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NCT04332991: ORCHID

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

Completed Phase 3 Results posted Last updated 17 March 2021
What this trial tests

Phase 3 trial testing Hydroxychloroquine in Coronavirus in 479 participants. Completed in 23 July 2020.

Timeline
2 April 2020
Primary endpoint
19 June 2020
23 July 2020

Quick facts

Lead sponsorMassachusetts General Hospital
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment479
Start date2 April 2020
Primary completion19 June 2020
Estimated completion23 July 2020
Sites40 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Massachusetts General Hospital

Who can join

18 and older, any sex, with Coronavirus or Acute Respiratory Infection. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

COVID Outcomes Scale Score on Study Day 15 (14 Days After Randomization) Primary · 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)

GroupValue95% CI
Hydroxychloroquine64 – 7
Placebo64 – 7
COVID Ordinal Outcomes Scale on Study Day 3 (2 Days After Randomization) Secondary · 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)

GroupValue95% CI
Hydroxychloroquine43 – 5
Placebo43 – 5
COVID Ordinal Outcomes Scale on Study Day 8 (7 Days After Randomization) Secondary · 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)

GroupValue95% CI
Hydroxychloroquine54 – 7
Placebo63 – 6
COVID Ordinal Outcomes Scale on Study Day 29 (28 Days After Randomization) Secondary · 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)

GroupValue95% CI
Hydroxychloroquine66 – 7
Placebo66 – 7
All-location, All-cause Mortality Assessed on Study Day 15 (14 Days After Randomization) Secondary · 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.

GroupValue95% CI
Hydroxychloroquine18
Placebo14
All-location, All-cause Mortality Assessed on Study Day 29 (28 Days After Randomization) Secondary · 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.

GroupValue95% CI
Hydroxychloroquine25
Placebo25
Number of Patients Dead or With Receipt of ECMO Between Enrollment and Day 28 Secondary · 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

GroupValue95% CI
Hydroxychloroquine29
Placebo28
Oxygen-free Days Through Day 28 Secondary · 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.

GroupValue95% CI
Hydroxychloroquine210 – 27
Placebo200 – 27
Ventilator-free Days Through Day 28 Secondary · 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.

GroupValue95% CI
Hydroxychloroquine2828 – 28
Placebo2828 – 28
Vasopressor-free Days Through Day 28 Secondary · 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.

GroupValue95% CI
Hydroxychloroquine2828 – 28
Placebo2828 – 28
ICU-free Days to Day 28 Secondary · 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.

GroupValue95% CI
Hydroxychloroquine2821 – 28
Placebo2818 – 28
Hospital-free Days to Day 28 Secondary · 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.

GroupValue95% CI
Hydroxychloroquine2111 – 24
Placebo2010 – 24

Adverse events — posted to ClinicalTrials.gov

Time frame: Subjects were assessed for adverse events from enrollment through study day 29 or discharge, whichever occurs first. Investigators will determine if the event is serious or related to study drug.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Hydroxychlorquine
Serious: 14/242 (6%)
Deaths: 25/242
Placebo
Serious: 11/237 (5%)
Deaths: 25/237

Serious adverse events (23 terms)

ReactionSystemHydroxychlorquinePlacebo
Cardiac ArrestCardiac disorders
DeathGeneral disorders
StrokeNervous system disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
PneumothoraxRespiratory, thoracic and mediastinal disorders
Myocardial InfarctionCardiac disorders
Ventricular TachycardiaCardiac disorders
Abdominal DistensionGastrointestinal disorders
Bleeding GastrointestinalGastrointestinal disorders
Gall stonesGastrointestinal disorders
Nausea, Vomiting, HematemesisGastrointestinal disorders
Obstruction BowelGastrointestinal disorders
HypokalemiaInvestigations
Reaction NonspecificInvestigations
Hematoma MuscleMusculoskeletal and connective tissue disorders
Joint PainMusculoskeletal and connective tissue disorders
Edema CerebralNervous system disorders
EncephalopathyNervous system disorders
HeadacheNervous system disorders
Intracranial hemorrhageNervous system disorders
Respiratory DistressRespiratory, thoracic and mediastinal disorders
Shortness of BreathRespiratory, thoracic and mediastinal disorders
Hemorrhage RetroperitonealVascular disorders
Other adverse events (30 terms — click to expand)

ReactionSystemHydroxychlorquinePlacebo
Multiple Liver Function Tests AbnormalInvestigations
Prolonged QTcCardiac disorders
HeadacheNervous system disorders
Atrial ArrythmiaCardiac disorders
BradycardiaCardiac disorders
Chest PainCardiac disorders
NauseaGastrointestinal disorders
LeukocytosisBlood and lymphatic system disorders
Cardiac ArrhythmiaCardiac disorders
CardiomyopathyCardiac disorders
Conduction DisorderCardiac disorders
EKG Abnormality: Non-SpecificCardiac disorders
Premature Ventricular ContractionsCardiac disorders
Sinus BradycardiaCardiac disorders
HypoglycemiaEndocrine disorders
DiarrheaGastrointestinal disorders
Nausea, VomitingGastrointestinal disorders
Nausea, DiarrheaGastrointestinal disorders
Contrast ExtravasationGeneral disorders
Allergic ReactionImmune system disorders
ALT IncreasedInvestigations
AST IncreasedInvestigations
Neuropathy PeripheralNervous system disorders
Kidney Function AbnormalRenal and urinary disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
ItchingSkin and subcutaneous tissue disorders
RashSkin and subcutaneous tissue disorders
FlushingVascular disorders
Vagal ReactionVascular disorders
NosebleedVascular disorders

Most-reported serious reactions: Cardiac Arrest, Death, Stroke, Hypoxia, Pneumothorax, Myocardial Infarction, Ventricular Tachycardia, Abdominal Distension.

Data from ClinicalTrials.gov NCT04332991 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.
    Cummings MJ, Baldwin MR, Abrams D, Jacobson SD, et al · · 2020 · cited 1603× · PMID 32442528 · DOI 10.1016/s0140-6736(20)31189-2
  2. Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic.
    Driggin E, Madhavan MV, Bikdeli B, Chuich T, et al · · 2020 · cited 1272× · PMID 32201335 · DOI 10.1016/j.jacc.2020.03.031
  3. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.
    Self WH, Semler MW, Leither LM, Casey JD, et al · · 2020 · cited 317× · PMID 33165621 · DOI 10.1001/jama.2020.22240
  4. Emerging treatment strategies for COVID-19 infection.
    Gavriatopoulou M, Ntanasis-Stathopoulos I, Korompoki E, Fotiou D, et al · · 2021 · cited 209× · PMID 33128197 · DOI 10.1007/s10238-020-00671-y
  5. An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment.
    Drożdżal S, Rosik J, Lechowicz K, Machaj F, et al · · 2021 · cited 186× · PMID 34991982 · DOI 10.1016/j.drup.2021.100794
  6. Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.
    Singh B, Ryan H, Kredo T, Chaplin M, et al · · 2021 · cited 140× · PMID 33624299 · DOI 10.1002/14651858.cd013587.pub2
  7. FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy.
    Drożdżal S, Rosik J, Lechowicz K, Machaj F, et al · · 2020 · cited 105× · PMID 32717568 · DOI 10.1016/j.drup.2020.100719
  8. The Drug Repurposing for COVID-19 Clinical Trials Provide Very Effective Therapeutic Combinations: Lessons Learned From Major Clinical Studies.
    Chakraborty C, Sharma AR, Bhattacharya M, Agoramoorthy G, et al · · 2021 · cited 97× · PMID 34867318 · DOI 10.3389/fphar.2021.704205

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Trials testing the same drug.

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