COVID-19, SARS-CoV-2
Conditions
Keywords
Outpatient, Treatment, COVID-19
Brief summary
This is a randomized trial for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in high-risk adults not requiring hospital admission.The overarching goal of this study is to assess the effectiveness of interventions on the incidence of lower respiratory tract infection (LRTI) progression among high-risk adult outpatients with SARS-CoV-2 infection to inform public health control strategies.
Detailed description
This is a randomized, multi-center, placebo-equivalent (ascorbic acid + folic acid)-controlled, blinded platform trial. Eligible participants will be enrolled and randomized to Hydrocychloroquine (HCQ) + placebo (folic acid), HCQ + azithromycin, lopinavir-ritonavir (LPV/r) or placebo (ascorbic acid + folic acid). Initially, this study will enroll up to 495 eligible adults ( with high risk for Lower respiratory tract infection (LRTI) progression at baseline who are PCR-confirmed SARS-CoV-2 infection (165 per arm). An additional cohort of 135 eligible adults without risk factors for LRTI progression at baseline who are PCR-confirmed SARS-CoV-2 infection will be enrolled for the co-primary virologic outcome. During the 28 study days, participants will take the medication, complete surveys, collect mid nasal swab for viral quantification, and assess symptoms for progression to LRTI. Additional arms will be added should new potential agents be discovered or combination treatments be proposed. In addition, arms may be dropped prior to completion if deemed futile or if there is a safety signal.
Interventions
DRUGAscorbic Acid
Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy
DRUGHydroxychloroquine Sulfate
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy
DRUGAzithromycin
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and azithromycin therapy
DRUGFolic Acid
Eligible participants in a household will receive folic acid and an additional intervention drug
DRUGLopinavir 200 MG / Ritonavir 50 MG [Kaletra]
Eligible participants in a household randomized to this study arm will receive lopinavir-ritonavir therapy
Sponsors
Bill and Melinda Gates Foundation
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Men or women 18 to 80 years of age, inclusive, at the time of signing the informed consent * Willing and able to provide informed consent * Laboratory confirmed SARS-CoV-2 infection, with test results within past 72 hours * COVID-19 symptoms, based on the following criteria: At least TWO of the following symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR o At least ONE of the following symptoms: cough, shortness of breath or difficulty breathing (Lopinavir-Ritonavir Platform) * Access to device and internet for Telehealth visits * At increased risk of developing severe COVID-19 disease (at least one of the following) 1. Age ≥60 years 2. Presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, emphysema 3. Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment 4. Hypertension, requiring at least 1 oral medication for treatment 5. Immunocompromised status due to disease (e.g., those living with human immunodeficiency virus with a CD4 T-cell count of \<200/mm3) 6. Immunocompromised status due to medication (e.g., persons taking 20 mg or more of prednisone equivalents a day, anti-inflammatory monoclonal antibody therapies, or cancer therapies) 7. Body mass index ≥30 (self-reported)
Exclusion criteria
* Known hypersensitivity to HCQ or other 4-aminoquinoline compounds * Known hypersensitivity to azithromycin or other azalide or macrolide antibiotics * Currently hospitalized * Signs of respiratory distress prior to randomization, including respiratory rate \>24 * Current medications include HCQ * Concomitant use of other anti-malarial treatment or chemoprophylaxis * History of retinopathy of any etiology * Psoriasis * Porphyria * Chronic kidney disease (Stage IV or receiving dialysis) * Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes \<1500) or thrombocytopenia (\<100 K) * Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen * Known cirrhosis * Known personal or family history of long QT syndrome * History of coronary artery disease with a history of graft or stent * History of heart failure, Class 2 or greater using the New York Heart Association functional class * Taking medications associated with prolonged QT and known risk of torsades de points. These medications may include some antipsychotic and antidepressant medications. (Lopinavir-Ritonavir Platform) * Taking medications associated with prolonged QT such as antipsychotic medications or antidepressants (e.g., citalopram, venlafaxine, and bupropion) and unable to stop during the trial * Taking warfarin (Coumadin or Jantoven) * Known history of glucose-6-phosphate-dehydrogenase deficiency * History of myasthenia gravis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough | 28 days from enrolment | Resting blood oxygen saturation (SpO2\<93%) level sustained for 2 readings 2 hours apart and presence of subjective dyspnea or cough |
| Number of Participants With Hospitalization or Mortality | Day 28 after enrolment | Number of participants with hospitalization or mortality |
| Time to Clearance of Nasal SARS-CoV-2 | Day 1 through Day 14 after enrolment | Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs |
| Time to Resolution of COVID-19 Symptom Resolution in Days | Day 1 through Day 14 after enrolment | COVID-19 symptoms are based on the following criteria: * At least TWO of the following symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR * At least ONE of the following symptoms: cough, shortness of breath or difficulty breathing, OR * Severe respiratory illness with at least 1 of the following: * Clinical or radiological evidence of pneumonia, OR * Acute respiratory distress syndrome (ARDS), OR * LRTI, defined by resting SpO2\<93% sustained for 2 readings 2 hours apart AND presence of subjective dyspnea or cough Death or COVID-19-related hospitalizations will count as a failure to resolve symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation | 28 days from enrolment | Serious adverse events (including death and hospitalization) and adverse events resulting in treatment discontinuation |
| COVID-19-related Hospitalization Days | 28 days from enrolment | Duration of hospitalization among persons who become hospitalized with COVID-19 disease |
Countries
United States
Participant flow
Pre-assignment details
This was a remotely conducted study. Participants who completed the informed consent process but did not complete the enrollment process after receiving the study materials are started but are not considered to have completed enrollment. This explains the discrepancy between Started and Completed Enrollment
Participants by arm
| Arm | Count |
|---|---|
| Ascorbic Acid and Folic Acid Ascorbic acid 500 mg orally twice on Day 1, followed by 250 mg orally twice daily for 9 days + folic acid 800 µg orally once on Day 1, followed by 400 µg orally once daily for an additional 4 days (Days 2 to 5)
Ascorbic Acid: Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy
Folic Acid: Eligible participants in a household will receive folic acid and an additional intervention drug | 83 |
| Hydroxychloroquine and Folic Acid HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an additional 9 days (Days 2 to 10) + placebo (folic acid 800 µg orally once on Day 1, followed by 400 µg orally once daily for an additional 4 days \[Days 2 to 5\])
Hydroxychloroquine Sulfate: Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy
Folic Acid: Eligible participants in a household will receive folic acid and an additional intervention drug | 71 |
| Hydroxychloroquine and Azithromycin HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an additional 9 days (Days 2 to 10) + azithromycin 500 mg orally once on Day 1, followed by 250 mg orally once daily for an additional 4 days (Days 2 to 5).
Hydroxychloroquine Sulfate: Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy
Azithromycin: Eligible participants in a household randomized to this study arm will receive hydrochloroquine and azithromycin therapy | 77 |
| Lopinavir-ritonavir LPV/r 800 mg-200 mg orally twice on Day 1, followed by 400 mg 100 mg orally twice daily for an additional 9 days (Days 2 to 10)
Lopinavir 200 MG / Ritonavir 50 MG \[Kaletra\]: Eligible participants in a household randomized to this study arm will receive lopinavir-ritonavir therapy | 29 |
| Ascorbic Acid Ascorbic acid 1 gm orally twice on Day 1, followed by 500 mg orally twice daily for 9 days
Ascorbic Acid: Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy | 29 |
| Total | 289 |
Baseline characteristics
| Characteristic | Hydroxychloroquine and Folic Acid | Hydroxychloroquine and Azithromycin | Lopinavir-ritonavir | Ascorbic Acid | Total | Ascorbic Acid and Folic Acid |
|---|---|---|---|---|---|---|
| Age, Customized 18-29 years | 19 Participants | 24 Participants | 7 Participants | 8 Participants | 79 Participants | 21 Participants |
| Age, Customized 30-39 years | 28 Participants | 21 Participants | 9 Participants | 9 Participants | 93 Participants | 26 Participants |
| Age, Customized 40-49 years | 13 Participants | 14 Participants | 7 Participants | 6 Participants | 56 Participants | 16 Participants |
| Age, Customized 50-59 years | 5 Participants | 9 Participants | 6 Participants | 3 Participants | 35 Participants | 12 Participants |
| Age, Customized 60-69 years | 5 Participants | 8 Participants | 0 Participants | 2 Participants | 22 Participants | 7 Participants |
| Age, Customized 70-80 years | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 18 Participants | 7 Participants | 4 Participants | 82 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 59 Participants | 22 Participants | 25 Participants | 206 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| High Risk | 37 Participants | 44 Participants | 8 Participants | 10 Participants | 147 Participants | 48 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 11 Participants | 16 Participants | 0 Participants | 0 Participants | 39 Participants | 12 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 0 Participants | 0 Participants | 11 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 9 Participants | 5 Participants | 4 Participants | 35 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 7 Participants | 6 Participants | 0 Participants | 38 Participants | 15 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 37 Participants | 39 Participants | 18 Participants | 24 Participants | 159 Participants | 41 Participants |
| Sex/Gender, Customized Female | 39 Participants | 47 Participants | 17 Participants | 20 Participants | 168 Participants | 45 Participants |
| Sex/Gender, Customized Male | 32 Participants | 30 Participants | 12 Participants | 9 Participants | 121 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 83 | 0 / 71 | 0 / 77 | 0 / 29 | 0 / 29 |
| other Total, other adverse events | 2 / 83 | 4 / 71 | 5 / 77 | 9 / 29 | 0 / 29 |
| serious Total, serious adverse events | 4 / 83 | 2 / 71 | 3 / 77 | 0 / 29 | 1 / 29 |
Outcome results
Primary
Number of Participants With Hospitalization or Mortality
Number of participants with hospitalization or mortality
Time frame: Day 28 after enrolment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ascorbic Acid and Folic Acid | Number of Participants With Hospitalization or Mortality | 4 Participants |
| Hydroxychloroquine and Folic Acid | Number of Participants With Hospitalization or Mortality | 2 Participants |
| Hydroxychloroquine and Azithromycin | Number of Participants With Hospitalization or Mortality | 3 Participants |
| Lopinavir-ritonavir | Number of Participants With Hospitalization or Mortality | 0 Participants |
| Ascorbic Acid | Number of Participants With Hospitalization or Mortality | 1 Participants |
Primary
Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough
Resting blood oxygen saturation (SpO2\<93%) level sustained for 2 readings 2 hours apart and presence of subjective dyspnea or cough
Time frame: 28 days from enrolment
Population: This outcome was analyzed in the first arm of the platform trial (Ascorbic Acid/Folic Acid HCQ, HCQ/AZ) among the high risk cohort only. The mITT cohort included only those without LRTI at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ascorbic Acid and Folic Acid | Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough | 2 Participants |
| Hydroxychloroquine and Folic Acid | Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough | 0 Participants |
| Hydroxychloroquine and Azithromycin | Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough | 4 Participants |
| Lopinavir-ritonavir | Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough | 2 Participants |
| Ascorbic Acid | Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough | 1 Participants |
Primary
Time to Clearance of Nasal SARS-CoV-2
Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs
Time frame: Day 1 through Day 14 after enrolment
Population: Included the mITT viral shedding cohort, which includes the mITT cohort participants who do not meet the definition for clearance of viral shedding at baseline (day 1 and 2 swabs negative).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ascorbic Acid and Folic Acid | Time to Clearance of Nasal SARS-CoV-2 | 7 Days |
| Hydroxychloroquine and Folic Acid | Time to Clearance of Nasal SARS-CoV-2 | 5 Days |
| Hydroxychloroquine and Azithromycin | Time to Clearance of Nasal SARS-CoV-2 | 6 Days |
| Lopinavir-ritonavir | Time to Clearance of Nasal SARS-CoV-2 | 4 Days |
| Ascorbic Acid | Time to Clearance of Nasal SARS-CoV-2 | 5 Days |
Primary
Time to Resolution of COVID-19 Symptom Resolution in Days
COVID-19 symptoms are based on the following criteria: * At least TWO of the following symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR * At least ONE of the following symptoms: cough, shortness of breath or difficulty breathing, OR * Severe respiratory illness with at least 1 of the following: * Clinical or radiological evidence of pneumonia, OR * Acute respiratory distress syndrome (ARDS), OR * LRTI, defined by resting SpO2\<93% sustained for 2 readings 2 hours apart AND presence of subjective dyspnea or cough Death or COVID-19-related hospitalizations will count as a failure to resolve symptoms.
Time frame: Day 1 through Day 14 after enrolment
Population: mITT Disease Resolution cohort includes participants who meet the COVID-19 disease criteria on day 1. The symptom resolution rate was the primary outcome of the lopinavir-ritonavir adaptive platform arms (lopinavir-ritonavir and ascorbic acid).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ascorbic Acid and Folic Acid | Time to Resolution of COVID-19 Symptom Resolution in Days | 11.5 Days |
| Hydroxychloroquine and Folic Acid | Time to Resolution of COVID-19 Symptom Resolution in Days | 10.5 Days |
| Hydroxychloroquine and Azithromycin | Time to Resolution of COVID-19 Symptom Resolution in Days | NA Days |
| Lopinavir-ritonavir | Time to Resolution of COVID-19 Symptom Resolution in Days | NA Days |
| Ascorbic Acid | Time to Resolution of COVID-19 Symptom Resolution in Days | NA Days |
Secondary
COVID-19-related Hospitalization Days
Duration of hospitalization among persons who become hospitalized with COVID-19 disease
Time frame: 28 days from enrolment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ascorbic Acid and Folic Acid | COVID-19-related Hospitalization Days | NA Days |
| Hydroxychloroquine and Folic Acid | COVID-19-related Hospitalization Days | NA Days |
| Hydroxychloroquine and Azithromycin | COVID-19-related Hospitalization Days | NA Days |
| Lopinavir-ritonavir | COVID-19-related Hospitalization Days | NA Days |
| Ascorbic Acid | COVID-19-related Hospitalization Days | NA Days |
Secondary
Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation
Serious adverse events (including death and hospitalization) and adverse events resulting in treatment discontinuation
Time frame: 28 days from enrolment
Population: All enrolled participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ascorbic Acid and Folic Acid | Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation | 6 Participants |
| Hydroxychloroquine and Folic Acid | Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation | 6 Participants |
| Hydroxychloroquine and Azithromycin | Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation | 8 Participants |
| Lopinavir-ritonavir | Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation | 9 Participants |
| Ascorbic Acid | Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation | 1 Participants |