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

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.

Study Overview

• Status: Completed
• Conditions: SARS-CoV Infection; Coronavirus; Acute Respiratory Infection
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Placebo

Detailed Description

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.

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• Study Type: Interventional
• Enrollment (Actual): 479
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85721
      • University of Arizona
  • California
    • Fresno, California, United States, 93701
      • UCSF Fresno
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Aurora, Colorado, United States, 80045
      • Medical Center of Aurora
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center
    • Denver, Colorado, United States, 80218
      • St. Joseph Hospital
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • University of Kentucky
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • University Medical Center
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02445
      • Brigham and Women's Hospital
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
    • Worcester, Massachusetts, United States, 01608
      • St. Vincent's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Detroit, Michigan, United States, 48025
      • Henry Ford Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center-Weiler
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center-Moses
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15261
      • UPMC Presbyterian/Mercy/Shadyside
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37221
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • VCU Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98122
      • Swedish Hospital First Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years
2. Currently hospitalized or in an emergency department with anticipated hospitalization.

3. Symptoms of acute respiratory infection, defined as one or more of the following:

   1. cough
   2. fever (> 37.5° C / 99.5° F)
   3. 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).
   4. sore throat
4. Laboratory-confirmed SARS-CoV-2 infection within the past 10 days prior to randomization.

Exclusion Criteria:

1. Prisoner
2. Pregnancy
3. Breast feeding
4. Symptoms of acute respiratory infection for >10 days before randomization
5. >48 hours between meeting inclusion criteria and randomization
6. Seizure disorder
7. Porphyria cutanea tarda
8. Diagnosis of Long QT syndrome
9. QTc >500 ms on electrocardiogram within 72 hours prior to enrollment
10. Known allergy to hydroxychloroquine, chloroquine, or amodiaquine
11. 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
12. Receipt of >1 dose of hydroxychloroquine or chloroquine in the 10 days prior to enrollment
13. Inability to receive enteral medications
14. Refusal or inability to be contacted on Day 15 for clinical outcome assessment if discharged prior to day 15
15. Previous enrollment in this trial
16. The treating clinical team does not believe equipoise exists regarding the use of hydroxychloroquine for the treatment of this patient

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydroxychlorquine; 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; 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.
Placebo Comparator: Placebo; 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; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Seizures to Day 28	We will determine the number of patients that experience seizure between randomization and day 28	28 days after randomization
Number of Patients With Atrial Arrhythmia to Day 28	We will determine the number of patients that experience atrial arrhythmia between randomization and day 28	28 days after randomization
Number of Patients With Ventricular Arrhythmia to Day 28	We will determine the number of patients that experience ventricular arrhythmia between randomization and day 28	28 days after randomization
Number of Patients With Cardiac Arrest to Day 28	We will determine the number of patients that experience cardiac arrest between randomization and day 28	28 days after randomization
Number of Patients With Elevation in Aspartate Aminotransferase or Alanine Aminotransferase to Twice the Local Upper Limit of Normal to Day 28	We will determine the number of patients that experience elevation in aspartate aminotransferase or alanine aminotransferase to twice the local upper limit of normal between randomization and day 28	28 days after randomization
Number of Patients With Acute Pancreatitis Arrest to Day 28	We will determine the number of patients that experience acute pancreatitis between randomization and day 28	28 days after randomization
Number of Patients With Acute Kidney Injury to day28	We will determine the number of patients that experience acute kidney injury between randomization and day 28	28 days after randomization
Number of Patients With Receipt of Renal Replacement Therapy to Day 28	We will determine the number of patients that experience renal replacement therapy between randomization and day 28	28 days after randomization
Number of Patients With Symptomatic Hypoglycemia to Day 28	We will determine the number of patients that experience symptomatic hypoglycemia between randomization and day 28	28 days after randomization
Number of Patients With Neutropenia to Day 28	We will determine the number of patients that experience neutropenia between randomization and day 28	28 days after randomization
Number of Patients With Lymphopenia to Day 28	We will determine the number of patients that experience lymphopenia between randomization and day 28	28 days after randomization
Number of Patients With Anemia to Day 28	We will determine the number of patients that experience anemia between randomization and day 28	28 days after randomization
Number of Patients With Thrombocytopenia to Day 28	We will determine the number of patients that experience thrombocytopenia between randomization and day 28	28 days after randomization
Number of Patients With Severe Dermatologic Reaction to Day 28	We will determine the number of patients that experience severe dermatologic reaction between randomization and day 28	28 days after randomization
Time to Recovery, Defined as Time to Reaching Level 5, 6, or 7 on the COVID Outcomes Scale, Which is the Time to the Earlier of Final Liberation From Supplemental Oxygen or Hospital Discharge	Time to recovery, defined as time to reaching level 5, 6, or 7 on the COVID Outcomes Scale, which is the time to the earlier of final liberation from supplemental oxygen or hospital discharge. Patients who die prior to day 28 are assigned 28 days for time to recovery.	28 days after randomization

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Boyd Taylor Thompson, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, Chang SY, Collins SP, Eppensteiner JC, Filbin MR, Files DC, Gibbs KW, Ginde AA, Gong MN, Harrell FE Jr, Hayden DL, Hough CL, Johnson NJ, Khan A, Lindsell CJ, Matthay MA, Moss M, Park PK, Rice TW, Robinson BRH, Schoenfeld DA, Shapiro NI, Steingrub JS, Ulysse CA, Weissman A, Yealy DM, Thompson BT, Brown SM; National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Steingrub J, Smithline H, Tiru B, Tidswell M, Kozikowski L, Thornton-Thompson S, De Souza L, Hou P, Baron R, Massaro A, Aisiku I, Fredenburgh L, Seethala R, Johnsky L, Riker R, Seder D, May T, Baumann M, Eldridge A, Lord C, Shapiro N, Talmor D, O'Mara T, Kirk C, Harrison K, Kurt L, Schermerhorn M, Banner-Goodspeed V, Boyle K, Dubosh N, Filbin M, Hibbert K, Parry B, Lavin-Parsons K, Pulido N, Lilley B, Lodenstein C, Margolin J, Brait K, Jones A, Galbraith J, Peacock R, Nandi U, Wachs T, Matthay M, Liu K, Kangelaris K, Wang R, Calfee C, Yee K, Hendey G, Chang S, Lim G, Qadir N, Tam A, Beutler R, Levitt J, Wilson J, Rogers A, Vojnik R, Roque J, Albertson T, Chenoweth J, Adams J, Pearson S, Juarez M, Almasri E, Fayed M, Hughes A, Hillard S, Huebinger R, Wang H, Vidales E, Patel B, Ginde A, Moss M, Baduashvili A, McKeehan J, Finck L, Higgins C, Howell M, Douglas I, Haukoos J, Hiller T, Lyle C, Cupelo A, Caruso E, Camacho C, Gravitz S, Finigan J, Griesmer C, Park P, Hyzy R, Nelson K, McDonough K, Olbrich N, Williams M, Kapoor R, Nash J, Willig M, Ford H, Gardner-Gray J, Ramesh M, Moses M, Ng Gong M, Aboodi M, Asghar A, Amosu O, Torres M, Kaur S, Chen JT, Hope A, Lopez B, Rosales K, Young You J, Mosier J, Hypes C, Natt B, Borg B, Salvagio Campbell E, Hite RD, Hudock K, Cresie A, Alhasan F, Gomez-Arroyo J, Duggal A, Mehkri O, Hastings A, Sahoo D, Abi Fadel F, Gole S, Shaner V, Wimer A, Meli Y, King A, Terndrup T, Exline M, Pannu S, Robart E, Karow S, Hough C, Robinson B, Johnson N, Henning D, Campo M, Gundel S, Seghal S, Katsandres S, Dean S, Khan A, Krol O, Jouzestani M, Huynh P, Weissman A, Yealy D, Scholl D, Adams P, McVerry B, Huang D, Angus D, Schooler J, Moore S, Files C, Miller C, Gibbs K, LaRose M, Flores L, Koehler L, Morse C, Sanders J, Langford C, Nanney K, MdalaGausi M, Yeboah P, Morris P, Sturgill J, Seif S, Cassity E, Dhar S, de Wit M, Mason J, Goodwin A, Hall G, Grady A, Chamberlain A, Brown S, Bledsoe J, Leither L, Peltan I, Starr N, Fergus M, Aston V, Montgomery Q, Smith R, Merrill M, Brown K, Armbruster B, Harris E, Middleton E, Paine R, Johnson S, Barrios M, Eppensteiner J, Limkakeng A, McGowan L, Porter T, Bouffler A, Leahy JC, deBoisblanc B, Lammi M, Happel K, Lauto P, Self W, Casey J, Semler M, Collins S, Harrell F, Lindsell C, Rice T, Stubblefield W, Gray C, Johnson J, Roth M, Hays M, Torr D, Zakaria A, Schoenfeld D, Thompson T, Hayden D, Ringwood N, Oldmixon C, Ulysse C, Morse R, Muzikansky A, Fitzgerald L, Whitaker S, Lagakos A, Brower R, Reineck L, Aggarwal N, Bienstock K, Freemer M, Maclawiw M, Weinmann G, Morrison L, Gillespie M, Kryscio R, Brodie D, Zareba W, Rompalo A, Boeckh M, Parsons P, Christie J, Hall J, Horton N, Zoloth L, Dickert N, Diercks D. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020 Dec 1;324(21):2165-2176. doi: 10.1001/jama.2020.22240.
• Casey JD, Johnson NJ, Semler MW, Collins SP, Aggarwal NR, Brower RG, Chang SY, Eppensteiner J, Filbin M, Gibbs KW, Ginde AA, Gong MN, Harrell F, Hayden DL, Hough CL, Khan A, Leither LM, Moss M, Oldmixon CF, Park PK, Reineck LA, Ringwood NJ, Robinson BRH, Schoenfeld DA, Shapiro NI, Steingrub JS, Torr DK, Weissman A, Lindsell CJ, Rice TW, Thompson BT, Brown SM, Self WH. Rationale and Design of ORCHID: A Randomized Placebo-controlled Clinical Trial of Hydroxychloroquine for Adults Hospitalized with COVID-19. Ann Am Thorac Soc. 2020 Sep;17(9):1144-1153. doi: 10.1513/AnnalsATS.202005-478SD.

Helpful Links

• Website for the PETAL Network

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2020
• Primary Completion (Actual): June 19, 2020
• Study Completion (Actual): July 23, 2020

Study Registration Dates

• First Submitted: March 31, 2020
• First Submitted That Met QC Criteria: March 31, 2020
• First Posted (Actual): April 3, 2020

Study Record Updates

• Last Update Posted (Actual): March 17, 2021
• Last Update Submitted That Met QC Criteria: March 12, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Severe Acute Respiratory Syndrome; COVID-19; Infections; Communicable Diseases; Respiratory Tract Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: PETAL 05 Orchid

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No