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Pfizer-BioNTech COVID-19 vaccine (BNT162b2) CDC Clinical Considerations Vaccine Characteristics - Generic Name: tozinameran (not yet approved by FDA)
- Brand Name: Comirnaty (not yet approved by FDA)
- Type: mRNA vaccine (encodes for viral proteins; uses host machinery to produce solitary viral proteins to induce immune response; does not produce whole virus)
- Dosing: 2 doses, 21 days apart
Efficacy data - Adults (≥16 yo): 91.3% effective through 6mo per topline analysis; 94% effective in health care personnel, per CDC
- Peds: 100% effective in adolescents 12-15 yo per phase 3 trial; additional studies for other age groups ongoing
- Variants: studies ongoing
Storage & Other Info - Store frozen between -112°F to -76°F
- May store frozen between -13°F and 5°F for up to 2wk
- May store thawed, undiluted vials between 35°F and 46°F for up to 1mo, or at room temperature for no more than 2h
- Store diluted vials between 35°F and 77°F for up to 6h
Moderna, Inc. COVID-19 vaccine (mRNA-1273) CDC Clinical Considerations Vaccine Characteristics - Generic Name: none
- Brand Name: none
- Type: mRNA vaccine (encodes for viral proteins; uses host machinery to produce solitary viral proteins to induce immune response; does not produce whole virus)
- Dosing: 2 doses, 28 days apart
Efficacy Data - Adults: 94.1% effective per preliminary analysis; 94% effective in health care personnel, per CDC
- Peds: 100% effective in adolescents 12-17 yo per phase 2/3 study; additional studies for other age groups ongoing
- Variants: studies ongoing
Storage & Other Info - Store frozen between -58°F to 5°F
- May store between 36°F and 46°F (refrigerated) for 30 days
- May store between 46°F and 77°F for 24h total
- Store punctured vials between 36°F and 77°F for up to 12h
Janssen COVID-19 vaccine (Johnson & Johnson, JNJ-78436735) CDC Clinical Considerations Vaccine Characteristics - Generic Name: none
- Brand Name: none
- Type: recombinant human adenovirus vaccine (adenovirus vector genetically modified to include select proteins from pathogen of interest to induce immune response)
- Dosing: 1 dose
Efficacy data - Adults: 67% effective in preventing moderate/severe dz, 85% effective in preventing severe/critical dz, per primary analysis
- Peds: studies ongoing
- Variants: studies ongoing
Storage & Other Info - Store vials between 36°F and 46°F (refrigerated)
- May store vials between 47°F and 77°F for up to 12h
- Store punctured vials btwn 36°F to 46°F for up to 6h, or up to 77°F for up to 2h
Select COVID-19 vaccines not yet authorized or approved in U.S. Pharmacology/Background: - mRNA vaccines: encodes for viral proteins; uses host machinery to produce solitary viral proteins to induce immune response; does not produce whole virus
- recombinant vector-based vaccines: virus vectors genetically modified to include select proteins from pathogen of interest to induce immune response
- inactivated vaccines: pathogenic agent killed by chemicals, heat, or radiation; antigens from inactivated virus induce immune response
- subunit vaccines: contain virus components rather than entire pathogen to minimize side effects; often require adjuvant to elicit stronger immune response for long-term immunity
- virus-like particle vaccines: self-assembling multiprotein structures mimicking authentic native virus but lacking viral genome; nonreplicative, nonpathogenic
AstraZeneca/University of Oxford (Vaxzevria; Covishield/India; AZD1222; ChAdOx1-S) - Emergency Use for ChAdOx1-S authorized by WHO for European Medicines Agency (EUL); South Korea (EUL); Australia (EUL); and Japan (EUL)
- Emergency Use for Covishield authorized by WHO (EUL)
- recombinant chimpanzee adenovirus vaccine given as 2 doses
- 76% effective per revised interim analysis (3/25/21)
- approved or authorized for use in countries outside U.S.
- ClinicalTrials.gov link: NCT04516746
Sinopharm & Beijing Institute of Biological Products Co., Ltd. (BBIBP-CorV) - Emergency Use authorized by WHO (EUL)
- inactivated SARS-CoV-2 virus vaccine given as 2 doses
- 78.1% effective per study results
- approved or authorized for use in other countries
Sinovac (CoronaVac) - Emergency Use authorized by WHO (EUL)
- 51% effective per WHO
- approved or authorized for use in other countries
Novavax (NVX-CoV2373)
- nanoparticle-based, recombinant protein subunit vaccine given as 2 doses; contains Matrix-M adjuvant
- 89.7% effective per Phase 3 study
- ClinicalTrials.gov link: NCT04611802
Medicago/GlaxoSmithKline (CoVLP) - virus-like particle given as 2 doses; plant-based, combined w/ adjuvants
- ClinicalTrials.gov link: NCT04636697
Pharmacology/Background: - Proposed mechanism: induces nonspecific immune effects
- Vaccines under investigation: BCG, MMR, zoster vaccine (recombinant), polio vaccines
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Drugs w/ antiviral activity (eg, remdesivir, hydroxycholoroquine)
Pharmacology/Background: - Proposed mechanism: terminates viral replication by binding to RNA-dependent RNA polymerase; circumvents proofreading activity by exonucleases
- FDA MedWatch: Remdesivir by Gilead Sciences: FDA Warns of Newly Discovered Potential Drug Interaction That May Reduce Effectiveness of Treatment; see FDA alert
Emergency Use Authorization: Remdesivir for the Treatment of Covid-19 – Final Report - KEY FINDINGS: RDV, esp if given early, shortened recovery time vs placebo
- Study considerations: primary outcome changed mid-study, but incl as secondary outcome; varied protocols for other COVID-19 tx; remote monitoring
- Multinational, double-blind, RCT; 1,062 hospitalized pts (mean age 58.9y, 89% severe dz) received RDV 200 mg IV x1, then 100 mg daily (n=541) or placebo (n=521) for up to 10 days total; supportive care and other COVID-19 tx per protocol; median 9 days btwn sx onset and tx
- Primary outcome of time to recovery: RDV 10 days vs placebo 15 days (rate ratio 1.29, 95% CI 1.12-1.49); in pts w/ severe dz, RDV 11 days vs placebo 18 days (rate ratio 1.31, 95% CI 1.12-1.52); no difference if mech vent or ECMO (rate ratio 0.98, 95% CI 0.76-1.57); significantly faster time to recovery w/ RDV vs placebo if randomized during 1st 10 days
- Secondary outcome of improvement odds at day 15 higher w/ RDV vs placebo (OR 1.5, 95% CI 1.2-1.9); lower mortality by day 15 w/ RDV (6.7% vs 11.9%) but no significant difference by day 29; no difference in ADR incidence
- Access N Engl J Med article
Remdesivir for 5 or 10 Days in Patients With Severe Covid-19 (SIMPLE-Severe) - KEY FINDINGS no significant difference between 5- or 10-day RDV in pts not requiring mech vent
- Study considerations: no placebo control; randomization not stratified; protocol amended mid-study to lower age eligibility limit; 10-day group sicker at baseline; not all pts completed full course of assigned RDV; viral load not evaluated; extension phase added to evaluate mech vent, ECMO, and multiorgan failure pts
- Randomized, multicenter, multinational, open-label study: 397 hospitalized pts w/ confirmed SARS-CoV-2, pneumonia, and O2 sat ≤94% on RA or receiving supplemental O2, randomized 1:1 to receive RDV 200 mg IV x1, then 100 mg IV q24h x5 days total (n=200, median age 61y) or 10 days total (n=197, median age 62y); 10-day group sicker at baseline
- Unadjusted analysis of 14-day clinical status improvement rate: 5-day 64%, 10-day 54%, w/ no difference after adjusted analysis; ADRs incl acute resp failure (5-day 5%, 10-day 9%), resp failure (5-day 2%, 10-day 5%), grade 4 CrCl reduction (5-day 3%, 10-day 12%); elevated LFTs (5-day 2.5%, 10-day 3.6%)
- Access N Engl J Med article
Remdesivir in Adults With Severe COVID-19: A Randomised, Double-blind, Placebo-controlled, Multicentre Trial - KEY FINDINGS: RDV not assoc w/ significant clinical benefits; early tx may reduce time to clinical improvement
- Study considerations: underpowered due to low enrollment; imbalanced baseline characteristics despite randomization; possible delay in tx start; questionable utility of subgroup analyses
- Double-blind RCT; 237 pts (median age, 65y) received RDV 200 mg x1, then 100 mg daily x9 days (n=158) or placebo (n=78); incl pts w/ SaO2 <94% on RA, <12 days after sx; pts also received LPV/r (18%), IFN (19%), and steroids (38%); more RDV pts w/ late tx start (>10 days after sx) and RDV group had higher rates of HTN, DM and CAD
- Terminated early due to low enrollment and control of epidemic in China; no difference in time to clinical improvement (RDV 21 days, placebo 23 days) or 28-day mortality (RDV 14%, placebo 13%); in pts w/ ≤10 days from sx, non-significant difference in time to clinical improvement (RDV 18 days, placebo 23 days) and 28-day mortality (RDV 11%, placebo 15%)
- Viral loads decreased at similar rates in both groups; ADRs similar btwn groups (RDV 66%, placebo 64%); higher D/C rates in RDV (12%) vs placebo (5%)
- Access Lancet article
Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial (SIMPLE-Moderate) - KEY FINDINGS: improved clinical status w/ 5 days RDV vs SOC, but not w/ 10 days RDV
- Study considerations: open-label; randomization not stratified; protocol amended mid-study for inclusion criteria and primary endpoint; discharge rates may have been influenced by RDV duration; SARS-CoV-2 viral load and other relevant labs not assessed; results w/ uncertain clinical importance; nonrandomized extension phase ongoing
- Access JAMA article
Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results - KEY FINDINGS: RDV had little/no effect on mortality, vent initiation, or length of stay
- Study considerations: randomized; interim analysis; significant proportion of pts received other potential treatments for COVID (varied by tx arm); sx duration not reported; excluded peds pts
- Access N Engl J Med article
Comparison of Time to Clinical Improvement With vs Without Remdesivir Treatment in Hospitalized Patients With COVID-19 - KEY FINDINGS: RDV assoc w/ faster clinical improvement in inpts but RDV plus steroids didn’t reduce mortality vs RDV alone
- Study considerations: retrospective study; multi-center but all hospitals w/in same health system; mostly non-White pts (81%); propensity-matched cohorts, but likely could not account for all variables; potentially underpowered to detect mortality difference
- Access JAMA Netw Open article
Note: For published studies on combo tx w/ baricitinib, refer to JAK inhibitors
Treatment trials: Inpatient Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Emergency Use Authorization revoked June 15, 2020: Effect of Hydroxychloroquine With or Without Azithromycin on the Mortality of COVID-19 Patients: A Systematic Review and Meta-analysis - KEY FINDINGS: HCQ alone not assoc w/ reduced mortality in hospitalized pts, but HCQ+AZ significantly increased mortality
- Study considerations: varying dz severity; HCQ admin (dosing, timing, duration) highly heterogeneous; aggregate analysis not w/ original pt data; mostly incl observational studies
- Meta-analysis incl 3 RCTs, 1 interventional non-randomized study (w/ critical bias risk), 25 observational studies (15 studies w/ mod or serious bias risk, 10 w/ critical bias risk); study quality lowered by lack of info for tx assignment, time to intervention, unbalance co-interventions, and confounder imbalance btwn groups
- HCQ not significantly assoc w/ mortality (pooled RR 0.83, 95% CI 0.65-1.06 for all studies, I2=84%; pooled RR 1.09, 95% CI 0.97-1.24 for RCTs, I2=0%); HCQ+AZ assoc w/ incr mortality (RR 1.27, 95% CI 1.04-1.54, I2=38%)
- Access Clin Microbiol Infect article
Effect of Hydroxychloroquine in Hospitalized Patients With Covid-19 (RECOVERY) - KEY FINDINGS: HCQ did not lower 28-day mortality vs SOC
- Study considerations: randomized but open label; HCQ dose based on PK modeling; limited number of intubated pts; no children enrolled; no collection of virological or laboratory parameters
- Randomized, controlled, open-label, adaptive platform study; current analysis incl HCQ vs SOC only, results for other tx arms published or forthcoming
- Hospitalized pts (mean age 65.4y) w/ suspected or confirmed COVID-19 randomized to HCQ 800 mg q6h x2, then 400 mg q12h plus SOC for up to 10 days (n=1,561) vs SOC only (n=3,155); at randomization 17% invasive mech vent, 60% O2 only
- 28-day all-cause mortality higher w/ HCQ vs SOC only (RR 1.09, 95% CI 0.97 to 1.23), similarly across subgroups; HCQ group less likely to be discharged alive w/in 28 days vs SOC (rate ratio 0.9, 95% CI 0.83-0.98); among pts not mech vent baseline, HCQ group w/ higher frequency of mech vent or death (risk ratio 1.14, 95% CI 1.03-1.27)
- Access N Engl J Med article
Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results - KEY FINDINGS: HCQ had little/no effect on mortality, vent initiation, or length of stay
- Study considerations: not peer-reviewed; randomized; interim analysis; significant proportion of pts received other potential treatments for COVID (varied by tx arm); sx duration not reported; excluded peds pts
- Multinational, randomized study; 11,266 hospitalized pts (~10% ventilated) w/ COVID-19 received either RDV (n=2,750), HCQ (n=954), LPV/r (n=1,411), IFN beta 1a + LPV/r (n=651), IFN beta 1a (n=1,412) or SOC (n=4,088); pts could receive other therapies incl CS, immunomodulators, and other non-study antivirals
- Overall 28-day mortality 12%; no significant difference in reduced mortality w/ death rate ratio vs control: RDV (RR 0.95, 95% CI 0.81-1.11), HCQ (RR 1.19, 95% CI 0.89-1.59); LPV/r (RR 1.00, 95% CI 0.79-1.25) and IFN (RR 1.16, 95% CI 0.96-1.39); no significant difference in ventilation or hospitalization duration
- Access New Engl J Med article
Observational Study of Hydroxychloroquine in Hospitalized Patients With COVID-19 - KEY FINDINGS: HCQ not assoc. w/ change in composite endpoint (intubation or death)
- Study considerations: non-randomized; weighted propensity score model; treatment bias, HCQ pts were generally sicker; missing data and inaccuracies in EHR
- Observational cohort study w/ propensity score matching; 1,376 consecutive hospitalized pts (60% pts >60y) w/ confirmed mod-severe COVID-19; 811 pts treated w/ HCQ 600 mg bid x2, then 400 mg daily x4 days, 565 pts did not receive HCQ; 45% pts also treated w/ AZ 500 mg x1, then 250 mg daily x4 days; pts eligible for tx w/ other investigational COVID-19 tx; HCQ pts generally older, sicker, and received more concurrent tx; 86% HCQ pts received tx w/in 48h of presenting to ED
- Primary composite endpoint (intubation or death) rates higher w/ HCQ (32%) vs no HCQ (15%) in unadjusted analysis (HR 2.37, 95% CI 1.84 to 3.02); adjusted analysis showed no significant association btwn HCQ use and composite endpoint (HR 1.04, 95% CI 0.82 to 1.32)
- Access N Engl J Med article
Hydroxychloroquine With or Without Azithromycin in Mild-to-Moderate Covid-19 - KEY FINDINGS: HCQ or HCQ+AZ did not improve clinical status at 15 days vs SOC
- Study considerations: randomized but open-label; pts had mild-mod. dz; primary outcome assessment changed mid-study to be more granular; observer bias
- Multicenter, open-label, RCT; 667 hospitalized pts (mean age 50y) w/ mild-mod COVID-19 (58% pts required no O2) and <15 days since sx onset, randomized to receive SOC alone (n=229), SOC plus HCQ 400 mg bid x7 days (n=221), or SOC plus HCQ 400 mg bid and AZ 500 mg daily x7 days (n=217); use of CS (19.8%), other immunodulators, abx, and antivirals allowed; median time from admission to randomization 1 day, median time from sx onset to randomization 7 days
- No significant difference in clinical status at day 15 w/ HCQ vs SOC alone (OR 1.21, 95% CI 0.69 to 2.11), or HCQ+AZ vs SOC alone (OR 0.99, 95% CI 0.57 to 1.73); no significant difference in secondary outcomes such as intubation w/in 15 days, O2 requirement, LOS; QT prolongation more frequent in HCQ groups; elevated LFTs more frequent in HCQ+AZ group vs SOC alone
- Access N Engl J Med article
Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial (ORCHID) - KEY FINDINGS: HCQ did not significantly improve clinical status at day 14 vs placebo
- Study considerations: terminated early due to low enrollment; included pts w/ respiratory sx for up to 10 days; f/u limited to 28 days; no eval for viral shedding, inflammatory biomarkers, effect of other tx
- Multicenter, blinded, RCT; 479 hospitalized pts (median age 57y) w/ severe dz received HCQ 400 mg bid x1 day, then 200 mg bid x4 days (n=242) vs placebo (n=237); median sx duration 5 days; pts also received RDV (21.7%), AZ (19%), CS (18.4%)
- No significant difference in clinical status at 14 days (adjusted OR 1.02, 95% CI 0.73-1.42); no significant difference in death rate at 28 days (adjust OR 1.07, 95% CI 0.54-2.09)
- Access JAMA article
Other studies: - Hydroxychloroquine in Patients With Mainly Mild to Moderate Coronavirus Disease 2019: An Open-label, Randomised, Controlled Trial; full-text BMJ article
- Azithromycin in Addition to Standard of Care Versus Standard of Care Alone in the Treatment of Patients Admitted to the Hospital With Severe COVID-19 in Brazil (COALITION II): A Randomised Clinical Trial; full-text Lancet article
- Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State; full-text JAMA article
- Treatment With Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized With COVID-19; full-text Int J Infect Dis article
- Clinical Efficacy of Hydroxychloroquine in Patients With COVID-19 Pneumonia Who Require Oxygen: Observational Comparative Study Using Routine Care Data; full-text BMJ article
- Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-randomized Clinical Trial; full-text Int J Antimicrob Agents article
- Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized With Covid-19; full-text Med article
Treatment trials: Outpatient Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Emergency Use Authorization revoked Jun 15, 2020: Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 - KEY FINDINGS: HCQ did not substantially reduce sx severity in early, mild infxn
- Study considerations: internet-based surveys in younger pts w/ mild sx; limited testing due to shortage; primary endpoint and sample size modified mid-study; study halted before secondary endpoints; medication adherence; loss to f/u
- Double-blind, multisite RCT; 423 non-hospitalized pts (median age 40y) w/ lab-confirmed or probable COVID-19 and <5 days of sx, randomly assigned 1:1 to receive HCQ 800 mg x1, then 600 mg in 6-8h, then 600 mg daily x4 more days (n=212) or placebo (n=211); 81% had lab-confirmed infxn or epidemiologic link to a person w/ lab-confirmed infxn, 58% received SARS-CoV-2 testing; 56% enrolled w/in 1 day of sx onset; comorbid conditions incl asthma (11%), HTN (11%), DM (4%); 68% w/o comorbid conditions
- No significant difference in overall sx severity over 14 days or incidence of hospitalization between groups; higher rate of ADRs w/ HCQ (43% vs 22%)
- Access Ann Intern Med article
Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial - KEY FINDINGS: no benefit of HCQ vs SOC
- Study considerations: randomized but open-label and not placebo-controlled; study protocol amended to remove DRV/c tx option and to incl. additional specimen collection at day 7; most pts were HCWs; self-reported compliance
- Multicenter, open-label, RCT; 293 non-hospitalized pts (mean age 41.6y) w/ confirmed SARS-CoV-2 infxn, mild dz, and <5 days of sx, received HCQ 800 mg PO x1, then 400 mg PO daily x6 days (n=136) or no antiviral tx (n=157); median time from sx onset to randomization 3 days; 53.2% w/ chronic health conditions; f/u 28 days
- No significant difference in mean viral load reduction at day 3 or day 7 b/w groups; no significant reduction in hospitalization or time to sx resolution b/w groups; no pts required mech vent or died during study period; no relevant tx-assoc ADRs reported
- Access Clin Infect Dis article
Other studies: - Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial; access JAMA Network Open article
Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Randomized Trial A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 Long-term Hydroxychloroquine Use in Patients With Rheumatic Conditions and Development of SARS-CoV-2 Infection: A Retrospective Cohort Study
Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
The QT Interval in Patients With COVID-19 Treated With Hydroxychloroquine and Azithromycin - KEY FINDINGS: QTc prolongation observed w/ HCQ+AZ
- Study considerations: non-comparative; small sample size; pts had other risk factors for QT prolongation besides HCQ plus AZ tx; HCQ and AZ dosing not provided
- Retrospective, observational study; 84 hospitalized pts (mean age, 63y) w/ confirmed SARS-CoV-2 treated w/ HCQ plus AZ; comorbidities incl CAD (11%), HTN (65%), CKD (7%), DM (20%), COPD (8%), CHF (2%); 7% on amiodarone tx
- Mean QTc interval increased from 435 msec at baseline to 463 msec; 30% pts had QTc prolonged by >40 msec; 11% pts developed QTc interval of >500 msec; no cases of torsade de pointes; acute renal failure only predictor of maximal QTc >500 msec on multivariate analysis
- Access Nat Med article
Other studies: - Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19); access JAMA Cardiol article
- Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease 2019 (COVID-19) Infection Treated With Hydroxychloroquine Alone or in Combination With Azithromycin in an Intensive Care Unit; access JAMA Cardiol article
Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Emergency Use Authorization revoked June 15, 2020: Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial - KEY FINDINGS: higher CQ doses not recommended for critically ill pts due to safety concerns
- Study considerations: small sample size; interim safety data, limited efficacy analysis; high-dose CQ arm had older pts w/ more comorbidities; no contemporaneous control group
- Double-blind RCT; 81 hospitalized pts (mean age 51y; 77% w/ confirmed COVID-19 at enrollment) randomized 1:1 to high-dose CQ (600 mg bid x10 days) or low-dose CQ (450 mg bid x1 day, then 450 mg daily x4 days); all pts received AZ 500 mg daily x5 days, 90% received oseltamivir for suspected influenza infxn
- High-dose CQ group halted early due to safety concerns and all pts converted to low-dose CQ; small sample size in low-dose CQ group limits efficacy analysis, but resp secretions negative at day 4 in 6 of 27 tested pts
- 27% pts died (39% w/ high-dose CQ, 15% w/ low-dose CQ); 15% pts developed QTc interval >500 msec (19% w/ high-dose CQ, 11% w/ low-dose CQ), 2 pts had ventricular tachycardia w/ 2 deaths
Preliminary Evidence From a Multicenter Prospective Observational Study of the Safety and Efficacy of Chloroquine for the Treatment of COVID-19 - KEY FINDINGS: CQ incr viral clearance and shortened duration of sx
- Study considerations: non-randomized; historical controls treated w/ various antivirals; demographics and tx differed across time and btwn sites, incl dosing and timing of tx start; mostly moderate dz; incomplete clinical and lab data collection
- Multicenter prospective observational study; 197 hospitalized pts (mean age 44y, 91% moderate dz) w/ confirmed SARS-CoV-2 received CQ (500 mg qd or bid for up to 10 days); 176 historical controls (mean age 46y) received other antiviral tx; time btwn sx onset and tx start longer in CQ by 4 days
- Primary endpoint of time to viral suppression shorter w/ CQ (difference, 6 days); higher rate of viral clearance w/ CQ vs controls by day 10 (96% vs 91%) and by day 14 (80% vs 57%); duration of fever shorter w/ CQ; no difference in LOS; similar rates of ADRs in both groups (CQ 27%, control 32%) w/ no serious ADRs in CQ group
- Access Natl Sci Rev article
HIV protease inhibitors (eg, lopinavir, darunavir) Pharmacology/Background: - Proposed mechanism: interferes w/ maturation of viral particles by inhibiting protease enzymes
- Drugs under investigation: lopinavir/ritonavir, darunavir w/ ritonavir, darunavir/cobicistat
A Trial of Lopinavir–Ritonavir in Adults Hospitalized With Severe Covid-19 - KEY FINDINGS: no benefit w/ LPV/r tx vs SOC
- Study considerations: randomized but open-label; delayed tx initiation from sx onset; viral kinetics showed possible lack of antiviral effect (LPV/r exposure at normal doses lower vs concentrations needed for anti-SARS-CoV-2 activity)
- Open-label RCT; 199 hospitalized pts (mean age, 58y) w/ confirmed SARS-CoV-2 and O2 sat ≤94% on RA randomized 1:1 to LPV/r 400 mg/100 mg bid x14 days plus SOC, or SOC alone; 13 days median time btwn sx onset and randomization; SOC group had higher rates of vasopressor use (27% vs 17%), noninvasive mech vent (19% vs 10%), and invasive mech vent (18% vs 14%)
- No difference in median time to clinical improvement (LPV/r 16 days vs SOC 16 days) or 28-day mortality (LPV/r 19% vs SOC 25%); rate of detectable viral load similar between groups at all sampling timepoints; similar rates of ADRs (LPV/r 48% vs SOC 50%), 14% of LPV/r pts D/C due to ADRs
- Access the free full-text N Engl J Med article
Lopinavir–Ritonavir in Patients Admitted to Hospital With COVID-19 (RECOVERY): A Randomised, Controlled, Open-Label, Platform Trial - KEY FINDINGS: compared w/ SOC, LPV/r did not lower 28-day mortality, length of stay, need for mech vent, or risk of death
- Study considerations: randomized but open-label; unclear if adequate dose used; limited number of intubated pts; no collection of virological or laboratory parameters
- Randomized, controlled, open-label, adaptive platform study; current analysis incl LPV/r vs SOC only, results for other tx arms published or forthcoming
- Hospitalized pts (mean age 66.2y) w/ suspected or confirmed COVID-19 randomized to LPV/r 400 mg/100 mg bid plus SOC for up to 10 days (n=1616) vs SOC only (n=3424); 25% pts w/ no ventilatory support, most pts needed O2 only, small proportion needed mech vent
- No significant difference in 28-day all-cause mortality (RR 1.03, 95% CI 0.91 to 1.17), incl across subgroups; no significant difference in time to discharge or proportion of pts discharged
- Access full-text Lancet article
Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results - KEY FINDINGS: LPV regimens had little/no effect on mortality, vent initiation, or length of stay
- Study considerations: not peer-reviewed; randomized; interim analysis; significant proportion of pts received other potential treatments for COVID (varied by tx arm); sx duration not reported; excluded peds pts
- Multinational, randomized study; 11,266 hospitalized pts (~10% ventilated) w/ COVID-19 received either RDV (n=2,750), HCQ (n=954), LPV/r (n=1,411), IFN beta 1a + LPV/r (n=651), IFN beta 1a (n=1,412) or SOC (n=4,088); pts could receive other therapies incl CS, immunomodulators, and other non-study antivirals
- Overall 28-day mortality 12%; no significant difference in reduced mortality w/ death rate ratio vs control: RDV (RR 0.95, 95% CI 0.81-1.11), HCQ (RR 1.19, 95% CI 0.89-1.59); LPV/r (RR 1.00, 95% CI 0.79-1.25) and IFN (RR 1.16, 95% CI 0.96-1.39); no significant difference in ventilation or hospitalization duration
- Access New Engl J Med article
Other studies: - Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial; access JAMA Network Open article
- Arbidol Monotherapy Is Superior to Lopinavir/Ritonavir in Treating COVID-19; access J Infect article
- Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients With Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial; access Med article
- Treating COVID-19 With Chloroquine [vs LPV/r]; access J Mol Cell Biol article
- Triple Combination of Interferon Beta-1b, Lopinavir-Ritonavir, and Ribavirin in the Treatment of Patients Admitted to Hospital With COVID-19: An Open-label, Randomized, Phase 2 Trial; access Lancet article
- Antiviral Activity and Safety of Darunavir/Cobicistat for the Treatment of COVID-19; access Open Forum Infect Dis article
Pharmacology/Background: - Proposed mechanism: reduces inhibition of host antiviral response by blocking transport of viral proteins into nucleus
- Pharmacokinetic studies show that doses up to 10x the usual human dose result in concentrations that are substantially lower than those assoc w/ in vitro antiviral activity
Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial - KEY FINDINGS: no significant difference in sx duration in pts w/ 5-day ivermectin tx vs placebo; findings don’t support ivermectin tx for mild COVID-19
- Study considerations: double-blind, RCT (N=476); primary outcome changed at 6wk; younger study population w/ few comorbidities; may have been underpowered to detect smaller reduction in primary end point; virological assessments not included; ivermectin plasma levels not measured; placebo used for 1st 65 pts differed in taste/smell from ivermectin
- Access JAMA article
A Five-day Course of Ivermectin for the Treatment of COVID-19 May Reduce the Duration of Illness - KEY FINDINGS: early viral clearance observed in ivermectin-treated pts vs placebo; 5-day course of ivermectin may be safe and effective in mild dz
- Study considerations: double-blind, RCT; small sample size (N=72); early viral clearance not shown in ivermectin + doxycycline group
- Access Int J Infect Dis article
Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019 - KEY FINDINGS: ivermectin tx associated w/ lower mortality, esp in pts w/ severe pulmonary involvement
- Study considerations: multihospital retrospective cohort study (N=280); possible timing bias as more of the control group enrolled in 1st weeks of study; pts also received other tx incl. HCQ, AZ, or both
- Access Chest article
Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection
- KEY FINDINGS: ivermectin reduces inflammatory markers, achieves viral clearance more quickly, and improves survival vs SOC in mild/moderate dz; no significant differences on survival in severe dz
- Study considerations: meta-analysis incl. 24 randomized trials, some open-label, many not peer reviewed; studies small and varied in dosage, tx duration, inclusion criteria, outcomes measures, other tx; comparators among studies varied; most trials in mild/moderate dz
- Meta-analysis incl 24 randomized trials (8 published, 9 preprints, 6 unpublished, 1 trial registry) w/ 3,328 pts
- Reduced mortality w/ ivermectin in 11 trials w/ moderate or severe infection, (ivermectin 3%, controls 9%, RR 0.44, 95% CI 0.25-0.77); no difference in the subgroup w/ severe dz only; incr. survival in moderate dz (RR 0.30, 95% CI 0.15-0.58); ivermectin associated w/ reduced time to recovery by 1.58 days (95% CI -2.8 to -0.35) and w/ shorter hospitalization (-4.27 days, 95% CI -8.6 to -0.06)
- Access Open Forum Infect Dis article
Therapeutic Potential of Ivermectin as Add On Treatment in COVID 19: A Systematic Review and Meta-analysis - KEY FINDINGS: reduced all-cause mortality and significant clinical improvement w/ add-on ivermectin tx
- Study considerations: meta-analysis incl 4 observational studies; quality of evidence low; publication bias due to small sample size
- Access J Pharm Pharm Sci article
Other studies: - Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19; Arch Bronconeumol article
- Effectiveness of Ivermectin in SARS-CoV-2/COVID-19 Patients; Int J Sci article
- Role of Ivermectin in the Prevention of SARS-CoV-2 Infection Among Healthcare Workers in India: A Matched Case-Control Study; PLoS One article
- Ivermectin Shows Clinical Benefits in Mild to Moderate COVID19: A Randomised Controlled Double-blind, Dose-response Study in Lagos; OJM article
ACEIs/ARBs (eg, losartan, ramipril) Pharmacology/Background: - Proposed mechanism: blocks viral entry by inhibiting ACE2 receptors
Published studies: - Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial; access JAMA article
- Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19; full-text N Engl J Med article
- Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19; full-text N Engl J Med article
Pharmacology/Background: - Proposed mechanism: binds to protease implicated in viral replication
Published studies: - Does Famotidine Reduce the Risk of Progression to Severe Disease, Death, and Intubation for COVID-19 Patients? A Systemic Review and Meta-Analysis; full-text Dig Dis Sci article
- Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients; full-text Am J Gastroenterol article
- Famotidine Use Is Not Associated With 30-day Mortality; A Coarsened Exact Match Study in 7185 Hospitalized COVID-19 Patients from a Large Healthcare System; full-text Gastroenterology article
- Famotidine Use is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study; full-text Gastroenterology article
- Famotidine Use and Quantitative Symptom Tracking for COVID-19 in Hon-hospitalized Patients: A Case Series: full-text Gut article
Pharmacology/Background: - Proposed mechanism: terminates viral replication by binding to RNA-dependent RNA polymerase
- Not currently available in the U.S. Used in Japan for tx of influenza. First approved drug in China for tx of COVID-19
- Also known as avifavir, favilavir, fapilavir, Avigan
Experimental Treatment With Favipiravir for COVID-19: An Open-Label Control Study - KEY FINDINGS: FPV decr dz progression and incr viral clearance vs LPV/r
- Study considerations: non-randomized, open-label study; excl older and severe pts; possible historical bias; relationship btwn viral titer and clinical prognosis not well defined
- Open-label, non-randomized, before-after controlled study; 80 pts (median age, 47y) w/ confirmed COVID-19 received either FPV 1,600 mg bid x2 doses, then 600 mg bid (n=35) or LPV/r 400 mg/100 mg bid (n=45) for up to 14 days or until viral clearance; pts excl if >7 days from sx onset, >75 yo, or severe clinical status, incl SaO2 <93%; all pts received inhaled IFN, and SOC
- Median time to viral clearance shorter in FPV pts (4 days vs 11 days); no difference in chest CT improvement rates on day 4 and 8, but higher rates seen in FPV pts on day 14 (91% vs 62%); higher CT improvement rates also assoc w/ pts w/ <7-day viral clearance time; more adverse events in LPV/r group (56% vs 11%)
- Access Engineering article
Other studies: - Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study; access Arch Virol article
- Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial; access Int J Infect Dis article
- A Prospective, Randomized, Open-Label Trial of Early Versus Late Favipiravir in Hospitalized Patients With COVID-19; access Antimicrob Agents Chemother article
- Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial; access Eur J Pharm Sci article
- Avifavir for Treatment of Patients With Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial; access Clin Infect Dis article
Pharmacology/Background: - Proposed mechanism: activates protein kinases leading to structural changes in ACE2 receptor and subsequent reduced SARS-CoV-2 binding affinity
Pharmacology/Background: - Proposed mechanism: terminated viral replication by binding to RNA-dependent RNA polymerase
Pharmacology/Background: - Proposed mechanism: inhibits fusion of viral and cellular membranes by intercalating into membrane lipids
- Not currently available in the U.S. Used in Russia and China for tx of influenza
- Also known as Arbidol
Published studies: - Efficacy and Safety of Umifenovir for Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-analysis; access J Med Virol article
- Arbidol Combined With LPV/r vs LPV/r Alone Against Corona Virus Disease 2019: A Retrospective Cohort Study; access J Infect article
- Arbidol Monotherapy Is Superior to Lopinavir/Ritonavir in Treating COVID-19; access J Infect article
- Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients With Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial; access Med article
- Effect of Arbidol (Umifenovir) on COVID-19: A Randomized Controlled Trial; BMC Infect Dis article
- Lopinavir-ritonavir alone or combined with arbidol in the treatment of 73 hospitalized patients with COVID-19: A pilot retrospective study; access Int J Clin Pharm Ther article
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Immunomodulating drugs (eg, corticosteroids, tocilizumab)
corticosteroids (eg, dexamethasone) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response via inhibition of multiple cytokines
- Drugs under investigation: dexamethasone, methylprednisolone, inhaled budesonide, inhaled ciclesonide
Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19 - KEY FINDINGS: CS use assoc w/ lower 28-day mortality in critically ill pts
- Study considerations: prospective meta-analysis of original pt data, only incl adults; heterogeneous definitions for mortality timeframe and critical illness; significant weight (57%) from RECOVERY trial based on preliminary data; meta-analysis of serious AEs not done, inconsistent definitions and not reported by RECOVERY; optimal CS dose/duration not assessed
- Prospective meta-analysis incl. 7 RCTs (6 studies w/ low bias risk, 1 study w/ “some concerns” of bias); 1,703 hospitalized, critically ill pts (mean age 60y) w/ COVID-19 treated w/ CS (dexamethasone, hydrocortisone, or methylprednisolone) (n=678) or SOC/placebo (n=1,025)
- 28-day all-cause mortality: CS 33% vs SOC/placebo 41% (summary OR 0.66, 95% CI 0.53-0.82 based on fixed-effect analysis; summary OR 0.7, 95% CI 0.48-1.01; I2=15.6% based on random-effects
- Access full-text JAMA article
Dexamethasone in Hospitalized Patients With COVID-19 — Preliminary Report (RECOVERY) - KEY FINDINGS: DEX reduced 28-day mortality in hospitalized pts receiving O2 or mech vent but not in pts not needing respiratory support
- Study considerations: randomized but open-label; incl limited numbers of peds, pregnant, and breastfeeding pts; excl pts w/ contraindication or definitive indication for dexamethasone
- Randomized, controlled, open-label, adaptive platform study; current analysis incl DEX vs SOC only, results for other tx arms forthcoming
- Hospitalized pts (mean age 66.1y) w/ suspected or confirmed COVID-19 (89% pts positive) randomized to DEX 6 mg PO/IV qd for up to 10 days (n=2,104) vs SOC only (n=4,321); other tx incl AZ (22%), HCQ (<1%), and IL-6 antagonist (1.9%); 16% pts needed mech vent or ECMO, 60% needed O2 only; median tx duration: 7 days; median sx duration before tx: 8-9 days
- 28-day all-cause mortality lower in DEX vs SOC group (RR 0.83, 95% CI 0.74 to 0.93); pre-specified subgroup analysis showed greater benefit in mech vent pts (36% RR reduction) and non-intubated pts on O2 (18% RR reduction) but no benefit in pts not needing resp support
- Hospital stay shorter w/ DEX vs SOC (12 vs 13 days) w/ greater probability of discharge w/in 28 days (RR 1.10, 95% CI 1.03-1.17) and lower risk of progression to invasive mech vent (RR 0.77, 95% CI 0.62-0.95)
- Access full-text N Engl J Med article
Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-blind, Phase IIb, Placebo-controlled Trial - KEY FINDINGS: short-course methylprednisolone did not reduce mortality in hospitalized pts
- Study considerations: randomized; small sample size; high overall mortality compared w/ other settings; late methylprednisolone admin. in some pts
- Randomized, double-blind, controlled study; 393 hospitalized pts (mean age 55-57y) w/ COVID-19 received methylprednisolone 0.5 mg/kg IV bid x5 days (n=194) or placebo (n=199); 81.3% pts w/ lab-confirmed dz
- No significant difference in 28-day mortality; possible lower mortality rate in pts ≥60 yo w/ methylprednisolone in subgroup analysis
- Access full-text Clin Infect Dis article
Early Short Course Corticosteroids in Hospitalized Patients With COVID-19 - KEY FINDINGS: early CS in mod-severe dz decr care escalation, improved clinical outcomes
- Study considerations: quasi-experimental design; varied antiviral tx and timing; guideline adherence in post-protocol group not universal; limited f/u
- Multicenter, quasi-experimental study; institutional protocol modified to incl early CS initiation; outcomes compared before and after protocol implementation; post group pts received early methylprednisolone 0.5-1 mg/kg/day IV divided in 2 doses x3 days (up to 7 days if ICU care); 57% pre-protocol and 68% post-protocol pts received CS
- 213 hospitalized pts (median 62y; 81 pre-protocol, 132 post-protocol) w/ confirmed mod-severe COVID-19 tx w/ SOC + antivirals; CS dose and duration similar btwn groups but earlier initiation in post group (2 vs 5 days); COPD more frequent in pre-protocol group
- Lower rate of composite endpoint (ICU transfer, mech vent, death) in post-protocol (35%) vs pre-protocol (54%); median LOS reduced by 3 days w/ CS use
- Access full-text Clin Infect Dis article
Other published studies: - Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19; access JAMA article
- Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19; access JAMA article
- Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19; access JAMA article
- Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial; access Clin Infect Dis article
- Historically Controlled Comparison of Glucocorticoids With or Without Tocilizumab versus Supportive Care Only in Patients With COVID-19-Associated Cytokine Storm Syndrome: Results of the CHIC Study; access Ann Rheum Dis article
- Effect of Systemic Glucocorticoids on Mortality or Mechanical Ventilation in Patients With COVID-19; access J Hosp Med article
- Risk of COVID-19-Related Death Among Patients With Chronic Obstructive Pulmonary Disease or Asthma Prescribed Inhaled Corticosteroids: An Observational Cohort Study Using the OpenSAFELY Platform; access Lancet Respir Med article
IL-6 inhibitors (eg, tocilizumab) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
Emergency Use Authorization: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis - KEY FINDINGS: IL-6 antagonists vs SOC/placebo associated w/ lower 28-day all-cause mortality
- Study considerations: meta-analysis incl 27 trials, some ongoing and not yet peer reviewed; majority of TCZ pts received CS at randomization; limited data for siltuximab; could not account for potential differences in tx effect due to differences in baseline risk of death; ADR reporting not consistent across trials
- Meta-analysis incl 27 trials in hospitalized pts (N=10,930, median age 61y) receiving IL-6 antagonists vs no immunomodulator tx except CS
- Absolute mortality risk for IL-6 antagonists 22% vs assumed morality risk 25% for SOC/placebo (OR 0.86, 95% CI 0.79-0.95); corresponding ORs 0.83, 95% CI 0.74-0.92 for TCZ and 1.08, 95% CI 0.86-1.36 for sarilumab
- Access JAMA article
Tocilizumab in Patients Admitted to Hospital With COVID-19 (RECOVERY): A Randomised, Controlled, Open-label, Platform Trial - KEY FINDINGS: TCZ improved survival and other clinical outcomes in inpts w/ hypoxia and systemic inflammation
- Study considerations: randomized, but open label; concomitant CS; 16% TCZ group did not receive tx; outcomes beyond 28 days not captured
- Randomized, controlled, open-label platform trial; current analysis incl TCZ vs SOC only, results for other tx arms published or forthcoming
- Hospitalized pts (mean age 63.6y) w/ hypoxia and CRP >75 received 1-2 doses of IV TCZ based on wt (n=2,022) or SOC (n=2,094); 14% w/ invasive mech vent, 41% w/ non-invasive respiratory support, 45% no respiratory support; median CRP 143; 82% pts received CS
- Lower 28-day mortality w/ TCZ vs SOC (31% vs 35%; RR 0.85, 95% CI 0.76-0.94); more likely to be discharged from hospital w/in 28 days w/ TCZ
- Access Lancet article
Interleukin-6 Receptor Antagonists in Critically Ill Patients With Covid-19 (REMAP-CAP) - KEY FINDINGS: TCZ and sarilumab improved outcomes, incl survival, in critically ill pts w/ COVID-19 on organ support
- Study considerations: open label; pragmatic design; preliminary report; complex statistical model
- Multinational, adaptive platform trial; critically ill pts (mean age 61.4y) w/ severe dz and w/in 24h of cardiopulmonary support received TCZ 8 mg/kg IV x1, max 800 mg/dose (n=353), sarilumab 400 mg IV x1 (n=48), or SOC (n=402) w/in 24h of ICU admission; 29% pts received 2nd TCZ dose per clinician discretion, (only 1 sarilumab dose allowed); 93% pts received CS
- Median organ support–free days: TCZ 10 vs sarilumab 11 vs control group 0 (adjusted OR 1.64 for TCZ, 1.76 for sarilumab); 90-day survival analysis: improved survival in pooled IL-6 antagonist group vs. control group (HR 1.61, 95% credible interval, 1.25 to 2.08)
- Access N Engl J Med article
Tocilizumab in Hospitalized Patients With Severe Covid-19 Pneumonia (COVACTA) - KEY FINDINGS: TCZ didn’t improve clinical status or mortality at 28 days vs. placebo
- Study considerations: lack of standardized tx across sites/countries; lower percentage of TCZ group received CS; possible selection bias since pts w/ 2nd TCZ dose had worse outcomes; dose relative to sx onset not evaluated
- Multicenter, multinational, double-blind, RCT; 438 hospitalized pts (mean age 60y) w/ severe dz received TCZ 8 mg/kg IV x1, max 800 mg/dose (n=294) or placebo (n=144); 25% pts received 2nd TCZ dose 8-24h after 1st dose; SOC included antiviral tx, low-dose CS, convalescent plasma
- No significant difference in 28-day clinical status (TCZ 1.0 vs placebo 2.0 on 7-category ordinal scale) or mortality (TCZ 19.7%, placebo 19.4%); similar rates of adverse events in both groups
- Access N Engl J Med article
Tocilizumab in Patients Hospitalized With Covid-19 Pneumonia (EMPACTA) - KEY FINDINGS: TCZ reduced likelihood of progression to composite outcome of mech vent or death but did not improve survival
- Study considerations: high-risk and racial/ethnic minority inclusion emphasized; small sample size; CS and antiviral tx used in both trial groups
- Multinational, double-blind RCT; 377 hospitalized pts (mean age 55.9y) w/ confirmed COVID-19 pneumonia not on mech vent received TCZ (n=249) 8 mg/kg IV x1-2 doses (max 800 mg/dose) or placebo (n=128); all pts received SOC; 84% pts were Hispanic, Latino, Black, or American Indian or Alaska Native
- TCZ group had lower composite outcome of mech vent or death by day 28 vs placebo (HR 0.56, 95% CI 0.33-0.97); serious ADR incidences similar (TCZ 15.2% vs placebo 19.7%)
- Access N Engl J Med article
Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia A Randomized Clinical Trial - KEY FINDINGS: Compared w/ usual care, TCZ did not decr dz progression at day 4 or death at day 28, but may reduce risk of ventilation/death at day 14
- Study considerations: randomized, but open-label; primary outcome amended mid-study; small sample size; usual care not standardized; earlier TCZ admin not evaluated; CS used more in usual care group
- Access JAMA Intern Med article
Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia A Randomized Clinical Trial - KEY FINDINGS: TCZ did not reduce clinical worsening vs SOC
- Study considerations: randomized, but open-label; small sample size, study interrupted due to low enrollment; excluded pts at risk for ICU admission; significant imbalances btwn groups, incl antiviral use and baseline labs
- Access JAMA Intern Med article
Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19 - KEY FINDINGS: early TCZ use assoc w/ lower in-hospital mortality in critically ill
- Study considerations: non-randomized; inverse probability weighting; significant imbalances btwn groups; number of TCZ doses not recorded; CS duration not recorded; missing data for some key variables
- Access JAMA Intern Med article
Efficacy of Tocilizumab in Patients Hospitalized With Covid-19 - KEY FINDINGS: TCZ did not prevent intubation or death in mod dz
- Study considerations: small sample size; SOC evolved during trial; significant baseline differences despite randomization
- Access N Engl J Med article
Effect of Tocilizumab on Clinical Outcomes at 15 days in Patients With Severe or Critical Coronavirus Disease 2019: Randomised Controlled Trial - KEY FINDINGS: TCZ + SOC not superior to SOC for improving clinical outcomes at 15 days in severe or critical COVID-19; TCZ may incr mortality
- Study considerations: randomized but open label; small sample size; trial stopped early; imbalanced baseline respiratory support and AZ use
- Access BMJ article
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
Expanded Access/Compassionate Use: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis - KEY FINDINGS: IL-6 antagonists vs SOC/placebo associated w/ lower 28-day all-cause mortality
- Study considerations: meta-analysis incl 27 trials, some ongoing and not yet peer reviewed; majority of TCZ pts received CS at randomization; limited data for siltuximab; could not account for potential differences in tx effect due to differences in baseline risk of death; ADR reporting not consistent across trials
- Meta-analysis incl 27 trials in hospitalized pts (N=10,930, median age 61y) receiving IL-6 antagonists vs no immunomodulator tx except CS
- Absolute mortality risk for IL-6 antagonists 22% vs assumed morality risk 25% for SOC/placebo (OR 0.86, 95% CI 0.79-0.95); corresponding ORs 0.83, 95% CI 0.74-0.92 for TCZ and 1.08, 95% CI 0.86-1.36 for sarilumab
- Access JAMA article
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
IL-1 inhibitors (eg, anakinra) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-1 receptors
- Drugs under investigation include: anakinra, canakinumab
Anakinra for Severe Forms of COVID-19: A Cohort Study - KEY FINDINGS: anakinra decr invasive mech vent or death risk in severe dz
- Study considerations: retrospective, small sample size, historical bias; imbalanced baseline characteristics
- Retrospective cohort study; 96 hospitalized non-ICU pts w/ severe COVID-19 managed w/ SOC, incl HCQ, AZ, other abx, CS, DVT prophylaxis; prospective cohort of 52 pts received anakinra (100 mg SC bid x72h, then 100 mg SC daily x7 days) + SOC; 44 pts as historical control treated w/ SOC only; anakinra group had lower BMI, longer sx duration, higher baseline plt count, higher concomitant HCQ and AZ use
- Composite primary outcome of mech vent or death: anakinra 25% vs SOC 73% (hazard ratio 0.22, 95% CI 0.1-0.49); elevated LFTs w/ anakinra 13% vs SOC 9%; similar results observed for death alone or need for mech vent alone
- Access full-text Lancet Rheumatol article
Interleukin-1 Blockade With High-dose Anakinra in Patients With COVID-19, Acute Respiratory Distress Syndrome, and Hyperinflammation: A Retrospective Cohort Study - KEY FINDINGS: high-dose anakinra assoc w/ clinical improvement and appears safe
- Study considerations: retrospective; small sample size; historical bias; selection bias; varied dosing regimens
- Retrospective cohort study; 52 hospitalized non-ICU pts w/ confirmed COVID-19, mod-severe ARDS, and hyperinflammation managed w/ non-invasive vent and SOC, incl HCQ and LPV/r; 29 pts (median age 62y) received high-dose (HD) anakinra 5 mg/kg IV bid until sustained clinical benefit; 16 pts (median age 70y) as historical comparator treated w/ SOC only; low-dose group (anakinra 100 mg SC bid; n=7) terminated early due to lack of efficacy
- Respiratory fxn improved in 72% HD vs 50% SOC; 10% HD pts died vs 44% SOC; higher cumulative survival in HD (90% vs 56%), no difference in mech vent-free survival; HD assoc w/ CRP decr at day 21 vs no decr w/ SOC
- 24% on high dose D/C due to ADRs; 14% HD pts vs 13% SOC pts developed bacteremia; 10% HD pts vs 31% SOC pts had incr LFTs; no rebound inflammation
- Access Lancet Rheumatol article
JAK inhibitors (eg, baricitinib, ruxolitinib, tofacitinib) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by disrupting cytokine pathways via inhibition of janus-associated kinases (JAK)
- Drugs under investigation include: baricitinib, ruxolitinib, tofacitinib
Emergency Use Authorization: Expanded Access/Compassionate Use - Expanded Access Program of Ruxolitinib for the Emergency Treatment of Cytokine Storm From COVID-19 Infection, NCT04355793
Ruxolitinib in Treatment of Severe Coronavirus Disease 2019 (COVID-19): A Multicenter, Single-blind, Randomized Controlled Trial - KEY FINDINGS: ruxolitinib significantly improved chest CT and lymphopenia recovery and was well-tolerated
- Study considerations: randomized but single-blind; small sample size and early termination; excluded critically ill and mech vent pts; inconclusive results based on limited data and analysis
- Prospective, single-blind, multicenter RCT; 41 pts (median age 63y) w/ severe COVID-19 randomly assigned 1:1 to receive ruxolitinib 5 mg PO bid + SOC (n=20) or vitamin C 100 mg PO bid + SOC (n=21); SOC incl antivirals, CS, and abx; median time btwn sx onset and randomization 20 days; no significant differences in baseline demographics; antivirals and CS used in 90% and 71% of pts, respectively
- No difference in time to, or rate of, clinical improvement; significant CT improvement at day 14 w/ ruxolitinib (90% vs 62%); 28% overall mortality at day 28 (ruxolitinib 0% vs vitamin C 14%), no difference in cumulative incidence of death btwn 2 groups
- No difference in total number of ADRs btwn 2 groups; no difference in median time of viral clearance; shorter median time of lymphopenia recovery in ruxolitinib group; cytokine levels significantly decreased in ruxolitinib group
- Access J Allergy Clin Immunol abstract
Baricitinib Plus Remdesivir for Hospitalized Adults With Covid-19 - KEY FINDINGS: baricitinib + RDV superior to RDV alone in reducing recovery time and accelerating clinical status improvement, particularly in pts w/ high-flow O2 or noninvasive vent
- Study considerations: other COVID-19 tx allowed, per hospital protocols; 12% pts received corticosteroid tx (6.6% DEX); median sx onset 8 days before enrollment
- Multicenter, randomized, double-blind study; 1,033 hospitalized pts (mean age 55.4y) w/ COVID-19 (68% mod. dz, 32% severe dz) received baricitinib 4 mg PO qd x14 days (n=515) or placebo (n=518); both groups received RDV 200 mg IV x1, then 100 mg IV qd x9 days; other experimental or off-label COVID-19 tx prohibited unless part of hospital protocol
- Primary outcome of time to recovery: baricitinib 7 days vs placebo 8 days (RR 1.16, 95% CI 1.01-1.32); in pts w/ high-flow O2 or noninvasive vent, baricitinib 10 days vs placebo 18 days (RR 1.51, 95% CI 1.1-2.08); no difference in 28-day mortality; fewer serious ADRs and new infxns w/ baricitinib vs placebo
- Access N Engl J Med article
Pharmacology/Background - Proposed mechanism: no direct antiviral activity; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ HCQ or CQ; monitor ECG; FDA MedWatch (4/24/20): Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial - KEY FINDINGS: AZ doesn’t reduce hospitalization risk or time to recovery in older adult pts in the community w/ suspected COVID-19 risk
- Study considerations: open-label, RCT; large sample size (N=2,265); incl pts w/ suspected dz w/in 14 days of sx onset; only 31% pts had confirmed SARS-CoV-2 PCR results; incl. pts ≥50y w/ comorbidities or ≥65y; primary outcome revised during trial; recovery was self-reported
- Access Lancet article
Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial - KEY FINDINGS: AZ didn’t improve survival or other clinical outcomes in hospitalized pts
- Study considerations: multicenter, open-label, RCT; large sample size (N=7,763); broad eligibility criteria; no detailed info regarding lab markers, inflammatory status, other abx
- Access Lancet article
Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection, A Randomized Clinical Trial - KEY FINDINGS: Single dose of oral AZ didn’t result in greater likelihood of being sx-free at day 14
- Study considerations: randomized trial; self-reported results; primary outcome changed prior to 1st interim analysis; underpowered for hospitalization end points; substantial nonadherence to study meds; missing adherence data; high loss to f/u
- Access JAMA article
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State - KEY FINDINGS: HCQ, AZ, or both not significantly assoc w/ in-hospital mortality vs no tx
- Study considerations: retrospective (N=1,438), random sampling; imbalanced baseline characteristics; treatment bias; varied dosing and duration; possible missed readmissions; ADRs at any time during hospital visit, potentially prior to tx
- Access JAMA article
Note: Published data summaries include AZ as mono-tx. For published studies on combo tx, refer to HCQ.
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting interleukin pathways via interference w/ inflammasome complex assembly; reduces cell infectivity by interrupting endocytosis via inhibition of microtubule polymerization
Colchicine for Community-treated Patients With COVID-19 (COLCORONA): A Phase 3, Randomised, Double-blinded, Adaptive, Placebo-controlled, Multicentre Trial - KEY FINDINGS: colchicine did not significantly reduce death or hospitalization among community-treated pts, but had possible benefit in subgroup of PCR-positive pts
- Study considerations: trial stopped w/ 75% pts recruited; f/u duration relative short (30 days)
- Multicenter, double-blind, adaptive, RCT; non-hospitalized pts (median 54y) w/ at ≥1 high-risk factor received colchicine 0.5 mg PO bid x3 days, then 0.5 mg PO qd x27 days (n=2,235) or placebo (n=2,253)
- Death or hospital admission not significantly less w/ colchine vs placebo (4.7% vs 5.8%; OR 0.79, CI 0.61-1.03); in subgroup of pts w/ PCR-confirmed dx, death or hospital admission significantly less in colchicine group (4.6% vs 6.3%; OR 0.75, CI 0.57-0.99); diarrhea reported more often w/ colchicine (13.7% vs 7.3%)
- Access full-text Lancet Respir Med article
Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial - KEY FINDINGS: colchicine significantly decr clinical deterioration rate
- Study considerations: randomized but open-label; small sample size; inconclusive results based on limited data and analysis
- Prospective, open-label, multicenter, randomized study; 105 hospitalized pts (median age 64y) w/ confirmed COVID-19 tx w/ colchicine 1.5 mg x1 then 0.5 mg after 60min, then 0.5 mg bid (n=55) + SOC or SOC only (n=50) for up to 3wk; most pts received CQ/HCQ (98%) and AZ (92%); study terminated early due to low enrollment
- Clinical deterioration rate lower in colchicine group (2% vs 14%); mean event-free survival time greater in colchicine group (20.7 vs 18.6 days); no difference in max high-sensitivity cardiac troponin levels or peak CRP levels; overall adverse events similar, but diarrhea more frequent w/ colchicine
- Access full-text JAMA Netw Open article
Other published studies: - Association Between Treatment With Colchicine and Improved Survival in a Single-Centre Cohort of Adult Hospitalised Patients With COVID-19 Pneumonia and Acute Respiratory Distress Syndrome; full-text Ann Rheum Dis article
complement inhibitors (eg, eculizumab) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by modulating activity of complement pathways
- Drugs under investigation include: eculizumab, ravalizumab
Expanded Access/Compassionate Use: Published studies: - Combination of Ruxolitinib and Eculizumab for Treatment of Severe SARS-CoV-2-Related Acute Respiratory Distress Syndrome: A Controlled Study; access Front Pharmacol article
Pharmacology/Background: - Proposed mechanism: binds to interferon receptors, modulates immune responses to some viral infxns; in vitro studies indicate weak IFN induction in SARS-CoV-2 infxn
- Generally used in combo w/ other antivirals; IFN beta more potent than IFN alpha for coronaviruses; IFN lambda has less inflammatory effects on respiratory tract
Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results - KEY FINDINGS: interferon had little/no effect on mortality, vent initiation, or length of stay
- Study considerations: not peer-reviewed; randomized; interim analysis; significant proportion of pts received other potential treatments for COVID (varied by tx arm); sx duration not reported; excluded peds pts
- Multinational, randomized study; 11,266 hospitalized pts (~10% ventilated) w/ COVID-19 received either RDV (n=2,750), HCQ (n=954), LPV/r (n=1,411), IFN beta 1a + LPV/r (n=651), IFN beta 1a (n=1,412) or SOC (n=4,088); pts could receive other therapies incl CS, immunomodulators, and other non-study antivirals
- Overall 28-day mortality 12%; no significant difference in reduced mortality w/ death rate ratio vs control: RDV (RR 0.95, 95% CI 0.81-1.11), HCQ (RR 1.19, 95% CI 0.89-1.59); LPV/r (RR 1.00, 95% CI 0.79-1.25) and IFN (RR 1.16, 95% CI 0.96-1.39); no significant difference in ventilation or hospitalization duration
- Access New Engl J Med article
SSRIs (fluoxetine, fluvoxamine) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors or binding to sigma-1 receptors
statins (eg, atorvastatin) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by mitigating cytokine activation pathways; attenuates CV component or complications assoc w/ COVID-19; epidemiological data suggest protective effects in influenza pneumonia
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Adjunctive drugs (eg, ascorbic acid, antithrombotics)
ascorbic acid (vitamin C) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response and production of reactive oxygen species via anti-inflammatory and antioxidant properties; supports host defenses and protects host cells against oxidative stress
- For additional info, see Alt Med Remedy Use in COVID-19
Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection--The COVID A to Z Randomized Clinical Trial - KEY FINDINGS: high-dose zinc gluconate and ascorbic acid, individually or combined, didn’t decrease sx duration vs SOC in outpts w/ COVID-19
- JAMA Netw Open article
Other studies: - Safety and effectiveness of high-dose vitamin C in patients with COVID-19: a randomized open-label clinical trial; access Eur J Med Res article
Pharmacology/Background: - Proposed mechanism: reduces susceptibility to infxn by supporting antimicrobial peptide production in respiratory epithelium; reduces inflammatory response by countering downregulation of ACE2 by SARS-CoV-2
- For additional info, see Alt Med Remedy Use in COVID-19
Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19 A Randomized Clinical Trial - KEY FINDINGS: a single high dose of vitamin D3 did not reduce hospital length of stay vs placebo in inpts w/ mod-severe COVID-19
- JAMA article
Pharmacology/Background: - Proposed mechanism: impairs replication of various viruses, incl coronaviruses, by inhibiting RNA-dependent RNA polymerase; intracellular concentrations increased by HCQ and CQ
- For additional info, see Alt Med Remedy Use in COVID-19
Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection--The COVID A to Z Randomized Clinical Trial - KEY FINDINGS: high-dose zinc gluconate and ascorbic acid, individually or combined, didn’t decrease sx duration vs SOC in outpts w/ COVID-19
- JAMA Netw Open article
antithrombotics (eg, heparin, LMWH, dipyridamole, argatroban, fondaparinux) Pharmacology/Background: - Mechanism: See individual drugs
- COVID-19 assoc w/ hypercoagulable state; thrombotic events reported despite pharmacologic VTE prophylaxis; higher prophylactic doses and/or prolonged courses may be needed; unclear role for empiric therapeutic-dose anticoagulation
- Anticoagulants under investigation: enoxaparin, heparin (IV, SC, neb, intranasal), argatroban, fondaparinux, apixaban, rivaroxaban
- Antiplatelet agents under investigation: aspirin, dipyridamole, aspirin/dipyridamole, clopidogrel
Published studies: - Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19; access Ann Intern Med article
- Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19; access J Am Coll Cardiol article
- Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit--The INSPIRATION Randomized Clinical Trial; access JAMA article
- The Association Between Treatment With Heparin and Survival in Patients With Covid-19; access J Thromb Thrombolysis article
- Anticoagulation, Mortality, Bleeding and Pathology Among Patients Hospitalized With COVID-19: A Single Health System Study; access J Am Coll Cardiol abstract
- The Impact of Protocol‐Based High‐Intensity Pharmacological Thromboprophylaxis on Thrombotic Events in Critically Ill COVID‐19 Patients; access Anaesthesia article
- Early Initiation of Prophylactic Anticoagulation for Prevention of Coronavirus Disease 2019 Mortality in Patients Admitted to Hospital in the United States: Cohort Study; access BMJ article
- Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019; access Anesth Analg article
epocrates drug links: heparin, enoxaparin, dalteparin, argatroban, fondaparinux, aspirin, dipyridamole, aspirin/dipyridamole, clopidogrel, apixaban, rivaroxaban
hormonal tx (eg, estrogen, antiandrogens) Pharmacology/Background: - Proposed mechanism: animal studies of SARS-CoV-1 suggest protective effects of estrogen, incl immunomodulating effects and wound repair processes; androgen receptor expression assoc w/ incr expression of host proteins needed for SARS-CoV-2 viral entry
- Drugs under investigation include: estrogen, progesterone, bicalutamide, degarelix, dutasteride, toremifene
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response via replenishment of glutathione and reduction of proinflammatory cytokines; supports host defenses and protects host cells against oxidative stress
- For additional info, see Alt Med Remedy Use in COVID-19
pulmonary vasodilators (eg, nitric oxide, epoprostenol, aviptadil) Pharmacology/Background: - Proposed mechanism: dilates pulmonary vasculature, leading to vasodilation and increased oxygenation
- Nitric oxide reported to have in vitro activity against other coronaviruses (eg, SARS-CoV)
- Drugs under investigation include: nitric oxide, sodium nitrite, epoprostenol, aviptadil
Expanded Access/Compassionate Use:
thrombolytics (eg, alteplase [tPA], tenecteplase) Pharmacology/Background: - Proposed mechanism: See individual drugs
- COVID-19 assoc w/ hypercoagulable state; thrombotic events reported despite pharmacologic VTE prophylaxis; unclear role for thrombolytic tx
- Drugs under investigation: alteplase (tPA), tenecteplase, defibrotide
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Antibody-based therapies (eg, convalescent plasma, monoclonal antibodies)
Emergency Use Authorization Expanded Access/Compassionate Use: Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19 A Systematic Review and Meta-analysis - KEY FINDINGS: convalescent plasma not associated w/ improved survival or other clinical outcomes in mod-severe dz
- Study considerations: 3 of 10 RCTs w/ some concerns or high risk of bias; relevant definition of outcomes outside of all-cause mortality for one trial insufficient or inconsistent; unable to perform subgroup analysis due to limited data; only incl mod-severe pts
- Meta-analysis incl 4 peer-reviewed published and 6 unpublished RCTs
- Mortality summary risk ratios 0.93 (4 published trials) and 1.02 (4 published + 6 unpublished trials), not statistically significant; among 4 peer-reviewed trials, no difference in length of hospital stay (HR 1.17, 95% CI 0.07-20.34) and mech vent use (summary RR 0.76, 95% CI 0.20-2.87)
- Access JAMA article
Convalescent Plasma in Patients Admitted to Hospital With COVID-19 (RECOVERY): A Randomised Controlled, Open-label, Platform Trial - KEY FINDINGS: convalescent plasma did not improve survival or other prespecified clinical outcomes
- Study considerations: randomized but open-label; incl limited numbers of peds, pregnant, and breastfeeding pts; does not address benefits if convalescent plasma given earlier; no evidence of differential effect due to B.1.1.7 variant
- Randomized, controlled, open-label, adaptive platform study; current analysis incl convalescent plasma vs SOC only, results for other tx arms forthcoming
- Hospitalized pts (mean age 63.5y) w/ suspected or confirmed COVID-19 randomized to convalescent plasma (n=5,795) vs SOC only (n=5,763); other tx incl CS (92%), AZ (10%), or colchicine (14%); at randomization, 5% received mech vent, 87% needed O2 only
- No significant difference in 28-day all-cause mortality: convalescent plasma 24% vs SOC 24% (RR 1, 95% CI 0.93-1.07); no significant difference in death rate/invasive mech vent composite endpoint
- Access Lancet article
A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia - KEY FINDINGS: convalescent plasma had no benefit in severe dz vs placebo
- Study considerations: randomized but open-label; tx non standardized among sites; CS and other tx used in both trial groups; cannot assess early admin effects
- Multicenter, randomized, controlled study; 333 hospitalized pts (median age 62y) w/ confirmed severe COVID-19 received convalescent plasma (n=228) or placebo (n=105); median time from sx onset to enrollment 8 days; median SARS-CoV-2 Ab titer 1:3200; >90% pts received CS; smaller percentage received LPV/r, TCZ, or ivermectin
- No significant difference in 7-, 14-, or 30-day clinical outcome, time to discharge, 30-day mortality, or overall ADRs
- Access N Engl J Med article
Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial - KEY FINDINGS: convalescent plasma did not significantly decr time to clinical improvement
- Study considerations: randomized, but open label; early termination due to epidemic containment; small sample size, possibly underpowered; median time 30 days btwn sx onset and randomization; SOC not protocolized, study center variability; limited f/u
- Multicenter, open-label, randomized study; 103 hospitalized pts (median age 70y) w/ confirmed severe or life-threatening COVID-19, randomized 1:1 by dz severity to receive convalescent plasma 200 mL (n=52) or SOC alone (n=51)
- Donors recovered from COVID-19, discharged from hospital >14 days, S-protein-specific Ab titers >1:640
- No significant difference in time to clinical improvement w/in 28 days overall (convalescent plasma 51.9%, control 43.1%); in pts w/ severe dz, time to clinical improvement rate higher w/ convalescent plasma (91.3%) vs control (68.2%); no significant difference vs placebo in 28-day mortality (15% vs 24%), time to discharge (51% vs 36%); higher negative viral PCR conversion rate w/ convalescent plasma (87.2%) vs control (27.5%)
- Access JAMA abstract
Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults - KEY FINDINGS: early admin of high-titer convalescent plasma reduced COVID-19 progression in older adults w/ mild dz
- Study considerations: early termination in October 2020 due to epidemic containment in Argentina; small sample size, possibly underpowered
- Randomized, double-blind, placebo-controlled study; 160 pts (mean age 77.2y) w/ mild COVID-19 received 250 mL convalescent plasma w/ IgG titer >1:1000 (n=80) or placebo (n=80) w/in 72h after sx onset
- Significantly less pts developed severe respiratory dz w/ convalescent plasma (16% vs 31%, RR 0.52, 95% CI 0.29-0.94); lower rates of dz progression w/ infusions w/ donor titers >1:3200 (73% relative risk reduction); no correlation w/ outcomes based on recipient antibody levels; no solicited ADRs observed
- Access N Engl J Med article
Convalescent Plasma Antibody Levels and the Risk of Death From Covid-19 - KEY FINDINGS: convalescent plasma w/ higher anti-SARS-CoV-2 IgG levels associated w/ lower risk of death
- Study considerations: non-comparative; results based on national registry/expanded access; sample size not determined a priori; pts received other tx
- Retrospective study; 3,082 hospitalized adult pts (56.5% >60y) w/ confirmed COVID-19 and at high risk of progression to severe/life-threatening dz, received one or more units of convalescent plasma w/ high, medium, or low anti-SARS-CoV-2 IgG levels, per protocol; other tx used incl CS, RDV
- Death w/in 30 days occurred in 26.9% of all pts (high-titer 23% vs medium-titer 27.4% vs low-titer 29.6%); lower 30-day death risk in pts w/o mech vent w/ high vs low-titer (RR 0.66, 95% CI 0.48-0.91), but no difference in pts on mech vent
- Access N Engl J Med article
SARS-CoV-2-specific monoclonal antibodies Pharmacology/Background:
- Proposed mechanism: binds to specific viral targets and acts as neutralizing antibodies; most agents target spike protein, preventing viral entry and replication
- Drugs under investigation include: casirivimab (REGN10933), imdevimab (REGN10987), bamlanivimab (LY-CoV555), etesevimab (LY-CoV016), sotrovimab (VIR-7831)
Emergency Use Authorization: Expanded Access/Compassionate Use
- Compassionate Use of REGN-COV2 for the Treatment of COVID-19; NCT04617535
Published studies: - REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients With Covid-19; N Engl J Med article
- Bamlanivimab Plus Etesevimab in Mild to Moderate COVID-19; N Engl J Med article
- SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients With Covid-19; N Engl J Med article
- Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial; JAMA article
- Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-1: A Randomized Clinical Trial; JAMA article
- A Neutralizing Monoclonal Antibody for Hospitalized Patients With Covid-19; N Engl J Med article
Pharmacology/Background: - Proposed mechanism: provided passive immunity
Clinical Efficacy of Intravenous Immunoglobulin Therapy in Critical Patients With COVID-19: A Multicenter Retrospective Cohort Study - KEY FINDINGS: no benefit in overall cohort; early high-dose use may improve prognosis in critically ill, per subgroup analysis
- Study considerations: retrospective; treatment bias; IVIG timing, dosing, and duration varied among sites
- Retrospective study; 325 hospitalized pts (mean age, 58y) w/ confirmed SARS-CoV-2 (68% severe, 32% critical); 174 pts received IVIG 0.1-0.5 g/kg daily x5-15 days, 151 pts received SOC only; IVIG pts had more severe dz (higher APACHE II, SOFA scores, O2 needs
- No significant difference in 28-day in-hospital mortality (13% in both groups) or 60-day in-hospital mortality (19% IVIG, 14% non-IVIG); IVIG group had longer LOS (23.5 vs 16 days) and longer dz duration (31 vs 23 days)
- Access Clin Transl Immunology article
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