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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
Emergency Use Authorization: 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
Remdesivir in Adults With Severe COVID-19: A Randomised, Double-blind, Placebo-controlled, Multicentre Trial - 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%)
- Study considerations: underpowered due to low enrollment; imbalanced baseline characteristics despite randomization; possible delay in tx start; questionable utility of subgroup analyses
- Access Lancet article
Compassionate Use of Remdesivir for Patients With Severe COVID-19 - Prospective, observational study: 53 hospitalized pts (median age, 64y) w/ O2 sat <94% on RA or receiving O2 support received RDV 200 mg IV x1 dose on day 1, then 100 mg daily x9 days (median time btwn sx and tx start, 12 days); 64% pts w/ invasive ventilation, 24% w/ minimal to no O2 support
- 68% of pts had improved O2 support category, 57% of pts w/ mech vent extubated, 13% of pts died; 60% experienced ADRs (23% serious); 23% of pts had elevated LFTs
- Study considerations: non-comparative; selection and sampling bias; no prespecified endpoints; duration of f/u shorter than planned; significant proportion had mild dz; delayed tx initiation from sx onset
- Access free N Engl J Med 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: Observational Study of Hydroxychloroquine in Hospitalized Patients With COVID-19 - 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)
- Study considerations: non-randomized; weighted propensity score model; treatment bias, HCQ pts were generally sicker; missing data and inaccuracies in EHR
- Access N Engl J Med article
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State - Retrospective multicenter cohort study; 1,438 randomly selected hospitalized pts (median age 63y) in NYC metro area w/ confirmed COVID-19 treated w/ HCQ (n=271) or AZ (n=211) alone, HCQ+AZ (n=735), or no tx (n=221); significant imbalances btwn groups, incl gender, comorbidities, and clinical severity
- Unadjusted analysis for in-hospital mortality (overall 20%), HCQ+AZ 26%, HCQ 20%, AZ 10%, no tx 13%; adjusted analysis for in-hospital mortality showed no differences when comparing pts w/ no tx to each drug group, and when comparing HCQ vs AZ
- Abnormal ECG more common in HCQ+AZ (27%) and HCQ (27%) vs AZ (16%) and no tx (14%), but no difference in adjusted analysis; more pts w/ cardiac arrest in HCQ+AZ (16%) and HCQ (14%) vs AZ (6%) and no tx (7%)
- Study considerations: retrospective, 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
Hydroxychloroquine in Patients With Mainly Mild to Moderate Coronavirus Disease 2019: An Open-label, Randomised, Controlled Trial - Multicenter, open-label, RCT; 150 hospitalized pts (mean age 46y; 99% mild or moderate dz; 63% received other antivirals) randomized 1:1 to SOC or SOC plus HCQ 1,200 daily x3 days, then 800 mg daily for total of 2-3wk based on dz severity; 17 days mean time btwn sx onset and randomization; study D/C early based on results from pre-planned interim analysis
- No difference in primary endpoint of viral clearance (85% HCQ vs 81% SOC) or secondary endpoint of sx improvement rate (60% HCQ vs 67% SOC); higher rate of ADRs in HCQ group (30% vs 9%)
- Study considerations: randomized but open-label; most pts received other potential antivirals; delayed tx initiation from sx onset; almost all pts had mild-moderate dz; higher HCQ dose and duration than other studies
- Access BMJ article
Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized With Covid-19 - Retrospective cohort study; 368 hospitalized pts (median age 69y) treated w/ HCQ (n=97), HCQ and AZ (n=113), or supportive care only (n=158); 32% of supportive care pts received AZ w/o HCQ; sicker pts more likely to receive HCQ or HCQ + AZ
- Unadjusted analysis: Death occurred in 28% of HCQ pts, 22% of HCQ + AZ pts, 11% of no-HCQ pts; mech vent occurred in 13% of HCQ pts, 7% of HCQ + AZ pts, 14% of no HCQ pts
- Analysis adjusted for baseline imbalances: higher risk of death in HCQ group vs no-HCQ (adjusted HR 2.61) but no difference in HCQ + AZ vs no-HCQ; no difference in mech vent in HCQ vs no-HCQ and HCQ + AZ vs no-HCQ
- Study considerations: non-randomized, retrospective w/ propensity score adjusted analysis; tx bias; cohort characteristics impact external validity; dosing and duration not provided; drug exposure based on dispensing records
- Access pre-print medRxiv article
The QT Interval in Patients With COVID-19 Treated With Hydroxychloroquine and Azithromycin - 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
- 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
- Access Nat Med article
Other studies:
- 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
- Early Treatment of COVID-19 Patients With Hydroxychloroquine and Azithromycin: A Retrospective Analysis of 1061 Cases in Marseille, France; full-text Travel Med Infect Dis article
- Clinical and Microbiological Effect of a Combination or Hydroxychloroquine and Azithromycin in 80 COVID-19 Patients With at Least a Six-Day Follow-up: An Observational Study; full-text Travel Med Infect Dis article
- No Evidence of Rapid Antiviral Clearance or Clinical Benefit With the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection; full-text article
- The QT Interval in Patients With COVID-10 Treated With Hydroxychloroquine and Azithromycin; full text Nat Med article
- 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:
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 - 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
- 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
- Access JAMA Netw Open article
Preliminary Evidence From a Multicenter Prospective Observational Study of the Safety and Efficacy of Chloroquine for the Treatment of COVID-19 - 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
- 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
- Access pre-print medRxiv article
Pharmacology/Background: - Proposed mechanism: interferes w/ maturation of viral particles by inhibiting protease enzymes
A Trial of Lopinavir–Ritonavir in Adults Hospitalized With Severe Covid-19 - 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
- 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)
- Access the free full-text N Engl J Med article
Other studies: - Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients With Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial; access Med article
- Lopinavir-Ritonavir Alone or Combined With Arbidol in the Treatment of 73 Hospitalized Patients With COVID-19: A Pilot Retrospective Study; access pre-print medRxiv 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
Pharmacology/Background: - Proposed mechanism: inhibits viral polymerase acidic protein endonuclease activity, inhibiting viral replication; reported in vitro activity against SARS-CoV-2
Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial; access pre-print medRxiv article
ACEIs/ARBs (eg, losartan, ramipril) Pharmacology/Background: - Proposed mechanism: blocks viral entry by inhibiting ACE2 receptors
Pharmacology/Background: - Proposed mechanism: activity against RNA-dependent RNA polymerases; in vitro activity against arboviruses (eg, Zika)
Pharmacology/Background: - Proposed mechanism: reduces infectivity and virulence by inhibiting conversion of plasminogen to plasmin (plasmin interacts w/ viral surface proteins to increase binding to cellular receptors)
DPP-4 inhibitors (eg, linagliptin) Pharmacology/Background: - Proposed mechanism: blocks viral entry; reportedly blocks MERS-CoV entry receptor (DPP-4)
Pharmacology/Background: - Proposed mechanism: targets mTOR complex involved in replication of various viruses, including coronaviruses
Pharmacology/Background: - Proposed mechanism: inhibits kinases which may play role in viral entry, replication, and egress; prevents viral/cell fusion via lysosomal alkalinization; anti-inflammatory activity in animal models attenuates acute lung injury
Pharmacology/Background: - Proposed mechanism: reduces inhibition of host antiviral response by blocking transport of viral proteins into nucleus
- 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
Pharmacology/Background: - Proposed mechanism: interferes w/ host-regulated pathways involved in viral replication rather than a virus-targeted mechanism; broad-spectrum in vitro activity against various viruses, including coronaviruses
Pharmacology/Background: - Proposed mechanism: binds to protease implicated in viral replication
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 favilavir, fapilavir, Avigan
Favipiravir vs Arbidol for COVID-19: A Randomized Controlled Trial - Prospective, open-label, multicenter RCT; 240 adult pts (71% age <65y; 42% pts w/ positive PCR for SARS-CoV-2; 96% w/ CT findings suggestive of COVID-19 pneumonia) received either umifenovir (Arbidol) 200 mg tid x7-10 days (n=120) or FPV 1,600 mg bid x1 on day 1, then 600 mg bid x7-10 days total (n=116); all pts received SOC
- No significant difference in primary endpoint of clinical recovery rate on day 7 (61% FPV, 51% umifenovir); quicker defervescence and sx relief w/ FPV in pts w/ moderate dz; no difference in rate of auxiliary O2 tx or noninvasive mechanical ventilation; higher serum uric acid in FPV group
- Study considerations: active control; more severe/critical pts in FPV group; pts received other antivirals and traditional Chinese medicine; limited observation time frame
- Access pre-print medRxiv article
Experimental Treatment With Favipiravir for COVID-19: An Open-Label Control Study - 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%)
- 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
- Access Engineering article
Other studies: - Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial; access pre-print medRxiv article
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
Favipiravir vs Arbidol for COVID-19: A Randomized Controlled Trial - Prospective, open-label, multicenter RCT; 240 adult pts (71% age <65y; 42% pts w/ positive PCR for SARS-CoV-2; 96% w/ CT findings suggestive of COVID-19 pneumonia) received either umifenovir (Arbidol) 200 mg tid x7-10 days (n=120) or FPV 1,600 mg bid x1 on day 1, then 600 mg bid x7-10 days total (n=116); all pts received SOC
- No significant difference in primary endpoint of clinical recovery rate on day 7 (61% FPV, 51% umifenovir); quicker defervescence and sx relief w/ FPV in pts w/ moderate dz; no difference in rate of auxiliary O2 tx or noninvasive mechanical ventilation; higher serum uric acid in FPV group
- Study considerations: active control; more severe/critical pts in FPV group; pts received other antivirals and traditional Chinese medicine; limited observation time frame
- Access pre-print medRxiv article
Other trials: - 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
- Lopinavir-Ritonavir Alone or Combined With Arbidol in the Treatment of 73 Hospitalized Patients With COVID-19: A Pilot Retrospective Study; access pre-print medRxiv article
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Immunomodulating drugs (eg, azithromycin, tocilizumab)
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
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State - Retrospective multicenter cohort study; 1,438 randomly selected hospitalized pts (median age 63y) in NYC metro area w/ confirmed COVID-19 treated w/ HCQ (n=271) or AZ (n=211) alone, HCQ+AZ (n=735), or no tx (n=221); significant imbalances btwn groups, incl gender, comorbidities, and clinical severity
- Unadjusted analysis for in-hospital mortality (overall 20%), HCQ+AZ 26%, HCQ 20%, AZ 10%, no tx 13%; adjusted analysis for in-hospital mortality showed no differences when comparing pts w/ no tx to each drug group, and when comparing HCQ vs AZ
- Abnormal ECG more common in HCQ+AZ (27%) and HCQ (27%) vs AZ (16%) and no tx (14%), but no difference in adjusted analysis; more pts w/ cardiac arrest in HCQ+AZ (16%) and HCQ (14%) vs AZ (6%) and no tx (7%)
- Study considerations: retrospective, 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.
corticosteroids (eg, methylprednisolone) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response via inhibition of multiple cytokines
Early Short Course Corticosteroids in Hospitalized Patients With COVID-19
- 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
- Study considerations: quasi-experimental design; varied antiviral tx and timing; guideline adherence in post-protocol group not universal; limited f/u
- Access pre-print medRxiv article
Pharmacology/Backgound: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
Effective Treatment of Severe COVID-19 Patients With Tocilizumab - Retrospective study; 21 severely ill, hospitalized pts (mean age 57y; 4 pts critically ill) w/ confirmed COVID-19 treated w/ TCZ 400 mg x1 after 7 days of routine tx (3 pts received 2nd dose w/in 12h); study pts also received LPV/r, methylprednisolone in addition to other SOC measures
- Treated pts had 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 19; lymphocyte count normalized in 10/19 by day 5; CRP decreased significantly in 16/19 pts; no serious ADRs, incl subsequent infxns; all pts discharged home on avg 15 days after tx
- Study considerations: non-comparative; retrospective; small sample size
- Access Proc Natl Acad Sci USA article
Tocilizumab Treatment in COVID-19: A Single Center Experience - Retrospective study; 15 hospitalized pts (mean age, 72y; 4 seriously ill, 7 critically ill) w/ confirmed COVID-19 treated w/ TCZ (doses ranged 80 mg to 600 mg per dose, 5 pts received >1 dose); 8 pts also received methylprednisolone
- CRP levels normalized in 11 pts; IL-6 levels were lower compared to pre-tx levels in 3 pts; 3 pts died; 2 pts had clinical dz progression
- Study considerations: non-comparative, retrospective, small sample size, varied dosing regimens, inconsistent monitoring of lab parameters, limited f/u
- Access J Med Virol article
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
Expanded Access/Compassionate Use:
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
Interleukin-1 Blockade With High-dose Anakinra in Patients With COVID-19, Acute Respiratory Distress Syndrome, and Hyperinflammation: A Retrospective Cohort Study - 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
- Study considerations: retrospective; small sample size; historical bias; selection bias; varied dosing regimens
- Access Lancet Rheumatol article
JAK inhibitors (eg, ruxolitinib) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by disrupting cytokine pathways via inhibition of janus-associated kinases (JAK)
- Drugs under investigation include: baricitinib, ruxolitinib
Expanded Access/Compassionate Use - Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very Severe COVID-19 Illness, NCT04337359
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:
BTK inhibitors (eg, acalabrutinib) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting malignant B-cell proliferation via inhibition of Bruton tyrosine kinase (BTK)
- Drugs under investigation include: acalabrutinib, ibrutinib, zanubrutinib
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by disrupting cytokine pathways via inhibition of exportin 1 (XPO1); XPO1 inhibitors have activity against many viruses, incl RNA viruses, and expected to have activity against SARS-CoV
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by disrupting cytokine pathways via inhibition of phosphatidylinositol 3-kinase (PI3K)
Pharmacology/background: - Proposed mechanism: reduces inflammatory response; has been effective for cytokine storm caused by other diseases; topoisomerase II inhibitors suppress RNA virus replication in vitro
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting dihydroorotate dehydrogenase; in vitro effects against SARS-CoV-2
- For U.S. trials, see ClinicalTrials.gov
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
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by blunting catecholamine effects on cytokine production
SSRIs (fluoxetine, fluvoxamine) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors or binding to sigma-1 receptors
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
Pharmacology/Background: - Proposed mechanism: binds to fibrin and converts tissue plasminogen to plasmin, promoting fibrinolysis of microvascular thromboses and occlusions in pulmonary vasculature
- For all trials, including international, see ClinicalTrials.gov
antithrombotics (eg, heparin, LMWH, dipyridamole) 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
- Drugs under investigation include: enoxaparin, heparin, nebulized heparin, dipyridamole
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
Pharmacology/Background: - Proposed mechanism: produces non-specific immune effects leading to improved response against non-mycobacterial pathogens
Pharmacology/Background: - Proposed mechanism: attenuates dysregulation of various mechanistic processes involved in acute illness, incl energy metabolism, autophagy, oxidative stress, tissue hypoxia, and inflammation
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
Pharmacology/Background: - Proposed mechanism: selectively dilates pulmonary vasculature, leading to vasodilation and increased oxygenation; in vitro activity against other coronaviruses (eg, SARS-CoV)
Expanded Access/Compassionate Use: - Expanded access emergency use of Genosyl for COVID-19: See manufacturer website
- For info on expanded access for the proprietary inhaled nitric oxide delivery system, INOpulse: See manufacturer website
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
Hydroxychloroquine and Azithromycin Plus Zinc vs Hydroxychloroquine and Azithromycin Alone: Outcomes in Hospitalized COVID-19 Patients; access pre-print medRxiv article
Pharmacology/Background: - Note: Not currently available in the U.S.
- Proposed mechanism: dilates pulmonary vasculature, leading to vasodilation and increased oxygenation
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Expanded Access/Compassionate Use: Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients - Multicenter open-label Expanded Access Program; 5,000 hospitalized pts (median age 62y, 63% male, 66% ICU pts) w/ severe or life-threatening COVID-19 (81%) or at high risk (19%) received ABO-compatible COVID-19 convalescent plasma 200-500 mL IV per protocol
- Outcomes w/ in 1st 4h of transfusion: 36 (<1%) serious adverse events (SAEs) incl death (n=15), transfusion-assoc circulatory overload (n=7), transfusion-related acute lung injury (n=11), severe allergic transfusion rxn (n=3); overall 7-day mortality rate 15%
- Study considerations: safety data only, no efficacy data; some reported SAEs may represent natural dz progression; other transfusion-related theoretical risks not reported; detailed training of study personnel lacking; web-based case reporting
- Access pre-print medRxiv article
Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma - Case series; 5 critically ill pts (ages 36-73y) w/ severe COVID-19 pneumonia and high viral load despite antiviral tx, PaO2/FiO2 <300, and current or prior mechanical ventilation; 400 mL convalescent plasma x1 given btwn 10-22 days after admission
- Donors recovered from COVID-19, asymptomatic for >10 days, SARS-CoV-2-specific Ab titers >1:1000, neutralizing Ab titer >40
- SOFA scores, PaO2/FiO2 ratios, and fever curves improved for all pts w/ negative viral load by day 12 post-transfusion; 3 of 5 pts extubated and discharged home, remaining 2 pts still on mechanical ventilation
- Study considerations: non-comparative; small sample size; pts received other antivirals; delayed tx initiation from hospital admission; safety data not reported
- Access full-text JAMA article
Effectiveness of Convalescent Plasma Therapy in Severe COVID-19 Patients - Case series; 10 pts (median age, 53y) w/ severe COVID-19; all pts received other antivirals, 6 pts received methylprednisolone; 3 pts mechanically ventilated, 3 pts on high-flow NC, 4 pts on low-flow NC or RA; all pts received 200 mL convalescent plasma x1 at 10-20 days after sx onset
- Donors recovered from COVID-19, afebrile for >3 days, negative viral load on consecutive samples; donor transfusions had neutralizing Ab titers >1:640
- Sx and oxygenation improved in all pts; 2 pts extubated, 1 pt D/C high-flow NC; all pts had negative viral load by day 6 post-transfusion (3 pts w/ negative viral load before transfusion); no serious safety events reported
- Study considerations: non-comparative; small sample size; excl pts w/ severe organ dysfxn; pts received other antiviral agents; delayed tx initiation from hospital admission
- Access full-text Proc Natl Acad Sci USA article
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Pharmacology/Background:
- Proposed mechanism: provides passive immunity
- 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 length of stay (23.5 vs 16 days) and longer dz duration (31 vs 23 days)
- Study considerations: retrospective; treatment bias; IVIG timing, dosing, and duration varied among sites
- Access pre-print medRxiv article
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Pharmacology/Background: - Proposed mechanism: induces antibody formation
Safety, Tolerability, and Immunogenicity of a Recombinant Adenovirus Type-5 Vectored COVID-19 Vaccine: A Dose-escalation, Open-label, Non-randomised, First-in-Human Trial; access Lancet article
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