Pneumonia, Bacterial
Conditions
Keywords
urease, Point-of-Care, Breath test
Brief summary
This is a Phase 1, open label, evaluation of a 13C-urea breath test for the detection of urease-producing bacteria in patient with pneumonia in the emergency department.
Detailed description
This is a Phase 1, open-label evaluation of an inhaled 13C-urea breath test in the identification of urease positive bacteria in patients diagnosed with pneumonia in the emergency department (ED). This study will enroll up to 75 adult male and female subjects in two cohorts. Adult subjects will be screened for participation in two dosing cohorts to be enrolled sequentially. Cohort A will enroll 15 subjects presenting to the ED with clinical concern for pneumonia and plan for outpatient treatment. Following enrollment and review of the safety of dosing in Cohort A, subjects receiving a diagnosis of pneumonia in the ED that are planned for admission will be screened for enrollment in Cohort B. Eligible subjects will provide informed consent, medical history, and samples for laboratory testing (including pregnancy testing for females of childbearing potential) during screening. Subjects will be evaluated for their CURB-65 Pneumonia Severity Score, and Community-Acquired Pneumonia Severity Index (PSI) where required data are available. Prior to breath test administration, subjects will provide a sputum sample for bacterial culture; sample may be induced, or collected as part of initial ED workup if appropriate culture has been ordered. Subjects will undergo breath test with collection of baseline breath samples (up to 6), followed by complete nebulization of 13C-urea solution. Immediately following the end of nebulization, breath collection bag samples will be collected at up to 6 time points with at least 1 minute intervals within 10 minutes post-nebulization. Exhaled breath bags will be centrally processed to determine the change in exhaled 13CO2 levels. Vital signs, including resting blood pressure, resting pulse, respiratory rate, peripheral oxygen saturation, and temperature will be collected prior to, and following completion of, nebulization treatment. In the event of bronchospasm, during or following nebulization, albuterol rescue will be available for treatment at the discretion of the investigator. Once required tests are complete, the subject will be treated/followed according to standard institutional protocol/practice. The subjects' clinical course will be followed for at least 24 hours, where possible, to document the final diagnosis and outcome.
Interventions
DEVICE13C-urea breath test
Subjects will undergo 13C-urea breath test involving collection of baseline breath samples, nebulization of 13C-urea, and collection of post-nebulization breath samples
Sponsors
Avisa Pharma Inc.
Malvern Consulting Group, Inc.
University of New Mexico
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Caregiver)
Masking description
Care Providers will not be provided with the results of the breath test, and will treat patients according to the current standards of care
Intervention model description
Open label evaluation of breath test for safety and detection of urease producing pathogens in two cohorts of emergency department patients with suspected bacterial pneumonia.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Cohort A Only: be a man or woman age 18-65, inclusive, with suspected bacterial pneumonia on presentation to the ED based on clinical signs and symptoms AND be planned for outpatient treatment OR Cohort B Only: be a man or woman age 18-85, inclusive, with a diagnosis of suspected bacterial pneumonia in the ED based on findings of a positive chest x-ray and clinical signs and symptoms AND be planned for admission to the hospital ward/floor 2. be capable of providing a spontaneous or induced sputum sample for analysis 3. be capable of completing the breath test according to the clinical judgement of the investigator 4. be able to understand the study procedures, agree to participate in the study program, and voluntarily provide written informed consent
Exclusion criteria
1. have a known allergy to urea or any excipient in the nebulized solution 2. be pregnant or have a positive urine pregnancy test 3. have evidence of active oral infection, such as abscess or dense exudate, that requires antibiotic therapy 4. have known diagnosis of cystic fibrosis or bronchiectasis 5. have a known or suspected acute asthma exacerbation on presentation to the ED 6. have received treatment with oral or intravenous (IV) antibiotics in the preceding 2 days prior to screening, unless antibiotic failure is suspected OR have received treatment in the ED with oral or IV antibiotics greater than 4 hours prior to breath test 7. have an acute illness or other condition that, as determined by the investigator, would preclude participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | Within 24-48 hours of breath test | Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. |
| Serious Adverse Events | Within 24-48 hours of breath test | Death, disability, incapacitation, escalation of level of care, prolongation of hospitalization, birth defect, or intervention to prevent the above. |
| Suspected Adverse Reaction | Within 24-48 hours of breath test | Any adverse event for which there is a reasonable possibility that the adverse event was caused by the study drug. |
| Serious Suspected Adverse Reaction | Within 24-48 hours of breath test | Any Suspected Adverse Reaction that is determined to be serious, based on the outcomes of a Serious Adverse Event; i.e. death, life-threatening, causes or prolongs inpatient hospitalization, causes a persistent of significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital abnormality/birth defect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Meeting Sensitivity Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | Collected at 6 minutes after nebulization and measured within 7 days of collection | This exploratory outcome was designed to assess whether the ¹³C-urea breath test (Δ¹³CO₂) is associated with the presence of urease-producing pathogens. Correlation between exhaled ¹³CO₂ levels and pathogen abundance (based on RNAseq bacterial counts) was to be evaluated using Spearman's correlation, with a pre-defined significance threshold of ρ \> 0.75. |
| Number of Participants Meeting Specificity Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | Collected at 6 minutes after nebulization and measured within 7 days of collection | This exploratory outcome was designed to assess the specificity of the ¹³C-urea breath test (Δ¹³CO₂) for detecting urease-producing pathogens. Specificity was defined as the proportion of participants without urease-producing pathogens (based on RNAseq bacterial profiles) who also did not meet the predefined breath test threshold. The planned analysis used Spearman correlation (ρ) between ¹³CO₂ enrichment and bacterial abundance, with ρ \< 0.75 indicating a negative test result. |
| Exhaled 13CO2 Concentration | Collected at 6 minutes after nebulization and measured within 7 days of collection | We recorded change in 13CO2/12CO2 ratio (delta over baseline or ΔOB, in units of ‰) between pre- and post-nebulization samples |
| Number of Participants Meeting Negative Predictive Value Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | Collected at 6 minutes after nebulization and measured within 7 days of collection | This exploratory outcome was designed to evaluate the number of participants meeting the negative predictive value (NPV) criterion of the ¹³C-urea breath test for detecting urease-producing pathogens. A participant was considered to meet the NPV criterion if they had a negative breath test result defined as a Spearman correlation coefficient (ρ) ≤ 0.75 between Δ¹³CO₂ and bacterial abundance and RNAseq-confirmed absence of urease-producing pathogens. |
| Number of Participants With Breath Test Positive and Confirmed Urease-Producing Pathogen (PPV Criterion) | Collected at 6 minutes after nebulization and measured within 7 days of collection | This exploratory outcome measured the number of participants who met the criteria for positive predictive value of the ¹³C-urea breath test. A participant was considered to meet the PPV criterion if they had a positive breath test result (Spearman ρ \> 0.75 between Δ¹³CO₂ and bacterial abundance) and also had RNAseq-confirmed presence of at least one urease-producing pathogen. |
| Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to Bacterial RNAseq Counts | Collected at 6 minutes after nebulization and measured within 7 days of collection | We recorded change in 13CO2/12CO2 ratio (delta over baseline or ΔOB, in units of ‰) between pre- and post-nebulization samples and compared with subject's causative pathogen based upon sputum or blood culture results |
| Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to CURB-65 Score in Urease-Positive Pneumonia | Collected at 6 minutes after nebulization and measured within 7 days of collection | Number of participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ \> 0.75) to CURB-65 Score in Urease-Positive Pneumonia |
| Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to Pneumonia Severity Index in Urease-Positive Pneumonia. | Collected at 6 minutes after nebulization and measured within 7 days of collection | Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ \> 0.75) to Pneumonia Severity Index in Urease-Positive Pneumonia. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the emergency departments of University of New Mexico Health Sciences Center and Henry Ford Hospital. Eligible participants presented with clinical suspicion for community-acquired pneumonia and were screened for outpatient (Cohort A) or inpatient (Cohort B) treatment enrollment.
Pre-assignment details
All subjects provided written informed consent prior to participation. Subjects were screened for eligibility, including medical history, vital signs, and ability to perform breath sampling. No randomization was performed; subjects were assigned to outpatient or inpatient cohorts based on clinical treatment plan.
Participants by arm
| Arm | Count |
|---|---|
| Outpatient Treatment Cohort (Cohort A) Subjects with suspected bacterial pneumonia planned for outpatient treatment who received the 13C-urea breath test. | 15 |
| Inpatient Treatment Cohort (Cohort B) Subjects with suspected bacterial pneumonia planned for inpatient hospital admission who received the 13C-urea breath test. | 60 |
| Total | 75 |
Baseline characteristics
| Characteristic | Total | Outpatient Treatment Cohort (Cohort A) | Inpatient Treatment Cohort (Cohort B) |
|---|---|---|---|
| Age, Continuous | 54 Years STANDARD_DEVIATION 14 | 45 Years STANDARD_DEVIATION 14 | 60 Years STANDARD_DEVIATION 14.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 0 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants | 0 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 0 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 34 Participants | 0 Participants | 34 Participants |
| Region of Enrollment United States | 75 Participants | 15 Participants | 60 Participants |
| Sex: Female, Male Female | 37 Participants | 9 Participants | 28 Participants |
| Sex: Female, Male Male | 38 Participants | 6 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 60 |
| other Total, other adverse events | 5 / 15 | 0 / 60 |
| serious Total, serious adverse events | 0 / 15 | 0 / 60 |
Outcome results
Primary
Adverse Events
Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.
Time frame: Within 24-48 hours of breath test
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Adverse Events | Brief Coughing | 3 Participants |
| Outpatient Treatment Cohort (Cohort A) | Adverse Events | Nausea | 1 Participants |
| Outpatient Treatment Cohort (Cohort A) | Adverse Events | Syncope 24 hours post nebulization | 1 Participants |
| Inpatient Treatment Cohort (Cohort B) | Adverse Events | Brief Coughing | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Adverse Events | Nausea | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Adverse Events | Syncope 24 hours post nebulization | 0 Participants |
Primary
Serious Adverse Events
Death, disability, incapacitation, escalation of level of care, prolongation of hospitalization, birth defect, or intervention to prevent the above.
Time frame: Within 24-48 hours of breath test
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Serious Adverse Events | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Serious Adverse Events | 0 Participants |
Primary
Serious Suspected Adverse Reaction
Any Suspected Adverse Reaction that is determined to be serious, based on the outcomes of a Serious Adverse Event; i.e. death, life-threatening, causes or prolongs inpatient hospitalization, causes a persistent of significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital abnormality/birth defect.
Time frame: Within 24-48 hours of breath test
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Serious Suspected Adverse Reaction | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Serious Suspected Adverse Reaction | 0 Participants |
Primary
Suspected Adverse Reaction
Any adverse event for which there is a reasonable possibility that the adverse event was caused by the study drug.
Time frame: Within 24-48 hours of breath test
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Suspected Adverse Reaction | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Suspected Adverse Reaction | 0 Participants |
Secondary
Exhaled 13CO2 Concentration
We recorded change in 13CO2/12CO2 ratio (delta over baseline or ΔOB, in units of ‰) between pre- and post-nebulization samples
Time frame: Collected at 6 minutes after nebulization and measured within 7 days of collection
Population: We recorded change in 13CO2/12CO2 ratio (delta over baseline or ΔOB, in units of ‰) between pre- and post-nebulization samples
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Exhaled 13CO2 Concentration | 1.3 Percent change | Standard Deviation 1.2 |
| Inpatient Treatment Cohort (Cohort B) | Exhaled 13CO2 Concentration | 14.92 Percent change | Standard Deviation 30.26 |
Secondary
Number of Participants Meeting Negative Predictive Value Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens
This exploratory outcome was designed to evaluate the number of participants meeting the negative predictive value (NPV) criterion of the ¹³C-urea breath test for detecting urease-producing pathogens. A participant was considered to meet the NPV criterion if they had a negative breath test result defined as a Spearman correlation coefficient (ρ) ≤ 0.75 between Δ¹³CO₂ and bacterial abundance and RNAseq-confirmed absence of urease-producing pathogens.
Time frame: Collected at 6 minutes after nebulization and measured within 7 days of collection
Population: Participants with both ¹³C-urea breath test data and RNAseq bacterial profiles were included in this analysis. Breath test negativity was pre-defined as Spearman ρ ≤ 0.75. Participants without detectable urease-producing pathogens based on RNAseq taxonomic analysis were considered pathogen-negative. The outcome represents the number of participants who were both test-negative and pathogen-negative.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Number of Participants Meeting Negative Predictive Value Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Number of Participants Meeting Negative Predictive Value Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | 0 Participants |
Secondary
Number of Participants Meeting Sensitivity Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens
This exploratory outcome was designed to assess whether the ¹³C-urea breath test (Δ¹³CO₂) is associated with the presence of urease-producing pathogens. Correlation between exhaled ¹³CO₂ levels and pathogen abundance (based on RNAseq bacterial counts) was to be evaluated using Spearman's correlation, with a pre-defined significance threshold of ρ \> 0.75.
Time frame: Collected at 6 minutes after nebulization and measured within 7 days of collection
Population: Participants with both breath test data and RNAseq-based bacterial abundance profiles were included in this analysis. Urease-producing pathogens were identified based on taxonomy and literature-reported activity. The outcome was defined as the number of participants with a Spearman correlation coefficient greater than 0.75 between Δ¹³CO₂ and pathogen abundance.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Number of Participants Meeting Sensitivity Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Number of Participants Meeting Sensitivity Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | 0 Participants |
Secondary
Number of Participants Meeting Specificity Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens
This exploratory outcome was designed to assess the specificity of the ¹³C-urea breath test (Δ¹³CO₂) for detecting urease-producing pathogens. Specificity was defined as the proportion of participants without urease-producing pathogens (based on RNAseq bacterial profiles) who also did not meet the predefined breath test threshold. The planned analysis used Spearman correlation (ρ) between ¹³CO₂ enrichment and bacterial abundance, with ρ \< 0.75 indicating a negative test result.
Time frame: Collected at 6 minutes after nebulization and measured within 7 days of collection
Population: Participants without RNAseq-detected urease-producing pathogens and with available breath test data were included in this analysis. A specific breath test response was defined as Spearman ρ \> 0.75 between Δ¹³CO₂ and pathogen abundance. Participants not meeting this criterion were considered test-negative. The outcome measured the proportion of participants correctly classified as negative by the breath test.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Number of Participants Meeting Specificity Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Number of Participants Meeting Specificity Criterion of ¹³C-Urea Breath Test for Urease-Producing Pathogens | 0 Participants |
Secondary
Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to Bacterial RNAseq Counts
We recorded change in 13CO2/12CO2 ratio (delta over baseline or ΔOB, in units of ‰) between pre- and post-nebulization samples and compared with subject's causative pathogen based upon sputum or blood culture results
Time frame: Collected at 6 minutes after nebulization and measured within 7 days of collection
Population: The change in 13CO2/12CO2 ratio (delta over baseline or ΔOB, in units of ‰) between pre- and post-nebulization samples was compared to RNAseq bacterial counts. Positive relationships and/or correlations were tested using Spearman's rank correlations. A Spearman value above 0.75 was selected as the cutoff, above which results would be determined to be a positive outcome. A spearman correlation \> 0.75 for any bacteria, the subject would be a positive outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to Bacterial RNAseq Counts | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to Bacterial RNAseq Counts | 0 Participants |
Secondary
Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to CURB-65 Score in Urease-Positive Pneumonia
Number of participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ \> 0.75) to CURB-65 Score in Urease-Positive Pneumonia
Time frame: Collected at 6 minutes after nebulization and measured within 7 days of collection
Population: Linear regression and Spearman correlation was used to determine if CURB65 score correlated with the change in 13CO2 divided by the baseline 13CO2. A spearman correlation \> 0.75 and/or a coefficient of determination \> .70 would mean the subject was listed as a positive outcome in the data table.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to CURB-65 Score in Urease-Positive Pneumonia | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to CURB-65 Score in Urease-Positive Pneumonia | 0 Participants |
Secondary
Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to Pneumonia Severity Index in Urease-Positive Pneumonia.
Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ \> 0.75) to Pneumonia Severity Index in Urease-Positive Pneumonia.
Time frame: Collected at 6 minutes after nebulization and measured within 7 days of collection
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to Pneumonia Severity Index in Urease-Positive Pneumonia. | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Number of Participants With ¹³CO₂/¹²CO₂ Ratio Correlated (ρ > 0.75) to Pneumonia Severity Index in Urease-Positive Pneumonia. | 0 Participants |
Secondary
Number of Participants With Breath Test Positive and Confirmed Urease-Producing Pathogen (PPV Criterion)
This exploratory outcome measured the number of participants who met the criteria for positive predictive value of the ¹³C-urea breath test. A participant was considered to meet the PPV criterion if they had a positive breath test result (Spearman ρ \> 0.75 between Δ¹³CO₂ and bacterial abundance) and also had RNAseq-confirmed presence of at least one urease-producing pathogen.
Time frame: Collected at 6 minutes after nebulization and measured within 7 days of collection
Population: Participants with both ¹³C-urea breath test results and RNAseq bacterial profiling were included in this analysis. Positive breath test results were defined by Spearman correlation ρ \> 0.75 between Δ¹³CO₂ and bacterial abundance. Urease-producing pathogens were identified based on taxonomic classification and known enzymatic activity. The outcome was the count of participants meeting both conditions.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Outpatient Treatment Cohort (Cohort A) | Number of Participants With Breath Test Positive and Confirmed Urease-Producing Pathogen (PPV Criterion) | 0 Participants |
| Inpatient Treatment Cohort (Cohort B) | Number of Participants With Breath Test Positive and Confirmed Urease-Producing Pathogen (PPV Criterion) | 0 Participants |