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 to severe community-acquired bacterial pneumonia.
Detailed description
Lefamulin is a potent, semi-synthetic antibacterial belonging to a novel class known as the pleuromutilins. Both the intravenous (IV) and oral dosage forms of lefamulin are 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
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
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 (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 \<4500 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 ≥III.
Exclusion criteria
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., 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). 7. Require mechanical ventilation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Clinical Response (ECR) | ECR was assessed 96 +/- 24 hours after the 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 (other than adjunctive linezolid, as allowed by the study protocol) 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; 5-10 days after the 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, Bosnia and Herzegovina, Brazil, Bulgaria, Georgia, Hungary, Latvia, Netherlands, Peru, Philippines, Poland, Romania, Russia, Serbia, South Africa, Thailand, Ukraine, United States
Participant flow
Recruitment details
The study was designed to enroll adults with CABP that was severe enough to require a minimum of at least 3 days of IV treatment. Subjects with a PORT score of III, IV and V were eligible. The first subject was randomized in February 2016 and the last subject was randomized in April 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 IV study drug.
Participants by arm
| Arm | Count |
|---|---|
| Lefamulin Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 6 doses of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA. | 276 |
| Moxifloxacin ± Linezolid Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 6 doses of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA. | 275 |
| Total | 551 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 3 |
| Overall Study | Lost to Follow-up | 5 | 3 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Randomized but not treated | 3 | 2 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 13 | 9 |
Baseline characteristics
| Characteristic | Moxifloxacin ± Linezolid | Total | Lefamulin |
|---|---|---|---|
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 14.86 | 60.3 Years STANDARD_DEVIATION 15.61 | 61 Years STANDARD_DEVIATION 16.31 |
| American Thoracic Society (ATS) Minor Severity Criteria | 48 Participants | 102 Participants | 54 Participants |
| Bacteremic | 3 Participants | 10 Participants | 7 Participants |
| CURB-65 Score 0 | 33 Participants | 57 Participants | 24 Participants |
| CURB-65 Score 1 | 121 Participants | 251 Participants | 130 Participants |
| CURB-65 Score 2 | 97 Participants | 195 Participants | 98 Participants |
| CURB-65 Score 3 | 22 Participants | 44 Participants | 22 Participants |
| CURB-65 Score 4 | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 18 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 265 Participants | 533 Participants | 268 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class II | 1 Participants | 1 Participants | 0 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class III | 201 Participants | 397 Participants | 196 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class IV | 70 Participants | 146 Participants | 76 Participants |
| Pneumonia Outcomes Research Team (PORT) Risk Class V | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 45 Participants | 25 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 23 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 4 Participants | 1 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 | 239 Participants | 478 Participants | 239 Participants |
| Received Single Dose Short Acting Systemic Antibacterial within 72 hrs of Randomization | 66 Participants | 132 Participants | 66 Participants |
| Region of Enrollment Argentina | 6 participants | 9 participants | 3 participants |
| Region of Enrollment Bosnia and Herzegovina | 14 participants | 25 participants | 11 participants |
| Region of Enrollment Brazil | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Bulgaria | 58 participants | 123 participants | 65 participants |
| Region of Enrollment Georgia | 29 participants | 54 participants | 25 participants |
| Region of Enrollment Hungary | 13 participants | 23 participants | 10 participants |
| Region of Enrollment Latvia | 11 participants | 28 participants | 17 participants |
| Region of Enrollment Netherlands | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Peru | 3 participants | 4 participants | 1 participants |
| Region of Enrollment Philippines | 17 participants | 40 participants | 23 participants |
| Region of Enrollment Poland | 1 participants | 7 participants | 6 participants |
| Region of Enrollment Romania | 4 participants | 11 participants | 7 participants |
| Region of Enrollment Russia | 13 participants | 21 participants | 8 participants |
| Region of Enrollment Serbia | 27 participants | 57 participants | 30 participants |
| Region of Enrollment South Africa | 15 participants | 27 participants | 12 participants |
| Region of Enrollment Thailand | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Ukraine | 61 participants | 116 participants | 55 participants |
| Region of Enrollment United States | 1 participants | 3 participants | 2 participants |
| Renal Status Mild Impairment (CrCl 60-<90mL/min) | 75 Participants | 164 Participants | 89 Participants |
| Renal Status Missing renal status | 1 Participants | 3 Participants | 2 Participants |
| Renal Status Moderate Impairment (CrCl 30-<60mL/min) | 62 Participants | 123 Participants | 61 Participants |
| Renal Status Normal Function (CrCl >=90mL/min) | 134 Participants | 255 Participants | 121 Participants |
| Renal Status Severe Impairment (CrCl <30mL/min) | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 160 Participants | 330 Participants | 170 Participants |
| Sex: Female, Male Male | 115 Participants | 221 Participants | 106 Participants |
| Systemic inflammatory response syndrome (SIRS) Criteria | 267 Participants | 535 Participants | 268 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 273 | 5 / 273 |
| other Total, other adverse events | 39 / 273 | 46 / 273 |
| serious Total, serious adverse events | 19 / 273 | 13 / 273 |
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 (other than adjunctive linezolid, as allowed by the study protocol) for the treatment of CABP through the ECR assessment.
Time frame: ECR was assessed 96 +/- 24 hours after the first dose of study drug.
Population: Intent to Treat Analysis Set: All randomized subjects
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lefamulin | Early Clinical Response (ECR) | Responder | 241 Participants |
| Lefamulin | Early Clinical Response (ECR) | Non-Responder | 29 Participants |
| Lefamulin | Early Clinical Response (ECR) | Indeterminate | 6 Participants |
| Moxifloxacin ± Linezolid | Early Clinical Response (ECR) | Responder | 248 Participants |
| Moxifloxacin ± Linezolid | Early Clinical Response (ECR) | Non-Responder | 21 Participants |
| Moxifloxacin ± Linezolid | Early Clinical Response (ECR) | Indeterminate | 6 Participants |
95% CI: [-8.5, 2.8]
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; 5-10 days after the 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) | Success | 223 Participants |
| Lefamulin | Investigator's Assessment of Clinical Response (IACR) | Indeterminate | 7 Participants |
| Lefamulin | Investigator's Assessment of Clinical Response (IACR) | Failure | 43 Participants |
| Moxifloxacin ± Linezolid | Investigator's Assessment of Clinical Response (IACR) | Success | 230 Participants |
| Moxifloxacin ± Linezolid | Investigator's Assessment of Clinical Response (IACR) | Failure | 40 Participants |
| Moxifloxacin ± Linezolid | Investigator's Assessment of Clinical Response (IACR) | Indeterminate | 3 Participants |
95% CI: [-8.9, 3.9]
95% CI: [-9.2, 4.1]
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 - 10 days after the 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 | 205 Participants |
| Lefamulin | Investigator's Assessment of Clinical Response (IACR) | Failure | 31 Participants |
| Moxifloxacin ± Linezolid | Investigator's Assessment of Clinical Response (IACR) | Success | 219 Participants |
| Moxifloxacin ± Linezolid | Investigator's Assessment of Clinical Response (IACR) | Failure | 26 Participants |
95% CI: [-8.4, 3.4]
95% CI: [-8.7, 3.7]