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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Healthy Volunteers, Bacterial Infections

Intervention / Treatment
-----------------
* Drug: RPX7009
* Drug: RPX2014
* Drug: Placebo
* Drug: Combination RPX7009 and RPX2014


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy adult males and females, 18 to 55 years of age (inclusive) at the time of screening. 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 (e.g., laboratory profiles, medical histories, ECGs, physical examination) as deemed by the PI. Non-tobacco/nicotine-containing product users for a minimum of Dose Study 6 months prior to Day 1. Voluntarily consent to participate in the study. Sexually abstinent or agree to use two approved methods of contraception. Exclusion Criteria: History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease. Positive urine drug/alcohol testing at screening or check-in (Day -1). Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV). History or presence of alcoholism or drug abuse within the 2 years prior to Day 1. 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. Blood donation or significant blood loss (i.e., > 500 mL) within 56 days prior to Day 1. Plasma donation within 7 days prior to Day 1. Participation in another investigational clinical trial within 30 days prior to Day 1. Subjects who have any abnormalities on laboratory values at screening or check-in (Day -1).

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single and multiple dose of RPX7009<br>Single and multiple dose of RPX7009 | Drug: RPX7009<br>* 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.<br>* Other names: (beta-lactamase inhibitor);|
| Experimental: Single and multiple dose of RPX2014<br>Single and multiple dose of RPX2014 | Drug: RPX2014<br>* 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.<br>|
| Placebo Comparator: Normal Saline<br>Single and multiple dose of normal saline | Drug: Placebo<br>* 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.<br>* Other names: Normal saline;|
| Experimental: Combination RPX7009 and RPX2014<br>Single and Multiple dose of Combination RPX7009 and RPX2014 | Drug: Combination RPX7009 and RPX2014<br>* 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.<br>|

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 |