Community Acquired Pneumonia
Conditions
Keywords
Pneumonia, CABP, CAP, Community acquired bacterial pneumonia
Brief summary
This study evaluates the safety and efficacy of lefamulin, a pleuromutilin, for the treatment of adults with moderate community-acquired bacterial pneumonia
Detailed description
Lefamulin is a potent, semi-synthetic antibacterial belonging to a novel class known as the pleuromutilins. The oral dosage form of lefamulin is under investigation in this study. Lefamulin's in vitro antibacterial profile includes the most important bacterial pathogens causing respiratory tract infection (RTI). The antibacterial spectrum comprises S. pneumoniae, H. influenzae, M. catarrhalis, the atypical respiratory pathogens L. pneumophila, C. pneumoniae, and M. pneumoniae, S. aureus including MRSA and CA-MRSA, ß-haemolytic streptococci including S. pyogenes and S. agalactiae, and Enterococcus faecium including vancomycin-resistant enterococci (VRE). Moreover, as demonstrated in cross-resistance studies, lefamulin remains active against clinical isolates resistant to the following antimicrobial(s) (classes): macrolides, lincosamides, streptogramin B, oxazolidinones, tetracyclines, ß lactams, quinolones, trimethoprim-sulfametoxazole, mupirocin, and vancomycin.
Interventions
DRUGlefamulin
antibacterial agent
DRUGMoxifloxacin
antibacterial agent
Sponsors
Nabriva Therapeutics AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each subject must: 1. Be male or female at least 18 years of age. 2. Provide written informed consent and be willing and able to adhere to the study-specified procedures and restrictions. 3. Have an acute illness (less than or equal to 7 days duration) with at least 3 of the following symptoms consistent with a lower respiratory tract infection (new or worsening): * Dyspnea. * New or increased cough. * Purulent sputum production. * Chest pain due to pneumonia. 4. Have at least 2 of the following vital sign abnormalities: * Fever (body temperature \> 38.0 °C (100.4 °F) measured orally or equivalent temperature from an alternate body site) or hypothermia (body temperature \< 35.0 °C (95.0 °F) measured orally or equivalent temperature from an alternate body site). * Hypotension (systolic blood pressure \< 90 mmHg). * Tachycardia (heart rate \> 100 beats/min). * Tachypnea (respiratory rate \> 20 breaths/min). 5. Have at least 1 other clinical sign or laboratory finding of CABP: * Hypoxemia (i.e., O2 saturation \< 90 % on room air or while receiving supplemental oxygen at subject's baseline requirement or PaO2 \< 60 mmHg). * Auscultatory and/or percussion findings consistent with pneumonia (e.g., crackles, egophony, dullness). * White blood cell (WBC) count \> 10 000 cells/mm3 or \< 4 500 cells/mm3 or \>15 % immature neutrophils (bands) regardless of total WBC count. 6. Have radiographically-documented pneumonia within 48 hours before enrollment (i.e., infiltrates in a lobar or multilobar distribution or diffuse opacities on chest x-ray or chest computed tomography scan consistent with acute bacterial pneumonia). 7. Have a Pneumonia Outcomes Research Team (PORT) Risk Class of II, III, or IV and be an appropriate candidate for oral antibiotic therapy as treatment for the current episode of CABP.
Exclusion criteria
Each subject must NOT: 1. Have received more than a single dose of a short-acting oral or IV antibacterial for CABP within 72 hours before randomization. 2. Require concomitant systemic antibacterial therapy potentially effective against CABP pathogens. 3. Have been hospitalized for 2 or more days within 90 days prior to the onset of symptoms or have resided in a nursing home or long-term healthcare facility within 30 days prior to the onset of symptoms. NOTE: Residence in an independent living facility is permitted. 4. Have confirmed or suspected CABP caused by a pathogen known to be resistant to any of the study drugs (e.g., MRSA, Pseudomonas aeruginosa, any pathogen of the Enterobacteriaceae Family) or attributable to etiologies other than community acquired bacterial pathogens (e.g., ventilator associated pneumonia, hospital acquired bacterial pneumonia, bacterial aspiration pneumonia, Pneumocystis jiroveci pneumonia or other fungal pneumonia, viral or mycobacterial infection of the lung). 5. Have a noninfectious cause of pulmonary infiltrates (e.g., pulmonary embolism, chemical pneumonitis from aspiration, hypersensitivity pneumonia, congestive heart failure, bronchial obstruction, lung cancer, cystic fibrosis). 6. Have confirmed or suspected pleural empyema (does not include sterile parapneumonic effusions).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Clinical Response (ECR) | 96 hours +/- 24 hours after first dose of study drug | ECR was defined as survival with improvement in at least 2 signs and symptoms of CABP (relative to baseline), no worsening of any CABP sign or symptom, and no use of concomitant antibiotics for the treatment of CABP through the ECR assessment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator's Assessment of Clinical Response (IACR) | IACR was assessed at the Test-of-Cure Visit; 5 to 10 days after last dose of study drug | IACR was defined as resolution or improvement of a subject's clinical signs and symptoms such that no additional antibacterial therapy was administered for the treatment of the current episode of CABP |
Countries
Argentina, Brazil, Bulgaria, Chile, Georgia, Hungary, Latvia, Mexico, Peru, Philippines, Poland, Romania, Russia, Serbia, South Africa, South Korea, Spain, Taiwan, Ukraine, United States
Participant flow
Recruitment details
The study was designed to enroll adults with CABP for which oral antibacterial therapy was appropriate. Subjects with PORT score of II, III and IV were eligible. The first subject was randomized in August 2016 and the last subject was randomized in December 2017
Pre-assignment details
Subjects who met inclusion criteria and did not meet exclusion criteria were randomly assigned to a treatment group. Administration of study drug was expected to occur as soon as possible after the diagnosis of CABP with all Screening/baseline assessments expected to be completed within 24 hours before the first dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Lefamulin oral lefamulin, 600mg | 370 |
| Moxifloxacin oral moxifloxacin, 400mg | 368 |
| Total | 738 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Patient hospitalized | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Randomized- did not receive study drug | 2 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 9 |
Baseline characteristics
| Characteristic | Total | Moxifloxacin | Lefamulin |
|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 16.3 | 57.7 years STANDARD_DEVIATION 16.2 | 57.4 years STANDARD_DEVIATION 16.4 |
| American Thoracic Society (ATS) Minor Severity Criteria | 68 Participants | 37 Participants | 31 Participants |
| Bacteremic | 15 Participants | 9 Participants | 6 Participants |
| CURB-65 Score 0 | 167 Participants | 80 Participants | 87 Participants |
| CURB-65 Score 1 | 393 Participants | 196 Participants | 197 Participants |
| CURB-65 Score 2 | 151 Participants | 77 Participants | 74 Participants |
| CURB-65 Score 3 | 25 Participants | 13 Participants | 12 Participants |
| CURB-65 Score 4 | 2 Participants | 2 Participants | 0 Participants |
| CURB-65 Score 5 | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 83 Participants | 38 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 655 Participants | 330 Participants | 325 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class I | 3 Participants | 2 Participants | 1 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class II | 372 Participants | 189 Participants | 183 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class III | 278 Participants | 133 Participants | 145 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class IV | 82 Participants | 42 Participants | 40 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class V | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 41 Participants | 17 Participants | 24 Participants |
| Race (NIH/OMB) Asian | 102 Participants | 53 Participants | 49 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants | 22 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 544 Participants | 270 Participants | 274 Participants |
| Received Single Dose Short-Acting Antibacterial within 72 hrs of Randomization | 149 Participants | 72 Participants | 77 Participants |
| Region of Enrollment Argentina | 13 participants | 7 participants | 6 participants |
| Region of Enrollment Bulgaria | 80 participants | 42 participants | 38 participants |
| Region of Enrollment Chile | 4 participants | 2 participants | 2 participants |
| Region of Enrollment Georgia | 41 participants | 19 participants | 22 participants |
| Region of Enrollment Hungary | 28 participants | 15 participants | 13 participants |
| Region of Enrollment Latvia | 3 participants | 0 participants | 3 participants |
| Region of Enrollment Mexico | 4 participants | 3 participants | 1 participants |
| Region of Enrollment Peru | 51 participants | 22 participants | 29 participants |
| Region of Enrollment Philippines | 71 participants | 36 participants | 35 participants |
| Region of Enrollment Poland | 7 participants | 3 participants | 4 participants |
| Region of Enrollment Romania | 18 participants | 7 participants | 11 participants |
| Region of Enrollment Russia | 55 participants | 24 participants | 31 participants |
| Region of Enrollment Serbia | 129 participants | 63 participants | 66 participants |
| Region of Enrollment South Africa | 55 participants | 34 participants | 21 participants |
| Region of Enrollment South Korea | 26 participants | 14 participants | 12 participants |
| Region of Enrollment Spain | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Taiwan | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Ukraine | 128 participants | 63 participants | 65 participants |
| Region of Enrollment United States | 23 participants | 12 participants | 11 participants |
| Renal Status Mild impairment (CrCl 60 to <90 mL/min) | 229 Participants | 117 Participants | 112 Participants |
| Renal Status Moderate impairment (CrCl 30 to <60 mL/min) | 134 Participants | 70 Participants | 64 Participants |
| Renal Status Normal function (CrCl >/= 90 mL/min) | 368 Participants | 178 Participants | 190 Participants |
| Renal Status Severe impairment (CrCl <30 mL/min) | 7 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Female | 351 Participants | 188 Participants | 163 Participants |
| Sex: Female, Male Male | 387 Participants | 180 Participants | 207 Participants |
| Systemic inflammatory response syndrome (SIRS) Criteria | 695 Participants | 342 Participants | 353 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 368 | 3 / 368 |
| other Total, other adverse events | 61 / 368 | 12 / 368 |
| serious Total, serious adverse events | 17 / 368 | 18 / 368 |
Outcome results
Primary
Early Clinical Response (ECR)
ECR was defined as survival with improvement in at least 2 signs and symptoms of CABP (relative to baseline), no worsening of any CABP sign or symptom, and no use of concomitant antibiotics for the treatment of CABP through the ECR assessment
Time frame: 96 hours +/- 24 hours after first dose of study drug
Population: Intent to Treat Analysis Set: All randomized subjects
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lefamulin | Early Clinical Response (ECR) | Non-responder | 29 Participants |
| Lefamulin | Early Clinical Response (ECR) | Responder | 336 Participants |
| Lefamulin | Early Clinical Response (ECR) | Indeterminate | 5 Participants |
| Moxifloxacin | Early Clinical Response (ECR) | Responder | 334 Participants |
| Moxifloxacin | Early Clinical Response (ECR) | Non-responder | 31 Participants |
| Moxifloxacin | Early Clinical Response (ECR) | Indeterminate | 3 Participants |
95% CI: [-4.4, 4.5]
Secondary
Investigator's Assessment of Clinical Response (IACR)
IACR was defined as resolution or improvement of a subject's clinical signs and symptoms such that no additional antibacterial therapy was administered for the treatment of the current episode of CABP
Time frame: IACR was assessed at the Test-of-Cure Visit; 5 to 10 days after last dose of study drug
Population: Modified ITT population: All randomized subjects who received any amount of study drug
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lefamulin | Investigator's Assessment of Clinical Response (IACR) | Failure | 44 Participants |
| Lefamulin | Investigator's Assessment of Clinical Response (IACR) | Success | 322 Participants |
| Lefamulin | Investigator's Assessment of Clinical Response (IACR) | Indeterminate | 2 Participants |
| Moxifloxacin | Investigator's Assessment of Clinical Response (IACR) | Success | 328 Participants |
| Moxifloxacin | Investigator's Assessment of Clinical Response (IACR) | Failure | 32 Participants |
| Moxifloxacin | Investigator's Assessment of Clinical Response (IACR) | Indeterminate | 8 Participants |
95% CI: [-6.3, 3.1]
95% CI: [-6.5, 3.3]
Secondary
Investigator's Assessment of Clinical Response (IACR)
IACR was defined as resolution or improvement of a subject's clinical signs and symptoms such that no additional antibacterial therapy was administered for the treatment of the current episode of CABP
Time frame: IACR was assessed at the Test-of-Cure Visit; 5 to 10 days after last dose of study drug
Population: Clinically Evaluable population: Subset of ITT population having met additional pre-defined criteria.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lefamulin | Investigator's Assessment of Clinical Response (IACR) | Success | 296 Participants |
| Lefamulin | Investigator's Assessment of Clinical Response (IACR) | Failure | 34 Participants |
| Moxifloxacin | Investigator's Assessment of Clinical Response (IACR) | Success | 305 Participants |
| Moxifloxacin | Investigator's Assessment of Clinical Response (IACR) | Failure | 21 Participants |
95% CI: [-8.2, 0.5]
95% CI: [-8.4, 0.7]