COVID-19 Therapeutics Update: Hydroxychloroquine & Remdesivir Studies (June 2020)

COVID-19 Therapeutics Update John Veillette, PharmD, BCPS Col. Todd J. Vento, MD, MPH, FACP, FIDSA, ID-DUDE 6/24/20

Outline ***All COVID-related treatment info*** Intranet Search: treatcovid/ OPE website: https://m.intermountain.net/PatientExperience /COVID-19/COVID-19CaregiverGuidance/COVID- 19ClinicalTrials/Pages/Home.aspx Virologic Therapies Hydroxychloroquine Remdesivir Convalescent plasma Immunologic Therapies Tocilizumab Steroids

Hydroxychloroquine Updates (June 2020) Date Update 6/3 NEJM study HCQ does NOT prevent COVID-19 following exposure 6/4 Lancet study retracted (suggested increased mortality with HCQ, questionable data) 6/5 RECOVERY Trial closes HCQ arm due to lack of benefit 6/15 FDA revokes HCQ Emergency Use Authorization (EUA) It is no longer reasonable to believe that HCQ may be effective in treating COVID-19, nor is it reasonable to believe that the benefits outweigh their risks Does not affect other indications for HCQ 6/15 FDA warning Remdesivir + hydroxychloroquine not recommended based on in-vitro antagonism 6/17 WHO SOLIDARITY Trial closes HCQ arm 6/19 Intermountain HCQ studies (HAHPS and ORCHID) permanently stopped

Remdesivir Data NEJM study (ACTT-1) Randomized, double-blind, placebo-controlled trial Primary outcome = Time to recovery Overall: faster recovery vs placebo (median 11 vs 15 days), lower mortality (7 vs 11.9%) Subgroup analysis: Median recovery: 7 vs 9 days 14-Day Mortality: 2.4 vs 10.9% Median recovery: 16 vs 22 days 14-Day Mortality: 15.2 vs 14.7%

Remdesivir Data Summary Benefit seen in patients requiring oxygen Less benefit for high flow No benefit seen for ventilated/ECMO Second NEJM study: No difference between 5-day and 10-day treatment courses Time from symptom onset to starting treatment NEJM ACTT-1 study: no difference if 10 days versus > 10 days Lancet study: numerically faster recovery if 10 days Safety/Adverse Effects Infusion reactions LFT elevations Rash

Remdesivir Criteria (Per State of Utah) Inclusion: 1. Confirmed SARS-COV-2 by PCR, admitted to the hospital for the first time for COVID-19 2. **9am each day** New, increased oxygen requirement 4 L/min up to high-flow nasal canula or non-invasive positive pressure ventilation Please notify your ID pharmacist for patients meeting these criteria!! Exclusion: 1. Mechanically ventilated or on extracorporeal membrane oxygenation (ECMO) 2. eGFR <30 mL/min 3. ALT >5x ULN or end-stage liver disease 4. Pregnancy or age <18 access to remdesivir under the separate emergency IND pathway ( Expanded Access Program ).

Remdesivir Logistics Allocation per State of Utah Criteria Reviewed in daily ID Pharm huddles 10am, 1:30pm No overnight starts Once approved, THEN provider approaches patient for informed consent Treatment course Maximum 5 days, even if intubated or still hospitalized Discontinued at discharge Safety monitoring Daily LFTs Dispensing log Notify ID Pharms of any ADRs Resources (OPE website) Provider and Patient fact sheets Nitty Gritty Pharmacist Guide IV Compounding guide https://m.intermountain.net/PatientExperience/COVID-19/COVID- 19CaregiverGuidance/COVID-19ClinicalTrials/Pages/Remdesivir.aspx

Convalescent Plasma Data JAMA study Multicenter, open-label RCT: standard treatment +/- plasma Primary outcome = time to clinical improvement within 28 days Overall: no significant difference in improvement 51.9 vs 43.1%, or mortality 15.7 vs 24.0% Subgroup analysis: Resp failure on ventilator; shock; other organ failure = = hospitalized on oxygen Improvement: 91% (plasma) vs 68% Mortality: 0% (plasma) vs 9% Improvement: 21% (plasma) vs 24% Mortality: 29% (plasma) vs 36%

Convalescent Plasma Data Summary Study limitations: Terminated early due to low enrollment (epidemic containment) Small sample size ~50 vs 50 pts Median time from symptom onset to randomization = 30 days Benefit seen in patients requiring oxygen Not seen for life-threatening disease Safety/Adverse Events Transfusion-related reactions Allergic (fever, chills, rash) Volume-related (SOB, dyspnea) caution in heart failure, volume overload

Convalescent Plasma Criteria

Convalescent Plasma Logistics Remdesivir + Plasma? Screen for remdesivir first monitor response before giving plasma If plasma given, can add remdesivir if they meet criteria Step-by-step plasma instructions: https://documents.intermountain.net/pharmserviceswebsite/Pharmacy%20Docume nts/Antimicrobial%20Stewardship/Convalescent_Plasma_Guidance_Document.pdf Expanded Access Program through Mayo Clinic and Red Cross Providers must register Local Hospitalists (priority) ID Telehealth Physicians (backup on weekdays) ABO screening Questions or request for Just-in-time training Aaron Silver (IMC/Alta View Hospitalist) SCORE line 801-50-SCORE Turnaround time (following informed consent) Up to 48-72 hours

Tocilizumab No RCT data for COVID 1 retrospective cohort study (pre-print) suggested mortality benefit REMDACTA study starting soon Remdesivir + placebo vs Remdesivir + tocilizumab Potential sites LDSH, IMED, Dixie, UVH What about non-study sites? Toci vs steroids? TBD by Therapeutics Committee

COVID-19 Macrophage Activation Syndrome (cMAS) Criteria Fever Tocilizumab ( off study ) 3 or more cMAS criteria AND clinically worsening Temperature >38.0 Hyperferritinemia Ferritin 700 Cytopenia Neutrophil to Lymphocyte Ratio 10 -or- Both: Hgb 9.2 AND Platelet 110k D-dimer 1.5 LDH 400 -or- AST 100 IL-6 20 -or- Triglycerides 150 Dexamethasone Considering 2 or more cMAS criteria (forthcoming recs) Coagulopathy Hepatic injury Cytokinemia

Steroids Retrospective cohort study found decreased LOS and mortality compared to standard care Pre-post study design with lots of confounding variables More comorbidities, sicker patients in standard care group Suggested early steroids may prevent progression Press release + Pre-print from RECOVERY Trial Suggests mortality benefit in ventilated patients Data not yet published High mortality rate! Unclear if we can generalize to our patients Specific criteria for use? TBD cMAS criteria, dose, and duration recs forthcoming Remember other indications for steroids (Asthma, COPD)

Summary Immunologic Therapies Tocilizumab Use within clinical trial where available Consider off-study use for select cases Steroids Promising preliminary data (awaiting publication) Consider using for 2 cMAS criteria Virologic Therapies Hydroxychloroquine No longer recommended! Remdesivir First priority (under FDA EUA) Limited supply follow the process! Convalescent plasma Second priority Consider for patients not meeting remdesivir criteria!

***All COVID ***All COVID- -related treatment info*** related treatment info*** Intranet Search: treatcovid/ OPE website: https://m.intermountain.net/PatientExperience /COVID-19/COVID-19CaregiverGuidance/COVID- 19ClinicalTrials/Pages/Home.aspx

Questions?? Call your friendly neighborhood ID Pharmacist!! Small Hospitals John V. 385-228-9549 (cell) Providers can also call SCORE line 801-50-SCORE

References 1. Boulware DR, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med 2020;NEJMoa2016638. Beigel JH, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med 2020;NEJMoa2007764 Goldman JD, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med 2020;NEJMoa2015301. Wang Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395(10236):1569-1578. 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;e2010044. Fadel R, et al. Early Short Course Corticosteroids in Hospitalized Patients with COVID-19. Clin Infect Dis 2020;ciaa601 2. 3. 4. 5. 6.