LYS228 PK, Clinical Response, Safety and Tolerability in Patients With Complicated Intra-abdominal Infection (cIAI)

A Randomized, Controlled, Evaluator-blinded, Multi-center Study to Evaluate LYS228 Pharmacokinetics, Clinical Response, Safety, and Tolerability in Patients With Complicated Intra-abdominal Infection

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.

Study Overview

• Status: Terminated
• Conditions: Intra-abdominal Infections
• Intervention / Treatment: Drug: Standard of care therapy; Drug: LYS228

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Somers Point, New Jersey, United States, 08230
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care; IV infusion of standard of care antibiotics for at least 5 days	Drug: Standard of care therapy; IV infusion of standard of care antibiotics
Experimental: LYS228; IV infusion every 6 hours for at least 5 days	Drug: LYS228; LYS228 IV infusion every 6 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 28
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	Day 5
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	Day 5
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	Day 5
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	Day 5
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	Day 5
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	Day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Adverse Events	Number of patients with at least one Adverse Event	Daily
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	Day 28

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Dean CR, Barkan DT, Bermingham A, Blais J, Casey F, Casarez A, Colvin R, Fuller J, Jones AK, Li C, Lopez S, Metzger LE 4th, Mostafavi M, Prathapam R, Rasper D, Reck F, Ruzin A, Shaul J, Shen X, Simmons RL, Skewes-Cox P, Takeoka KT, Tamrakar P, Uehara T, Wei JR. Mode of Action of the Monobactam LYS228 and Mechanisms Decreasing In Vitro Susceptibility in Escherichia coli and Klebsiella pneumoniae. Antimicrob Agents Chemother. 2018 Sep 24;62(10):e01200-18. doi: 10.1128/AAC.01200-18. Print 2018 Oct.

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2018
• Primary Completion (Actual): September 24, 2018
• Study Completion (Actual): September 24, 2018

Study Registration Dates

• First Submitted: November 22, 2017
• First Submitted That Met QC Criteria: November 22, 2017
• First Posted (Actual): November 28, 2017

Study Record Updates

• Last Update Posted (Actual): October 11, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: creatinine clearance; enterobacteriaceae; Intra-abdominal infection; LYS228; beta-lactam antibiotics
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Intraabdominal Infections
• Other Study ID Numbers: CLYS228X2202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No