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)
Overview
- Phase
- Not Applicable
- Intervention
- Azithromycin
- Conditions
- Lower Respiratory Tract Infection
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 514
- Locations
- 5
- Primary Endpoint
- Clinical Improvement at Day 5 Visit (D5V)
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
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.
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
- •Males and females age \> / = 18 years old.
- •Presentation \> / = 24 hours and \< / = 28 days after the onset of at least one qualifying symptom related to the acute episode of illness.
- •Ability to understand study procedures and willing and able to comply with all required procedures and visits for the entire length of study.
- •Provide written informed consent before initiation of any study procedures.
Exclusion Criteria
- •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.
- •Chronic pulmonary conditions at the investigator's discretion\*.
- •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.
- •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.
- •Current enrollment in another clinical trial of an investigational agent.
- •Known or suspected infection at any other anatomic site requiring antibacterial therapy.
- •Immunosuppression\*
- •\*Includes:
Arms & Interventions
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
Intervention: Azithromycin
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
Intervention: VIDAS B.R.A.H.M.S Procalcitonin Test (PCT)
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
Intervention: Placebo
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
Intervention: VIDAS B.R.A.H.M.S Procalcitonin Test (PCT)
Outcomes
Primary Outcomes
Clinical Improvement at Day 5 Visit (D5V)
Time Frame: Day 5 Visit
Clinical improvement at Day 5 Visit is defined as fulfilling all of the following criteria: 1. Improvement in at least two symptoms present at enrollment or one symptom and at least one vital sign abnormality present at enrollment 2. Absence of deterioration in any qualifying symptom or new vital sign abnormality not present at enrollment 3. Absence of fever in the day preceding or at the D5V 4. 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 Outcomes
- Clinical Improvement at Day 28 Visit (D28V)(Day 28 Visit)
- Number of Participants Exhibiting Improvement in at Least Two Presenting Signs or Symptoms at Day 5 Visit(Day 5 Visit)
- 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)
- 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)
- Number of Participants Exhibiting Improvement in One or More LRTI Symptoms or Fever at Day 28 Visit(Day 28 Visit)
- Number of Participants Exhibiting Worsening or Deterioration in One or More Symptoms at Day 5 Visit(Day 5 Visit)
- 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)
- 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)
- 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)
- Clinical Improvement at Day 11 Visit (D11V)(Day 11 Visit)
- Number of Participants Exhibiting Improvement in One or More LRTI Symptoms or Fever at Day 11 Visit(Day 11 Visit)
- Number of Participants Reporting Solicited Adverse Events From Day 1 Through Day 5 Visit(Day 1 through Day 5 Visit)
- 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)
- Number of Participants With a New Occurrence of a Vital Sign Abnormality at Day 5 Visit(Day 5 Visit)
- Quantification of All Antibiotic Use From Day 1 Through Day 11 Visit(Day 1 through Day 11 Visit)
- 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)
- 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)
- Quantification of All Antibiotic Use From Day 1 Through Day 28 Visit(Day 1 through Day 28 Visit)