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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04332991
Recruitment Status : Active, not recruiting
First Posted : April 3, 2020
Last Update Posted : June 23, 2020
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Boyd Taylor Thompson, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE March 31, 2020
First Posted Date  ICMJE April 3, 2020
Last Update Posted Date June 23, 2020
Actual Study Start Date  ICMJE April 2, 2020
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 31, 2020)
COVID Ordinal Outcomes Scale on Day 15 [ 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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 31, 2020)
  • all-location, all-cause mortality assessed on day 15 [ 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
  • all-location, all-cause mortality assessed on day 29 [ 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
  • COVID Ordinal Outcomes Scale on Study Day 3 [ Time Frame: assessed on study day 3 ]
    We will determine the COVID Ordinal Scale for all patients on study day 3
  • COVID Ordinal Outcomes Scale on Study Day 8 [ Time Frame: assessed on study day 8 ]
    We will determine the COVID Ordinal Scale on study day 8
  • COVID Ordinal Outcomes Scale on Study Day 29 [ Time Frame: assessed on study day 29 ]
    We will determine the COVID Ordinal Scale on study day 29
  • 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
  • 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.
  • 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.
  • 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.
  • ICU-free days to Day 28 [ Time Frame: 28 days after randomization ]
    The number of days spent out of the ICU to day 28.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 2, 2020)
  • 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
  • Number of patients with atrial or 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Number of patients with neutropenia, lymphopenia, anemia, or thrombocytopenia to day 28 [ Time Frame: 28 days after randomization ]
    We will determine the number of patients that experience neutropenia, lymphopenia, anemia, or thrombocytopenia between randomization and day 28
  • 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
  • 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
Original Other Pre-specified Outcome Measures
 (submitted: March 31, 2020)
  • 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
  • Number of patients with atrial or 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Number of patients with neutropenia, lymphopenia, anemia, or thrombocytopenia to day 28 [ Time Frame: 28 days after randomization ]
    We will determine the number of patients that experience neutropenia, lymphopenia, anemia, or thrombocytopenia between randomization and day 28
  • 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
 
Descriptive Information
Brief Title  ICMJE Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease
Official Title  ICMJE Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease
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.
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.

.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • Coronavirus
  • Acute Respiratory Infection
  • SARS-CoV Infection
Intervention  ICMJE
  • 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.

  • 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.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Hydroxychloroquine
  • 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.
    Intervention: Drug: Placebo
Publications * 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 BR, Schoenfeld DA, Shapiro NI, Steingrub JS, Torr DK, Weissman A, Lindsell CJ, Rice TW, Thompson BT, Brown SM, Self WH; ORCHID Protocol Committee and the National Heart, Lung and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Investigators. Rationale and Design of ORCHID: A Randomized Placebo-Controlled Trial of Hydroxychloroquine for Adults Hospitalized with COVID-19. Ann Am Thorac Soc. 2020 Jun 3. doi: 10.1513/AnnalsATS.202005-478SD. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 22, 2020)
479
Original Estimated Enrollment  ICMJE
 (submitted: March 31, 2020)
510
Estimated Study Completion Date  ICMJE July 2020
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04332991
Other Study ID Numbers  ICMJE PETAL 05 Orchid
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boyd Taylor Thompson, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Boyd Taylor Thompson, MD Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP