Treatment of COVID-19: A Brief Overview

Emily S. Spivak, MD, MHS

Associate Professor of Medicine

University of Utah School of Medicine

Investigational Agents

• Lopinavir/ritonavir

• Chloroquine

• Hydroxychloroquine

• Remdesivir

• Immunomodulatory agents

No controlled data supporting the use of any of these agents

Efficacy for COVID-19 is unknown

Coronavirus Treatment

• Cell culture screen of 350 FDA-approved drugs

• Four compounds inhibit viral replication in low micro-molar range

• Hits = chloroquine, chlorpromazine, loperamide, lopinavir

AAC 2014

SARS-CoV-2 Treatment

• No known therapies exist for COVID-19

bioRxiv 2020

bioRxiv 2020

Cell Research 2020

Cell 2020

SARS-CoV-2 Treatment

• RCT (n=199)

• LPVr po BID x 14 days vs standard of care

• No difference in time to clinical improvement

• No mortality difference at 28 days (19.2% vs 25%)

NEJM 2020

Chloroquine / HydroxychloroquineChloroquine

• Anti-malarial and immunomodulator

• Increases endosomal pH blocking viral entry

• Interferes with glycosylation of cellular receptors of SARS-CoV-2

• In vitro activity against SARS-CoV-2

• Included in China’s National SARS-CoV-2 treatment guidelines, and reported efficacy but no published primary data

• Chloroquine has shown in vitro activity against other viruses with f/u clinical studies showing no benefit or harm

Hydroxychloroquine (HCQ)

• Same mechanism of action

• In vitro activity against SARS-CoV-2

• More tolerable safety profile

• Based on physiologically-based pharmacokinetic models (PBPK), HCQ found to be more potent

• EC50=0.72μM vs. EC50=5.47μM

Cortegiani A, et al.J Crit Care. 2020; PMID 32171130

Yao, X, et al. Clin Infect Dis. 2020; PMID 32150618

Gautret et al. (2020) International Journal of Antimicrobial Agents – In Press 17 March 2020 DOI:10.1016/j.ijantimicag.2020.105949

HCQ in vivo evidence: March 18• Aimed to enroll hospitalized patients

(age >12) to evaluate efficacy of HCQ

• Administered 200mg HCQ po TID x 10 days

• Patients who refused intervention were followed as controls

• Outcome measure = nasopharyngeal clearance of SARS-CoV-2 by PCR

• HCQ n=26, control n=16

• 6 HCQ participants lost to follow up and not included in analysis

• 6 HCQ participants also received azithromycin

• No clinical outcomes are reported

International Journal of Antimicrobial Agents 2020

GroupSARS-CoV-2 PCR negative

at Day 6 (%)

HCQ + Azithro (n=6) 100.0

HCQ alone (n=14) 57.1

Control (n=16) 12.5

HCQ in vivo evidence: March 28• Aimed to reproduce results of HCQ /

azithro in hospitalized patients

• Enrolled 11 participants

• One died, two transferred to ICU during study period

• At day six, 8 / 10 participants had + PCR for SARS-CoV-2 Medecine et Maladies Infectieuses 2020

Latest on HCQ

MedRxiv 2020

• Retrospective analysis of all confirmed SARS CoV-2 infection admitted VA until April 11, 2020

• 368 patients

• HCQ = 97, HCQ + AZ = 113, No HCQ = 158

• No difference in need for ventilation

• Higher all-cause mortality in HCQ group

• Adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03

https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or

Remdesivir

• Nucleotide prodrug that is metabolized into an analog of adenosine triphosphate to inhibit viral RNA polymerases• Broad spectrum activity against number of viruses (e.g. Ebola, Marburg, SARS-

CoV, MERS-CoV, RSV, Nipah virus, Hendra virus)

• In vitro activity and therapeutic benefit in a mouse model

• Reported clinical benefit in China and Washington

Remdesivir

Grein J, et al. N Engl J Med. 2020 Apr 10. doi: 10.1056/NEJMoa2007016. [Epub ahead of print]

• Inpatients with severe SARS CoV-2 infection

• January 25, 2020, through March 7, 2020

• 61 patients (8 could not be analyzed)

• At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) on ECMO

• 36 patients (68%) had an improvement in oxygen status

• 25 patients (47%) were discharged, and 7 patients (13%) died

Other Investigational Agents• Tocilizumab –

• Recombinant humanized monoclonal antibody against IL-6

• Uncontrolled study of 21 patients in China with severe COVID-19 respiratory disease, reduced oxygen requirement, normalized the CRP, and increased the lymphocyte count, 19/21 discharged

• Steroids• Conflicting data

• WHO and CDC recommend against given evidence of harm and delayed viral clearance for other respiratory viruses

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

In sum

• We have several therapeutic candidates to treat COVID-19

• We desperately need RCT evidence for safety and efficacy

• LPVr is probably ineffective

• HCQ and remdesivir are being actively studied…

• Suspect HCQ is ineffective and potentially toxic…

JAMA 2020

University of Utah Approach

• Preference for all patients to enroll in clinical trials

• Inpatient use of investigational agents for COVID-19 restricted to Antimicrobial Stewardship approval

• Recommend on a case by case basis for inpatients with severe COVID-19 disease• Less as literature has evolved

University of Utah Clinical Trials

Outpatient• Hydroxychloroquine for Outpatients with

Confirmed COVID-19 (HCQ Trial)

• Phase 2, prospective, open-label, parallel group, randomized controlled

• Hydroxychloroquine versus Placebo

• Patient age > 44 years, competent to provide consent

• Within 48 hours of positive test for COVID-19

• Primary outcome:

• Change in viral shedding, measured on days 1 - 14 and 28

• Secondary outcomes:

• Duration of COVID-19-attributable symptoms

• Hospitalization within 14 days of enrollment

• Adult household contact viral acquisition

Inpatient• Two randomized, open-label Remdesivir trials:

• Moderate disease (NCT04292730): 5 days RDV vs 10 days RDV vs standard of care

• Severe disease (NCT04292899): 5 days RDV vs 10 days RDV

• Hydroxychloroquine vs. Azithromycin for Hospitalized Patients With Suspected or Confirmed COVID-19

• 5 days of Hydroxychloroquine vs. 5 days of Azithromycin

• COVID Ordinal Outcomes Scale at 14 days

Convalescent Plasma

CCP Clinical Studies

1. Expanded Access Program authorized by the FDA• Mayo-led case-control study (COVID-19 inpatients treated with CCP vs. untreated)

2. CCP to Stem Coronavirus: A Randomized Controlled Double-Blinded Phase 2 Study Comparing the Efficacy and Safety of CCP vs. Control non-immune plasma among Adults Exposed to COVID-19

3. CCP to Limit Coronavirus Associated Complications: Randomized, Double-Blind, Controlled, Phase 2 Study Comparing the Efficacy and Safety of CCP vs. Control Plasma among Outpatients with COVID-19

4. CCP to Treat Coronavirus - Associated Severe Pulmonary Complications: A Feasibility (Phase 1) Study Assessing the Safety of Multiple Doses of Anti-SARS-CoV-2 Plasma in Mechanically Ventilated Intubated Patients with Respiratory Failure due to COVID-19

CCP Clinical Studies

1. Expanded Access Program authorized by the FDA• Mayo-led case-control study (COVID-19 inpatients treated with CCP vs. untreated)

2. CCP to Stem Coronavirus: A Randomized Controlled Double-Blinded Phase 2 Study Comparing the Efficacy and Safety of CCP vs. Control non-immune plasma among Adults Exposed to COVID-19

3. CCP to Limit Coronavirus Associated Complications: Randomized, Double-Blind, Controlled, Phase 2 Study Comparing the Efficacy and Safety of CCP vs. Control Plasma among Outpatients with COVID-19

4. CCP to Treat Coronavirus - Associated Severe Pulmonary Complications: A Feasibility (Phase 1) Study Assessing the Safety of Multiple Doses of Anti-SARS-CoV-2 Plasma in Mechanically Ventilated Intubated Patients with Respiratory Failure due to COVID-19

Other CCP Trials

https://ccpp19.org/healthcare_providers/component_3/index.html