A novel coronavirus, SARS-CoV-2, is responsible for a rapidly spreading pandemic that has reached 160 countries, infecting over 500,000 individuals and killing more than 24,000 people. SARS-CoV-2 causes an acute and potentially lethal respiratory illness, known as COVID-19, that is threatening to overwhelm health care systems due to a dramatic surge in hospitalized and critically ill patients. Patients hospitalized with COVID-19 typically have been symptomatic for 5-7 days prior to admission, indicating that there is a window during which an effective intervention could significantly alter the course of illness, lessen disease spread, and alleviate the stress on hospital resources. There is no known treatment for COVID-19, though in vitro and one poorly controlled study have identified a potential antiviral activity for HCQ. The rationale for this clinical trial is to measure the efficacy and safety of hydroxychloroquine for reducing viral load and shedding in adult outpatients with confirmed COVID-19.
Background COVID-19 is pandemic with high mortality among hospitalized patients despite a
benign course in the large majority of patients infected. Limited data are available from
small outpatient studies and have not shown efficacy in preventing hospitalization.
Hydroxychloroquine (HCQ) and chloroquine have antiviral and immune-modulating effects, but
there are no data concerning their efficacy in reducing viral load and shedding in
outpatients.
Evidence supporting possible efficacy for hydroxychloroquine. In cell models, chloroquine
both interferes with terminal glycosylation of the ACE2 receptor (the cell surface receptor
by which SARS-CoV2 enters human cells) and increases endosomal pH, which interferes (at least
in vitro) with a crucial step in viral replication.1,2 HCQ is 5x more potent than chloroquine
in a Vero cell model of SARS-CoV-2 infection. In independent experiments, chloroquine has
confirmed in vitro activity against SARS-CoV-2. Additionally, HCQ has in vitro efficacy
against SARS-CoV-1. According to news releases, an as-yet-unpublished set of case series in
China (N reportedly 120) suggests the possibility of rapid viral clearance and low rates of
progression to critical illness. In addition to in vitro anti-viral effects chloroquine and
HCQ appear to have immune-modulatory effects, especially via suppression of release of TNF
and IL6, especially in macrophages.
Evidence against efficacy for hydroxychloroquine. Chloroquine and HCQ have been promoted as
extremely broad anti-infective agents for decades. The reported effects include suppression
of fungi, atypical bacteria, and viruses. Other than the effects on ACE2 glycosylation, the
mechanisms invoked as evidence for efficacy against SARS-CoV-2 have also been invoked for a
wide range of viruses. However, when chloroquine and HCQ have been studied in humans, neither
agent has demonstrated consistent efficacy in clinical trials, including in HIV, influenza,
hepatitis, and Dengue. In one trial, chloroquine resulted in increased viral replication in
Chikungunya virus [Roques et al, Viruses 2018 May 17;10(5)] while in another
hydroxychloroquine was associated with increased HIV viral load [Paton et al, JAMA 2012 Jul
25;308(4):353]. Expert opinion advises against HCQ for MERS, another serious coronavirus. An
underpowered (n=30) study of HCQ in COVID-19 recently published in China did not demonstrate
any clinical benefit [Chen et al, J Zhejiang University, 2020 March 9]. The long history of
clinical failure despite in vitro anti-viral activity suggests a low probability of efficacy.
Rationale for Trial There is significant publicity concerning the potential use of HCQ in
this pandemic, and many patients are seeking access to this unproven therapy. The ANZICS
guidelines emphasize that novel treatments should be administered within clinical trials; the
Surviving Sepsis Campaign guidelines (http://bit.ly/SSCCOVID-19) also affirm the lack of
evidence to support the clinical use of (hydroxy)chloroquine. WHO guidance
(https://apps.who.int/iris/bitstream/handle/10665/331446/WHO-2019-nCoV-c…
f) also strongly affirms that "investigational anti-COVID-19 therapeutics should be done
under ethically approved, randomized, controlled trials." The evidence thus strongly favors
equipoise.
Drug: Hydroxychloroquine
HCQ 400mg po BID x 1 day, then 200mg po BID x 4 days
Drug: Placebo oral tablet
Placebo to be taken on the same schedule as HCQ.
Inclusion Criteria:
- Patient age ≥18 years, competent to provide consent
- Within 48 hours of positive nucleic acid test for SARS-CoV-2
Exclusion Criteria:
- Patient already prescribed chloroquine or hydroxychloroquine
- Allergy to hydroxychloroquine
- History of bone marrow or solid organ transplant
- Known G6PD deficiency
- Chronic hemodialysis, peritoneal dialysis, continuous renal replacement therapy or
Glomerular Filtration Rate < 20ml/min/1.73m2
- Known liver disease (e.g. Child Pugh score ≥ B or AST>2 times upper limit)
- Psoriasis
- Porphyria
- Known cardiac conduction delay (QTc > 500mSec) or taking any prescription medications
known to prolong QT interval
- Concomitant use of digitalis, flecainide, amiodarone, procainamide, or propafenone
- Seizure disorder
- Prisoner
- Weight < 35kg
- Inability to follow-up - no cell phone or no address or not Spanish or English
speaking
- Receipt of any experimental treatment for SARS-CoV-2 (off-label, compassionate use, or
trial related) within the 30 days prior to the time of the screening evaluation
- Patient or another member of patient's household has been already enrolled in this
study.
University of Utah
Salt Lake City, Utah, United States
Adam Spivak, MD, Principal Investigator
University of Utah