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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Healthy Volunteers, Bacterial Infections

Intervention / Treatment
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* Drug: RPX7009
* Drug: Biapenem
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Normal saline<br>Single and multiple dose of normal saline | Drug: Normal saline<br>* Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo)<br>* Other names: Placebo;|
| Experimental: Single dose IV of biapenem or RPX7009<br>Single dose IV infusion of biapenem or RPX7009 | Drug: RPX7009<br>* Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo)<br>* Other names: (beta-lactamase inhibitor);Drug: Biapenem<br>* Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo)<br>* Other names: RPX2003;|
| Experimental: Single dose of biapenem or RPX7009<br>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<br>* Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo)<br>* Other names: (beta-lactamase inhibitor);Drug: Biapenem<br>* Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo)<br>* Other names: RPX2003;|
| Experimental: Biapenem and RPX7009 in combination<br>Single dose followed by a multiple dose of biapenem and RPX7009 in combination | Drug: RPX7009<br>* Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo)<br>* Other names: (beta-lactamase inhibitor);Drug: Biapenem<br>* Up to three (3) cohorts of 10 healthy adult subjects (8 active, 2 placebo)<br>* Other names: RPX2003;|

What is the study measuring?
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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 |