COVID-19, SARS-CoV-2
Conditions
Brief summary
This individually randomized telemedicine-based trial aims to evaluate the efficacy of a single dose of azithromycin for prevention of progression of COVID-19 in patients with a recent positive SARS-CoV-2 test who are not currently hospitalized.
Detailed description
Identification of a safe, effective treatment for individuals with mild or moderate COVID-19 that prevents disease progression and reduces hospitalization would reduce the burden on the health system. High dose hydroxychloroquine is being evaluated for SARS-CoV-2 prevention and COVID-19 disease treatment, but has a high risk of a number of potentially severe adverse events. Recent evidence has indicated that the broad-spectrum macrolide azithromycin may have some activity against coronaviruses. Here we propose an individually-randomized, placebo-controlled trial to determine the efficacy of a single dose of azithromycin for prevention of COVID-19. Potential participants will undergo remote eligibility screening with study staff prior to enrollment. Upon determination of eligibility and signing electronic informed consent documents, participants will be emailed baseline study forms and will be mailed their randomized study treatment. At the end of the study (21 days), participants will be emailed a final study questionnaire. Note that there will no contact between study staff and participants in this trial, minimizing risk of infection spread.
Interventions
DRUGAzithromycin
Participants will be shipped a single 1.2 g dose of oral azithromycin
DRUGPlacebos
Participants will be shipped a dose of matching placebo
Sponsors
Bill and Melinda Gates Foundation
Pfizer
Stanford University
Thomas M. Lietman
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Evidence of a positive SARS-CoV-2 test and test results received within the previous seven days * Not currently hospitalized * Willing and able to receive study drug by mail * Willing and able to do the study questionnaires at baseline, day 3, 7, 14, 21 days via email or over the phone * No known allergy or other contraindication to macrolides * Age 18 years or older at the time of enrollment * No known history of prolongation of the QT interval (eg. History of torsades de pointes, congenital long QT syndrome, bradyarrhthmia) * No recent use of hydroxychloroquine within the past 7 days for participants \>55 years of age * Not currently taking nelfinavir or warfarin (Coumadin) * Provision of informed consent * Not currently pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Symptom Free at Day 14 | 14 days | Binary assessment of whether the participant is experiencing any symptoms at Day 14 (yes or no) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Hospitalization | 21 Days | Number of hospitalizations defined as a hospital stay or ER stay longer than 24 hours through 21 days post enrollment |
| Viral Load - Nasal Swab | 3 days | Viral load by self-collected nasal swab |
| Viral Load - Saliva Swab | 3 days | Viral load by self-collected saliva swab |
| Mortality | 14 days | All-cause mortality |
| Adverse Events | 3 days | Percentage of participants experiencing adverse events, including gastrointestinal side effects and rash |
| Positive SARS-CoV-2 Test - Nasal Swab | 3 days | Prevalence of positive SARS-CoV-2 test by self-collected nasal swab |
| Positive SARS-CoV-2 Test - Saliva Swab | 3 days | Prevalence of positive SARS-CoV-2 test by self-collected saliva swab |
| Secondary Outcomes Through Day 21 | Cumulative over 21 days reported (assessed at 3, 7, 14, 21 days) | Prevalence of cough, fever, myalgia, anosmia, shortness of breath, fatigue, conjunctivitis, and orthostatic symptoms through Day 21 |
| Number of Participants With Emergency Room Visits | 21 days | Number of emergency room visits \<24 hours |
| Number of Household Members With COVID-19 (Confirmed or Symptomatic) | 21 days | Number of household members with confirmed or symptomatic COVID-19 through Day 21 |
| Positive SARS-CoV-2 Test - Rectal Swab | 3 days | Prevalence of positive SARS-CoV-2 test by self-collected rectal swab |
| Genetic Macrolide Resistance Determinants | 3 days | Prevalence of genetic macrolide resistance determinants by self-collected rectal swab |
| Number of Participants That Died | 21 days | Deaths within the study |
Countries
United States
Participant flow
Recruitment details
Between May 22, 2020 and March 16, 2021, 604 participants were screened and 263 participants were enrolled. All study recruitment and enrollment was done remotely.
Pre-assignment details
Common reasons for ineligibility included a negative COVID-19 test result (n=70), a COVID-19 test result outside of the 7 day window (n=118), could not be reached for consent (n=73), and under the age of 18 (19). A total of 341 screened participants were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin 1.2g of oral azithromycin
Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin | 171 |
| Placebo Matching placebo
Placebos: Participants will be shipped a dose of matching placebo | 92 |
| Total | 263 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Day 14 | Lost to Follow-up | 13 | 4 |
| Day 14 | Missing outcome data | 4 | 4 |
| Day 21 | Lost to Follow-up | 10 | 2 |
| Day 3 | Lost to Follow-up | 23 | 14 |
| Day 3 | Missing outcome data | 3 | 6 |
Baseline characteristics
| Characteristic | Azithromycin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 42 years | 44 years | 43 years |
| Alcohol consumption >3x/week | 23 Participants | 9 Participants | 32 Participants |
| Comorbidities Asthma | 21 Participants | 11 Participants | 32 Participants |
| Comorbidities Cancer | 1 Participants | 0 Participants | 1 Participants |
| Comorbidities Chronic kidney disease | 1 Participants | 1 Participants | 2 Participants |
| Comorbidities Chronic obstructive pulmonary disease | 4 Participants | 0 Participants | 4 Participants |
| Comorbidities Diabetes | 5 Participants | 5 Participants | 10 Participants |
| Comorbidities Hypertension | 20 Participants | 12 Participants | 32 Participants |
| Comorbidities Stroke | 1 Participants | 1 Participants | 2 Participants |
| Current cigarette smoker | 13 Participants | 5 Participants | 18 Participants |
| Current cigar use | 1 Participants | 1 Participants | 2 Participants |
| Current e-cigarette/vaping | 8 Participants | 2 Participants | 10 Participants |
| Current marijuana user | 9 Participants | 6 Participants | 15 Participants |
| Current medications ACE/ARB inhibitor | 15 Participants | 14 Participants | 29 Participants |
| Current medications Metformin | 4 Participants | 3 Participants | 7 Participants |
| Current medications Omeprazole | 1 Participants | 1 Participants | 2 Participants |
| Current medications Tacrolimus | 1 Participants | 0 Participants | 1 Participants |
| Current vitamin/supplement use Multivitamin | 52 Participants | 27 Participants | 79 Participants |
| Current vitamin/supplement use Omega-3 fatty acid | 14 Participants | 6 Participants | 20 Participants |
| Current vitamin/supplement use Vitamin C | 61 Participants | 33 Participants | 94 Participants |
| Current vitamin/supplement use Vitamin D | 64 Participants | 37 Participants | 101 Participants |
| Current vitamin/supplement use Zinc | 49 Participants | 20 Participants | 69 Participants |
| Days between positive test and enrollment | 3 days | 2 days | 3 days |
| Duration of symptoms prior to test | 3 days | 3 days | 3 days |
| Geographic region Midwest | 21 Participants | 16 Participants | 37 Participants |
| Geographic region Northeast | 9 Participants | 6 Participants | 15 Participants |
| Geographic region Southeast | 38 Participants | 14 Participants | 52 Participants |
| Geographic region Southwest | 24 Participants | 16 Participants | 40 Participants |
| Geographic region West | 79 Participants | 40 Participants | 119 Participants |
| Number of symptoms | 5 Number of symptoms | 4 Number of symptoms | 4 Number of symptoms |
| Race/Ethnicity, Customized Latinx/Hispanic | 49 Participants | 27 Participants | 76 Participants |
| Race/Ethnicity, Customized Mixed Race | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Non-Hispanic Asian | 6 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 11 Participants | 1 Participants | 12 Participants |
| Race/Ethnicity, Customized Non-Hispanic Middle Eastern/Arab | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Non-Hispanic Native American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 94 Participants | 56 Participants | 150 Participants |
| Race/Ethnicity, Customized Not reported (missing) | 4 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Prefer not to answer | 1 Participants | 0 Participants | 1 Participants |
| Recent hydroxychloroquine use (<7 days) | 1 Participants | 0 Participants | 1 Participants |
| Recent macrolide use (<30 days) | 22 Participants | 11 Participants | 33 Participants |
| Self-reported symptoms Abdominal pain | 29 Participants | 12 Participants | 41 Participants |
| Self-reported symptoms Anosmia | 80 Participants | 39 Participants | 119 Participants |
| Self-reported symptoms Conjunctivitis | 8 Participants | 2 Participants | 10 Participants |
| Self-reported symptoms Cough | 111 Participants | 61 Participants | 172 Participants |
| Self-reported symptoms Diarrhea | 45 Participants | 20 Participants | 65 Participants |
| Self-reported symptoms Dizziness | 39 Participants | 15 Participants | 54 Participants |
| Self-reported symptoms Fatigue | 107 Participants | 55 Participants | 162 Participants |
| Self-reported symptoms Fever | 87 Participants | 40 Participants | 127 Participants |
| Self-reported symptoms Multiple symptoms | 152 Participants | 82 Participants | 234 Participants |
| Self-reported symptoms Myalgia | 82 Participants | 40 Participants | 122 Participants |
| Self-reported symptoms None | 12 Participants | 6 Participants | 18 Participants |
| Self-reported symptoms Shortness of breath | 45 Participants | 17 Participants | 62 Participants |
| Self-reported symptoms Sore throat | 71 Participants | 37 Participants | 108 Participants |
| Sex: Female, Male Female | 117 Participants | 57 Participants | 174 Participants |
| Sex: Female, Male Male | 51 Participants | 35 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 145 | 0 / 72 |
| other Total, other adverse events | 132 / 145 | 25 / 72 |
| serious Total, serious adverse events | 0 / 145 | 0 / 72 |
Outcome results
Primary
Number of Participants Who Were Symptom Free at Day 14
Binary assessment of whether the participant is experiencing any symptoms at Day 14 (yes or no)
Time frame: 14 days
Population: Percentage of participants who were symptom free at day 14 by randomized treatment group, overall and in pre-specified subgroups. Note that a single participant in the Azithromycin group did not have baseline symptom information.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Azithromycin | Number of Participants Who Were Symptom Free at Day 14 | Age <= 60 years | 61 Participants |
| Azithromycin | Number of Participants Who Were Symptom Free at Day 14 | Asymptomatic at baseline | 9 Participants |
| Azithromycin | Number of Participants Who Were Symptom Free at Day 14 | Age > 60 years | 5 Participants |
| Azithromycin | Number of Participants Who Were Symptom Free at Day 14 | Symptomatic at baseline | 57 Participants |
| Azithromycin | Number of Participants Who Were Symptom Free at Day 14 | Overall | 66 Participants |
| Placebo | Number of Participants Who Were Symptom Free at Day 14 | Symptomatic at baseline | 32 Participants |
| Placebo | Number of Participants Who Were Symptom Free at Day 14 | Overall | 35 Participants |
| Placebo | Number of Participants Who Were Symptom Free at Day 14 | Age <= 60 years | 31 Participants |
| Placebo | Number of Participants Who Were Symptom Free at Day 14 | Age > 60 years | 4 Participants |
| Placebo | Number of Participants Who Were Symptom Free at Day 14 | Asymptomatic at baseline | 3 Participants |
Secondary
Adverse Events
Percentage of participants experiencing adverse events, including gastrointestinal side effects and rash
Time frame: 3 days
Population: Adverse events were recorded at day 3 of the trial via an online questionnaire. Other adverse events were recorded in an open text field and included stomach cramps, light headedness, fatigue, ansomia, cough, and painful respiration.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Azithromycin | Adverse Events | Diarrhea | 60 Participants |
| Azithromycin | Adverse Events | Nausea | 32 Participants |
| Azithromycin | Adverse Events | Abdominal Pain | 25 Participants |
| Azithromycin | Adverse Events | Vomiting | 5 Participants |
| Azithromycin | Adverse Events | Rash | 4 Participants |
| Azithromycin | Adverse Events | Other | 10 Participants |
| Azithromycin | Adverse Events | None | 9 Participants |
| Placebo | Adverse Events | Vomiting | 2 Participants |
| Placebo | Adverse Events | Diarrhea | 12 Participants |
| Placebo | Adverse Events | Rash | 2 Participants |
| Placebo | Adverse Events | Nausea | 7 Participants |
| Placebo | Adverse Events | None | 45 Participants |
| Placebo | Adverse Events | Abdominal Pain | 1 Participants |
| Placebo | Adverse Events | Other | 3 Participants |
Secondary
Genetic Macrolide Resistance Determinants
Prevalence of genetic macrolide resistance determinants by self-collected rectal swab
Time frame: 3 days
Population: Participants whose samples were received back by the study team. The trial was terminated for futility, funding was withdraw and samples not analyzed and won't ever be analyzed
Secondary
Mortality
All-cause mortality
Time frame: 14 days
Population: This outcome is based on the 125 participants in the azithromycin group and the 72 participants in the placebo group who completed the trial.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Mortality | 0 Participants |
| Placebo | Mortality | 0 Participants |
Secondary
Number of Household Members With COVID-19 (Confirmed or Symptomatic)
Number of household members with confirmed or symptomatic COVID-19 through Day 21
Time frame: 21 days
Population: Includes the total number of participants from 69 households in the placebo group and 134 households in the azithromycin group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Number of Household Members With COVID-19 (Confirmed or Symptomatic) | 33 Participants |
| Placebo | Number of Household Members With COVID-19 (Confirmed or Symptomatic) | 20 Participants |
Secondary
Number of Participants Reporting Hospitalization
Number of hospitalizations defined as a hospital stay or ER stay longer than 24 hours through 21 days post enrollment
Time frame: 21 Days
Population: Number of patients who reported hospitalization information through Day 21
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Number of Participants Reporting Hospitalization | 5 Participants |
| Placebo | Number of Participants Reporting Hospitalization | 0 Participants |
Secondary
Number of Participants That Died
Deaths within the study
Time frame: 21 days
Population: Participants that completed the day 21 questionnaire were included in this secondary analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Number of Participants That Died | 0 Participants |
| Placebo | Number of Participants That Died | 0 Participants |
Secondary
Number of Participants With Emergency Room Visits
Number of emergency room visits \<24 hours
Time frame: 21 days
Population: Number of patients who reported emergency room visit information through Day 21
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Number of Participants With Emergency Room Visits | 18 Participants |
| Placebo | Number of Participants With Emergency Room Visits | 2 Participants |
Secondary
Positive SARS-CoV-2 Test - Nasal Swab
Prevalence of positive SARS-CoV-2 test by self-collected nasal swab
Time frame: 3 days
Population: Participants whose samples were received back by the study team. The trial was terminated for futility, funding was withdraw and samples not analyzed and won't ever be analyzed
Secondary
Positive SARS-CoV-2 Test - Rectal Swab
Prevalence of positive SARS-CoV-2 test by self-collected rectal swab
Time frame: 3 days
Population: Participants whose samples were received back by the study team. The trial was terminated for futility, funding was withdraw and samples not analyzed and won't ever be analyzed
Secondary
Positive SARS-CoV-2 Test - Saliva Swab
Prevalence of positive SARS-CoV-2 test by self-collected saliva swab
Time frame: 3 days
Population: Participants whose samples were received back by the study team. The trial was terminated for futility, funding was withdraw and samples not analyzed and won't ever be analyzed
Secondary
Secondary Outcomes Through Day 21
Prevalence of cough, fever, myalgia, anosmia, shortness of breath, fatigue, conjunctivitis, and orthostatic symptoms through Day 21
Time frame: Cumulative over 21 days reported (assessed at 3, 7, 14, 21 days)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Azithromycin | Secondary Outcomes Through Day 21 | Absence of symptoms | 71 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Fever | 1 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Cough | 14 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Diarrhea | 4 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Abdominal pain | 0 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Fatigue | 32 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Dizziness | 6 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Other | 10 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Anosmia | 12 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Conjunctivitis | 2 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Sore throat | 4 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Shortness of breath | 16 Participants |
| Azithromycin | Secondary Outcomes Through Day 21 | Myalgia | 5 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Dizziness | 3 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Absence of symptoms | 43 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Conjunctivitis | 0 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Fever | 1 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Other | 9 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Cough | 13 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Abdominal pain | 1 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Diarrhea | 1 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Shortness of breath | 4 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Myalgia | 3 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Anosmia | 9 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Fatigue | 17 Participants |
| Placebo | Secondary Outcomes Through Day 21 | Sore throat | 4 Participants |
Secondary
Viral Load - Nasal Swab
Viral load by self-collected nasal swab
Time frame: 3 days
Population: Participants whose samples were received back by the study team. The trial was terminated for futility, funding was withdraw and samples not analyzed and will never be analyzed
Secondary
Viral Load - Saliva Swab
Viral load by self-collected saliva swab
Time frame: 3 days
Population: Participants whose samples were received back by the study team. The trial was terminated for futility, funding was withdraw and samples not analyzed and won't ever be analyzed