ACTION: Azithromycin for COVID-19 Treatment in Outpatients Nationwide

• Sponsor: Thomas M. Lietman (Other)
• Overall Status: Terminated
• CT.gov ID: NCT04332107
• Collaborator: Bill and Melinda Gates Foundation (Other), Pfizer (Industry), Stanford University (Other)
• Enrollment: 263
• Location: 1
• Arms: 2
• Actual Duration (Months): 10.3
• Patients Per Site Per Month: 25.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19; SARS-CoV-2	Drug: Azithromycin; Drug: Placebos	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 263 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Azithromycin for Prevention of Disease Progression in Patients With Mild or Moderate COVID-19
• Actual Study Start Date: May 22, 2020
• Actual Primary Completion Date: Mar 16, 2021
• Actual Study Completion Date: Mar 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azithromycin 1.2g of oral azithromycin	Drug: Azithromycin; Participants will be shipped a single 1.2 g dose of oral azithromycin
Placebo Comparator: Placebo Matching placebo	Drug: Placebos; Participants will be shipped a dose of matching placebo

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Viral Load [3 days]

   Viral load by self-collected nasal swab

2. Viral Load [3 days]

   Viral load by self-collected saliva swab

3. Mortality [14 days]

   All-cause mortality

4. Adverse Events [3 days]

   Percentage of participants experiencing adverse events, including gastrointestinal side effects and rash

5. Positive SARS-CoV-2 Test - Nasal Swab [3 days]

   Prevalence of positive SARS-CoV-2 test by self-collected nasal swab

6. Positive SARS-CoV-2 Test - Saliva Swab [3 days]

   Prevalence of positive SARS-CoV-2 test by self-collected saliva swab

7. Positive SARS-CoV-2 Test - Rectal Swab [3 days]

   Prevalence of positive SARS-CoV-2 test by self-collected rectal swab

8. Genetic Macrolide Resistance Determinants [3 days]

   Prevalence of genetic macrolide resistance determinants by self-collected rectal swab

9. 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

10. Number of Participants With Emergency Room Visits [21 days]

    Number of emergency room visits <24 hours

11. 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

12. Number of Participants That Died [21 days]

    Deaths within the study

13. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco	San Francisco	California	United States	94143

Sponsors and Collaborators

• Thomas M. Lietman
• Bill and Melinda Gates Foundation
• Pfizer
• Stanford University

Investigators

• Principal Investigator: Catherine Oldenburg, ScD, MPH, University of California, San Francisco
• Principal Investigator: Thuy Doan, MD, PhD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol - Apr 5, 2021
• Statistical Analysis Plan - May 29, 2020

More Information

Publications

None provided.

• Responsible Party: Thomas M. Lietman, Professor, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT04332107
• Other Study ID Numbers: 20-30504
• First Posted: Apr 2, 2020
• Last Update Posted: Oct 7, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: COVID-19; Azithromycin

Study Results

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 Detail	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.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Period Title: Day 3
STARTED	171	92
COMPLETED	145	72
NOT COMPLETED	26	20
Period Title: Day 3
STARTED	148	78
COMPLETED	131	70
NOT COMPLETED	17	8
Period Title: Day 3
STARTED	135	74
COMPLETED	125	72
NOT COMPLETED	10	2

Baseline Characteristics

Arm/Group Title	Azithromycin	Placebo	Total
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo	Total of all reporting groups
Overall Participants	171	92	263
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	42	44	43
Sex: Female, Male (Count of Participants)
Female	117 68.4%	57 62%	174 66.2%
Male	51 29.8%	35 38%	86 32.7%
Race/Ethnicity, Customized (Count of Participants)
Non-Hispanic White	94 55%	56 60.9%	150 57%
Latinx/Hispanic	49 28.7%	27 29.3%	76 28.9%
Non-Hispanic Black	11 6.4%	1 1.1%	12 4.6%
Non-Hispanic Asian	6 3.5%	3 3.3%	9 3.4%
Mixed Race	4 2.3%	3 3.3%	7 2.7%
Non-Hispanic Middle Eastern/Arab	2 1.2%	1 1.1%	3 1.1%
Prefer not to answer	1 0.6%	0 0%	1 0.4%
Not reported (missing)	4 2.3%	0 0%	4 1.5%
Non-Hispanic Native American	0 0%	1 1.1%	1 0.4%
Geographic region (Count of Participants)
West	79 46.2%	40 43.5%	119 45.2%
Southeast	38 22.2%	14 15.2%	52 19.8%
Southwest	24 14%	16 17.4%	40 15.2%
Midwest	21 12.3%	16 17.4%	37 14.1%
Northeast	9 5.3%	6 6.5%	15 5.7%
Alcohol consumption >3x/week (Count of Participants)
Count of Participants [Participants]	23 13.5%	9 9.8%	32 12.2%
Current cigarette smoker (Count of Participants)
Count of Participants [Participants]	13 7.6%	5 5.4%	18 6.8%
Current marijuana user (Count of Participants)
Count of Participants [Participants]	9 5.3%	6 6.5%	15 5.7%
Current e-cigarette/vaping (Count of Participants)
Count of Participants [Participants]	8 4.7%	2 2.2%	10 3.8%
Current cigar use (Count of Participants)
Count of Participants [Participants]	1 0.6%	1 1.1%	2 0.8%
Comorbidities (Count of Participants)
Asthma	21 12.3%	11 12%	32 12.2%
Hypertension	20 11.7%	12 13%	32 12.2%
Diabetes	5 2.9%	5 5.4%	10 3.8%
Chronic obstructive pulmonary disease	4 2.3%	0 0%	4 1.5%
Chronic kidney disease	1 0.6%	1 1.1%	2 0.8%
Cancer	1 0.6%	0 0%	1 0.4%
Stroke	1 0.6%	1 1.1%	2 0.8%
Recent macrolide use (<30 days) (Count of Participants)
Count of Participants [Participants]	22 12.9%	11 12%	33 12.5%
Recent hydroxychloroquine use (<7 days) (Count of Participants)
Count of Participants [Participants]	1 0.6%	0 0%	1 0.4%
Current medications (Count of Participants)
ACE/ARB inhibitor	15 8.8%	14 15.2%	29 11%
Metformin	4 2.3%	3 3.3%	7 2.7%
Omeprazole	1 0.6%	1 1.1%	2 0.8%
Tacrolimus	1 0.6%	0 0%	1 0.4%
Current vitamin/supplement use (Count of Participants)
Vitamin D	64 37.4%	37 40.2%	101 38.4%
Vitamin C	61 35.7%	33 35.9%	94 35.7%
Multivitamin	52 30.4%	27 29.3%	79 30%
Zinc	49 28.7%	20 21.7%	69 26.2%
Omega-3 fatty acid	14 8.2%	6 6.5%	20 7.6%
Self-reported symptoms (Count of Participants)
Multiple symptoms	152 88.9%	82 89.1%	234 89%
Cough	111 64.9%	61 66.3%	172 65.4%
Fatigue	107 62.6%	55 59.8%	162 61.6%
Fever	87 50.9%	40 43.5%	127 48.3%
Myalgia	82 48%	40 43.5%	122 46.4%
Anosmia	80 46.8%	39 42.4%	119 45.2%
Sore throat	71 41.5%	37 40.2%	108 41.1%
Diarrhea	45 26.3%	20 21.7%	65 24.7%
Shortness of breath	45 26.3%	17 18.5%	62 23.6%
Dizziness	39 22.8%	15 16.3%	54 20.5%
Abdominal pain	29 17%	12 13%	41 15.6%
None	12 7%	6 6.5%	18 6.8%
Conjunctivitis	8 4.7%	2 2.2%	10 3.8%
Number of symptoms (Number of symptoms) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Number of symptoms]	5	4	4
Duration of symptoms prior to test (days) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [days]	3	3	3
Days between positive test and enrollment (days) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [days]	3	2	3

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Were Symptom Free at Day 14
Description	Binary assessment of whether the participant is experiencing any symptoms at Day 14 (yes or no)
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Measure Participants	131	70
Overall	66 38.6%	35 38%
Age <= 60 years	61 35.7%	31 33.7%
Age > 60 years	5 2.9%	4 4.3%
Asymptomatic at baseline	9 5.3%	3 3.3%
Symptomatic at baseline	57 33.3%	32 34.8%

2. Secondary Outcome

Title	Viral Load
Description	Viral load by self-collected nasal swab
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Viral Load
Description	Viral load by self-collected saliva swab
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Mortality
Description	All-cause mortality
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Measure Participants	125	72
Count of Participants [Participants]	0 0%	0 0%

5. Secondary Outcome

Title	Adverse Events
Description	Percentage of participants experiencing adverse events, including gastrointestinal side effects and rash
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Measure Participants	145	72
Diarrhea	60 35.1%	12 13%
Nausea	32 18.7%	7 7.6%
Abdominal Pain	25 14.6%	1 1.1%
Vomiting	5 2.9%	2 2.2%
Rash	4 2.3%	2 2.2%
Other	10 5.8%	3 3.3%
None	9 5.3%	45 48.9%

6. Secondary Outcome

Title	Positive SARS-CoV-2 Test - Nasal Swab
Description	Prevalence of positive SARS-CoV-2 test by self-collected nasal swab
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Positive SARS-CoV-2 Test - Saliva Swab
Description	Prevalence of positive SARS-CoV-2 test by self-collected saliva swab
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Positive SARS-CoV-2 Test - Rectal Swab
Description	Prevalence of positive SARS-CoV-2 test by self-collected rectal swab
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Genetic Macrolide Resistance Determinants
Description	Prevalence of genetic macrolide resistance determinants by self-collected rectal swab
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Secondary Outcomes Through Day 21
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Measure Participants	125	72
Absence of symptoms	71 41.5%	43 46.7%
Fever	1 0.6%	1 1.1%
Cough	14 8.2%	13 14.1%
Diarrhea	4 2.3%	1 1.1%
Abdominal pain	0 0%	1 1.1%
Anosmia	12 7%	9 9.8%
Conjunctivitis	2 1.2%	0 0%
Sore throat	4 2.3%	4 4.3%
Shortness of breath	16 9.4%	4 4.3%
Myalgia	5 2.9%	3 3.3%
Fatigue	32 18.7%	17 18.5%
Dizziness	6 3.5%	3 3.3%
Other	10 5.8%	9 9.8%

11. Secondary Outcome

Title	Number of Participants With Emergency Room Visits
Description	Number of emergency room visits <24 hours
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

Number of patients who reported emergency room visit information through Day 21

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Measure Participants	125	72
Count of Participants [Participants]	18 10.5%	2 2.2%

12. Secondary Outcome

Title	Number of Household Members With COVID-19 (Confirmed or Symptomatic)
Description	Number of household members with confirmed or symptomatic COVID-19 through Day 21
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

Includes the total number of participants from 69 households in the placebo group and 134 households in the azithromycin group

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Measure Participants	522	278
Count of Participants [Participants]	33 19.3%	20 21.7%

13. Secondary Outcome

Title	Number of Participants That Died
Description	Deaths within the study
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

Participants that completed the day 21 questionnaire were included in this secondary analysis.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Measure Participants	125	72
Count of Participants [Participants]	0 0%	0 0%

14. Secondary Outcome

Title	Number of Participants Reporting Hospitalization
Description	Number of hospitalizations defined as a hospital stay or ER stay longer than 24 hours through 21 days post enrollment
Time Frame	21 Days

Outcome Measure Data

Analysis Population Description

Number of patients who reported hospitalization information through Day 21

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin	Matching placebo Placebos: Participants will be shipped a dose of matching placebo
Measure Participants	125	72
Count of Participants [Participants]	5 2.9%	0 0%

Adverse Events

Time Frame	21 days
Adverse Event Reporting Description	Participants completed a survey at day 3 where they were asked if they had experienced any of the following symptoms since they took their study medication to assess possible adverse events: vomiting, nausea, diarrhea, rash, or abdominal pain. Participants were asked at every time point if they had stayed in a hospital setting (defined as in the emergency department or admitted to the hospital for >= 24 hours) and/or if they had visited an emergency department or urgent care center.
Arm/Group Title	Azithromycin		Placebo
Arm/Group Description	1.2g of oral azithromycin Azithromycin: Participants will be shipped a single 1.2 g dose of oral azithromycin		Matching placebo Placebos: Participants will be shipped a dose of matching placebo
All Cause Mortality
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/145 (0%)		0/72 (0%)
Serious Adverse Events
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/145 (0%)		0/72 (0%)
Other (Not Including Serious) Adverse Events
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/145 (91%)		25/72 (34.7%)
Gastrointestinal disorders
Diarrhea	60/145 (41.4%)		12/72 (16.7%)
Nausea	32/145 (22.1%)		7/72 (9.7%)
Abdominal pain	25/145 (17.2%)		1/72 (1.4%)
Vomiting	5/145 (3.4%)		2/72 (2.8%)
Other	10/145 (6.9%)		3/72 (4.2%)

Limitations/Caveats

This trial was terminated early by the DSMC for futility on March 16, 2021. Therefore, we were not able to complete the analysis for all secondary outcomes because funds were returned to the sponsor following the completion of the study. Please note that the number of participants varies by period as participants could opt to complete some questionnaires but not others. For example, a participant may skip the day 3 questionnaire, but complete the day 14 questionnaire.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.