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Subsections
COVID-19 Investigational Therapy (Overview)

COVID-19 INVESTIGATIONAL THERAPY

NOTE: Currently under investigation for treatment of COVID-19, however safety and efficacy only established with remdesivir

Anti-Malarials

  • Hydroxychloroquine +/- Azithromycin or Chloroquine
    • FDA Emergency Use Authorization revoked due to emerging data displaying no significant benefit in Tx of COVID-19 and risks of serious cardiac/other ADRs (see FDA press release)
    • Randomized controlled trial observed no benefit in symptom severity or time to resolution of early intervention HCQ (≤4 days S/S) vs placebo in mild outpatient infections
      • At Day 14 24% (49 of 201 pt) of HCQ group had ongoing symptoms vs 30% (59 of 194) receiving placebo (P = 0.21)
    • Initial RECOVERY trial data found no significant benefit in 28-day mortality in hospitalized pts vs usual care alone (25.7% hydroxychloroquine vs. 23.5% usual care); no evidence of reduction in hospital stay duration
    • Interim data from WHO SOLIDARITY trial displayed no overall reduction in 28-day mortality RR=1.19 (0.89-1.59, p=0.23)
    • Open-label, randomized trial of mild-moderate cases found no improvement in rate of viral clearance vs SOC (84% vs 81%) or symptomatic improvement (60% vs 66%) by day 28 with use of hydroxychloroquine
    • Randomized, double-blind, placebo-controlled trial investigating hydroxychloroquine for post-exposure prophylaxis found no significant differences in incidence of new illness vs placebo (49 of 414 [11.8%] vs 58 of 407 [14.3%])
    • Study comparing chloroquine 600 mg BID x10 days (high dose) vs 450 mg BID on day 1, then qD x4 days (low dose) - outcomes after 13 days:
      • Death: HD 39% (16 of 41) vs LD 15% (6 of 40); QTc prolongation: HD 18.9% (7 of 37) vs LD 11.1% (4 of 36)
    • IDSA Guidelines recommend against use of hydroxychloroquine/chloroquine with/without azithromycin in hospitalized pts

Antivirals

  • Favipiravir (Not commercially available in US)
    • Open-label, nonrandomized control study showed improved viral clearance time and chest CT vs lopinavir/ritonavir in non-severe, non-ICU pts (4 days vs. 11 days, respectively)
    • Small randomized, controlled, open-label trial compared favipiravir to umifenovir in clinical recovery rate of Day 7 with mild infection; no significant difference was found between groups (71/116 vs 62/120)
      • Favipiravir led to shorter latencies to relief for both pyrexia and cough in secondary outcome assessment (-1.70 and -1.75 days, respectively)
    • Open-label randomized, multicenter Phase III trial in mild to moderate infection displayed 40% faster achievement of clinical cure as determined by physician assessment (HR 1.749 [95% CI 1.096, 2.792]; p=0.029)
    • Investigational dosing:
      • 1600 mg PO BID x1 day, then 600 mg PO BID (7-14 days total Tx)
  • Lopinavir/Ritonavir
    • Initial RECOVERY trial data found no significant difference in 28-day mortality in hospitalized pts vs usual care alone (22.1% lopinavir/ritonavir vs. 21.3% usual care)
      • No evidence of benefit in risk of progression to mechanical ventilation or length of hospital stay observed
    • Randomized, open-label trial assessed time to clinical improvement in hospitalized COVID-19 pts; no benefit found vs standard of care alone (16 days vs 16 days)
      • Non-significant trend towards reduced mortality did occur in lopinavir-ritonavir group, especially if Tx initiated within 12 days of S/S onset
    • Small randomized, open-label, phase II trial compared lopinavir/ritonavir + ribavirin + interferon beta-1b combo vs lopinavir/ritonavir alone in time to negative nasopharyngeal swab
      • Combo group displayed significantly shorter time to negative nasopharyngeal swab vs lopinavir/ritonavir alone (median 7 days vs 12 days)
    • Interim data from WHO SOLIDARITY trial displayed no overall reduction in 28-day mortality with lopinavir, RR=1.00 (0.79-1.25, p=0.97)
    • IDSA Guidelines recommend against use in hospitalized pneumonia pts
    • Investigational dosing
      • 400 mg/100 mg PO (10 mg/kg for children; NMT adult dose) BID x14 day course or until discharge
  • Remdesivir
    • FDA has approved for use in hospitalized adults and peds ≥12 yo
    • Emergency Use Authorization issued for use in hospitalized peds not covered under FDA approval
    • NIAID ACTT-1 Study found 10-day course yielded a faster time to recovery versus placebo (10 days vs 15 days); results also suggest survival benefit (mortality by day 29, 11.4% with remdesivir vs 15.2% with placebo)
    • Open-label study assessed compassionate use in severe COVID-19 hospitalized pts needing O2 support; 36 of 53 pts (68%) showed clinical improvement, 7 pts (13%) died during 18-day median follow-up
    • Phase III trial reviewing 5 or 10-day therapy vs SOC in moderate COVID-19 complete (SIMPLE studies)
      • Data suggests pts receiving 5-day course are 65% more likely to display clinical improvement at day 11 vs SOC (p=0.017) and 31% more likely with 10-day course (p=0.18)
    • Small randomized, double-blinded study assessed time to clinical improvement in remdesivir vs placebo; no significant difference was observed (median 21 vs 23 days); study halted early due to poor enrollment
    • Randomized, open-label, phase III trial compared 5 and 10 day course in hospitalized, non-vent/ECMO pts; rate of clinical improvement and discharge with 5-day was 65% and 60% vs 54% and 52% with 10-day course
    • Interim data from WHO SOLIDARITY trial displayed no overall reduction in 28-day mortality RR=0.95 (0.81-1.11, p=0.50)
    • NIAID ACTT-2 Study initiated, comparing time to clinical recovery in remdesivir + baricitinib vs remdesivir alone; key secondary outcome will analyze pt outcome at day-15 ranging from recovery to death
      • Initial data found statistically significant reduction (approx one-day) in median recovery time with combination Tx vs remdesivir alone [HR: 1.15 (95% CI 1.00, 1.31); p=0.047]
      • Baricitinib + remdesivir pts were more likely to have better clinical status at Day 15 compared to remdesivir alone [OR: 1.26 (95% CI 1.01, 1.57); p=0.044]
      • FDA has issued EUA for baricitinib for use with concomitant remdesivir in hospitalized pts requiring supplemental O2, invasive mechanical ventilation, or ECMO (see monograph)
    • IDSA Guidelines recommend remdesivir over no antiviral Tx in severe hospitalized pts; most benefit displayed with pts on supplemental O2 vs mechanical ventilation or ECMO
      • Recommend Tx with 5 days course over 10 days in severe pts on supplemental O2 but not on mechanical ventilation or ECMO (10 days suggested with mechanical ventilation or ECMO)
      • Recommend against use in hospitalized pts without need for supplemental O2 and O2 sat >94% on room air

Corticosteroids

  • Dexamethasone
    • RECOVERY trial displayed significant reduction in 28-day mortality with dexamethasone vs. usual care alone in hospitalized pts requiring invasive mechanical ventilation (29.3% vs. 41.4%; RR, 0.64) and oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; RR, 0.82)
      • However no benefit, with trend towards harm, was found with dexamethasone in hospitalized pts not receiving respiratory support (17.8% vs. 14.0%; RR, 1.19)
    • IDSA Guidelines suggest glucocorticoid use over no glucocorticoids in severe or critically ill (SpO2 ≤94% on room air, and those requiring supplemental O2, mechanical ventilation, or ECMO) hospitalized pts
      • In hospitalized pts without hypoxemia requiring supplemental O2, guideline suggests against use of glucocorticoids
    • Investigational dosing
      • 6 mg (or equivalent) IV/PO qD x10 days or discharge if earlier
  • Methylprednisolone
    • Preprint data in single pre-test, single post-test experiment found significantly lower rate of escalation of care from ward to ICU, new requirement for mechanical ventilation, and mortality in pre- and post-methylprednisolone groups (54.3% vs 34.9%)
    • Investigational dosing
      • 0.5-1 mg/kg/day div BID IV x3 days

H2 Antagonists

  • Famotidine
    • Retrospective cohort study compared rate of intubation or death in 84 hospitalized pts treated with famotidine vs 1536 pts not receiving famotidine Tx (420 pt matched on baseline characteristics); study found:
      • Use of famotidine was associated with reduced risk for death or intubation (aHR 0.42, 95% CI 0.21-0.85), AND
      • Reduced risk for death alone (aHR 0.30, 95% CI 0.11-0.80)
    • IDSA Guidelines suggest against famotidine use for sole purpose of treating COVID-19 outside of the context of a clinical trial in hospitalized pts with severe infection
    • Investigational dosing
      • 120 mg IV TID for NMT 14 days, or hospital discharge, whichever comes first

IL-6 Antagonists

  • Sarilumab
    • Adaptive Phase II/III, randomized, double-blind, placebo-controlled trial assessing safety/efficacy for hospitalized pts with severe or critical respiratory illness caused by COVID-19
      • Phase II data displayed negative trends with "severe" treated group vs positive trends with "critical" treated group, however not replicated with current Phase III data
      • Amended Phase III including only "critical" group with high dose therapy halted in US due to non-significant positive trends only
    • NIH recommends against the use of IL-6 antagonists outside the context of a clinical trial
    • Investigational dosing
      • 400 mg IV x1 dose
  • Siltuximab
    • Observational cohort study compared siltuximab + SOC vs SOC alone; Tx group was found to significantly lower 30-day mortality as compared to matched-control cohort pts (HR 0.462, 95% CI 0.221-0.965); p=0.0399)
    • NIH recommends against the use of IL-6 antagonists outside the context of a clinical trial
    • Investigational dosing
      • 11 mg/kg IV x1 dose
  • Tocilizumab
    • Pilot prospective open, single-arm multicenter study found no major ADRs attributed to use in 63 hospitalized pts; significant improvement in ferritin, CRP, D-dimer levels observed (14-day mortality 11%)
    • Randomized, double-blind, placebo-controlled trial shows no effect in preventing intubation or death in moderately ill hospitalized pts, HR 0.83 (95% CI, 0.38 to 1.81; P=0.64)
    • NIH recommends use in addition to SOC in certain hospitalized pts exhibiting rapid respiratory decompensation
    • IDSA Guidelines recommend use in severe or critical hospitalized pts with elevated markers of systemic inflammation in addition to SOC
    • Investigational dosing
      • 8 mg/kg (NMT 800 mg/dose) q12hrs x2 doses
      • 8 mg/kg x1 dose (NMT 800 mg)

Immunosuppressants

  • Colchicine
    • Small, open-labeled, randomized controlled trial evaluated colchicine vs SOC alone in 105 hospitalized pts (randomized 1:1); primary endpoints were clinical deterioration, CRP and maximum high-sensitivity cardiac troponin level increase
      • Study found significant reduction in rate of clinical deterioration, 1.8% (1 of 55 pts) in colchicine group vs 14.0% (7 of 50 pts) in control group; however no significant difference observed in biomarker change between groups
    • Investigational dosing
      • 1.5 mg x1, then 0.5 mg 1 hr later; maintenance 0.5 mg BID up to 3 wks
  • Sirolimus
    • Randomized, double-blind, placebo-controlled study; Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia (The SCOPE Trial) investigating proportion of pts who progress to require advanced respiratory support
    • Investigational dosing
      • 6 mg on day 1, then 2 mg daily x13 days (total 14 days or hospital discharge)
  • Tacrolimus
    • Clinical Trial to Evaluate Methylprednisolone Pulses and Tacrolimus in Patients With COVID-19 Lung Injury (TACROVID) measuring primary outcome of time to clinical stability in hospitalized pts with elevated inflammatory parameters and severe COVID-19 lung injury
    • Investigational dosing
      • Methylprednisolone pulses 120mg/day x3 days (if not previously administered) with tacrolimus to achieve plasma levels of 8-10 ng/ml

Monoclonal Antibodies

  • Bamlanivimab
    • Emergency Use Authorization revoked due to lack of efficacy against emerging viral variants
    • ACTIV-3 (NIAID) exploring use in hospitalized pts halted due to lack of efficacy
      • ACTIV-2 will continue in non-hospitalized pts investigating duration of S/S and viral clearance (via nasopharyngeal swab)
    • Interim analysis of the BLAZE-1 trial displayed decrease in viral load from baseline of −0.53 (95% CI, −0.98 to −0.08; P=0.02) at Day 11 in mild-moderate outpt cases vs placebo
    • IDSA recommends against monoTx use in severe hospitalized pts
    • NIH recommends against use in hospitalized pts except in clinical trial; recommends neither for or against use in mild-moderate disease
  • Bamlanivimab/Etesevimab
    • Emergency Use Authorization issued by FDA for use in non-hospitalized pts with COVID-19 (see monograph)
    • IDSA recommends use in mild-moderate pts at high risk of progression to severe disease
    • NIH recommendations mirror IDSA
  • Casirivimab/Imdevimab
    • Emergency Use Authorization issued by FDA for use in non-hospitalized pts with COVID-19 (see monograph)
    • Initial data from Phase 2/3 randomized, double-blind trial REGN-COV2 reduced COVID-19 related medical visits by 57% through day 29 (2.8% combined dose groups; 6.5% placebo; p=0.024)
    • Difference in time weighted average of viral load from Day 1-7 for pooled doses of casirivimab and imdevimab vs placebo was -0.36 log10 copies/mL (p<0.0001)
    • NIH recommends against use in hospitalized pts except in clinical trial; recommends neither for or against use in mild-moderate disease

Others

  • RLF-100 (Aviptadil)
    • Synthetic form of human vasoactive intestinal peptide; target VPAC1 receptor on Alveolar Type II cells in lungs; blocks cytokines release, prevents apoptosis, and upregulates surfactant production
    • Initial reports of rapid clearance of classic pneumonitis findings on x-ray, improved O2 status, and >50% reduction in lab markers for COVID-19 inflammation in critical pts
    • Multiple clinical trials underway investigating both IV (critical pts with respiratory failure) and inhalation (moderate or severe pts with no evidence of respiratory failure) administration
    • FDA granted Expanded Access Protocol for Respiratory Failure in COVID-19 (https://www.clinicaltrials.gov/ct2/show/NCT04453839)
    • Investigational dosing
      • 12 hr infusions at ascending doses of 50/100/150 pmol/kg/hr on 3 successive days
      • 100μg inhaled TID
  • Camostat mesilate (Not commercially available in US)
    • Serine protease inhibitor which blocks TMPRSS-2 mediated cell entry of SARS-CoV-2
    • Several clinical trials initiated investigating effectiveness in hospitalized pts as monotherapy and in combination with hydroxychloroquine
    • Investigational dosing
      • 400 mg PO TID x7 days with hydroxychloroquine 400 mg BID on day 1, then 200 mg BID days 2-7
      • 200 mg TID x5 days
  • Convalescent Plasma (COVID-19)
    • Emergency Use Authorization issued by FDA for use in hospitalized pts with COVID-19 (see monograph)
    • Randomized controlled trial compared time to clinical improvement within 28 days with convalescent plasma vs standard care alone; Tx group clinical improvement time found to be 2.15 days shorter (95% CI, −5.28 to 0.99 days)
      • Clinical improvement at 28 days occurred in 51.9% (27 of 52 pts) in Tx group vs 43.1% (22 of 52 pts) in control group (difference, 8.8%; 95% CI, −10.4% to 28%; HR, 1.40 [95% CI, 0.79-2.49]; P = .26)
      • Non-significant difference in outcome may be attributed to lack of enrollment/underpowering
    • Open-label, multicenter, randomized clinical trial evaluated use vs standard care alone in severe or life-threatening cases; no significant difference found in rate of clinical improvement (51.9% vs 43.1%) or 28-day mortality (15.7% vs 24.0%) respectively
      • Convalescent plasma associated with negative conversion rate of viral PCR at 72 hrs in 87.2% of pts vs 37.5% in control group
    • Case series observed viral load decrease, SOFA score decrease, and PaO2/FiO2 increase within 12 days in severe COVID-19 treated pts
    • Review of 5000 hospitalized pts with severe/life-threatening infection (66% ICU) found incidence of SAEs in hrs following transfusion was <1%; only 2 of 36 reported SAEs were deemed related to transfusion
    • RCT of 160 pts saw 48% relative risk reduction of progression from mild to severe infection with high-titer admin within 72 hrs of S/S in older adults (mean age 77.2 yo)
    • IDSA Guidelines recommend use in hospitalized pts only in context of clinical trial (see FDA guidance at https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma)

References

  1. Baricitinib in Combination with Remdesivir Reduces Time to Recovery in Hospitalized Patients with COVID-19 in NIAID-Sponsored ACTT-2 Trial [press release]. Indianapolis, IN: September 14, 2020. https://investor.lilly.com/news-releases/news-release-details/baricitinib-combination-remdesivir-reduces-time-recovery
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  15. FDA Emergency Use Authorization bamlanivimab (fact sheet for healthcare providers) https://www.fda.gov/media/143603/download (Accessed November 2020)
  16. FDA Emergency Use Authorization baricitinib (fact sheet for healthcare providers) https://www.fda.gov/media/143823/download (Accessed November 2020)
  17. FDA Emergency Use Authorization casirivimab/imdevimab (fact sheet for healthcare providers) https://www.fda.gov/media/143892/download (Accessed November 2020)
  18. FDA Emergency Use Authorization chloroquine phosphate https://www.fda.gov/media/136535/download (Accessed March 2020)
  19. FDA Emergency Use Authorization COVID-19 convalescent plasma https://www.fda.gov/media/141478/download (Accessed August 2020)
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  21. FDA Emergency Use Authorization remdesivir https://www.fda.gov/media/137566/download (Accessed August 2020)
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  44. RECOVERY trial investigators. No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY. https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-hospitalised-covid-19-patients-studied-in-recovery
  45. Sanofi and Regeneron begin global Kevzara® (sarilumab) clinical trial program in patients with severe COVID-19 [press release]. Cambridge, Mass and Tarrytown, NY; Sano-fi: March 16, 2020. http://www.news.sanofi.us/2020-03-16-Sanofi-and-Regeneron-begin-global-Kevzara-R-sarilumab-clinical-trial-program-in-patients-with-severe-COVID-19.
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  47. Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia (SCOPE). NCT04341675. (https://clinicaltrials.gov/ct2/show/NCT04341675)
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  49. Study Assessing the Efficacy and Safety of Anti-Spike SARS CoV-2 Monoclonal Antibodies for Prevention of SARS CoV-2 Infection Asymptomatic in Healthy Adults Who Are Household Contacts to an Individual With a Positive SARS-CoV-2 RT-PCR Assay. NCT04452318. (https://clinicaltrials.gov/ct2/show/NCT04452318)
  50. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734) in participants with moderate coronavirus disease (COVID-19) compared to standard of care treatment. NCT04292730. (https://www.clinicaltrials.gov/ct2/show/NCT04292730)
  51. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734) in participants with severe coronavirus disease (COVID-19). NCT04292899. (https://www.clinicaltrials.gov/ct2/show/NCT04 292899)
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Updated/Reviewed: March, 2021