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

• ClinicalTrials.gov Identifier: NCT04332991
• Recruitment Status: Completed
• First Posted: April 3, 2020
• Results First Posted: March 17, 2021
• Last Update Posted: March 17, 2021
• Sponsor: Massachusetts General Hospital
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Boyd Taylor Thompson, Massachusetts General Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Coronavirus; Acute Respiratory Infection; SARS-CoV Infection	Drug: Hydroxychloroquine; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 479 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Patients, treating clinicians, trial personnel, and outcome assessors will be blinded to group assignment.
• Primary Purpose: Treatment
• Official Title: Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease
• Actual Study Start Date: April 2, 2020
• Actual Primary Completion Date: June 19, 2020
• Actual Study Completion Date: July 23, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. COVID Outcomes Scale Score on Study Day 15 (14 Days After Randomization) [ Time Frame: Assessed on study day 15 ]

   We will determine the COVID Ordinal Scale for all patients on study day 15

   COVID Ordinal Scale defined as:

   1. Death
   2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation)
   3. Hospitalized on non-invasive ventilation or high flow nasal cannula
   4. Hospitalized on supplemental oxygen
   5. Hospitalized not on supplemental oxygen
   6. Not hospitalized with limitation in activity (continued symptoms)
   7. Not hospitalized without limitation in activity (no symptoms)

Secondary Outcome Measures :

1. COVID Ordinal Outcomes Scale on Study Day 3 (2 Days After Randomization) [ Time Frame: assessed on study day 3 ]

   We will determine the COVID Ordinal Scale for all patients on study day 3

   COVID Ordinal Scale defined as:

   1. Death
   2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation)
   3. Hospitalized on non-invasive ventilation or high flow nasal cannula
   4. Hospitalized on supplemental oxygen
   5. Hospitalized not on supplemental oxygen
   6. Not hospitalized with limitation in activity (continued symptoms)
   7. Not hospitalized without limitation in activity (no symptoms)
2. COVID Ordinal Outcomes Scale on Study Day 8 (7 Days After Randomization) [ Time Frame: assessed on study day 8 ]

   We will determine the COVID Ordinal Scale on study day 8

   COVID Ordinal Scale defined as:

   1. Death
   2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation)
   3. Hospitalized on non-invasive ventilation or high flow nasal cannula
   4. Hospitalized on supplemental oxygen
   5. Hospitalized not on supplemental oxygen
   6. Not hospitalized with limitation in activity (continued symptoms)
   7. Not hospitalized without limitation in activity (no symptoms)
3. COVID Ordinal Outcomes Scale on Study Day 29 (28 Days After Randomization) [ Time Frame: assessed on study day 29 ]

   We will determine the COVID Ordinal Scale on study day 29

   COVID Ordinal Scale defined as:

   1. Death
   2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation)
   3. Hospitalized on non-invasive ventilation or high flow nasal cannula
   4. Hospitalized on supplemental oxygen
   5. Hospitalized not on supplemental oxygen
   6. Not hospitalized with limitation in activity (continued symptoms)
   7. Not hospitalized without limitation in activity (no symptoms)
4. All-location, All-cause Mortality Assessed on Study Day 15 (14 Days After Randomization) [ Time Frame: assessed on study day 15 ]

   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.

5. All-location, All-cause Mortality Assessed on Study Day 29 (28 Days After Randomization) [ Time Frame: assessed on study day 29 ]

   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.

6. Number of Patients Dead or With Receipt of ECMO Between Enrollment and Day 28 [ Time Frame: Enrollment to Day 28 ]
   We will determine the number of patients who are either dead or on ECMO ( extracorporeal membrane oxygenation) between enrollment and day 28
7. Oxygen-free Days Through Day 28 [ Time Frame: 28 days after randomization ]
   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.
8. Ventilator-free Days Through Day 28 [ Time Frame: 28 days after randomization ]
   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.
9. Vasopressor-free Days Through Day 28 [ Time Frame: 28 days after randomization ]
   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.
10. ICU-free Days to Day 28 [ Time Frame: 28 days after randomization ]
    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.
11. Hospital-free Days to Day 28 [ Time Frame: 28 days after randomization ]
    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.

Other Outcome Measures:

1. Number of Patients With Seizures to Day 28 [ Time Frame: 28 days after randomization ]
   We will determine the number of patients that experience seizure between randomization and day 28
2. Number of Patients With Atrial Arrhythmia to Day 28 [ Time Frame: 28 days after randomization ]
   We will determine the number of patients that experience atrial arrhythmia between randomization and day 28
3. Number of Patients With Ventricular Arrhythmia to Day 28 [ Time Frame: 28 days after randomization ]
   We will determine the number of patients that experience ventricular arrhythmia between randomization and day 28
4. Number of Patients With Cardiac Arrest to Day 28 [ Time Frame: 28 days after randomization ]
   We will determine the number of patients that experience cardiac arrest between randomization and day 28
5. Number of Patients With Elevation in Aspartate Aminotransferase or Alanine Aminotransferase to Twice the Local Upper Limit of Normal to Day 28 [ Time Frame: 28 days after randomization ]
   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
6. Number of Patients With Acute Pancreatitis Arrest to Day 28 [ Time Frame: 28 days after randomization ]
   We will determine the number of patients that experience acute pancreatitis between randomization and day 28
7. Number of Patients With Acute Kidney Injury to day28 [ Time Frame: 28 days after randomization ]
   We will determine the number of patients that experience acute kidney injury between randomization and day 28
8. Number of Patients With Receipt of Renal Replacement Therapy to Day 28 [ Time Frame: 28 days after randomization ]
   We will determine the number of patients that experience renal replacement therapy between randomization and day 28
9. Number of Patients With Symptomatic Hypoglycemia to Day 28 [ Time Frame: 28 days after randomization ]
   We will determine the number of patients that experience symptomatic hypoglycemia between randomization and day 28
10. Number of Patients With Neutropenia to Day 28 [ Time Frame: 28 days after randomization ]
    We will determine the number of patients that experience neutropenia between randomization and day 28
11. Number of Patients With Lymphopenia to Day 28 [ Time Frame: 28 days after randomization ]
    We will determine the number of patients that experience lymphopenia between randomization and day 28
12. Number of Patients With Anemia to Day 28 [ Time Frame: 28 days after randomization ]
    We will determine the number of patients that experience anemia between randomization and day 28
13. Number of Patients With Thrombocytopenia to Day 28 [ Time Frame: 28 days after randomization ]
    We will determine the number of patients that experience thrombocytopenia between randomization and day 28
14. Number of Patients With Severe Dermatologic Reaction to Day 28 [ Time Frame: 28 days after randomization ]
    We will determine the number of patients that experience severe dermatologic reaction between randomization and day 28
15. 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 Frame: 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. Patients who die prior to day 28 are assigned 28 days for time to recovery.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

University of Arizona

Tucson, Arizona, United States, 85721

United States, California

UCSF Fresno

Fresno, California, United States, 93701

Ronald Reagan UCLA Medical Center

Los Angeles, California, United States, 90095

UC Davis Medical Center

Sacramento, California, United States, 95817

UCSF Medical Center

San Francisco, California, United States, 94143

Stanford University

Stanford, California, United States, 94305

United States, Colorado

Medical Center of Aurora

Aurora, Colorado, United States, 80045

University of Colorado Hospital

Aurora, Colorado, United States, 80045

Denver Health Medical Center

Denver, Colorado, United States, 80204

St. Joseph Hospital

Denver, Colorado, United States, 80218

United States, Florida

University of Florida

Gainesville, Florida, United States, 32608

United States, Kentucky

University of Kentucky

Lexington, Kentucky, United States, 40506

United States, Louisiana

University Medical Center

New Orleans, Louisiana, United States, 70112

United States, Maine

Maine Medical Center

Portland, Maine, United States, 04102

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02115

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02445

Baystate Medical Center

Springfield, Massachusetts, United States, 01199

St. Vincent's Hospital

Worcester, Massachusetts, United States, 01608

United States, Michigan

University of Michigan Medical Center

Ann Arbor, Michigan, United States, 48109

Henry Ford Medical Center

Detroit, Michigan, United States, 48025

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, New York

Montefiore Medical Center-Weiler

Bronx, New York, United States, 10461

Montefiore Medical Center-Moses

Bronx, New York, United States, 10467

United States, North Carolina

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

University of Cincinnati Medical Center

Cincinnati, Ohio, United States, 45219

Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44195

Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Penn State Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

Temple University Hospital

Philadelphia, Pennsylvania, United States, 19140

UPMC Presbyterian/Mercy/Shadyside

Pittsburgh, Pennsylvania, United States, 15261

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37221

United States, Texas

University of Texas Health Science Center

Houston, Texas, United States, 77030

United States, Utah

Intermountain Medical Center

Murray, Utah, United States, 84107

University of Utah Hospital

Salt Lake City, Utah, United States, 84132

United States, Virginia

VCU Medical Center

Richmond, Virginia, United States, 23298

United States, Washington

Harborview Medical Center

Seattle, Washington, United States, 98104

Swedish Hospital First Hill

Seattle, Washington, United States, 98122

Sponsors and Collaborators

Massachusetts General Hospital

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Boyd Taylor Thompson, MD; Massachusetts General Hospital

  Study Documents (Full-Text)

Documents provided by Boyd Taylor Thompson, Massachusetts General Hospital:

Study Protocol  [PDF] June 4, 2020

Statistical Analysis Plan  [PDF] June 17, 2020

More Information

Additional Information:

Website for the PETAL Network 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Boyd Taylor Thompson, Co-Prinicipal Investigator PETAL CCC, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT04332991
• Other Study ID Numbers: PETAL 05 Orchid
• First Posted: April 3, 2020
• Results First Posted: March 17, 2021
• Last Update Posted: March 17, 2021
• Last Verified: March 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Boyd Taylor Thompson, Massachusetts General Hospital:

COVID-19

Additional relevant MeSH terms:

Infections; Communicable Diseases; COVID-19; Respiratory Tract Infections; Severe Acute Respiratory Syndrome; Disease Attributes; Pathologic Processes; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Hydroxychloroquine; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents