Intra-abdominal Infections
Conditions
Keywords
Intra-abdominal infection, LYS228, beta-lactam antibiotics, creatinine clearance, enterobacteriaceae
Brief summary
The purpose of the study was to evaluate whether LYS228 can be developed for the treatment of complicated intra-abdominal infections. It was planned that LYS228 exposure across patients with varying renal function would be evaluated during the study to confirm that LYS228 concentrations are predicted to be adequate to treat the patient population. It was planned that the PK exposure of the initial 8 patients would be analyzed. PK analysis was not conducted as per protocol the first analysis required 8 patients.
Interventions
DRUGLYS228
LYS228 IV infusion every 6 hours
IV infusion of standard of care antibiotics
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Masking description
A blinded evaluator performed the safety and efficacy assessments
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients 18 to 85 years of age with visual confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis including at least one inclusionary diagnosis during surgical intervention.
Exclusion criteria
* Any of the excluded diagnoses: abdominal wall abscess, small bowel obstruction, traumatic bowel perforation undergoing surgery within 12 hours, perforation of gastroduodenal ulcer with surgery within 24 hours, an intra-abdominal process that is not likely caused by infection. * Pre-operative treatment of any duration with non-study Drug systemic antibiotic therapy for peritonitis or abscess is not allowed unless certain criteria are met. * Concomitant bacterial infection at time of enrollment requiring non-Study Drug antibiotics and that may interfere with the evaluation of clinical response to the study antibiotic. * Known non-abdominal source of infection, including endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to enrollment. * Patient has an Acute Physiology and Chronic Health Evaluation II (APACHE II) score \> 30 or is considered, in the judgement of the investigator, unlikely to survive 4 weeks (e.g. rapidly progressive terminal illness, including septic shock). * Patients that meet sepsis criteria as defined by the quick sequential sepsis-related organ failure assessment (qSOFA). * Women of child-bearing potential unless they are using highly effective methods of contraception during dosing and for 7 days after stopping study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Pharmacokinetics (PK) of LYS228: The Terminal Elimination Half-life (T1/2) | Day 5 | Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5 |
| Plasma Pharmacokinetics (PK) of LYS228: The Systemic (or Total Body) Clearance From Plasma Following Intravenous Administration (CL) | Day 5 | Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5 |
| Plasma Pharmacokinetics (PK) of LYS228: The Volume of Distribution at Steady State Following Intravenous Administration (Vss) | Day 5 | Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5 |
| Clinical Success at Day 28 | Day 28 | Clinical success is defined as resolution, or substantial improvement (i.e. reduction of severity of all baseline signs and symptoms and worsening of none) of all or most baseline signs and symptoms of cIAI infection without the need for additional antibiotic therapy other than any oral antibiotics given to complete treatment at home following discontinuation of Study Drug and no drainage or surgical reintervention required 96 hours after the start of Study Drug. |
| Plasma Pharmacokinetics (PK) of LYS228: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) | Day 5 | Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5 |
| Plasma Pharmacokinetics (PK) of LYS228: The Observed Maximum Plasma Concentration Following Drug Administration (Cmax) | Day 5 | Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5 |
| Plasma Pharmacokinetics (PK) of LYS228: The Time to Reach the Maximum Concentration After Drug Administration (Tmax) | Day 5 | Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Microbiological Response at Day 28 | Day 28 | Microbiologic success at 28 days after randomization determined by microbial growth in culture from the intra-abdominal focus of infection when available or presumed eradication based on clinical success |
| Number of Patients With Adverse Events | Daily | Number of patients with at least one Adverse Event |
Countries
United States
Participant flow
Recruitment details
Approximately 60 patients were planned to be randomized to LYS228 or a comparator (standard of care therapy preferably piperacillin/tazobactam) in a 2:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| LYS228 IV infusion every 6 hours for at least 5 days | 2 |
| Standard of Care IV infusion of standard of care antibiotics for at least 5 days | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | Standard of Care | Total | LYS228 |
|---|---|---|---|
| Age, Continuous | 63 years | 63 years | 63.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 0 / 2 | 1 / 1 |
Outcome results
Primary
Clinical Success at Day 28
Clinical success is defined as resolution, or substantial improvement (i.e. reduction of severity of all baseline signs and symptoms and worsening of none) of all or most baseline signs and symptoms of cIAI infection without the need for additional antibiotic therapy other than any oral antibiotics given to complete treatment at home following discontinuation of Study Drug and no drainage or surgical reintervention required 96 hours after the start of Study Drug.
Time frame: Day 28
Population: All patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LYS228 | Clinical Success at Day 28 | 2 Participants |
| Standard of Care | Clinical Success at Day 28 | 0 Participants |
Primary
Plasma Pharmacokinetics (PK) of LYS228: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau)
Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5
Time frame: Day 5
Population: PK analysis for the 2 patients enrolled that received LYS228 was not conducted as per protocol the first analysis required 8 patients.
Primary
Plasma Pharmacokinetics (PK) of LYS228: The Observed Maximum Plasma Concentration Following Drug Administration (Cmax)
Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5
Time frame: Day 5
Population: PK analysis for the 2 patients enrolled that received LYS228 was not conducted as per protocol the first analysis required 8 patients
Primary
Plasma Pharmacokinetics (PK) of LYS228: The Systemic (or Total Body) Clearance From Plasma Following Intravenous Administration (CL)
Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5
Time frame: Day 5
Population: PK analysis for the 2 patients enrolled that received LYS228 was not conducted as per protocol the first analysis required 8 patients
Primary
Plasma Pharmacokinetics (PK) of LYS228: The Terminal Elimination Half-life (T1/2)
Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5
Time frame: Day 5
Population: PK analysis for the 2 patients enrolled that received LYS228 was not conducted as per protocol the first analysis required 8 patients
Primary
Plasma Pharmacokinetics (PK) of LYS228: The Time to Reach the Maximum Concentration After Drug Administration (Tmax)
Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5
Time frame: Day 5
Population: PK analysis for the 2 patients enrolled that received LYS228 was not conducted as per protocol the first analysis required 8 patients
Primary
Plasma Pharmacokinetics (PK) of LYS228: The Volume of Distribution at Steady State Following Intravenous Administration (Vss)
Calculated based on LYS228 concentration in blood at different time points following drug administration on Day 5
Time frame: Day 5
Population: PK analysis for the 2 patients enrolled that received LYS228 was not conducted as per protocol the first analysis required 8 patients
Secondary
Microbiological Response at Day 28
Microbiologic success at 28 days after randomization determined by microbial growth in culture from the intra-abdominal focus of infection when available or presumed eradication based on clinical success
Time frame: Day 28
Population: All patients with a microbiological response assessment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LYS228 | Microbiological Response at Day 28 | 2 Participants |
| Standard of Care | Microbiological Response at Day 28 | 0 Participants |
Secondary
Number of Patients With Adverse Events
Number of patients with at least one Adverse Event
Time frame: Daily
Population: All patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LYS228 | Number of Patients With Adverse Events | 2 Participants |
| Standard of Care | Number of Patients With Adverse Events | 1 Participants |