Providers, NCT04312243
Expanded Access/Compassionate Use
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favipiravir, umifenovir, aviptadil
Pharmacology/Background: - Note: These agents not currently available in the U.S.
- Favipravir (AKA favilavir, fapilavir, Avigan): used in Japan for tx of influenza; first approved drug in China for tx of COVID-19; proposed mechanism: terminates viral replication by binding to RNA-dependent RNA polymerase
- Umifenovir (Arbidol): used in Russia & China for tx of influenza; proposed mechanism: inhibits fusion of viral and cellular membranes by intercalating into membrane lipids
- Aviptadil: analog of vasoactive intestinal peptide (VIP); used in Europe for tx of erectile dysfunction, studied in sarcoidosis, pulmonary fibrosis, bronchospasm, and ARDS
Upcoming U.S. trials: - Intravenous Aviptadil for COVID-19 Associated Acute Respiratory Distress, NCT04311697
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Pharmacology/Background: - Proposed mechanism: provides passive immunity
Upcoming U.S. trials: - Convalescent Plasma to Limit Coronavirus Associated Complications: An Open Label, Phase 2A Study of High-Titer Anti-SARS-CoV-2 Plasma in Hospitalized Patients With COVID-19, NCT04325672
- Evaluating Convalescent Plasma to Decrease Coronavirus Associated Complications. A Phase I Study Comparing the Efficacy and Safety of High-titer Anti-Sars-CoV-2 Plasma vs Best Supportive Care in Hospitalized Patients With Interstitial Pneumonia Due to COVID-19, NCT04333251
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Pharmacology/Background: - Proposed mechanism: induces antibody formation
Active U.S. trials: - Phase I, Open-Label, Dose-Ranging Study of the Safety and Immunogenicity of 2019-nCoV Vaccine (mRNA-1273) in Healthy Adults, NCT04283461
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