Acinetobacter Baumannii-calcoaceticus Complex, Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, Bacteremia, Colistin Resistant ABC
Conditions
Brief summary
This is a 2-part study, with Part A being the randomized, controlled portion of the study in patients with ABC hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or bacteremia. Part B is the single-group portion of the study and includes ABC infections that are resistant to or have failed colistin or polymyxin B treatment, as detailed in the inclusion criteria.
Interventions
DRUGSulbactam
1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h).
DRUGDurlobactam
1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h). Sulbactam-Durlobactam: Treatment for 7 days up to 14 days if clinically indicated.
DRUGColistin
Treatment for 7 days up to 14 days if clinically indicated.
DRUGImipenem/Cilastatin 500 mg/500 mg
1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. Treatment for 7 days up to 14 days if clinically indicated.
Sponsors
Entasis Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Study drugs will not be masked due to logistical reasons, every attempt will be made to maintain the blind for patients, all staff at the site, and the Sponsor or its designees, except for the treatment physician and other immediate healthcare providers.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
PART A 1. A confirmed diagnosis of a serious infection that will require treatment with IV antibiotics; 2. A known infection caused by ABC (bacteremia, HABP, VABP, VP, cUTI or AP, or surgical or post-traumatic wound infections) as either a single pathogen or member of a polymicrobial infection based on evidence from culture or, if available, rapid diagnostic test from a sample collected within 72 hours prior to randomization (HABP/VABP/VP patients), AND 1 of the following: 1. Has received no more than 48 hrs of potentially effective (ie, Gram negative coverage) antimicrobial therapy prior to the first dose of study drug; 2. Is clinically failing prior treatment regimens 3. APACHE II score 10 and 30 inclusive, or SOFA score between 7 and 11 inclusive, at time of diagnosis 4. Expectation, in the judgment of the Investigator, that the patient will benefit from effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study 5. Women of childbearing potential (ie, not post-menopausal or surgically sterilized) must have a negative highly sensitive urine or serum pregnancy test before randomization. Participating women of childbearing potential must be willing to consistently use one highly effective method of contraception (ie, condom, combined oral contraceptive, implant, injectable, indwelling intrauterine device, or a vasectomized partner) from Screening until at least 30 days after administration of the last dose of study drug. PART B 1\. Has an infection (HABP, VABP, VP, bacteremia, cUTI, AP, or surgical or post-traumatic wound infections) caused by ABC organisms known to be resistant to colistin (defined as MIC ≥4 mg/L by a non-agar based method); 1. Known to be resistant to colistin or polymyxin B; or 2. Known intolerance to colistin; or 3. Has myasthenia gravis or another neuromuscular syndrome(s) that contraindicates colistin and is not ventilated; or 4. Has acute kidney injury and is receiving renal replacement therapy at study entry.
Exclusion criteria
1. Evidence of active concurrent pneumonia requiring additional antimicrobial treatment 2. Presence of suspected or confirmed deep seated bacterial infections such as bacterial Gram negative osteomyelitis, endocarditis, or meningitis requiring prolonged therapy, as determined by history and/or physical examination; 3. Sustained shock with persisting hypotension requiring vasopressors to maintain mean arterial pressure (MAP) ≥ 60 mmHg; 4. Pregnant or breastfeeding women; 5. Receiving peritoneal dialysis; 6. Requirement for continuing treatment with probenecid, methotrexate, ganciclovir, valproic acid, or divalproex sodium during the study; 7. Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis, hepatic cirrhosis, hepatic failure, chronic ascites, or hepatic encephalopathy;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With All-Cause Mortality in CRABC m-MITT Population | 28 Days | The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT population in Part A. |
| Proportion of Patients With Nephrotoxicity | 28 days | The primary safety endpoint for the study is nephrotoxicity, as measured by the Risk-Injury-Failure-Loss-End-stage renal disease (RIFLE) criteria, in the MITT population in Part A. |
Countries
Belarus, Brazil, China, Greece, Hungary, India, Israel, Lithuania, Mexico, Peru, Puerto Rico, Russia, South Korea, Taiwan, Thailand, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
The total number of participants enrolled in the study was 207. However, two (2) patients were transferred from Part A to part B. These participants were analyzed at each arm until/ from the time point of transfer.
Participants by arm
| Arm | Count |
|---|---|
| Part A- Group 1 Experimental. Group 1 (experimental): 1.0 g sulbactam/1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h; | 92 |
| Part A - Group 2 Control Group (active comparator). Group 2 (control group): 2.5 mg/kg colistin IV infused over 30 minutes every 12 hours (after an initial loading dose of colistin 2.5 to 5 mg/kg) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. | 89 |
| Part B - Group 3 Experimental. Group 3: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. | 26 |
| Total | 207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Death | 15 | 21 | 4 |
| Overall Study | No growth of ABC | 2 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 1 |
| Overall Study | Prohibited concomitant medication | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Transferred to other arm/group | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 1 |
Baseline characteristics
| Characteristic | Part A- Group 1 | Part A - Group 2 | Part B - Group 3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 49 Participants | 52 Participants | 8 Participants | 109 Participants |
| Age, Categorical Between 18 and 65 years | 43 Participants | 37 Participants | 18 Participants | 98 Participants |
| Age, Continuous | 63.4 years STANDARD_DEVIATION 15.42 | 66.9 years STANDARD_DEVIATION 17.13 | 56.2 years STANDARD_DEVIATION 16.33 | 59.8 years STANDARD_DEVIATION 16.45 |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 2 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 33 Participants | 44 Participants | 3 Participants | 80 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) White | 48 Participants | 41 Participants | 23 Participants | 112 Participants |
| Sex: Female, Male Female | 24 Participants | 23 Participants | 5 Participants | 52 Participants |
| Sex: Female, Male Male | 68 Participants | 66 Participants | 21 Participants | 155 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 25 / 91 | 31 / 86 | 4 / 28 |
| other Total, other adverse events | 48 / 91 | 53 / 86 | 14 / 28 |
| serious Total, serious adverse events | 36 / 91 | 42 / 86 | 9 / 28 |
Outcome results
Primary
Proportion of Patients With All-Cause Mortality in CRABC m-MITT Population
The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT population in Part A.
Time frame: 28 Days
Population: CRABC m-MITT (Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex Microbiologically Modified Intent-to-Treat Population).~The CRABC m-MITT Population included patients who met m-MITT criteria and had a baseline ABC organism that was confirmed to be carbapenem-resistant (MIC of imipenem/meropenem ≥8 ug/mL) by the central laboratory or by the local laboratory.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A - Group 1 | Proportion of Patients With All-Cause Mortality in CRABC m-MITT Population | 12 Participants |
| Part A - Group 2 | Proportion of Patients With All-Cause Mortality in CRABC m-MITT Population | 20 Participants |
Comparison: The non-inferiority assessment was based on the 2-sided 95% CIs computed using a continuity-corrected Z-statistic for the difference (\[sulbactam-durlobactam + imipenem/cilastatin\] - \[colistin + imipenem/cilastatin\]) in 28-day all-cause mortality rates between the treatment groups.95% CI: [-30, 3.5]
Primary
Proportion of Patients With Nephrotoxicity
The primary safety endpoint for the study is nephrotoxicity, as measured by the Risk-Injury-Failure-Loss-End-stage renal disease (RIFLE) criteria, in the MITT population in Part A.
Time frame: 28 days
Population: MITT (Modified Intent To Treat population containing all patients who received any amount of study drug).~Analysis of patients with nephrotoxicity as measured by RIFLE criteria at any post-baseline visit based on the Investigator's opinion for the Safety Population for Part A, excluding patients with chronic hemodialysis at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A - Group 1 | Proportion of Patients With Nephrotoxicity | 12 Participants |
| Part A - Group 2 | Proportion of Patients With Nephrotoxicity | 32 Participants |
Comparison: Analysis of patients with nephrotoxicity as measured by RIFLE criteria at any post-baseline visit based on the Investigator's opinion for the Safety Population for Part A, excluding patients with chronic hemodialysis at baseline baseline.p-value: 0.0002Chi-squared