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Pfizer-BioNTech COVID-19 vaccine (Comirnaty) Approved 2-dose primary vaccine series to prevent COVID-19 prevention in individuals ≥16 yo Emergency use authorization for 2-dose primary vaccine series to prevent COVID-19 in children and adolescents ages 5 to 15 yo, third primary series dose in those ≥5 yo w/ certain types of immunocompromise, and booster dose in individuals ≥12 yo CDC Clinical Considerations Vaccine Characteristics - Type: mRNA vaccine (encodes for viral proteins; uses host machinery to produce solitary viral proteins to induce immune response; does not produce whole virus)
- Primary series (5-11 yo): 2 doses (10 μg, 0.2 mL), 21 days apart; in solid organ transplant or equivalently immunocompromised, give 3rd dose (10 mg, 0.2 mL) ≥28 days after 2nd dose
- Primary series (≥12 yo): 2 doses (30 μg, 0.3 mL), 21 days apart; in solid organ transplant or equivalently immunocompromised pts, give 3rd dose (30 μg, 0.3 mL) ≥28 days after 2nd dose; may consider delaying 2nd dose until 8wk after 1st dose in immunocompetent pts <65 yo
- Booster doses (≥12 yo): 1 dose (30 μg, 0.3 mL) ≥5mo after primary series (may give heterologous booster doses if 18 yo and older, but eligibility criteria and dosing interval should follow primary series product); in pts ≥50 yo or moderately-severely immunocompromised pts, give 2nd dose (30 μg, 0.3 mL) >4mo after 2nd dose
- Note: may mix and match any COVID-19 vaccine for 1st booster dose; may mix and match any mRNA vaccine for 2nd booster dose
Efficacy data (Adults/Adolescents, ≥16 yo) - 91.3% effective through 6mo, per topline analysis
- 88% effective against hospitalization in immunocompetent pts, per CDC; effectiveness decreased ≥4mo after vaccination from 91% to 77%
- 94% effective in health care personnel, per CDC
- Booster dose 95.6% relative vaccine efficacy compared w/ no booster dose, per preliminary analysis
Efficacy data (Peds) - 100% effective in adolescents 12-15 yo, per follow-up analysis
- Strong antibody response in children 5-11 yo, similar to 16-25 yo, per preliminary analysis
- 93% effective against hospitalization in 12-18 yo, per CDC
- Additional studies for other age groups ongoing
Pregnancy Registries - COVID-19 Vaccines Pregnancy Registry (MotherToBaby): website
- COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER): website
- CDC V-Safe tool: website
Moderna COVID-19 vaccine (Spikevax) Approved for two-dose primary vaccine series to prevent COVID-19 in individuals ≥18 yo Emergency use authorization for third primary series dose in those ≥18 yo w/ certain types of immunocompromise, and booster dose in individuals >18 yo CDC Clinical Considerations Vaccine Characteristics - Type: mRNA vaccine (encodes for viral proteins; uses host machinery to produce solitary viral proteins to induce immune response; does not produce whole virus)
- Primary series (≥18 yo): 2 doses (100 μg), 28 days apart; in solid organ transplant or equivalently immunocompromised pts, give 3rd dose (100 μg, 0.5 mL) ≥28 days after 2nd dose; may consider delaying 2nd dose until 8wk after 1st dose in immunocompetent pts <65 yo
- Booster doses (≥18 yo): 1 dose (50 μg) ≥5mo after primary series (may give heterologous booster doses, but eligibility and dosing interval should follow primary series product); in pts ≥50 yo or moderately-severely immunocompromised pts, give 2nd dose (50 μg) >4mo after 2nd dose
- Note: may mix and match any COVID-19 vaccine for 1st booster dose; may mix and match any mRNA vaccine for 2nd booster dose
Efficacy Data (Adults) - 94.1% effective per preliminary analysis
- 93% effective against hospitalization in immunocompetent pts, per CDC; effectiveness decreased >4mo after vaccination from 93% to 92%
- 94% effective in health care personnel, per CDC
Efficacy Data (Peds)
- 100% effective in adolescents 12-17 yo, per phase 2/3 study
- Strong antibody response in children 5-11 yo, similar to young adults, per phase 2/3 study (press release)
- Robust neutralizing antibody titers in children 6 mo to <6 yo, similar to adults (press release)
Pregnancy Registries - Moderna COVID-19 Vaccine Pregnancy Registry: 1-866-663-3762
- COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER): website
- CDC V-Safe tool: website
- COVID-19 Vaccines Pregnancy Registry (MotherToBaby): website
Janssen COVID-19 vaccine (Johnson & Johnson, JNJ-78436735) Emergency Use Authorization for primary and booster dose to prevent COVID-19 in individuals ≥18 yo for whom other approved/authorized vaccines are not accessible or appropriate 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)
- Primary series: 1 dose
- Booster dose: 1 dose >2mo after primary series (may give heterologous booster doses, but eligibility and dosing interval should follow primary series product)
- Note: may mix and match any COVID-19 vaccine for 1st booster dose; may mix and match any mRNA vaccine for 2nd booster dose
- Note: give mRNA vaccine as 2nd booster if received Janssen COVID-19 vaccine as primary and 1st booster
Efficacy data (Adults) - 67% effective in preventing moderate/severe dz, 85% effective in preventing severe/critical dz, per primary analysis
- 71% effective against hospitalization in immunocompetent pts, per CDC; effectiveness decreased >1mo after vaccination to 68%
Pregnancy Registries - COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER): website
- CDC V-Safe tool: website
- COVID-19 Vaccines Pregnancy Registry (MotherToBaby): website
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 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.
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)
- inactivated SARS-CoV-2 virus vaccine given as 2 doses
- 51% effective per WHO
- approved or authorized for use in other countries
Bharat Biotech (COVAXIN) - Emergency Use authorized by WHO (EUL)
- inactivated SARS-CoV-2 virus vaccine given as 2 doses
- 64% effective against asymptomatic infection, 78% effective against symptomatic dz, 93% effective against severe dz, per final analysis
- approved or authorized for use in other countries
Novavax (Nuvaxovid; Covovax; NVX-CoV2373)
- Emergency Use authorized by WHO (EUL)
- nanoparticle-based, recombinant protein subunit vaccine given as 2 doses; contains Matrix-M adjuvant
- 89.7% effective per Phase 3 study
- CDC considers participants in the Novavax PREVENT-19 Phase 3 trial meet criteria to be fully vaccinated 2wk after they have completed the vaccine series; if they didn’t receive the full 2-dose series, pts should be encouraged to follow current prevention measures and offered an FDA-authorized or approved vaccine series; company press release
Medicago/GlaxoSmithKline (CoVLP) - virus-like particle given as 2 doses; plant-based, combined w/ adjuvants
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, Paxlovid, molnupiravir)
Approved for COVID-19 tx in pts ≥28 days old weighing ≥3 kg
Pharmacology/Background: - Proposed mechanism: terminates viral replication by binding to RNA-dependent RNA polymerase; circumvents proofreading activity by exonucleases
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Remdesivir by Gilead Sciences: FDA Warns of Newly Discovered Potential Drug Interaction That May Reduce Effectiveness of Treatment; see FDA alert
Key Study Takeaways: - 3-day course reduces hospitalization or death risk in outpts1
- No survival benefit but may improve other outcomes (eg, recovery time, need for mech vent), particularly when given early in inpts2-4
- Improved clinical status in moderate COVID-19 w/ 5-day course but not 10-day course,4 but no difference between 5-day and 10-day courses in severe COVID-19 in inpts not requiring mech vent5
Note: For published studies on combo tx w/ baricitinib, refer to JAK inhibitors Footnotes 1 Gottlieb RL, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022. Jan 27;386(4):305-315. Full-text article
2 Beigel JH, et al. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med.
2020. Nov 5;383(19):1813-1826. Full-text article
3 Wang Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020. May 16;395(10236):1569-1578. Full-text article
4 Ali K, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. CMAJ. 2022. Jan 19;cmaj.2111698. Full-text article
5 Spinner CD, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020. Sep 15;324(11):1048-1057. Full-text article
6 Goldman JD, et al. Remdesivir for 5 or 10 Days in Patients With Severe Covid-19. NEJM. 2020. Nov 5;383(19):1827-18-37. Full-text article
nirmatrelvir and ritonavir (Paxlovid) Emergency Use Authorization for mild-moderate COVID-19 tx in SARS-CoV-2-positive outpts ≥12 yo and ≥40 kg at high risk for severe dz, incl hospitalization or death
Pharmacology/Background: - Proposed mechanism: SARS-CoV-2-3CL protease inhibitor; given w/ low-dose ritonavir as a pharmacokinetic booster
- Phase 2/3 studies showed 89% reduction in hospitalization or death in high-risk population (EPIC-HR) and 70% reduction in hospitalization w/ no deaths in standard-risk population (EPIC-SR): company press release
Emergency Use Authorization for mild-moderate COVID-19 tx in SARS-CoV-2-positive outpts ≥12 yo and ≥40 kg at high risk for severe dz, incl hospitalization or death
Pharmacology/Background:
- Proposed mechanism: terminated viral replication by binding to RNA-dependent RNA polymerase
- Phase 3 trial showed 30% reduction in risk of hospitalization or death: company press release
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
- CDC Health Advisory (8/26/21): CDC warns about rapid increase in ivermectin prescriptions and reports of severe illness associated with use of ivermectin-containing products to prevent or treat COVID-19
Key Study Takeaways: - Multiple studies, mostly non-RCTs or small RCTs, showed conflicting results w/ some demonstrating clinical benefits1-4 while others, including a recent large RCT, did not5-7
- One case-control study showed reduced SARS-CoV-2 infection w/ ivermectin chemoprophylaxis8
- Meta-analysis showed possible clinical benefit for treatment and prevention,9 although some data have since been retracted
- Additional meta-analysis showing possible clinical benefit for treatment but was retracted pending revision d/t inclusion of study w/ fraudulent data10
Footnotes 1 Ahmed S, et al. Five-day Course of Ivermectin for the Treatment of COVID-19 May Reduce the Duration of Illness. Int J Infect Dis. 2021. Feb;103:214-216. Full-text article
2 Rajter JC, et al. Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019. Chest. 2021 Jan;159(1):85-92. Full-text article
3 Khan, SI. Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19. Arch Bronconeumol (Engl Ed). 2020. Dec;56(12):828-830. Full-text article
4 Babalola OE, et al. Ivermectin Shows Clinical Benefits in Mild to Moderate COVID19: A Randomised Controlled Double-blind, Dose-response Study in Lagos. QJM. 2022. Jan 5;114(11):780-788. Full-text article
5 Khan Chachar AZ, et al. Effectiveness of Ivermectin in SARS-CoV-2/COVID-19 Patients. International J of Sciences. 2020. 09(2020):31-35. Full-text article
6 Lopez-Medina E, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA. 2021. April 13;325(14):1426-1435. Full-text article
7 Reis G, et al. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med. 2022. Mar 30.doi: 10.1056/NEJMoa2115869. Online ahead of print. Full-text article
8 Behera P, et al. Role of Ivermectin in the Prevention of SARS-CoV-2 Infection Among Healthcare Workers in India: A Matched Case-Control Study. PLoS One. 2021. Feb 16;16(2):e0247163. Full-text article
9 Bryant A, et al. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. Am J Ther. 2021. June 12;28(4):e434-e460. Full-text article
10 Hill A, et al. Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection. Open Forum Infect Dis. 2021. Jul 6;8(11):ofab358. Full-text article
hydroxychloroquine, chloroquine 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
Key Study Takeaways: - No clinical benefit w/ HCQ or CQ as tx for both inpts and outpts according to multiple RCTs1-10 and non-RCTs11-16
- Incr risk of QT prolongation w/ HCQ +/- AZ17,18 and high-dose CQ;10 HCQ + AZ combo may incr mortality risk19
- HCQ provided no benefit as both pre-exposure20,21 and post-exposure prophylaxis22,23
Footnotes 1 Horby P, et al. Effect of Hydroxychloroquine in Hospitalized Patients With Covid-19 (RECOVERY). N Engl J Med. 2020. Nov 19;383(21):2030-2040. Full-text article
2 Pan H, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021. Feb 11;384(6):497-511. Full-text article
3 Cavalcanti AB, et al. Hydroxychloroquine With or Without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med. 2020. Nov 19;383(21):2041-2052. Full-text article
4 Self WH, et al. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020. Dec 1:324(21):2165-2176. Full-text article
5 Tang W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020. May 14:369:m1849. Full-text article
6 Furtado Remo HM, et al. 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. Lancet. 2020. Oct 3;396(10256):959-967. Full-text article
7 Skipper CP, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial. Ann Intern Med. 2020. Oct 20;173(8):623-631. Full-text article
8 Mitja O, et al. Hydroxychloroquine for Early Treatment of Adults with Mild Coronavirus Disease 2019: A Randomized-Controlled Trial. Clin Infect Dis. 2021. Dec 6;73(11):e4073-e4081. Full-text article
9 Reis G, et al. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open. 2021. Apr 1;4(4):e216468. Full-text article
10 Borba MGS, et al. 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. JAMA Netw Open. 2020. Apr 24;3(4):e208857. Full-text article
11 Geleris J, et al. Oservational Study of Hydroxychloroquine in Hospitalized Patients With COVID-19. N Engl J Med. 2020. Jun 18;382(25):2411-2418. Full-text article
12 Rosenberg ES, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Hospital Mortality in Patients With COVID-19 in New York State. JAMA. 2020. Jun 23:323(24):2493-2502. Full-text article
13 Arshad S, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis. 2020. Aug;97:396-403. Full-text article
14 Mahevas M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020. May 14;369:m1844. Full-text article
15 Gautret P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. Jul;56(1):105949. Full-text article
16 Magagnoli J, et al. Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID-19. Med (NY). 2020. Dec 18;1(1):114-127.e3. Full-text article
17 Chorin E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med. 2020. Jun;26(6):808-809. Full-text article
18 Mercuro NJ, et al. 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). JAMA Cardiol. 2020. Sep 1;5(9):1036-1041. Full-text article
19 Fiolet T, et al. Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Clin Microbiol Infect. 2021. Jan;27(1):19-27. Full-text article
20 Abella BS, et al. Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial. JAMA Intern Med. 2021. Feb 1;181(2):195-202. Full-text article
21 Rajasingham R, et al. Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial. Clin Infect Dis. 2021. Jun 1:72(11):e835-e843. Full-text article
22 Barnabas RV, et al. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Randomized Trial. Ann Intern Med. 2021. Mar;174(3):344-352. Full-text article
23 Boulware DR, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020. Aug 6:383(6):517-525. Full-text 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
Key Study Takeaways: - No clinical benefit w/ LPV/r given either alone or in combo w/ other agents1-4
- DRV/c did not significantly incr viral clearance compared w/ SOC5
Footnotes 1 Cao B, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized With Severe Covid-19. N Engl J Med. 2020. May 7;382(19):1787-1799. Full-text article
2 RECOVERY Collaborative Group. Lopinavir–Ritonavir in Patients Admitted to Hospital With COVID-19 (RECOVERY): A Randomised, Controlled, Open-Label, Platform Trial. Lancet. 2020. Oct 24;396(10259):1345-1352. Full-text article
3 Pan H, et al. Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results. N Engl J Med. 2021. Feb 11;384(6):497-511. Full-text article
4 Reis G, et al. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open. 2021. Apr 1;4(4):e216468. Full-text article
5 Chen J, et al. Antiviral Activity and Safety of Darunavir/Cobicistat for the Treatment of COVID-19. Open Forum Infect Dis. 2020. Jun 21;7(7):ofaa241. Full-text article
ACEIs/ARBs (eg, losartan, ramipril) Pharmacology/Background: - Proposed mechanism: blocks viral entry by inhibiting ACE2 receptors
Published studies: - Efficacy of Losartan in Hospitalized Patients With COVID-19–Induced Lung Injury: A Randomized Clinical Trial; access JAMA Netw Open article
- 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: - Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial; full-text Gut article
- 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: activates protein kinases leading to structural changes in ACE2 receptor and subsequent reduced SARS-CoV-2 binding affinity
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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
Key Study Takeaways:
- Dexamethasone improved survival in critically ill pts or pts requiring respiratory support1-3
- Methylprednisolone didn’t improve survival in hospitalized pts but may improve other clinical outcomes if given early4,5
- Hydrocortisone didn’t improve clinical outcomes in critically ill pts6,7
- Inhaled budesonide improved time to recovery and may reduce need for urgent care or hospitalization among outpts8,9
Footnotes 1 WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19. JAMA. 2020. Oct 6;324(13):1330-1341. Full-text article
2 RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients With COVID-19 — Preliminary Report (RECOVERY). N Engl J Med. 2021. Feb 25;384(8):693-704. Full-text article
3 Tomazini BM, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA Netw Open. 2020. Oct 6;324(13):1307-1316. Full-text article
4 Jeronimo CMP, et al. Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-blind, Phase IIb, Placebo-controlled Trial. Clin Infect Dis. 2021. May 4;72(9):e373-e381. Full-text article
5 Fadel R, et al. Early Short Course Corticosteroids in Hospitalized Patients With COVID-19. Clin Infect Dis. 2020. Nov 19;71(16):2114-2120. Full-text article
6 Angus DC, et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA. 2020. Oct 6;324(13):1317-1329. Full-text article
7 Dequin PF, et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020. Oct 6;324(13):1298-1306. Full-text article
8 Ramakrishnan S, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021. Jul;9(7):763-772. Full-text article
9 Yu LM, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021. Sep 4;398(10303):843-855. Full-text article
IL-6 inhibitors (eg, tocilizumab, sarilumab, siltuximab) Emergency Use Authorization for tocilizumab for COVID-19 tx w/ corticosteroids in pts ≥2 yo requiring supplemental O 2, mechanical ventilation, or ECMO Pharmacology/Background - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors (tocilizumab, sarilumab) or IL-6 itself (siltuximab)
- Drugs under investigation: tocilizumab, sarilumab, siltuximab
Key Study Takeaways: - No survival benefit in hospitalized pts w/ mod-severe COVID-19 pneumonia w/ mixed results for prevention of dz progression1-5
- Survival benefit seen in pts w/ hypoxia and systemic inflammation6 or critically ill pts requiring organ support7
- Meta-analysis of 27 RCTs showed IL-6 receptor antagonists associated w/ improved survival8
- Second meta-analysis of individual pt data from 11 RCTs also showed mortality benefit9
Footnotes 1 Rosas IO, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021. Apr 22:384(16):1503-1516. Full-text article
2 Salama C, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021. Jan 7;384(1):20-30. Full-text article
3 Stone JH, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020. Dec 10:383(24):2333-2344. Full-text article
4 Lescure FX, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021. May;9(5):522-532. Full-text article
5 Sivapalasingam S, et al. Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. Clin Infect Dis. 2022. Mar 21;online ahead of print. Full-text article
6 RECOVERY Collaborative Group. Tocilizumab in Patients Admitted to Hospital With COVID-19 (RECOVERY): A Randomised, Controlled, Open-label, Platform Trial. Lancet. 2021. May 1;397(10285):1637-1645. Full-text article
7 REMAP-CAP Investigators. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021. Apr 22:384(16):1491-1502. Full-text article
8 WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA. 2021. Aug 10;326(6):499-518. Full-text article
9 Tasoudis PT, et al. Interleukin-6 inhibitors reduce mortality in coronavirus disease-2019: An individual patient data meta-analysis from randomized controlled trials. Eur J Intern Med. 2022 Apr 7:S0953-6205(22)00140-6. Full-text article
JAK inhibitors (eg, baricitinib, ruxolitinib, tofacitinib) Baricitinib approved for COVID-19 tx in hospitalized adults requiring supplemental O2, noninvasive or invasive mechanical ventilation, or ECMO Emergency Use Authorization for baricitinib for COVID-19 tx in pts 2 to <18 yo requiring supplemental O 2, mechanical ventilation, or ECMO 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
Key Study Takeaways: - Baricitinib improved survival in hospitalized pts, incl critically ill pts receiving mech vent or ECMO1,2
- Baricitinib w/ remdesivir improved clinical recovery vs remdesivir alone in pts receiving high-flow O2 or non-invasive ventilation3
- Ruxolitinib improved radiography but no difference in clinical improvement or survival4
- Tofacitinib reduced mortality and respiratory failure in hospitalized pts5
Footnotes 1 Marconi VC, et al. Efficacy and safety of baricitinib for the treatment of hospitalized adults with COVID-19 (COV-BARRIER): A randomized, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021. Dec;9(12):1407-1418. Full-text article
2 Ely EW, et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: An exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022. Feb 3:S2213-2600(22)00006-6. Full-text article
3 Kalil AC, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021. March 4;384(9):795-807. Full-text article
4 Cao Y, et al. Ruxolitinib in Treatment of Severe Coronavirus Disease 2019 (COVID-19): A Multicenter, Single-blind, Randomized Controlled Trial. J Allergy Clin Immunol. 2020. Jul;146(1):137-146.e3. Full-text article
5 Guimaraes PO, et al. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021. July 29;385(5):406-415. Full-text 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
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
Other studies: - Early Treatment of COVID-19 With Anakinra Guided by Soluble Urokinase Plasminogen Receptor Plasma Levels: A Double-blind, Randomized Controlled Phase 3 Trial; full-text Nat Med article
- Favorable Anakinra Responses in Severe COVID-19 Patients With Secondary Hemophagocytic Lymphohistiocytosis; full-text Cell Host Microbe article
- Targeting the Inflammatory Cascade With Anakinra in Moderate to Severe COVID-19 Pneumonia: Case Series; full-text Ann Rheum Dis 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
-
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
Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial - KEY FINDINGS: thromboprophylaxis w/ therapeutic-dose LMWH reduces major VTE and death in high-risk inpts vs standard-dose LMWH or UFH
- JAMA Intern Med article
Effectiveness of Therapeutic Heparin versus Prophylactic Heparin on Death, Mechanical Ventilation, or Intensive Care Unit Admission in Moderately Ill Patients With Covid-19 Admitted to Hospital: RAPID Randomized Clinical Trial - KEY FINDINGS: therapeutic heparin assoc w/ decr in odds of death at 28 days but not assoc w/ composite outcome reduction (death, mech vent, or ICU admission up to day 28)
- BMJ article
Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19 - KEY FINDINGS: therapeutic-dose heparin incr survival probability vs usual-care thromboprophylaxis, also reduces CV or resp organ support need
- N Engl J Med article
Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19 - KEY FINDINGS: no difference in survival probability or CV/resp organ support need between therapeutic-dose heparin and usual-care thromboprophylaxis
- N Engl J Med 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 - KEY FINDINGS: no difference in primary composite outcome (venous or arterial thrombosis, ECMO, 30-day mortality) between intermediate- and standard-dose thromboprophylaxis
- JAMA 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
-
Antibody-based therapies (eg, convalescent plasma, monoclonal antibodies)
SARS-CoV-2-specific monoclonal antibodies Emergency Use Authorizations for COVID-19 tx and prophylaxis: Pharmacology/Background:
- Proposed mechanism: binds to specific viral targets and acts as neutralizing antibodies; most agents target spike protein, preventing viral entry and replication
Distribution & Availability - REGEN-COV, bamlanivimab and etesevimab distribution currently halted due to high frequency of nonsusceptible variants (ASPR announcement)
- Sotrovimab distribution currently halted due to high frequency of nonsusceptible variants (ASPR announcement)
Published studies: - Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial; JAMA article
- Early Treatment for Covid-19 With SARS-CoV-2 Neutralizing Antibody Sotrovimab (COMET-ICE trial); N Engl J Med article
- 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
- Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19; N Engl J Med article
Pharmacology/Background:
- Proposed mechanism: provides passive immunity
Key Study Takeaways: - Multiple studies showed no clinical benefit w/ convalescent plasma1-7
- Studies for high-titer convalescent plasma show conflicting results8-11
Footnotes 1 Janieaud P, et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021. Mar 23;325(12):1185-1195. Full-text article
2 Piechotta V, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review. Cochrane Database Syst Rev. 2020. July 10;7(7):CD013600. Full-text article
3 Writing Committee for the REMAP-CAP Investigators. Effect of Convalescent Plasma on Organ Support–Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2021. Nov 2;326(17):1690-1702. Full-text article
4 Korley FK, et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. N Engl J Med. 2021. Nov 18;385(21):1951-1960. Full-text article
5 Begin P, et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med. 2021. Nov;27(11):2012-2024. Full-text article
6 Li L, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020. Aug 4;324(5):460-470. Full-text article
7 Simonovich VA, et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2021. Feb 18;384(7):619-629. Full-text article
8 Libster R, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021. Feb 18;384(7):610-618. Full-text article
9 Ortigoza MB, et al. Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial. JAMA Intern Med. 2022. Feb 1;182(2):115-126. Full-text article
10 RECOVERY Collaborative Group. Convalescent Plasma in Patients Admitted to Hospital With COVID-19 (RECOVERY): A Randomised Controlled, Open-label, Platform Trial. Lancet. 2021. May 29;397(10289):2049-2059. Full-text article
11 Sullivan DJ, et al. Early Outpatient Treatment for Covid-19 with Convalescent Plasma. N Engl J Med. 2022. Mar 30. Doi: 10.1056/NEJMoa2119657. Epub ahead of print. Full-text article
Pharmacology/Background: - Proposed mechanism: provided passive immunity
Key Study Takeaways:
- Retrospective cohort studies showed conflicting results1-3
- RCTs w/ small sample sizes showed some clinical benefit,4-7 but a larger RCT showed no benefit for COVID-19-associated ARDS8
Footnotes 1 Shao Z, et al. Clinical Efficacy of Intravenous Immunoglobulin Therapy in Critical Ill Patients With COVID-19: A Multicenter Retrospective Cohort Study. Clin Transl Immunology. 2020. Oct 14;9(10):e1192. Full-text article
2 Huang C, et al. Efficacy Evaluation of Intravenous Immunoglobulin in Non-severe Patients With COVID-19: A Retrospective Cohort Study Based on Propensity Score Matching. Int J Infect Dis. 2021. Apr;105:525-531. Full-text article
3 Esen F, et al. Effects of Adjunct Treatment With Intravenous Immunoglobulins on the Course of Severe COVID-19: Results From a Retrospective Cohort Study. Curr Med Res Opin. 2021. Apr;37(4):543-548. Full-text article
4 Gharebaghi N, et al. The Use of Intravenous Immunoglobulin gamma for the Treatment of Severe Coronavirus Disease 2019: A Randomized Placebo-controlled Double-blind Clinical Trial. BMC Infect Dis. 2020. Oct 21;20(1):786. Full-text article
5 Tabarsi P, et al. Evaluating the Effects of Intravenous Immunoglobulin (IVIg) on the Management of Severe COVID-19 Cases: A Randomized Controlled Trial. Int Immunopharmacol. 2021. Jan;90:107205. Full-text article
6 Sakoulas G, et al. Intravenous Immunoglobulin Plus Methylprednisolone Mitigate Respiratory Morbidity in Coronavirus Disease 2019. Crit Care Explor. 2020. Nov 16;2(11):e0280. Full-text article
7 Raman RS, et al. A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in Coronavirus Disease 2019 Patients With Regular Intravenous Immunoglobulin Therapy. J Infect Dis. 2021. May 20;223(9):1538-1543. Full-text article
8 Mazeraud A, et al. Intravenous Immunoglobulins in Patients With COVID-19-Associated Moderate-to-Severe Acute Respiratory Distress Syndrome (ICAR): Multicentre, Double-blind, Placebo-controlled, Phase 3 Trial. Lancet Respir Med. 2022. Feb;10(2):158-166. Full-text article
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