Safety Study of Intravenous Biapenem (RPX2003) and RPX7009 Given Alone and in Combination

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Ascending Single and Multiple-Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Biapenem (RPX2003) and RPX7009 Given Alone and in Combination in Healthy Adult Subjects.

RPX7009 (beta-lactamase inhibitor) is being studies in combination with a carbapenem biapenem to treat bacterial infections, including those due to multi-drug resistant bacteria.

Study Overview

• Status: Completed
• Conditions: Bacterial Infections; Healthy Volunteers
• Intervention / Treatment: Drug: Normal saline; Drug: RPX7009; Drug: Biapenem

Detailed Description

The worldwide spread of resistance to antibiotics among Gram-negative bacteria, particularly members of the ESKAPE group of pathogens, has resulted in a crisis in the treatment of hospital acquired infections. In particular, the recent dissemination of a serine carbapenemase (e.g., KPC) in Enterobacteriaceae in US hospitals now poses a considerable threat to the carbapenems and other members of the beta-lactam class of antimicrobial agents.

Rempex is developing a fixed combination antibiotic of a carbapenem (RPX2003 or biapenem) plus a new beta-lactamase inhibitor (RPX7009) which has activity against serine beta-lactamases, including KPC. This Phase 1 study will assess the safety, tolerability and pharmacokinetics and pharmacodynamics of Intravenous Biapenem and RPX7009, administered alone and in combination in healthy adult subjects.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • CMAX

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy adult males and/or females, 18 to 55 years of age
• Body mass index (BMI) ≥ 18.5 and ≤ 29.9 (kg/m2) and weight between 55.0 and 100.0 kg (inclusive).
• Medically healthy with clinically insignificant screening results
• Non-tobacco/nicotine-containing product users for a minimum of 6 months prior to Day 1.
• Sexually abstinent or use acceptable methods of birth control

Exclusion Criteria:

• History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease.
• History or presence of alcoholism or drug abuse within the 2 years prior to Day 1.
• Hypersensitivity or idiosyncratic reaction to beta-lactam antibiotics (e.g. penicillins, cephalosporins, carbapenems, etc.).
• Use of any over-the-counter (OTC) medication, including herbal products and vitamins, within the 7 days prior to Day 1. Up to 2 grams per day of acetaminophen is allowed for acute events at the discretion of the PI.
• Plasma donation within 7 days prior to Day 1.
• Subjects who have any abnormalities on laboratory values at screening or check-in (Day -1).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Normal saline; Single and multiple dose of normal saline	Drug: Normal saline; Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo); Other Names: Placebo
EXPERIMENTAL: Single dose IV of biapenem or RPX7009; Single dose IV infusion of biapenem or RPX7009	Drug: RPX7009; Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo); Other Names: (beta-lactamase inhibitor); Drug: Biapenem; Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo); Other Names: RPX2003
EXPERIMENTAL: Single dose of biapenem or RPX7009; Single IV dose of biapenem or RPX7009 (for those on active drug, this will be the drug not given in the first IV treatment)	Drug: RPX7009; Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo); Other Names: (beta-lactamase inhibitor); Drug: Biapenem; Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo); Other Names: RPX2003
EXPERIMENTAL: Biapenem and RPX7009 in combination; Single dose followed by a multiple dose of biapenem and RPX7009 in combination	Drug: RPX7009; Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo); Other Names: (beta-lactamase inhibitor); Drug: Biapenem; Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo); Other Names: RPX2003

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety from baseline to the end of the study	Number of patients with adverse events; assessed by patient reporting, collection of vital signs, ECGs and absolute values and changes over time of hematology, chemistry and urinalysis.	Day 1 - Day 17

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Pharmacokinetic (PK) parameters of RPX7009, biapenem & the combination following ascending single and multiple dose administration.	Comparison will be performed between the cohorts for the plasma AUC0-t, AUC0-inf, Cmax, and Tmax. Urine PK parameters such as amount excreted and % dose excreted will be calculated from urinary excretion data.	Day 1 - Day 14
Composite of Pharmacodynamic (PD) parameters of RPX7009, biapenem & the combination following ascending single and multiple dose administration.	Serum for bactericidal titers (SBT) assessments will be collected on Days 1, 4, 7 and 14 (at the end-of-infusion (EOI)), and at 2, 4, and 8 hours after start of infusion.	Days 1-14

Collaborators and Investigators

• Sponsor: Rempex Pharmaceuticals (a wholly owned subsidiary of The Medicines Company)

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (ACTUAL): March 1, 2013
• Study Completion (ACTUAL): March 1, 2013

Study Registration Dates

• First Submitted: January 16, 2013
• First Submitted That Met QC Criteria: January 17, 2013
• First Posted (ESTIMATE): January 21, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): July 11, 2013
• Last Update Submitted That Met QC Criteria: July 9, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Bacterial Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Biapenem
• Other Study ID Numbers: Rempex 403