Community-acquired Pneumonia
Conditions
Brief summary
The purpose of this study is to evaluate the pharmacokinetics of an oral omadacycline dosing regimen in the treatment of adults with CABP.
Interventions
DRUGOmadacycline
Omadacycline: PO Tablets
Sponsors
Paratek Pharmaceuticals Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participants, age 18 or older who have signed the informed consent form * Must have a qualifying community-acquired bacterial pneumonia * Has disease severity such that oral antibiotics therapy is appropriate * Participants must not be pregnant at the time of enrollment * Must agree to a reliable method of birth control during the study and for 30 days following the last dose of study drug * Must be able to swallow tablets and comply with all of the requirements of the study
Exclusion criteria
* Has received more than 24 hours of a potentially effective systemic antibacterial therapy within the 72 hours prior to the first dose of test article * Known or suspected infection caused by a pathogen that may be resistant to test article * Participants who reside in a long-term care or nursing home * Evidence of empyema * Evidence of significant immunological disease * Evidence of liver impairment or disease * Evidence of unstable cardiac disease * Severe renal disease or requirement for dialysis * Evidence of septic shock * Has a history of hypersensitivity or allergic reaction to any tetracycline * Has received an investigational drug within the past 30 days * Participants who are pregnant or nursing * Unable or unwilling to comply with the protocol requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Elimination Half-life Associated With the Terminal Slope of the Semilogarithmic Concentration-time Curve (T1/2) of Oral Omadacycline on Day 1 and Day 2 | Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5,14, 14.5, 15, 16, and 24 hours post dose; Day 2: pre-dose; 1, 1.5, 2,2.5, 3, 4, and 6 hours post dose | T1/2 was calculated using the linear regression of the terminal portion of the natural log-plasma concentration versus time curve. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis. |
| Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Oral Omadacycline on Day 1 and Day 2 | Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5,14, 14.5, 15, 16, and 24 hours post dose; Day 2: pre-dose; 1, 1.5, 2,2.5, 3, 4, and 6 hours post dose | Cmax was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated SAS program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis. |
| Median Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Oral Omadacycline on Day 1 and Day 2 | Day 1: Pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5,14, 14.5, 15, 16, 24 hours post dose; Day 2: Pre-dose, 1, 1.5, 2,2.5, 3, 4, 6 hours post-dose | Tmax was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated SAS program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis. |
| Log Geometric Mean Area Under the Concentration Versus Time Curve (AUC) From Time 0 to 48 Hours After Dosing (AUC[0-48]) of Oral Omadacycline on Day 2 | Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5, 14, 14.5, 15, 16, and 24 hours post dose. Day 2: pre-dose; 1, 1.5, 2, 2.5, 3, 4, and 6 hours post dose | AUC(0-48) was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated statistical analysis software (SAS) program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this pharmacokinetic (PK) endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis. Data for 100 mg intravenous (IV) omadacycline treatment group which was used for comparison in the statistical analysis were obtained from 6 completed studies: PTK 0796-SDES-0501, PTK 0796-BEQU-0801, PTK 0796 WOIV-0703, CPTK796-A2104, CPTK796-A2201, and PTK 0796-RENL-15102. NCT numbers of these studies were not available. |
| Log Geometric Mean AUC From Time 0 to 24 Hours After Dosing (AUC[0-24]) of Oral Omadacycline on Day 1 | Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5, 14, 14.5, 15, 16, and 24 hours post dose | AUC(0-24) was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated SAS program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Day 1, the participant was excluded from PK Analysis. Data for 100 mg intravenous (IV) omadacycline treatment group which was used for comparison in the statistical analysis were obtained from 6 completed studies: PTK 0796-SDES-0501, PTK 0796-BEQU-0801, PTK 0796 WOIV-0703, CPTK796-A2104, CPTK796-A2201, and PTK 0796-RENL-15102. NCT numbers of these studies were not available. |
| Geometric Mean AUC From Time 0 to the Last Quantifiable Concentration (AUClast) of Oral Omadacycline on Day 1 and Day 2 | Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5,14, 14.5, 15, 16, and 24 hours post dose; Day 2: pre-dose; 1, 1.5, 2,2.5, 3, 4, and 6 hours post dose | AUClast was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated SAS program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Treatment-related TEAE, and Serious Adverse Event (SAE) | From the first dose of study drug up to 37 days | AEs were defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as AEs that began (or pre-existing AEs that worsened) on or after the first dose. SAEs were defined as any untoward medical occurrence that, at any dose resulted in: death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event that may have jeopardized the participant or may have required medical or surgical intervention. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Success, Clinical Failure and Indeterminate Clinical Response at the End of Treatment (EOT) as Determined by Investigator Assessment (IGA) | Up to 37 days | The investigator determined whether or not the participant met the criteria of 1 of the following clinical outcomes: Clinical success, clinical failure, and indeterminate. Clinical success: Participant was alive and the infection was sufficiently resolved such that further antibacterial therapy was not needed. Clinical Failure: Participant required alternative antibacterial treatment for community-acquired bacterial pneumonia (CABP) prior to EOT related to either progression or development of new symptoms of CABP or development of infectious complications of CABP (eg, empyema, lung abscess) or participant developed an AE that required discontinuation of study therapy. Indeterminate: the clinical response to test article could not be adequately inferred. |
Countries
United States
Participant flow
Pre-assignment details
A total of 20 participants were screened. Of these, 2 participants failed screening, and 18 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| 300 mg PO Omadacycline Participants received omadacycline 300 milligrams (mg) per oral (PO) twice daily (BID) on Day 1, followed by omadacycline 300 mg PO once daily (QD) from Day 2 through Day 10. | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | 300 mg PO Omadacycline |
|---|---|
| Age, Continuous | 60.7 Years STANDARD_DEVIATION 11.81 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 10 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Geometric Mean AUC From Time 0 to the Last Quantifiable Concentration (AUClast) of Oral Omadacycline on Day 1 and Day 2
AUClast was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated SAS program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis.
Time frame: Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5,14, 14.5, 15, 16, and 24 hours post dose; Day 2: pre-dose; 1, 1.5, 2,2.5, 3, 4, and 6 hours post dose
Population: PK population. Two participants who reported emesis within 4 hours post-dose were excluded from the analysis. Additionally, 1 participant with only Day 1 PK profile and no sampling on Day 2, was excluded from the Day 2 analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 300 mg PO Omadacycline | Geometric Mean AUC From Time 0 to the Last Quantifiable Concentration (AUClast) of Oral Omadacycline on Day 1 and Day 2 | Day 2 | 8467.8 h*ng/mL | Geometric Coefficient of Variation 69.9 |
| 300 mg PO Omadacycline | Geometric Mean AUC From Time 0 to the Last Quantifiable Concentration (AUClast) of Oral Omadacycline on Day 1 and Day 2 | Day 1 | 8468.9 h*ng/mL | Geometric Coefficient of Variation 89.9 |
Primary
Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Oral Omadacycline on Day 1 and Day 2
Cmax was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated SAS program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis.
Time frame: Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5,14, 14.5, 15, 16, and 24 hours post dose; Day 2: pre-dose; 1, 1.5, 2,2.5, 3, 4, and 6 hours post dose
Population: PK population. Two participants who reported emesis within 4 hours post-dose were excluded from the Day 1 analysis. Additionally, 1 participant with only Day 1 PK profile and no sampling on Day 2, was excluded from the Day 2 analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 300 mg PO Omadacycline | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Oral Omadacycline on Day 1 and Day 2 | Day 1 | 721.2 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 83.9 |
| 300 mg PO Omadacycline | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Oral Omadacycline on Day 1 and Day 2 | Day 2 | 708.6 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 68.7 |
Primary
Log Geometric Mean Area Under the Concentration Versus Time Curve (AUC) From Time 0 to 48 Hours After Dosing (AUC[0-48]) of Oral Omadacycline on Day 2
AUC(0-48) was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated statistical analysis software (SAS) program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this pharmacokinetic (PK) endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis. Data for 100 mg intravenous (IV) omadacycline treatment group which was used for comparison in the statistical analysis were obtained from 6 completed studies: PTK 0796-SDES-0501, PTK 0796-BEQU-0801, PTK 0796 WOIV-0703, CPTK796-A2104, CPTK796-A2201, and PTK 0796-RENL-15102. NCT numbers of these studies were not available.
Time frame: Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5, 14, 14.5, 15, 16, and 24 hours post dose. Day 2: pre-dose; 1, 1.5, 2, 2.5, 3, 4, and 6 hours post dose
Population: Pharmacokinetic (PK) Population: All participants who received omadacycline and had at least 1 evaluable PK parameter. Two participants who reported emesis within 4 hours post-dose and 1 participant with only Day 1 PK profile and no sampling on Day 2, were excluded from the analysis in 300 mg omadacycline treatment arm. Two additional participants with unusually low PK concentrations deemed as outliers were excluded from the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 300 mg PO Omadacycline | Log Geometric Mean Area Under the Concentration Versus Time Curve (AUC) From Time 0 to 48 Hours After Dosing (AUC[0-48]) of Oral Omadacycline on Day 2 | 9.93 Hours x nanograms/milliliter (h*ng/mL) | Standard Deviation 0.364 |
Comparison: Comparison was performed with the 100 mg intravenous (IV) omadacycline treatment group (data were obtained from 6 completed studies-NCT numbers not available). Using the Day 1 plasma concentration profile of the 100 mg IV QD dosing from these studies, a BID dosing on Day 1 and a QD dosing on Day 2 was simulated using the superposition principle. Log Geometric Mean (GM) AUC(0-48) of omadacycline for the 100 mg IV omadacycline group was as follows:Participants analyzed=63; GM (SD)=9.98 (0.2091).90% CI: [84.2, 107.5]
Primary
Log Geometric Mean AUC From Time 0 to 24 Hours After Dosing (AUC[0-24]) of Oral Omadacycline on Day 1
AUC(0-24) was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated SAS program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Day 1, the participant was excluded from PK Analysis. Data for 100 mg intravenous (IV) omadacycline treatment group which was used for comparison in the statistical analysis were obtained from 6 completed studies: PTK 0796-SDES-0501, PTK 0796-BEQU-0801, PTK 0796 WOIV-0703, CPTK796-A2104, CPTK796-A2201, and PTK 0796-RENL-15102. NCT numbers of these studies were not available.
Time frame: Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5, 14, 14.5, 15, 16, and 24 hours post dose
Population: PK population. Two participants who reported emesis within 4 hours post-dose on Day 1 were excluded from the analysis in 300 mg omadacycline treatment arm. Two additional participants with unusually low PK concentrations deemed as outliers were excluded from the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 300 mg PO Omadacycline | Log Geometric Mean AUC From Time 0 to 24 Hours After Dosing (AUC[0-24]) of Oral Omadacycline on Day 1 | 9.27 h*ng/mL | Standard Deviation 0.502 |
Comparison: Comparison was performed with the 100 mg IV omadacycline treatment group (data were obtained from 6 completed studies-NCT numbers not available). Using the Day 1 plasma concentration profile of the 100 mg IV QD dosing from these studies, a BID dosing on Day 1 and a QD dosing on Day 2 was simulated using the superposition principle. Log GM AUC(0-24) of omadacycline for the 100 mg IV omadacycline group was as follows:Participants analyzed=63; GM (SD)=9.26 (0.1985).90% CI: [88, 115.5]
Primary
Median Elimination Half-life Associated With the Terminal Slope of the Semilogarithmic Concentration-time Curve (T1/2) of Oral Omadacycline on Day 1 and Day 2
T1/2 was calculated using the linear regression of the terminal portion of the natural log-plasma concentration versus time curve. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis.
Time frame: Day 1: pre-dose; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5,14, 14.5, 15, 16, and 24 hours post dose; Day 2: pre-dose; 1, 1.5, 2,2.5, 3, 4, and 6 hours post dose
Population: PK population. Two participants who reported emesis within 4 hours post-dose were excluded from the Day 1 analysis. Additionally, 1 participant with only Day 1 PK profile and no sampling on Day 2, was excluded from the Day 2 analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 300 mg PO Omadacycline | Median Elimination Half-life Associated With the Terminal Slope of the Semilogarithmic Concentration-time Curve (T1/2) of Oral Omadacycline on Day 1 and Day 2 | Day 1 | 8.0 Hours |
| 300 mg PO Omadacycline | Median Elimination Half-life Associated With the Terminal Slope of the Semilogarithmic Concentration-time Curve (T1/2) of Oral Omadacycline on Day 1 and Day 2 | Day 2 | 13.1 Hours |
Primary
Median Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Oral Omadacycline on Day 1 and Day 2
Tmax was calculated using the linear trapezoidal linear interpolation method using WinNonlin validated SAS program. Participants with plasma concentration data above the limit of quantification were included in the analysis for this PK endpoint. If any participant had an emesis within 4 hours after dosing on Study Days 1 and 2, the participant was excluded from PK Analysis.
Time frame: Day 1: Pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 13, 13.5,14, 14.5, 15, 16, 24 hours post dose; Day 2: Pre-dose, 1, 1.5, 2,2.5, 3, 4, 6 hours post-dose
Population: PK population. Two participants who reported emesis within 4 hours post-dose were excluded from the Day 1 analysis. Additionally, 1 participant with only Day 1 PK profile and no sampling on Day 2, was excluded from the Day 2 analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 300 mg PO Omadacycline | Median Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Oral Omadacycline on Day 1 and Day 2 | Day 1 | 3.0 Hours |
| 300 mg PO Omadacycline | Median Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Oral Omadacycline on Day 1 and Day 2 | Day 2 | 2.1 Hours |
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Treatment-related TEAE, and Serious Adverse Event (SAE)
AEs were defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as AEs that began (or pre-existing AEs that worsened) on or after the first dose. SAEs were defined as any untoward medical occurrence that, at any dose resulted in: death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event that may have jeopardized the participant or may have required medical or surgical intervention.
Time frame: From the first dose of study drug up to 37 days
Population: Safety Population: all enrolled participants who received at least one dose of omadacycline during the study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 300 mg PO Omadacycline | Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Treatment-related TEAE, and Serious Adverse Event (SAE) | SAEs | 0 Participants |
| 300 mg PO Omadacycline | Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Treatment-related TEAE, and Serious Adverse Event (SAE) | TEAEs | 10 Participants |
| 300 mg PO Omadacycline | Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Treatment-related TEAE, and Serious Adverse Event (SAE) | Treatment-related TEAEs | 8 Participants |
Other Pre-specified
Number of Participants With Clinical Success, Clinical Failure and Indeterminate Clinical Response at the End of Treatment (EOT) as Determined by Investigator Assessment (IGA)
The investigator determined whether or not the participant met the criteria of 1 of the following clinical outcomes: Clinical success, clinical failure, and indeterminate. Clinical success: Participant was alive and the infection was sufficiently resolved such that further antibacterial therapy was not needed. Clinical Failure: Participant required alternative antibacterial treatment for community-acquired bacterial pneumonia (CABP) prior to EOT related to either progression or development of new symptoms of CABP or development of infectious complications of CABP (eg, empyema, lung abscess) or participant developed an AE that required discontinuation of study therapy. Indeterminate: the clinical response to test article could not be adequately inferred.
Time frame: Up to 37 days
Population: Intent-to-Treat (ITT) Population: All enrolled participants regardless of whether they received the study drug. However, all enrolled participants had received oral omadacycline during this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 300 mg PO Omadacycline | Number of Participants With Clinical Success, Clinical Failure and Indeterminate Clinical Response at the End of Treatment (EOT) as Determined by Investigator Assessment (IGA) | Clinical Failure | 0 Participants |
| 300 mg PO Omadacycline | Number of Participants With Clinical Success, Clinical Failure and Indeterminate Clinical Response at the End of Treatment (EOT) as Determined by Investigator Assessment (IGA) | Clinical Success | 18 Participants |
| 300 mg PO Omadacycline | Number of Participants With Clinical Success, Clinical Failure and Indeterminate Clinical Response at the End of Treatment (EOT) as Determined by Investigator Assessment (IGA) | Indeterminate | 0 Participants |