Placebo-Controlled Trial of Antibiotic Therapy in Adults With Suspect Lower Respiratory Tract Infection (LRTI) and a Procalcitonin Level

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT03341273
• Collaborator: (none)
• Enrollment: 514
• Locations: 5
• Arms: 2
• Actual Duration (Months): 27.7
• Patients Per Site: 102.8
• Patients Per Site Per Month: 3.7

Study Details

Study Description

Brief Summary

This is a randomized, double-blinded, placebo-controlled, non-inferiority multicenter clinical trial of azithromycin vs. placebo in adults presenting as outpatients with suspect Lower Respiratory Tract Infection (LRTI) and a Procalcitonin (PCT) level of < / = 0.25 ng/mL, as a strategy for reducing antibiotic prescriptions. The study is designed to compare the efficacy of azithromycin versus placebo on Day 5 (i.e., after 4 days of treatment) in subjects with suspect LRTI and PCT levels of < / = 0.25 ng/mL at enrollment using a non-inferiority approach. The study will recruit potential subjects 18 years of age or older who are suspected to have LRTI. The enrollment cap will be 840 participants, for the goal of approximately 674 randomized participants who will be randomized 1:1 to receive oral azithromycin or placebo for five days. Randomized subjects will have efficacy measured from the time of the first dose of study drug (Day 1) through approximately Day 28. The Primary Objective is to compare the efficacy of azithromycin versus placebo on Day 5 (i.e., after 4 days of treatment) in subjects with suspect LRTI and PCT levels of < / = 0.25 ng/mL at enrollment using a non-inferiority approach.

Condition or Disease	Intervention/Treatment	Phase
Lower Respiratory Tract Infection	Drug: Azithromycin; Other: Placebo; Device: VIDAS B.R.A.H.M.S Procalcitonin Test (PCT)	N/A

Detailed Description

This is a randomized, double-blinded, placebo-controlled, non-inferiority multicenter clinical trial of azithromycin vs. placebo in adults presenting as outpatients with suspect Lower Respiratory Tract Infection (LRTI) and a Procalcitonin (PCT) level of < / = 0.25 ng/mL, as a strategy for reducing antibiotic prescriptions. The study is designed to compare the efficacy of azithromycin versus placebo on Day 5 (i.e., after 4 days of treatment) in subjects with suspect LRTI and PCT levels of < / = 0.25 ng/mL at enrollment using a non-inferiority approach. The study will recruit potential subjects 18 years of age or older who are suspected to have LRTI. The enrollment cap will be 840 participants, for the goal of approximately 674 randomized participants who will be randomized 1:1 to receive oral azithromycin or placebo for five days. Randomized subjects will have efficacy measured from the time of the first dose of study drug (Day 1) through approximately Day 28. The primary objective is to compare the efficacy of azithromycin versus placebo on Day 5 (i.e., after 4 days of treatment) in subjects with suspect LRTI and PCT levels of < / = 0.25 ng/mL at enrollment using a non-inferiority approach. The secondary objectives are to compare:1) groups receiving azithromycin versus placebo with regard to all antibiotic use by Days 11 and 28; 2) groups receiving azithromycin versus placebo with regard to return visits to a physician's office or urgent care by Days 11 and 28; 3) groups receiving azithromycin versus placebo with regard to emergency department visits by Days 11 and 28; 4) groups receiving azithromycin versus placebo with regard to hospitalization by Days 11 and 28 if not hospitalized at the enrollment and randomization visit; 5) groups receiving azithromycin versus placebo with regard to improvement in presenting symptoms by Days 11 and 28; 6) the efficacy of azithromycin versus placebo on Day 11 in subjects with suspect LRTI and PCT levels of < / = 0.25 ng/mL at enrollment using a non-inferiority approach; 7) the efficacy of azithromycin versus placebo on Day 28 in subjects with suspect LRTI and PCT levels of < / = 0.25 ng/mL at enrollment using a non-inferiority approach; 8) the efficacy of azithromycin versus placebo in subjects with suspected LRTI and PCT levels of < / = 0.25 ng/mL at Day 5 using a superiority approach, employing the "Response Adjusted for Days of Antibiotic Risk (RADAR)" methodology; 9) groups receiving azithromycin versus placebo in regard to solicited events by Day 5; 10) groups receiving azithromycin versus placebo in regard to hospitalization or visits to an Emergency Department (ED), outpatient clinic, or urgent care center for worsening or persistent LRTI after randomization by Day 5; 11) groups receiving azithromycin versus placebo in regard to improvement in vital sign abnormalities or symptoms present at enrollment, on Day 5; 12) groups receiving azithromycin versus placebo in regard to new vital sign abnormalities or symptoms on Day 5, or deterioration in symptoms relative to the enrollment visit on Day 5.

Study Design

• Study Type: Interventional
• Actual Enrollment: 514 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Diagnostic
• Official Title: Targeted Reduction of Antibiotics Using Procalcitonin in a Multi-center, Randomized, Double-Blinded, Placebo-Controlled Non-Inferiority Study of Azithromycin Treatment in Outpatient Adults With Suspect Lower Respiratory Tract Infection (LRTI) and a Procalcitonin (PCT) Level of < / = 0.25 ng/mL (TRAP-LRTI)
• Actual Study Start Date: Dec 8, 2017
• Actual Primary Completion Date: Mar 30, 2020
• Actual Study Completion Date: Mar 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azithromycin 500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5). N=337	Drug: Azithromycin; Azithromycin is an azalide antibiotic and is derived from erythromycin used to treat many different types of infections caused by bacteria, such as respiratory infections.; Device: VIDAS B.R.A.H.M.S Procalcitonin Test (PCT); The VIDAS B.R.A.H.M.S PCT is an automated test for use on the VIDAS instruments for the determination of human procalcitonin in human serum or plasma using the Enzyme-Linked Fluorescent Assay (ELFA) technique.
Placebo Comparator: Placebo 2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5). N=337	Other: Placebo; Placebo will be a matching capsule the same size, weight, and color as the capsules containing Azithromycin tablets.; Device: VIDAS B.R.A.H.M.S Procalcitonin Test (PCT); The VIDAS B.R.A.H.M.S PCT is an automated test for use on the VIDAS instruments for the determination of human procalcitonin in human serum or plasma using the Enzyme-Linked Fluorescent Assay (ELFA) technique.

Outcome Measures

Primary Outcome Measures

1. Clinical Improvement at Day 5 Visit (D5V) [Day 5 Visit]

   Clinical improvement at Day 5 Visit is defined as fulfilling all of the following criteria: Improvement in at least two symptoms present at enrollment or one symptom and at least one vital sign abnormality present at enrollment Absence of deterioration in any qualifying symptom or new vital sign abnormality not present at enrollment Absence of fever in the day preceding or at the D5V No medically attended visit to an ambulatory medical facility or hospitalization for persistent or worsening Lower Respiratory Tract Infection (LRTI) at any time after randomization

Secondary Outcome Measures

1. Clinical Improvement at Day 11 Visit (D11V) [Day 11 Visit]

   Clinical improvement at Day 11 Visit is defined as fulfilling all of the following criteria: Improvement in at least two symptoms present at enrollment or one symptom and at least one vital sign abnormality present at enrollment Absence of deterioration in any qualifying symptom or new vital sign abnormality not present at enrollment Absence of fever in the day preceding or at the D11V No medically attended visit to an ambulatory medical facility or hospitalization for persistent or worsening LRTI at any time after randomization The ITT population includes all participants with PCT = 0.25 ng/mL who were randomized to receive study product.

2. Clinical Improvement at Day 28 Visit (D28V) [Day 28 Visit]

   Clinical improvement at Day 28 Visit is defined as fulfilling all of the following criteria: Improvement in at least two symptoms present at enrollment or one symptom and at least one vital sign abnormality present at enrollment Absence of deterioration in any qualifying symptom or new vital sign abnormality not present at enrollment Absence of fever in the day preceding or at the D11V No medically attended visit to an ambulatory medical facility or hospitalization for persistent or worsening LRTI at any time after randomization

3. Composite Overall Desirability of Outcome Ranking (DOOR) Assessed Employing a Superiority Analysis Using the "Response Adjusted for Days of Antibiotic Risk (RADAR)" Approach at Day 5 Visit [Day 5 Visit]

   DOOR is a composite endpoint created using clinical outcomes from Day 1 through Day 5 Visit. It is based on adequate clinical improvement at Day 5 Visit and solicited events from Day 1 through Day 5 Visit. When comparing two participants with different ordinal clinical outcomes (OCOs), the participant with a better OCO receives a higher DOOR rank. When comparing two participants with the same OCOs, the participant with fewer days of antibiotic use receives a higher DOOR rank.

4. Number of Participants Exhibiting Improvement in One or More LRTI Symptoms or Fever at Day 11 Visit [Day 11 Visit]

   Improvement in LRTI symptoms was defined as presence of at least one-step improvement in the symptom present at baseline. For fever, improvement was defined as changing from presence of fever at baseline to absence of fever at Day 11 Visit.

5. Number of Participants Exhibiting Improvement in One or More LRTI Symptoms or Fever at Day 28 Visit [Day 28 Visit]

   Improvement in LRTI symptoms was defined as presence of at least one-step improvement in the symptom present at baseline. For fever, improvement was defined as changing from presence of fever at baseline to absence of fever at Day 28 Visit.

6. Number of Participants Exhibiting Improvement in at Least Two Presenting Signs or Symptoms at Day 5 Visit [Day 5 Visit]

   Improvement in LRTI symptoms was defined as presence of at least one-step improvement in at least two symptoms present at baseline for participants who qualified based on two symptoms or improvement in one LRTI symptom present at baseline and normalization of one abnormal vital sign at Day 5 Visit for participants who qualified based on one symptom and one vital sign abnormality.

7. Number of Participants Exhibiting Worsening or Deterioration in One or More Symptoms at Day 5 Visit [Day 5 Visit]

   Clinical deterioration at D5V is defined as at least one-step deterioration (worsening from mild to moderate for example) in any qualifying symptoms or presence of a new vital abnormality at D5V not present at enrollment.

8. Number of Participants Reporting One or More Hospitalization or Visits to an Emergency Department (ED), Outpatient Clinic, or Urgent Care Center (After Randomization) for Worsening or Persistent Lower Respiratory Tract Infection [Day 1 through Day 5 Visit]

   This table summarizes the number and percentage of participants reporting any medically attended visits any time after randomization. Note that receipt of a non-study antibiotic after study Day 5 Visit will was not regarded as satisfying this definition if it is related to a new non-respiratory process that is unrelated to the prior diagnosis of LRTI.

9. Number of Participants Reporting Solicited Adverse Events From Day 1 Through Day 5 Visit [Day 1 through Day 5 Visit]

   This table summarizes the number and percentage of participants experiencing any solicited events of mild, moderate or severe severity from Day 1 to Day 5 Visit.

10. Number of Participants With One or More Emergency Department Visits for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 11 Visit [Day 1 through Day 11]

    This table summarizes the number of participants with one or more Emergency Department Visits for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 11 Visit.

11. Number of Participants With One or More Emergency Department Visits for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 28 Visit [Day 1 through Day 28 Visit]

    This table summarizes the number of participants with one or more Emergency Department Visits for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) in Azithromycin Group from Day 1 through Day 28 Visit.

12. Number of Participants With One or More Hospitalizations (if Not Hospitalized at Enrollment) for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 11 Visit [Day 1 through Day 11 Visit]

    This table summarizes the number of participants with one or more hospitalizations for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 11 Visit.

13. Number of Participants With One or More Hospitalizations (if Not Hospitalized at Enrollment) for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 28 Visit [Day 1 through Day 28 Visit]

    This table summarizes the number of participants with one or more hospitalizations for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 28 Visit.

14. Number of Participants With One or More Unplanned Return to a Physician's Office or Urgent Care for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 11 Visit [Day 1 through Day 11 Visit]

    This table summarizes the number of participants with one or more unplanned Return to a Physician's Office or Urgent Care for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 11 Visit.

15. Number of Participants With One or More Unplanned Return to a Physician's Office or Urgent Care for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 28 Visit [Day 1 through Day 28 Visit]

    This table summarizes the number of participants with one or more unplanned Return to a Physician's Office or Urgent Care for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 28 Visit.

16. Number of Participants With a New Occurrence of a Vital Sign Abnormality at Day 5 Visit [Day 5 Visit]

    This table summarizes the number and percentage of participants experiencing new vital signs abnormalities at Day 5 Visit that were not present at baseline.

17. Quantification of All Antibiotic Use From Day 1 Through Day 11 Visit [Day 1 through Day 11 Visit]

    The table summarizes the mean number of days of antibiotic use including study and non-study antibiotics for participants from Day 1 through Day 11 Visit.

18. Quantification of All Antibiotic Use From Day 1 Through Day 28 Visit [Day 1 through Day 28 Visit]

    The table summarizes the mean number of days of antibiotic use including study and non-study antibiotics for participants from Day 1 through Day 28 Visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Clinician suspected Lower Respiratory Tract Infection (LRTI)* based on the presence of at least two qualifying symptoms** OR one qualifying symptom and at least one qualifying vital sign***.

*LRTI will include acute bronchitis, tracheitis, tracheobronchitis, asthma exacerbation, and acute exacerbation of Chronic obstructive pulmonary disease (COPD) but does not include known pneumonia.

**New cough, worsening of chronic cough, new sputum production, increased volume or purulence of chronic sputum production, chest pain, and difficulty breathing.

***Fever (Provider or patient-measured temperature > / = 37.8 degrees Celsius (100.0 degrees Fahrenheit) or patient-reported feverishness), tachycardia of > / = 90 beats/minute, tachypnea of > 20 breaths/minute.

1. Males and females age > / = 18 years old.

2. Presentation > / = 24 hours and < / = 28 days after the onset of at least one qualifying symptom related to the acute episode of illness.

3. Ability to understand study procedures and willing and able to comply with all required procedures and visits for the entire length of study.

4. Provide written informed consent before initiation of any study procedures.

Exclusion Criteria:

1. Hospitalized prior to screening and enrollment. Subjects enrolled in clinic or Emergency Department (ED) setting and then hospitalized during the same clinical encounter may be included.

2. Chronic pulmonary conditions at the investigator's discretion*.

*Such as:

• Noninvasive ventilation use for any indication other than obstructive sleep apnea

• Long-term invasive mechanical ventilation for any indication

• Known diagnosis of cystic fibrosis or chronic bronchiectasis.

1. Receipt of an investigational product within 30 days prior to Day 1 or plans to potentially start any investigational product within 30 days after the subject's anticipated study completion.

2. Current enrollment in another clinical trial of an investigational agent.

3. Known or suspected infection at any other anatomic site requiring antibacterial therapy.

4. Immunosuppression*

*Includes:

• Human Immunodeficiency Virus (HIV) infection with CD4 < 200 based on last known measurement or patient-reported value

• History of hematologic malignancies

• Receipt of chemotherapy within the previous 6 months or anticipated receipt of chemotherapy during the study period (1 month)

• Known to have an absolute neutrophil count of < 500 cells/mL or an expectation of an absolute neutrophil count of < 500 cells/mL during course of the study

• Current systemic corticosteroid use (equivalent of 20mg prednisone per day for > / = 2 weeks within the last month)

• Systemic non-steroid immunosuppressive or biologic therapy for transplant, rheumatologic conditions, or other conditions within the last month. Biologics used specifically for control of moderate to severe asthma, including anti-IgE monoclonal antibody therapy (Xolair) or IL-5 monoclonal antibodies (Mepolizumab and Reslizumab) are allowed

1. Contraindication to the use of azithromycin including history of allergy or intolerance to azithromycin or known prolonged QTc interval (> 500 msec).

2. Any condition that in the judgment of the referring provider or site investigator precludes participation because it could affect subject safety or ability of subject to participate in this trial.

3. Prior use of azithromycin in the past two weeks.

4. Use of any systemic antibiotic in the previous 24 hours.

5. Previous randomization in this trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory Vaccine Center - The Hope Clinic	Atlanta	Georgia	United States	30332
2	Atlanta VA Medical Center - Infectious Diseases Clinic	Decatur	Georgia	United States	30033
3	Durham VA Medical Center	Durham	North Carolina	United States	27705-3875
4	Duke Human Vaccine Institute - Duke Vaccine and Trials Unit	Durham	North Carolina	United States	27708
5	Texas Medical Center - Michael E. DeBakey Veterans Affairs	Houston	Texas	United States	77030-4211

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 28, 2020
• Statistical Analysis Plan - Jan 28, 2021

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03341273
• Other Study ID Numbers: 15-0020; HHSN272201300015I
• First Posted: Nov 14, 2017
• Last Update Posted: Aug 24, 2021
• Last Verified: Mar 12, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Antibiotic Reduction; Antibiotic Therapy; Azyithromycin; Lower Respiratory Tract Infection; Procalcitonin
• Additional relevant MeSH terms: Infections; Communicable Diseases; Respiratory Tract Infections; Azithromycin

Study Results

Participant Flow

Recruitment Details	Adult participants, males and non-pregnant females, aged >=18 years, presenting as outpatients with suspected Lower Respiratory Tract Infection (LRTI) with a Procalcitonin (PCT) level of <=0.25 ng/mL were recruited from the community at large. Participants were enrolled between 08DEC2017 and 09MAR2020.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5). Azithromycin: Azithromycin is an azalide antibiotic and is derived from erythromycin used to treat many different types of infections caused by bacteria, such as respiratory infections. VIDAS B.R.A.H.M.S Procalcitonin Test (PCT): The VIDAS B.R.A.H.M.S PCT is an automated test for use on the VIDAS instruments for the determination of human procalcitonin in human serum or plasma using the Enzyme-Linked Fluorescent Assay (ELFA) technique.	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5). Placebo: Placebo will be a matching capsule the same size, weight, and color as the capsules containing Azithromycin tablets. VIDAS B.R.A.H.M.S Procalcitonin Test (PCT): The VIDAS B.R.A.H.M.S PCT is an automated test for use on the VIDAS instruments for the determination of human procalcitonin in human serum or plasma using the Enzyme-Linked Fluorescent Assay (ELFA) technique.
Period Title: Overall Study
STARTED	249	250
COMPLETED	229	238
NOT COMPLETED	20	12

Baseline Characteristics

Arm/Group Title	Azithromycin	Placebo	Total
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).	Total of all reporting groups
Overall Participants	249	250	499
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.8 (15.9)	51.7 (15.0)	52.2 (15.5)
Sex: Female, Male (Count of Participants)
Female	80 32.1%	96 38.4%	176 35.3%
Male	169 67.9%	154 61.6%	323 64.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 6.8%	16 6.4%	33 6.6%
Not Hispanic or Latino	228 91.6%	233 93.2%	461 92.4%
Unknown or Not Reported	4 1.6%	1 0.4%	5 1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	3 1.2%	3 0.6%
Asian	4 1.6%	1 0.4%	5 1%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.4%	1 0.2%
Black or African American	159 63.9%	146 58.4%	305 61.1%
White	81 32.5%	89 35.6%	170 34.1%
More than one race	2 0.8%	8 3.2%	10 2%
Unknown or Not Reported	3 1.2%	2 0.8%	5 1%
Region of Enrollment (participants) [Number]
United States	249 100%	250 100%	499 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Improvement at Day 5 Visit (D5V)
Description	Clinical improvement at Day 5 Visit is defined as fulfilling all of the following criteria: Improvement in at least two symptoms present at enrollment or one symptom and at least one vital sign abnormality present at enrollment Absence of deterioration in any qualifying symptom or new vital sign abnormality not present at enrollment Absence of fever in the day preceding or at the D5V No medically attended visit to an ambulatory medical facility or hospitalization for persistent or worsening Lower Respiratory Tract Infection (LRTI) at any time after randomization
Time Frame	Day 5 Visit

Outcome Measure Data

Analysis Population Description

The ITT population includes all participants with PCT <= 0.25 ng/mL who were randomized to receive study product.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	249	250
Number (95% Confidence Interval) [percentage of participants]	69 27.7%	63 25.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Azithromycin, Placebo
	Comments	Null Hypothesis: Proportion in placebo - Proportion in azithromycin = -12.5%
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin is 12.5%. Non-inferiority of placebo is concluded if the lower limit of the 95% confidence interval for the difference in proportions of clinical improvement is greater than -12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-6
	Confidence Interval	(2-Sided) 95%; -15 to 2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Multiple imputation with a linear model to impute missing clinical values of improvement. The study day that D5V occurred on was included as a covariate in the final model and the estimates for risk difference assume that study day of D5V is 5.

2. Secondary Outcome

Title	Clinical Improvement at Day 11 Visit (D11V)
Description	Clinical improvement at Day 11 Visit is defined as fulfilling all of the following criteria: Improvement in at least two symptoms present at enrollment or one symptom and at least one vital sign abnormality present at enrollment Absence of deterioration in any qualifying symptom or new vital sign abnormality not present at enrollment Absence of fever in the day preceding or at the D11V No medically attended visit to an ambulatory medical facility or hospitalization for persistent or worsening LRTI at any time after randomization The ITT population includes all participants with PCT = 0.25 ng/mL who were randomized to receive study product.
Time Frame	Day 11 Visit

Outcome Measure Data

Analysis Population Description

The ITT population includes all participants with PCT <= 0.25 ng/mL who were randomized to receive study product.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	249	250
Number (95% Confidence Interval) [percentage of participants]	81 32.5%	76 30.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Azithromycin, Placebo
	Comments	Null Hypothesis: Proportion in placebo - Proportion in azithromycin = -12.5%
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin is 12.5%. Non-inferiority of placebo is concluded if the lower limit of the 95% confidence interval for the difference in proportions of clinical improvement is greater than -12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-4
	Confidence Interval	(2-Sided) 95%; -12 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Multiple imputation with a linear model to impute missing clinical values of improvement. The study day that D11V occurred on was included as a covariate in the final model and the estimates for risk difference assume that study day of D11V is 11.

3. Secondary Outcome

Title	Clinical Improvement at Day 28 Visit (D28V)
Description	Clinical improvement at Day 28 Visit is defined as fulfilling all of the following criteria: Improvement in at least two symptoms present at enrollment or one symptom and at least one vital sign abnormality present at enrollment Absence of deterioration in any qualifying symptom or new vital sign abnormality not present at enrollment Absence of fever in the day preceding or at the D11V No medically attended visit to an ambulatory medical facility or hospitalization for persistent or worsening LRTI at any time after randomization
Time Frame	Day 28 Visit

Outcome Measure Data

Analysis Population Description

The ITT population includes all participants with PCT <= 0.25 ng/mL who were randomized to receive study product.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	249	250
Number (95% Confidence Interval) [percentage of participants]	88 35.3%	82 32.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Azithromycin, Placebo
	Comments	Null Hypothesis: Proportion in placebo - Proportion in azithromycin = -12.5%
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin is 12.5%. Non-inferiority of placebo is concluded if the lower limit of the 95% confidence interval for the difference in proportions of clinical improvement is greater than -12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-7
	Confidence Interval	(2-Sided) 95%; -13 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Multiple imputation with a linear model to impute missing clinical values of improvement. The study day that D11V occurred on was included as a covariate in the final model and the estimates for risk difference assume that study day of D28V is 28.

4. Secondary Outcome

Title	Composite Overall Desirability of Outcome Ranking (DOOR) Assessed Employing a Superiority Analysis Using the "Response Adjusted for Days of Antibiotic Risk (RADAR)" Approach at Day 5 Visit
Description	DOOR is a composite endpoint created using clinical outcomes from Day 1 through Day 5 Visit. It is based on adequate clinical improvement at Day 5 Visit and solicited events from Day 1 through Day 5 Visit. When comparing two participants with different ordinal clinical outcomes (OCOs), the participant with a better OCO receives a higher DOOR rank. When comparing two participants with the same OCOs, the participant with fewer days of antibiotic use receives a higher DOOR rank.
Time Frame	Day 5 Visit

Outcome Measure Data

Analysis Population Description

The ITT population includes all participants with PCT<= 0.25 ng/mL who were randomized to receive study product.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	249	250
Adequate clinical improvement (ACI) with no adverse events	82 32.9%	94 37.6%
Adequate clinical improvement with mild adverse events	47 18.9%	33 13.2%
Adequate clinical improvement with moderate adverse events	25 10%	18 7.2%
Adequate clinical improvement with severe adverse events	1 0.4%	3 1.2%
No adequate clinical improvement with no medically attended events	62 24.9%	72 28.8%
No ACI with ED, outpatient clinic, or urgent care center visit but no hospitalization	9 3.6%	15 6%
No adequate clinical improvement with hospitalization	1 0.4%	3 1.2%
8: Death (any cause)	0 0%	0 0%
Missing	22 8.8%	12 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Azithromycin, Placebo
	Comments	Null: The sum of the probability that a participant assigned to placebo will have a higher DOOR at Day 5 visit than if assigned to the Azithromycin plus one-half the probability of equal DOORs at Day 5 Visit is 50% (i.e., no difference in DOOR at Day 5 Visit).
	Type of Statistical Test	Superiority
	Comments	DOOR is a composite endpoint created using clinical outcomes from Day 1 through Day 5 Visit. It is based on adequate clinical improvement at Day 5 Visit and solicited events from Day 1 through Day 5 Visit.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Missing DOOR values at Day 5 Visit were first imputed using linear regression using baseline covariates and available DOOR components as covariates.
	Method	Wilcoxon (Mann-Whitney)
	Comments	The Mann-Whitney test was run on the multiple imputed datasets to generate estimates of DOOR probability and p-value
Method of Estimation	Estimation Parameter	Pr(Higher DOOR in Placebo at Day 5 Visit
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.57 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants Exhibiting Improvement in One or More LRTI Symptoms or Fever at Day 11 Visit
Description	Improvement in LRTI symptoms was defined as presence of at least one-step improvement in the symptom present at baseline. For fever, improvement was defined as changing from presence of fever at baseline to absence of fever at Day 11 Visit.
Time Frame	Day 11 Visit

Outcome Measure Data

Analysis Population Description

According-to-protocol at Day 11 (ATP-11) Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D11V within the protocol defined time window, and had sufficient data to define clinical improvement at D11V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	211	225
Count of Participants [Participants]	206 82.7%	221 88.4%

6. Secondary Outcome

Title	Number of Participants Exhibiting Improvement in One or More LRTI Symptoms or Fever at Day 28 Visit
Description	Improvement in LRTI symptoms was defined as presence of at least one-step improvement in the symptom present at baseline. For fever, improvement was defined as changing from presence of fever at baseline to absence of fever at Day 28 Visit.
Time Frame	Day 28 Visit

Outcome Measure Data

Analysis Population Description

ATP-28 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D28V within the protocol defined time window, and had sufficient data to define clinical improvement at D28V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	210	223
Count of Participants [Participants]	207 83.1%	220 88%

7. Secondary Outcome

Title	Number of Participants Exhibiting Improvement in at Least Two Presenting Signs or Symptoms at Day 5 Visit
Description	Improvement in LRTI symptoms was defined as presence of at least one-step improvement in at least two symptoms present at baseline for participants who qualified based on two symptoms or improvement in one LRTI symptom present at baseline and normalization of one abnormal vital sign at Day 5 Visit for participants who qualified based on one symptom and one vital sign abnormality.
Time Frame	Day 5 Visit

Outcome Measure Data

Analysis Population Description

ATP-5 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D5V in person within the protocol defined time window, and had sufficient data to define clinical improvement at D5V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	204	221
Count of Participants [Participants]	166 66.7%	177 70.8%

8. Secondary Outcome

Title	Number of Participants Exhibiting Worsening or Deterioration in One or More Symptoms at Day 5 Visit
Description	Clinical deterioration at D5V is defined as at least one-step deterioration (worsening from mild to moderate for example) in any qualifying symptoms or presence of a new vital abnormality at D5V not present at enrollment.
Time Frame	Day 5 Visit

Outcome Measure Data

Analysis Population Description

ATP-5 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D5V in person within the protocol defined time window, and had sufficient data to define clinical improvement at D5V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	204	221
Count of Participants [Participants]	29 11.6%	32 12.8%

9. Secondary Outcome

Title	Number of Participants Reporting One or More Hospitalization or Visits to an Emergency Department (ED), Outpatient Clinic, or Urgent Care Center (After Randomization) for Worsening or Persistent Lower Respiratory Tract Infection
Description	This table summarizes the number and percentage of participants reporting any medically attended visits any time after randomization. Note that receipt of a non-study antibiotic after study Day 5 Visit will was not regarded as satisfying this definition if it is related to a new non-respiratory process that is unrelated to the prior diagnosis of LRTI.
Time Frame	Day 1 through Day 5 Visit

Outcome Measure Data

Analysis Population Description

ATP-5 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D5V in person within the protocol defined time window, and had sufficient data to define clinical improvement at D5V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	204	221
Count of Participants [Participants]	9 3.6%	15 6%

10. Secondary Outcome

Title	Number of Participants Reporting Solicited Adverse Events From Day 1 Through Day 5 Visit
Description	This table summarizes the number and percentage of participants experiencing any solicited events of mild, moderate or severe severity from Day 1 to Day 5 Visit.
Time Frame	Day 1 through Day 5 Visit

Outcome Measure Data

Analysis Population Description

ATP-5 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D5V in person within the protocol defined time window, and had sufficient data to define clinical improvement at D5V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	204	221
Any Event	90 36.1%	77 30.8%
Abdominal Pain	47 18.9%	35 14%
Vomiting	13 5.2%	10 4%
Diarrhea	53 21.3%	55 22%
Allergic Reaction	8 3.2%	9 3.6%
Candidiasis	8 3.2%	8 3.2%

11. Secondary Outcome

Title	Number of Participants With One or More Emergency Department Visits for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 11 Visit
Description	This table summarizes the number of participants with one or more Emergency Department Visits for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 11 Visit.
Time Frame	Day 1 through Day 11

Outcome Measure Data

Analysis Population Description

ATP-11 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D11V within the protocol defined time window, and had sufficient data to define clinical improvement at D11V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	221	225
Count of Participants [Participants]	3 1.2%	9 3.6%

12. Secondary Outcome

Title	Number of Participants With One or More Emergency Department Visits for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 28 Visit
Description	This table summarizes the number of participants with one or more Emergency Department Visits for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) in Azithromycin Group from Day 1 through Day 28 Visit.
Time Frame	Day 1 through Day 28 Visit

Outcome Measure Data

Analysis Population Description

ATP-28 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D28V within the protocol defined time window, and had sufficient data to define clinical improvement at D28V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	210	223
Count of Participants [Participants]	3 1.2%	9 3.6%

13. Secondary Outcome

Title	Number of Participants With One or More Hospitalizations (if Not Hospitalized at Enrollment) for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 11 Visit
Description	This table summarizes the number of participants with one or more hospitalizations for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 11 Visit.
Time Frame	Day 1 through Day 11 Visit

Outcome Measure Data

Analysis Population Description

ATP-11 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D11V within the protocol defined time window, and had sufficient data to define clinical improvement at D11V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	211	225
Count of Participants [Participants]	1 0.4%	1 0.4%

14. Secondary Outcome

Title	Number of Participants With One or More Hospitalizations (if Not Hospitalized at Enrollment) for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 28 Visit
Description	This table summarizes the number of participants with one or more hospitalizations for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 28 Visit.
Time Frame	Day 1 through Day 28 Visit

Outcome Measure Data

Analysis Population Description

ATP-28 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D28V within the protocol defined time window, and had sufficient data to define clinical improvement at D28V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	210	223
Count of Participants [Participants]	1 0.4%	1 0.4%

15. Secondary Outcome

Title	Number of Participants With One or More Unplanned Return to a Physician's Office or Urgent Care for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 11 Visit
Description	This table summarizes the number of participants with one or more unplanned Return to a Physician's Office or Urgent Care for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 11 Visit.
Time Frame	Day 1 through Day 11 Visit

Outcome Measure Data

Analysis Population Description

ATP-11 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D11V within the protocol defined time window, and had sufficient data to define clinical improvement at D11V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	211	225
Count of Participants [Participants]	5 2%	7 2.8%

16. Secondary Outcome

Title	Number of Participants With One or More Unplanned Return to a Physician's Office or Urgent Care for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) by Day 28 Visit
Description	This table summarizes the number of participants with one or more unplanned Return to a Physician's Office or Urgent Care for Persistent or Worsening Lower Respiratory Tract Infection (LRTI) from Day 1 through Day 28 Visit.
Time Frame	Day 1 through Day 28 Visit

Outcome Measure Data

Analysis Population Description

ATP-28 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D28V within the protocol defined time window, and had sufficient data to define clinical improvement at D28V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	210	223
Count of Participants [Participants]	6 2.4%	7 2.8%

17. Secondary Outcome

Title	Number of Participants With a New Occurrence of a Vital Sign Abnormality at Day 5 Visit
Description	This table summarizes the number and percentage of participants experiencing new vital signs abnormalities at Day 5 Visit that were not present at baseline.
Time Frame	Day 5 Visit

Outcome Measure Data

Analysis Population Description

ATP-5 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D5V in person within the protocol defined time window, and had sufficient data to define clinical improvement at D5V. For vital signs, only participants with without the vital sign abnormality are analyzed. For fever, only participants with non-missing values for fever are analyzed.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	202	216
Any Vital Sign	19 7.6%	24 9.6%
Temperature	0 0%	0 0%
Pulse	17 6.8%	19 7.6%
Respiratory Rate	3 1.2%	5 2%

18. Secondary Outcome

Title	Quantification of All Antibiotic Use From Day 1 Through Day 11 Visit
Description	The table summarizes the mean number of days of antibiotic use including study and non-study antibiotics for participants from Day 1 through Day 11 Visit.
Time Frame	Day 1 through Day 11 Visit

Outcome Measure Data

Analysis Population Description

ATP-11 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D11V within the protocol defined time window, and had sufficient data to define clinical improvement at D11V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	211	225
Mean (95% Confidence Interval) [days]	5.1	0.3

19. Secondary Outcome

Title	Quantification of All Antibiotic Use From Day 1 Through Day 28 Visit
Description	The table summarizes the mean number of days of antibiotic use including study and non-study antibiotics for participants from Day 1 through Day 28 Visit.
Time Frame	Day 1 through Day 28 Visit

Outcome Measure Data

Analysis Population Description

ATP-28 Population includes randomized participants who had no major protocol deviations and consumed 5 doses of study product by D5V, completed their D28V within the protocol defined time window, and had sufficient data to define clinical improvement at D28V.

Arm/Group Title	Azithromycin	Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).	2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
Measure Participants	210	223
Mean (95% Confidence Interval) [days]	5.5	0.9

Adverse Events

Time Frame	Solicited Adverse Events were collected from Day 1 through Day 11. As the safety profile of azithromycin is well established, and this trial was not powered to detect new, unknown safety signals, there was no azithromycin-related Adverse Event (AE) collection or Serious Adverse Events (SAEs) reporting during this study. Unanticipated adverse device effect (UADE) were unexpected, but were to be reported appropriately if they occurred during the study.
Adverse Event Reporting Description	Serious adverse events were not collected for this study, therefore the number of participants at risk for serious adverse events is zero.
Arm/Group Title	Azithromycin		Placebo
Arm/Group Description	500 mg of Azithromycin (2 capsules of 250 mg) administered orally as a single dose on Day 1, followed by 250 mg capsule of Azithromycin administered orally once daily for 4 days (Day 2 through Day 5).		2 capsules of Azithromycin placebo administered orally as a single dose on Day 1, followed by 1 capsule of Azithromycin placebo administered orally once daily for 4 days (Day 2 through Day 5).
All Cause Mortality
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/242 (0%)		0/247 (0%)
Serious Adverse Events
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Azithromycin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	114/242 (47.1%)		97/247 (39.3%)
Gastrointestinal disorders
Abdominal Pain	61/242 (25.2%)	160	43/247 (17.4%)	119
Diarrhoea	73/242 (30.2%)	232	65/247 (26.3%)	229
Vomiting	16/242 (6.6%)	30	16/247 (6.5%)	33
Infections and infestations
Candida Infection	14/242 (5.8%)	59	0/247 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.