Constance Benson, MD Professor of Medicine and Director of the UC San Diego AntiViral Research Center Division of Infectious Diseases & Global Public Health Department of Medicine University of California, San Diego

1. HIV & Global Health Rounds
The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease and global public health clinicians,
physicians, and researchers. The goal of these presentations is to
provide the most current research, clinical practices, and trends in HIV,
HBV, HCV, TB, and other infectious diseases of global significance.
The slides from the HIV & Global Health Rounds presentation that you
are about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.

2. Slide 2
COVID-19 Update: Clinical Trials
Currently In Progress at UCSD
Constance A. Benson, M.D.
Professor of Medicine
Director, AntiViral Research Center
PI, UCSD CD4 Collaborative HIV Clinical Trials Unit
Division of Infectious Diseases & Global Public Health
University of California, San Diego

3. Outline
• Brief epidemiology update
• Background on antiviral and anti-inflammatory
drugs under investigation
• Review of human participant clinical trials being
conducted at UCSD
– Remdesivir vs. placebo (DMID 20-0006)
– Tocilizumab vs. placebo (Roche WA42380)
– Hydroxychloroquine/Azithromycin (ACTG A5395)
– Other planned RCTs

4. • (CoVs) positive-stranded RNA viruses; crown-like
appearance due to the presence of spike glycoproteins
on the envelope
o Human CoVs: cause common colds and self-limiting
upper respiratory infections; in
immunocompromised individuals and the elderly,
lower respiratory tract infections can occur (e.g.
HCoV-OC43 and HCoV-HKU1; HCoV-229E and HCoV-
NL63)2
o Some human CoVs cause epidemics with variable
clinical severity featuring respiratory and extra-
respiratory manifestations (e.g. SARS-CoV, SARS-CoV-
2 and MERS-CoV)
COVID-19 Pneumonia – Caused by a
novel coronavirus SARS-CoV-2
Nucleotide identity1
• 89% with bat SARS-like-CoVZXC21
• 82% with human SARS-CoV
Cascella M, Rajnik M, Cuomo A, et al. StatPearls Publishing. 2020. ePub; Available from:
https://www.ncbi.nlm.nih.gov/books/NBK554776/; Chen Y, Liu Q, Guo D. J Med Virol. 2020;92:418–423.

5. Global COVID-19 Update
www.coronavirus.jhu.edu

6. Global COVID-19 Update April 16, 2020
www.worldometers.info
Total 2,183,475
Total 146,847

7. California Coronavirus Update
April 16, 2020

8. COVID-19 San Diego County
April 16, 2020

9. 9
FOR INTERNAL TRAINING PURPOSES ONLY – NOTFOR EXTERNALUSE
COVID-19 Clinical Manifestations
*Anosmia, dysgeusia
Mild disease(81%): non-pneumoniaandmildpneumonia
* the ratio between the blood pressure of the oxygen
(PaO2) and the percentage of oxygen supplied (FiO2)
2 (likely 3)clinicalscenarios:
Severedisease(14%): dyspnea,respiratoryfrequency≥30/min,
bloodoxygensaturation(SpO2) ≤93%,PaO2/FiO2ratio*<300
and/orlunginfiltrates>50%within24 to48 hours
Criticaldisease(5%): respiratoryfailure,septicshockand/or
multipleorgandysfunction(MOD) orfailure(MOF)
1. Wang D, et al. JAMA. 2020;323:1061-1069. 2. Wu Z, et al. JAMA. 24 February 2020. doi:10.1001/jama.2020.2648
BasedonChineseCentersforDiseaseControlreporton
72,314patients2
1

10. 10
FOR INTERNAL TRAINING PURPOSES ONLY – NOTFOR EXTERNALUSE
Timeline of onset to ICU admission in
severely and critically ill patients*
• ARDS, acuterespiratory distress syndrome.
• HuangC, etal. Lancet. 2020;395:497–506.
0 1 2 3 4 5 6 7 1098 11
Hospital
admission
Shortnessof breath
Onsetof
symptoms
ARDS
Intensivecareunit
admission
Numberof days(mediantimefromonsetofsymptoms,includingfever[in98%of patients],cough[75%],myalgiaorfatigue[44%]
andothers)
*41patientsinWuhan,China

11. Drugs and Targets for SARS-CoV-2

12. Remdesivir

13. Remdesivir and the SARS-CoV-2
Replicative Cycle
• SARS-CoV-2 enters target cells by binding to the ACE2 receptor on the cell surface
• Releases its RNA, translates its RNA-dependent RNA polymerase (RdRp) or RNA replicase
• Remdesivir acts as a RNA-dependent RNA polymerase inhibitor

14. Remdesivir
• Remdesivir is a pro-drug of a nucleoside analog, GS-
466547; inhibits viral RNA polymerases
– EC50 of 0.137 – 0.77 µM against SARS-CoV-2 in Vero cells
• It has broad spectrum activity against members of the
filoviruses (Ebola, Marburg, SARS-CoV, MERS-CoV) and
paramyxoviruses (RSV, Nipah and Hendra)
– Demonstrated prophylactic and therapeutic efficacy in a
mouse model of SARS-CoV
– Demonstrated prophylactic and therapeutic efficacy in MERS-
CoV mouse and rhesus macaque models
– Reduced lung viral loads, lung pathology, and clinical signs of
pulmonary dysfunction De Wit, et al. PNAS 2020;
Sheahan et al., Nature Comm 2020

15. Remdesivir
• Generally favorable safety profile based on > 500 pts
treated (healthy volunteers in phase 1 studies and pts with
acute Ebola disease)
– Treatment emergent AEs elevations in ALT, AST
• PK profile indicates high and persistent levels of the
active nucleoside triphosphate metabolites in PBMCs
 once daily dosing
– t1/2 of active metabolite in PBMCs 32-48h with Cmax > 10
µM
– Plasma t1/2 0.66-1h after infusion
• Renally excreted; CYP3A4 inhibitor but significant DDIs
unlikely due to rapid clearance after IV administration;
no induction of enzymes or transporters
Gilead Investigator’s Brochure; 2020

16. DMID 20-0006: Adaptive COVID-19
Treatment Trial
• Adaptive, randomized, double-blind, placebo-
controlled multicenter trial of remdesivir (IV) vs
placebo
• Inclusion
– PCR positive for SARS-CoV-2
– Symptoms > 72h duration + at least one of the
following: radiographic infiltrates or RA SpO2 < 94%
or requiring supplemental O2 or ventilation
• Exclusion
– ALT or AST > 5x ULN; estimated GFR < 30 ml/min;
pregnancy or breast feeding; anticipated d/c or
transfer out within 72h

17. DMID 20-0006: Adaptive COVID-19
Treatment Trial
• Primary outcome is time to recovery by day 29
based on reaching one of the following
categories:
– Hospitalized, not requiring supplemental O2;
longer requiring ongoing medical care
– Not hospitalized; limitation on activities and/or
requiring home oxygen
– Not hospitalized; no limitations on activities

18. DMID 20-0006: Adaptive COVID-19
Treatment Trial Progress
• As of April 17, 2020
– 915 enrolled at ~60 sites in 5 countries
– 18 enrolled at UCSD
– Total enrollment completed over ~60 days
– Stage 1 enrollment will be completed at 12MN on April 19
– Preliminary analysis aimed at 400 evaluable “recovered” pts due May 8

19. DMID 20-0006: Adaptive COVID-19
Treatment Trial (ACTT) - 2
• Adaptive design allows new therapeutic
agents to be added as they are identified and
ready for inclusion in clinical trials
• ACTT-2 will be adding baricitinib as part of a
new 2-arm or potentially a 2x2 randomization
to a 4-arm trial
• ACTT-2 arms scheduled to open April 27

20. Baricitinib: JAK1 and JAK2 Inhibitor
• Identified as a potentially
useful drug for treatment
of SARS-CoV-2 based on
AI
• Both anti-inflammatory
and antiviral potential
– Inhibits cytokine signaling
and potentially viral entry
at ACE2 receptor interface
• Risk of serious infection
due to
immunosuppression and
venous thrombosis in pts
with RA and other
autoimmune disorders
Richardson et al., Lancet 2020; 95:e30

21. Tocilizumab

22. Tocilizumab
• Recombinant humanized anti-human monoclonal antibody
• Binds to soluble IL-6R and membrane-bound IL-6R to inhibit
IL-6R-mediated signaling
– IL-6proinflammatory cytokine involved in T-cell activation;
induction of acute phase proteins; stimulation of hematopoietic
precursor cell growth and differentiation and other cell metabolic
functions
– Elevated IL-6 levels implicated in several inflammatory and
autoimmune disorders (RA, Castleman disease, giant cell arteritis,
systemic sclerosis and importantly cytokine release syndrome
– Inhibition of IL-6R is effective in reducing the inflammatory
sequelae of these disorders
• IV formulations generally well-tolerated; terminal t1/2 21-32
days; no appreciable drug-drug interactions

23. 23
FOR INTERNAL TRAINING PURPOSES ONLY – NOTFOR EXTERNALUSE
• Observational study of 21 patients in China with severe* (n = 17)
or critical† (n = 4) COVID-19 pneumonia1
• All patients received SOC + tocilizumab (400 mg IV); 18 pts single
dose; 3 received second dose
• Outcomes:
• In all patients, body temperature returned to normal on day 1
• Peripheral oxygen saturation improved in 15 patients (71%)
• Opacities in lungs significantly improved in 19 patients (90.5%)
• 19 patients (90%) have been discharged
• No subsequent pulmonary infections or death and no adverse
drug reactions reported
Tocilizumab: Observational experience in
patients with COVID-19 pneumonia
Wu X, et al. March 2020. chinaXiv:202003.00026v1.

24. 24
FOR INTERNAL TRAINING PURPOSES ONLY – NOTFOR EXTERNALUSE
Tocilizumab observational studies:
Improvements in CRP, temperature, O2
inhalation and saturation, lung opacities
Wu X, et al. March 2020. chinaXiv:202003.00026v1.
BeforeTCZtreatment
AfterTCZtreatment
CRP Bodytemperature
Oxygeninhalation Oxygensaturation
SaO2(%)Temperature(°C)
CRP(mg/L)
Concentrationofoxygeninhalation(%)
Before D1 D2 D3 D4 D5
Before D1 D2 D3 D4 D5
Before D1 D2 D3 D4 D5
Before D1 D3 D5
100
98
96
94
92
90
41
40
39
38
37
36
250
200
150
100
50
0
100
80
60
40
20

25. WA42380: Tocilizumab in COVID-19
Pneumonia
• Randomized, double-blind, placebo-
controlled, multicenter study

26. WA42380: Tocilizumab in COVID-19
Pneumonia
• Inclusion:
– Age > 18; PCR positive SARS-CoV-2; hospitalized with
radiographic evidence of pneumonia; SpO2 < 93% or
PaO2/FiO2 < 300 mmHg
• Exclusion:
– Active TB or suspected bacterial, fungal, other viral
infection; oral anti-rejection or immunomodulatory
drugs within past 6 months or participation in other
clinical trials (exceptions for COVID-19 antiviral trials) or
treatment with other investigational drugs within 30d
– ALT or AST > 10x ULN; ANC < 1,000/mm3; platelet <
50,000/mm3; pregnancy or lactation

27. WA42380: Tocilizumab in COVID-19
Pneumonia
• Efficacy endpoints
– Primary: Clinical status based on 7-category ordinal scale
at day 28
– Secondary:
• Time to clinical improvement (NEWS2) < 2 maintained for 24h
• Incidence of mechanical ventilation; ventilator free days; organ
failure free days; duration of ICU stay; time to clinical failure
(death, mechanical ventilation, or ICU); mortality; time to hospital
discharge; duration of supplemental O2
• Safety endpoints
– Incidence and severity of AEs, SARS-CoV-2 viral load over
time; time to RT-PCR negative; change from baseline in
targeted laboratory test results
– Biomarkers (TCZ PK/PD, sIL-6R, IL-6, CRP, ferritin)

28. WA42380: Tocilizumab Interim
Analyses and Timelines
• Enrollment began April 2020
• We have randomized 2 at UCSD
• The total length of the study, from screening of first
patient to the end of the study is expected to be
approximately 5 months
• The first efficacy interim analysis will be conducted
when approximately 75 patients (50 TCZ and 25
placebo) have reached the 28-day follow-up time
point and will be based on the mortality rate at 28
days (secondary endpoint)

29. Hydroxychloroquine and
Azithromycin

30. A5395: HAz COVID Trial
• Rationale:
– HCQ blocks viral infection by
increasing endosomal pH
interfering with viral/cell fusion
• May also modulate immune
response
– AZ may potentiate the activity by
increasing lysosomal pH
– Uncontrolled study in COVID-19
pts suggested that HCQ + AZ
reduced proportion of pts with
SARS-CoV-2 PCR (+) samples by
95% over 6d
– F/U study of 80 pts  83% NP
swab PCR neg by 7d and 93% by
8d; 97.5% culture neg by 5d of
followup Gautret P, et al. Int J Antimicrobial Agents 2020;
PAHO/WHO 2020 report

31. A5395 HAz COVID Trial Study Design
• Randomized, double-blind, placebo-controlled multicenter trial
• Pts randomized 1:1 to receive either HCQ + Azithro (Arm A) or Placebo
for 1 week; followed for 3 weeks post-treatment; 24 wk F/U
• N = 2000 (1000 in each arm)
• Stratification by age and comorbidities

32. Objectives
Primary Objective
• Determine if HCQ + Azithro will prevent the composite endpoint of either
hospitalization or death by 21 days from study entry, as compared to placebo
Secondary Objectives
• Frequency of adverse events of special interest (AESI), including 1) AEs leading
to early discontinuation of treatment with HCQ and Azithro or 2) cardiac AEs
• To determine if HCQ and Azithro reduces the frequency of detection and
levels of SARS-CoV-2 RNA in nasopharyngeal (NP) swabs in subset of
participants.
• To determine if HCQ and Azithro change the severity and duration of self-
reported symptoms of COVID-19.
• To determine if HCQ and Azithro will prevent the composite endpoint of either
hospitalization or death by 24 weeks after study entry.
• To determine the comparability between site-collected NP swabs and self-
collected nasal swabs for the detection of SARS-CoV-2 shedding.

33. Exploratory Objectives
• To explore if outpatient HCQ and Azithro change the hospital
course once a participant requires hospitalization.
• To identify pretreatment biomarkers that are associated with
outcomes.
• To explore differences in outcomes between HCQ and Azithro
versus placebo treatment groups among subgroups of the
population, notably by sex, race/ethnicity, and risk groups
defined by age and co-morbidities.
• To explore possible predictors of outcomes across the study
population, notably sex, race/ethnicity, and risk groups defined
by age and co-morbidities.

34. Inclusion/Exclusion Criteria
• Persons ≥18 years of age
• Lab-confirmed active SARS-CoV-2 infection
• Presents with at least one infection symptom of:
– fever, cough, or shortness of breath
• Enrollment within 96 hours of positive CoV-2 test
• Pregnancy and breast feeding allowed
• History of ventricular arrhythmia, except isolated premature
ventricular complexes, or personal or family history of prolonged QT
syndrome.
• Use of drugs with anti-SARS-CoV-2 activity or drugs known to cause
drug-induced prolonged QT syndrome, or antiarrhythmic drugs.
• When co-enrollment is not allowed.
• SARS-CoV-2 vaccination prior to study entry.

35. • Screening and Study Entry (Day 0): in-person but ‘low touch’ or
remote visit:
– Documented SARS-CoV-2+ PCR
– Demographics, COVID-19 symptoms, medical history, and medication history
– Start study treatment on Day 0
• Days 2, 6, 9, 13, 17: telephone visits
– Review of Study Diaries: daily symptoms, temps and adherence
– Review study endpoints
• Day 20: in-person visit
– Turn in Study Diaries
– Review study endpoints
• Weeks 12 and 24: telephone visits
– Review of Study Diaries: daily symptoms, temps and adherence
– Review study endpoints
• Site-Specific Intensive Sampling: in-person
– 100 participants in each arm
– Days 0, 6, and 20: site-collected NP Swab, self-collected nasal swab and blood
Data Collection and Sampling

36. Drug Safety
• Main risks of short course HCQ and Azithro is prolonged
QT syndrome and torsades de pointes
–Considerable safety data from large malaria studies using
chloroquine + azithro; while chloroquine and HCQ are different
compounds animal toxicity studies indicate HCQ is 2-3 times less
toxic across different species.
• Same molecule in HCQ and Chloroquine that prolong QT
–Will exclude persons who have concomitant meds that have
been demonstrated to prolong QT
–Need to balance safety of study personnel with modest benefit
of doing EKG at study entry
(Kimani Et al PLoS One 2016).

37. Staff Safety
• During acute infection persons with SARS-CoV-
2 can shed billions of copies of virus in their
respiratory secretions.
• Shed virus can linger for hours on fomites.
• Therefore, the trial is designed to limit
participant contact, while obtaining maximal
data.

38. Outcomes
• Primary Outcomes
– Hospitalization (>24 hours in acute care setting) or death by 3 weeks after entry
• Secondary Outcomes
– Death or hospitalization from any cause of 24 weeks from study entry
– Premature discontinuation of study treatment due to an AE
– Treatment related Cardiac AE
– Duration of fever or symptoms
– Time to self-reported return to usual
– Duration and change of SARS-CoV-2 nasal shedding
• Exploratory Outcomes
– Hospital course once a participant requires hospitalization
• Death
• Hospitalized: 1) on mechanical ventilation or ECMO; 2) on non-invasive ventilation; 3)
on high flow oxygen devices; 4) requiring supplemental oxygen; 5) not requiring
supplemental oxygen; 6) ICU admission; 7) Length of ICU stay; 8) length of hospital stay
– Blood inflammatory, hematologic and chemistry changes.

39. A5395: Interim Analyses
• Three planned interim analyses
–After 25%, 50%, and 75% enrollment (i.e. 500,
1000, 1500 participants).
–First review may occur earlier than 500 participants
if 62 participants are hospitalized or die across both
combined arms.
–Interim efficacy and futility analyses

41. Slide 41
Questions?
To Be Continued in Microbiology
Lab…