Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease

Study Overview
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Brief Summary
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ORCHID is a multicenter, blinded, placebo-controlled, randomized clinical trial evaluating hydroxychloroquine for the treatment of adults hospitalized with COVID-19. Patients, treating clinicians, and study personnel will all be blinded to study group assignment.

Detailed Description
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Effective therapies for COVID-19 are urgently needed. Hydroxychloroquine is an antimicrobial agent with immunomodulatory and antiviral properties that has demonstrated in vitro activity against SARS-CoV-2, the virus that causes COVID-19. Preliminary reports suggest potential efficacy in small human studies. Clinical trial data are needed to determine whether hydroxychloroquine is effective in treating COVID-19. Study Aim: To compare the effect of hydroxychloroquine versus placebo on clinical outcomes, measured using the COVID Ordinal Outcomes Scale at Day 15, among adults with COVID-19 requiring hospitalization. Study Hypothesis: Among adults hospitalized with COVID-19, administration of hydroxychloroquine will improve clinical outcomes at Day 15. .

Official Title
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Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease

Conditions
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Coronavirus, Acute Respiratory Infection, SARS-CoV Infection

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Currently hospitalized or in an emergency department with anticipated hospitalization. Symptoms of acute respiratory infection, defined as one or more of the following: cough fever (> 37.5° C / 99.5° F) shortness of breath (operationalized as any of the following: subjective shortness of breath reported by patient or surrogate; tachypnea with respiratory rate ≥22 /minute; hypoxemia, defined as SpO2 <92% on room air, new receipt of supplemental oxygen to maintain SpO2 ≥92%, or increased supplemental oxygen to maintain SpO2 ≥92% for a patient on chronic oxygen therapy). sore throat Laboratory-confirmed SARS-CoV-2 infection within the past 10 days prior to randomization. Exclusion Criteria: Prisoner Pregnancy Breast feeding Symptoms of acute respiratory infection for >10 days before randomization >48 hours between meeting inclusion criteria and randomization Seizure disorder Porphyria cutanea tarda Diagnosis of Long QT syndrome QTc >500 ms on electrocardiogram within 72 hours prior to enrollment Known allergy to hydroxychloroquine, chloroquine, or amodiaquine Receipt in the 12 hours prior to enrollment, or planned administration during the 5-day study period that treating clinicians feel cannot be substituted for another medication, of any of the following: amiodarone; cimetidine; dofetilide; phenobarbital; phenytoin; sotalol Receipt of >1 dose of hydroxychloroquine or chloroquine in the 10 days prior to enrollment Inability to receive enteral medications Refusal or inability to be contacted on Day 15 for clinical outcome assessment if discharged prior to day 15 Previous enrollment in this trial The treating clinical team does not believe equipoise exists regarding the use of hydroxychloroquine for the treatment of this patient

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: Eligible participants will be randomized 1:1 to hydroxychloroquine versus placebo. Randomization will be stratified by site and be in permuted blocks of variable size.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydroxychlorquine<br>Participants assigned to the hydroxychloroquine arm will receive hydroxychloroquine sulfate 400 mg twice daily on the day of enrollment, then 200 mg twice daily for the next 4 days for a 5 day total course. | Drug: Hydroxychloroquine<br>* Hydroxychloroquine is available in 200 mg oral tablets of hydroxychloroquine sulfate. For this COVID-19 trial, we will use an oral or enteral dose of hydroxychloroquine 400 mg twice daily on the day of enrollment, then 200 mg twice daily for the next 4 days for a 5 day total course.<br>|
| Placebo Comparator: Placebo<br>Participants randomized to the control group will receive a dose of placebo enterally twice daily for 5 days (a total of 10 doses). The placebo pills will be as similar as possible to the hydroxychloroquine pills to ensure blinding. | Drug: Placebo<br>* Participants randomized to the control group will receive a dose of placebo enterally twice daily for 5 days (a total of 10 doses). The placebo pills will be as similar as possible to the hydroxychloroquine pills to ensure blinding.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COVID Outcomes Scale Score on Study Day 15 (14 Days After Randomization) | We will determine the COVID Ordinal Scale for all patients on study day 15 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms) | Assessed on study day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COVID Ordinal Outcomes Scale on Study Day 3 (2 Days After Randomization) | We will determine the COVID Ordinal Scale for all patients on study day 3 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms) | assessed on study day 3 | 
| COVID Ordinal Outcomes Scale on Study Day 8 (7 Days After Randomization) | We will determine the COVID Ordinal Scale on study day 8 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms) | assessed on study day 8 | 
| COVID Ordinal Outcomes Scale on Study Day 29 (28 Days After Randomization) | We will determine the COVID Ordinal Scale on study day 29 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms) | assessed on study day 29 | 
| All-location, All-cause Mortality Assessed on Study Day 15 (14 Days After Randomization) | Vital status of the patient on day 15 will be determined using any of the following methods: medical record review, phone calls to patient or proxy. There were two patients for whom we were unable to collect their vital status. | assessed on study day 15 | 
| All-location, All-cause Mortality Assessed on Study Day 29 (28 Days After Randomization) | Vital status of the patient at day 28 will be determined using any of the following methods: medical record review, phone calls to patient or proxy. There were two patients for whom we were unable to collect their vital status. | assessed on study day 29 | 
| Number of Patients Dead or With Receipt of ECMO Between Enrollment and Day 28 | We will determine the number of patients who are either dead or on ECMO ( extracorporeal membrane oxygenation) between enrollment and day 28 | Enrollment to Day 28 | 
| Oxygen-free Days Through Day 28 | The number of calendar days between randomization and 28 days later that the patient is alive and without the use of oxygen therapy. Patients who die prior to day 28 are assigned zero oxygen free days. | 28 days after randomization | 
| Ventilator-free Days Through Day 28 | Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days. | 28 days after randomization | 
| Vasopressor-free Days Through Day 28 | The number of calendar days between randomization and 28 days later that the patient is alive and without the use of vasopressor therapy. Patients who die prior to day 28 are assigned zero vasopressor free days. | 28 days after randomization | 
| ICU-free Days to Day 28 | The number of days spent out of the ICU to day 28. Patients who die prior to day 28 are assigned zero ICU free days. | 28 days after randomization | 
| Hospital-free Days to Day 28 | Defined as 28 days minus the number of days from randomization to discharge home.If a patient has not been discharged home prior to day 28 or dies prior to day 28, hospital free days will be zero. | 28 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19