1. Combatting Bacterial Resistance in Europe – Carbapenem Resistance WP2B
COMBACTE-CARE
Combatting Bacterial Resistance in Europe – Carbapenem Resistance WP2B
Yehuda Carmeli, George Daikos, Michal Paul

2. Study design
A Phase III prospective, randomized, multicenter, open label, central assessor blinded, parallel group, comparative study to determine the efficacy, safety and tolerability of aztreonam avibactam (ATM AVI) versus meropenem±colistin (MER COL) for the treatment of serious infections due to Gram negative bacteria, including metallo β lactamase (MBL) – producing multi-drug resistant pathogens, for which there are limited or no treatment options
The comparative, 2 arm study design is sufficient to enable a comprehensive efficacy, safety and tolerability analysis. There is no requirement for blinding except for the central assessor.
The 2:1 ratio for randomization (to ATM AVI versus MER COL, respectively) is chosen in order to enrich the number of patients treated with ATM AVI and increase the number of potential MBL producing Gram negative pathogens in that group.

3. Planed timeline and enrollment

4. Indications and patients
The study will randomize approximately 300 patients (approximately 225 patients with cIAI and 75 patients with HAP/VAP) in regions with emerging and/or high incidence of carbapenem resistance, including MBL producing pathogens.
At least 100 in Europe
The number of patients with a perforated appendix or appendiceal abscess will be limited to approximately 40% of the study population with cIAI. It is estimated that approximately 20 patients identified with MBL producing Gram‑negative pathogens may be evaluable in the ATM‑AVI treatment arm and there may be approximately 10 patients identified with MBL producing Gram‑negative pathogens in the MER‑COL treatment arm.

6. Primary Objective
To evaluate the efficacy of ATM‑AVI compared to MER‑COL at TOC for the treatment of selected serious infections due to susceptible Gram‑negative bacteria, including those due to MBL‑producing MDR pathogens.
Outcome Measure:
Proportion of patients with clinical cure at TOC visit in the modified intent‑to‑treat (MITT) and clinically evaluable (CE) analysis sets. For the US, the MITT analysis set will be used for the primary analysis.

7. Candidate countries Region* Africa Americas Asia-Pacific Europe
 Middle East
Country
South Africa
Brazil
Mexico
United States
China
India
Philippines
Singapore
South Korea
Taiwan
Thailand
Viet Nam
Bulgaria**
Czech Republic**
Greece**
Hungary**
Italy**
Romania**
Russia
Spain**
Ukraine**
Serbia**
Israel**
*Regional identification is based on AstraZeneca Patient Recruitment Framework
**COMBACTE-CARE countries

8. Secondary Objectives
To evaluate the efficacy of ATM‐AVI compared to MER‐COL at TOC in the clinically evaluable (CE) population.
To assess the microbiological response to ATM‐AVI at EOT, TOC and LFU in the microbiologically modified intent‐to‐treat (mMITT) and microbiologically evaluable (ME) populations.
To evaluate the PK of aztreonam and avibactam in patients with serious infections and to characterize the relationship between exposure and clinical and microbiological response for ATM‐AVI.
To evaluate the safety and tolerability profile of ATM‐AVI compared to MER‐COL.
To assess 28‐day mortality

9. Status of the study
The study is supported by Astra-Zeneca and by contacts with IMI (Europe) and BARDA (global)
Study design has been at its final stage.
The WP2B study protocol is in advanced stages of development.
Was intended to start during second quarter of 2017
Astra-Zeneca sold its antibiotic development program to Pfizer, the deal will be finalized in December further decisions are pending Pfizer decisions.