University of Utah COVID-19 Hydrochloroquine Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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 According to news releases, an as-yet-unpublished set of case series in China (N reportedly 120) suggests the possibility of rapid viral clearance and low rates of progression to critical illness.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-clinical-2020.4-eng.pdf) also strongly affirms that investigational anti-COVID-19 therapeutics should be done under ethically approved, randomized, controlled trials. The evidence thus strongly favors equipoise.

Official Title
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Hydroxychloroquine for Outpatients With Confirmed COVID-19

Conditions
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Coronavirus Infection, Coronavirus, Infectious Disease

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 2, prospective, placebo-controlled, parallel group, randomized trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HCQ<br>Participants randomized to the HCQ arm will receive HCQ 400mg po BID x 1 day, then 200mg po BID x 4 days. The drug dose (2.4 gm over 5 days) falls at the lower end of doses proposed in various international trials, but it has proven in vitro efficacy, with a ratio of lung tissue trough concentrations to the EC50 (effective concentration to suppress 50% of viral activity) of >20. | Drug: Hydroxychloroquine<br>* HCQ 400mg po BID x 1 day, then 200mg po BID x 4 days<br>|
| Placebo Comparator: Placebo<br>Those randomized to placebo will receive a placebo to be taken on the same schedule. | Drug: Placebo oral tablet<br>* Placebo to be taken on the same schedule as HCQ.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Viral Shedding | Duration of viral shedding, as defined by time from randomization to the first of two consecutive negative swabs, measured on days 1 - 14. | Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of COVID-19-attributable Symptoms | Duration of COVID-19 symptoms (through DayA15): this is an integer-valued outcome which is defined as date of first asymptomatic date through the start date. To determine the end date, first each symptom assessment from baseline through DayA15, inclusive, will be classified as symptomatic, asymptomatic, or unknown. A symptomatic day is one in which at least one of the core symptoms is observed to exceed the permissible threshold: not experiencing for fever and chills; extremely mild for shortness of breath, diarrhea, and muscle aches; mild for cough and tiredness. If at most one symptom level is missing on a given day and all observed core symptoms' levels are at or below the permissible threshold, the day will be classified as asymptomatic. Otherwise (i.e. if at most five of the core symptoms have a reported symptom level and none of the reported symptom levels exceeded the threshold), the day will be considered unknown. | Days 1-15 | 
| Hospitalization | Outcome is summarized by treatment received; all other summaries show treatment assigned | within 14 days of enrollment | 
| Number of Participants With Viral Shedding on Day 28 | The definition of the persistence of viral shedding on Day 28 outcome relies heavily on the Day 28 swab and is limited to those who have a test result for the Day 28 swab or who are not known to have died on or before DayR + 30 (there is a 2 day window for collecting the Day 28 swab). If the Day 28 swab result is known, the result will be used to define the outcome (yes if positive, no if negative). Otherwise, subjects with a confirmed cessation of viral shedding when considering daily swab results from DayR + 1 to DayR + 25, inclusive (with the requirement for confirmation waived if the latest available daily result in this interval is negative), and a missing Day 28 value will be assumed to be negative on Day 28; otherwise subjects hospitalized on any of the days DayR + 26{DayR + 30 with a missing Day 28 value will be assumed to be positive on Day 28; otherwise, multiple imputation will be performed. | Day 28 | 
| Adult Household Contact Viral Acquisition | This outcome will be analyzed for households with at least two adults for which no other adult besides the index study subject is positive for COVID-19 at baseline and for which the index study subject is in the ITT population. This binary outcome will be at the household level and will be a yes if there is a positive swab by one or more adult household contacts for any of the study-administered swabs from days DayR + 1 to DayR + 14, inclusive. If there are no positive swabs but at least one negative swab, the outcome will be a no; otherwise it will be missing. | Days 1-14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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coronavirus, COVID-19, hydrochloroquine, placebo