Safety, Tolerability, Pharmacokinetics of Intravenous RPX2014 and RPX7009 in Healthy Adult Subjects

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple Ascending-dose Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous RPX2014 and RPX7009 Alone and in Combination in Healthy Adult Subjects

RPX7009 (beta-lactamase inhibitor) is being studied in combination with a carbapenem (RPX2014) to treat bacterial infections, including those due to multi-drug resistant bacteria.

Study Overview

• Status: Completed
• Conditions: Bacterial Infections; Healthy Volunteers
• Intervention / Treatment: Drug: RPX7009; Drug: RPX2014; Drug: Placebo; Drug: Combination RPX7009 and RPX2014

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 (RPX2014) 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 of intravenous RPX2014 and RPX7009, administered alone and in combination, in healthy adult subjects.

• Study Type: Interventional
• Enrollment (Actual): 94
• 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: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy adult males and females, 18 to 55 years of age (inclusive) at the time of screening.
2. Body mass index (BMI) ≥ 18.5 and ≤ 29.9 (kg/m2) and weight between 55.0 and 100.0 kg (inclusive).
3. Medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical histories, ECGs, physical examination) as deemed by the PI.
4. Non-tobacco/nicotine-containing product users for a minimum of Dose Study 6 months prior to Day 1.
5. Voluntarily consent to participate in the study.
6. Sexually abstinent or agree to use two approved methods of contraception.

Exclusion Criteria:

1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease.
2. Positive urine drug/alcohol testing at screening or check-in (Day -1).
3. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV).
4. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1.
5. 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.
6. Blood donation or significant blood loss (i.e., > 500 mL) within 56 days prior to Day 1.
7. Plasma donation within 7 days prior to Day 1.
8. Participation in another investigational clinical trial within 30 days prior to Day 1.
9. 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 Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single and multiple dose of RPX7009	Drug: RPX7009; Two (2) groups of 15 subjects (12 active and 3 placebo) are planned for evaluation in cohort 1. Cohorts 2-5, 14 subjects (11 active and 3 placebo) are planned for evaluation in each cohort. 14 subjects (12 active and 2 placebo) are planned for evaluation in cohort 6.; Other Names: (beta-lactamase inhibitor)
Experimental: Single and multiple dose of RPX2014	Drug: RPX2014; Two (2) groups of 15 subjects (12 active and 3 placebo) are planned for evaluation for cohort 1. Cohorts 2-5, 14 subjects (11 active and 3 placebo) are planned for evaluation in each cohort. 14 subjects (12 active and 2 placebo) are planned for evaluation in cohort 6.
Placebo Comparator: Normal Saline; Single and multiple dose of normal saline	Drug: Placebo; Two (2) groups of 15 subjects (12 active and 3 placebo) are planned for evaluation for cohort 1. Cohorts 2-5, 14 subjects (11 active and 3 placebo) are planned for evaluation in each cohort. 14 subjects (12 active and 2 placebo) are planned for evaluation in cohort 6.; Other Names: Normal saline
Experimental: Combination RPX7009 and RPX2014; Single and Multiple dose of Combination RPX7009 and RPX2014	Drug: Combination RPX7009 and RPX2014; Two (2) groups of 15 subjects (12 active and 3 placebo) are planned for evaluation in cohort 1. Cohorts 2-5, 14 subjects (11 active and 3 placebo) are planned for evaluation in each cohort. 14 subjects (12 active and 2 placebo) are planned for evaluation in cohort 6.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety from baseline through 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.	Study Day 1 to Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of PK parameters RPX7009, RPX2014, combination of RPX7009 and RPX2014 & placebo following single and multiple dose administration.	Plasma AUC0-t, AUC0-inf, Cmax, and Tmax.	Study Day1 to Day 14

Collaborators and Investigators

• Sponsor: Rempex Pharmaceuticals (a wholly owned subsidiary of The Medicines Company)
• Investigators: Study Director: Jeffery Loutit, Sponsor GmbH

Publications and helpful links

General Publications

• Rubino CM, Bhavnani SM, Loutit JS, Morgan EE, White D, Dudley MN, Griffith DC. Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects. Antimicrob Agents Chemother. 2018 Mar 27;62(4):e02228-17. doi: 10.1128/AAC.02228-17. Print 2018 Apr.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: July 9, 2013
• First Submitted That Met QC Criteria: July 9, 2013
• First Posted (Estimate): July 12, 2013

Study Record Updates

• Last Update Posted (Estimate): April 29, 2014
• Last Update Submitted That Met QC Criteria: April 27, 2014
• Last Verified: April 1, 2014

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
• Other Study ID Numbers: Rempex 501

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No