Community Acquired Bacterial Pneumonia
Conditions
Keywords
Pneumonia
Brief summary
The purpose of this study is to evaluate the safety and efficacy of delafloxacin compared to moxifloxacin in the treatment of adult patients with community-acquired pneumonia.
Detailed description
The purpose of this study is to determine if delafloxacin, an investigational drug, is safe and effective in the treatment of community-acquired bacterial pneumonia compared with moxifloxacin, or linezolid in the case of confirmed MRSA.
Interventions
DRUGDelafloxacin
Antibacterial agent, 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total
DRUGMoxifloxacin
Antibacterial Agent, 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total
DRUGLinezolid
Antibacterial Agent, at local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
Sponsors
Melinta Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female 18 years of age or older 2. Evidence of acute onset of CABP with 2 or more of the following symptoms (new or worsening) * Cough * Production of purulent sputum consistent with bacterial infection * Difficulty breathing * Chest pain due to pneumonia AND have at least 2 of the following findings: * Fever (oral temperature \>38.0°C) * Hypothermia (oral temperature \<35.0°C) * Tachycardia (heart rate \>100 beats/min) * Tachypnea (respiratory rate \>18 breaths/min) AND have at least 1 of the following findings: * Hypoxemia (oxygen saturation \<90% or PaO2 \< 60 mmHg) on room air or with subject's baseline (pre-CABP under study) supplemental oxygen * Clinical evidence of pulmonary consolidation and/or presence of pulmonary rales * An elevated white blood cell count (WBC) \>10,000/mm3 or 15% immature neutrophils (bands), regardless of total peripheral WBC count or leukopenia with WBC \<4500/mm\^3 3. Presence of lobar, multilobar, or patchy parenchymal infiltrate(s) consistent with acute bacterial pneumonia on a pulmonary imaging study within 48 hours before the first dose of study drug 4. PORT risk class of II to V (PSI score \>50) 5. Must be a suitable candidate for possible IV to oral switch antibiotic therapy and must also be able to swallow large tablets/capsules intact without crushing
Exclusion criteria
1. A medical history of significant hypersensitivity or allergic reaction to antibiotics of the quinolone or oxazolidinone class or study drug excipients according to the investigator 2. Any infection expected to require other systemic antibiotics in addition to study drug 3. Receipt of systemic antibiotic therapy in the 7 days before enrollment unless 1 of the following is documented: * Received at least 48 hours of antibiotic therapy for CABP and clinic notes document treatment failure (i.e., not by patient history or pulmonary imaging alone) with new or worsening symptoms while on pre-study therapy * Received 1 dose of a single, potentially effective, short-acting antibacterial drug or drug regimen for CABP within 24 hours before enrollment (limited to 25% of enrolled patients) 4. Respiratory infection confirmed or suspected to be secondary to hospital-acquired or ventilator-associated pneumonia OR requires treatment in an intensive care setting, OR requires mechanical ventilation 5. Current or suspected diagnosis of viral, fungal, or aspiration pneumonia, noninfectious causes of pulmonary infiltrates, lung cancer, cystic fibrosis, tuberculosis, empyema (not including sterile parapneumonic effusions) 6. Known anatomical or pathological bronchial obstruction OR history of bronchiectasis OR GOLD Stage 4 COPD OR history of post obstructive pneumonia 7. Severely compromised immune system 8. Known history of Child-Pugh Class B or C liver disease 9. History of post-antibiotic colitis within last 3 months 10. Other exclusions include those described in the safety label for drugs in the quinolone and/or oxazolidinone classes such as QT prolongation, proarrhythmic conditions, concomitant use of drugs known to cause QT prolongation, peripheral neuropathy, tendon disorders, history of myasthenia gravis, liver disease, severe renal disease, seizures and concomitant use of MAO A or B inhibitor agents and adrenergic serotonergic agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Clinical Response | 96 (+/- 24) hours after the first dose of study drug | Early clinical response defined as improvement in at least 2 of the following symptoms (as assessed by the investigator): chest pain, frequency or severity of cough, amount and quality of productive sputum, and difficulty breathing, and no worsening of the other symptoms in the ITT population. Symptom severity evaluated by the investigator on a 4-point scale: Absent (0), Mild (1), Moderate (2), Severe (3). Improvement defined as at least a 1-point decrease from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early Clinical Response Plus Improvement in Vital Signs and no Worsening of the 4 Symptoms | 96 (+/- 24) hours after the first dose of study drug | Early clinical response with the addition of improvement in vital signs and no worsening of the following 4 symptoms: chest pain, cough, productive sputum, and difficulty breathing in the ITT population. Symptom severity evaluated by the investigator on a 4-point scale: Absent (0), Mild (1), Moderate (2), Severe (3). Improvement defined as at least a 1-point decrease from baseline. Improvement in vital signs defined as a return to normal of any abnormal vital signs at baseline, and no worsening (ie, be abnormal) of any vital sign that was normal at baseline. |
| Clinical Outcome at Test of Cure | 5 to 10 days after the last dose of study drug | Clinical outcome (Success, Failure, or Indeterminate/missing) based on the investigator's assessment of the patient's signs and symptoms of infection in the ITT population. |
| Clinical Outcome at End of Treatment | Up to 24 (+4) hours after the last dose of study drug | Clinical outcome (Success, Failure, or Indeterminate/missing) based on the investigator's assessment of the patient's signs and symptoms of infection in the ITT population. |
| Microbiologic Response | 5 to 10 days after the last dose of study drug | Microbiological response for subjects in the MITT set will be based on results of the baseline and follow-up cultures and susceptibility testing or serology. |
| All-cause Mortality | Day 28 (+/- 2 days) | Time to all-cause Mortality was assessed on Day 28. |
Countries
Argentina, Bulgaria, Colombia, Dominican Republic, Georgia, Germany, Hungary, Latvia, Peru, Poland, Romania, Russia, Serbia, Slovenia, South Africa, Spain, Ukraine, United States
Participant flow
Pre-assignment details
860 subjects were planned to be enrolled in the study but 859 are included in the ITT population. One subject mistakenly was randomized into the IXRS but did not provide informed consent; therefore, this subject was not included in the ITT population.
Participants by arm
| Arm | Count |
|---|---|
| Delafloxacin Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total | 431 |
| Moxifloxacin/Linezolid Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total
Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses | 428 |
| Total | 859 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 6 |
| Overall Study | Could not complete required study visits | 6 | 2 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Lack of Efficacy | 12 | 15 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Physician Decision | 2 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 9 |
Baseline characteristics
| Characteristic | Delafloxacin | Moxifloxacin/Linezolid | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 203 Participants | 179 Participants | 382 Participants |
| Age, Categorical Between 18 and 65 years | 228 Participants | 249 Participants | 477 Participants |
| Age, Continuous | 60.7 years STANDARD_DEVIATION 16.06 | 59.3 years STANDARD_DEVIATION 61 | 60.0 years STANDARD_DEVIATION 16.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 23 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 399 Participants | 405 Participants | 804 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| PORT Risk Class II | 54 Participants | 57 Participants | 111 Participants |
| PORT Risk Class III | 258 Participants | 260 Participants | 518 Participants |
| PORT Risk Class IV | 115 Participants | 103 Participants | 218 Participants |
| PORT Risk Class V | 4 Participants | 8 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 5 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 33 Participants | 55 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 398 Participants | 388 Participants | 786 Participants |
| Region of Enrollment Argentina | 12 participants | 8 participants | 20 participants |
| Region of Enrollment Bulgaria | 33 participants | 25 participants | 58 participants |
| Region of Enrollment Colombia | 11 participants | 9 participants | 20 participants |
| Region of Enrollment Dominican Republic | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Georgia | 45 participants | 50 participants | 95 participants |
| Region of Enrollment Germany | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Hungary | 14 participants | 12 participants | 26 participants |
| Region of Enrollment Latvia | 19 participants | 21 participants | 40 participants |
| Region of Enrollment Peru | 4 participants | 0 participants | 4 participants |
| Region of Enrollment Poland | 20 participants | 8 participants | 28 participants |
| Region of Enrollment Romania | 30 participants | 29 participants | 59 participants |
| Region of Enrollment Russia | 38 participants | 42 participants | 80 participants |
| Region of Enrollment Serbia | 69 participants | 73 participants | 142 participants |
| Region of Enrollment Slovenia | 8 participants | 7 participants | 15 participants |
| Region of Enrollment South Africa | 30 participants | 41 participants | 71 participants |
| Region of Enrollment Spain | 10 participants | 14 participants | 24 participants |
| Region of Enrollment Ukraine | 84 participants | 84 participants | 168 participants |
| Region of Enrollment United States | 1 participants | 5 participants | 6 participants |
| Sex: Female, Male Female | 180 Participants | 175 Participants | 355 Participants |
| Sex: Female, Male Male | 251 Participants | 253 Participants | 504 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 429 | 6 / 427 |
| other Total, other adverse events | 40 / 429 | 30 / 427 |
| serious Total, serious adverse events | 23 / 429 | 20 / 427 |
Outcome results
Primary
Early Clinical Response
Early clinical response defined as improvement in at least 2 of the following symptoms (as assessed by the investigator): chest pain, frequency or severity of cough, amount and quality of productive sputum, and difficulty breathing, and no worsening of the other symptoms in the ITT population. Symptom severity evaluated by the investigator on a 4-point scale: Absent (0), Mild (1), Moderate (2), Severe (3). Improvement defined as at least a 1-point decrease from baseline.
Time frame: 96 (+/- 24) hours after the first dose of study drug
Population: ITT (intent-to-treat) Population is all the randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delafloxacin | Early Clinical Response | 383 Participants |
| Moxifloxacin/Linezolid | Early Clinical Response | 381 Participants |
Comparison: The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were:~H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm \> -0.125 where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively.~The treatment difference (delafloxacin - moxifloxacin) were presented, and the Miettinen-Nurminen test, without stratification, was used for the 2 sided 95% CI on the difference in response rate.95% CI: [-4.4, 4.1]
Secondary
All-cause Mortality
Time to all-cause Mortality was assessed on Day 28.
Time frame: Day 28 (+/- 2 days)
Population: ITT (intent-to-treat) Population is all the randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delafloxacin | All-cause Mortality | 8 Participants |
| Moxifloxacin/Linezolid | All-cause Mortality | 6 Participants |
p-value: 0.5951Log Rank
Secondary
Clinical Outcome at End of Treatment
Clinical outcome (Success, Failure, or Indeterminate/missing) based on the investigator's assessment of the patient's signs and symptoms of infection in the ITT population.
Time frame: Up to 24 (+4) hours after the last dose of study drug
Population: ITT (intent-to-treat) Population is all the randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Delafloxacin | Clinical Outcome at End of Treatment | Success | 396 Participants |
| Delafloxacin | Clinical Outcome at End of Treatment | Failure | 19 Participants |
| Delafloxacin | Clinical Outcome at End of Treatment | Indeterminate/Missing | 16 Participants |
| Moxifloxacin/Linezolid | Clinical Outcome at End of Treatment | Failure | 20 Participants |
| Moxifloxacin/Linezolid | Clinical Outcome at End of Treatment | Success | 390 Participants |
| Moxifloxacin/Linezolid | Clinical Outcome at End of Treatment | Indeterminate/Missing | 18 Participants |
Comparison: The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were:~H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm \> -0.125~where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively.~The treatment difference (delafloxacin - moxifloxacin) was presented, and the Miettinen-Nurminen test without stratification was used for the 2 sided 95% CI on the difference in response rate.95% CI: [-3, 4.6]
Secondary
Clinical Outcome at Test of Cure
Clinical outcome (Success, Failure, or Indeterminate/missing) based on the investigator's assessment of the patient's signs and symptoms of infection in the ITT population.
Time frame: 5 to 10 days after the last dose of study drug
Population: ITT (intent-to-treat) Population is all the randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Delafloxacin | Clinical Outcome at Test of Cure | Success | 390 Participants |
| Delafloxacin | Clinical Outcome at Test of Cure | Failure | 21 Participants |
| Delafloxacin | Clinical Outcome at Test of Cure | Indeterminate/Missing | 20 Participants |
| Moxifloxacin/Linezolid | Clinical Outcome at Test of Cure | Success | 384 Participants |
| Moxifloxacin/Linezolid | Clinical Outcome at Test of Cure | Failure | 21 Participants |
| Moxifloxacin/Linezolid | Clinical Outcome at Test of Cure | Indeterminate/Missing | 23 Participants |
Comparison: The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were:~H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm \> -0.125~where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively.~The treatment difference (delafloxacin - moxifloxacin) was presented, and the Miettinen-Nurminen test without stratification was used for the 2 sided 95% CI on the difference in response rate.95% CI: [-3.3, 4.8]
Secondary
Early Clinical Response Plus Improvement in Vital Signs and no Worsening of the 4 Symptoms
Early clinical response with the addition of improvement in vital signs and no worsening of the following 4 symptoms: chest pain, cough, productive sputum, and difficulty breathing in the ITT population. Symptom severity evaluated by the investigator on a 4-point scale: Absent (0), Mild (1), Moderate (2), Severe (3). Improvement defined as at least a 1-point decrease from baseline. Improvement in vital signs defined as a return to normal of any abnormal vital signs at baseline, and no worsening (ie, be abnormal) of any vital sign that was normal at baseline.
Time frame: 96 (+/- 24) hours after the first dose of study drug
Population: ITT (intent-to-treat) Population is all randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delafloxacin | Early Clinical Response Plus Improvement in Vital Signs and no Worsening of the 4 Symptoms | 227 Participants |
| Moxifloxacin/Linezolid | Early Clinical Response Plus Improvement in Vital Signs and no Worsening of the 4 Symptoms | 184 Participants |
Comparison: The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were:~H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm \> -0.125~where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively.~The treatment difference (delafloxacin - moxifloxacin) was presented, and the Miettinen-Nurminen test without stratification was used for the 2 sided 95% CI on the difference in response rate.95% CI: [3, 16.3]
Secondary
Microbiologic Response
Microbiological response for subjects in the MITT set will be based on results of the baseline and follow-up cultures and susceptibility testing or serology.
Time frame: 5 to 10 days after the last dose of study drug
Population: Microbiological ITT 1 (MITT-1) includes all subjects in the ITT population with a baseline bacterial pathogen identified that was known to cause CABP and against which the study drug had antibacterial activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delafloxacin | Microbiologic Response | 231 Participants |
| Moxifloxacin/Linezolid | Microbiologic Response | 235 Participants |
Comparison: The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were:~H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm \> -0.125~where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively.~The treatment difference (delafloxacin - moxifloxacin) was presented, and the Miettinen-Nurminen test without stratification was used for the 2 sided 95% CI on the difference in response rate.95% CI: [-4.8, 5.9]