E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complicated intra-abdominal infection (cIAI) and hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP) |
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E.1.1.1 | Medical condition in easily understood language |
cIAI: Bacterial infections in the abdominal cavity due to perforation of the gut.
HAP/VAP: Infection of the lungs due to exposure to bacteria while in hospital or on a ventilator. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of aztreonam-avibactam±metronidazole and meropenem±colistin at Test of Cure visit for the treatment of serious infections due to Gram-negative bacteria, including those due to metallo-β-lactamase-producing multidrug resistant pathogens |
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E.2.2 | Secondary objectives of the trial |
- To evaluate efficacy of aztreonam-avibactam±metronidazole and meropenem±colistin at the Test of Cure visit in the microbiological Intent-To-Treat and Microbiologically Evaluable analysis sets - To evaluate the efficacy of aztreonam-avibactam±metronidazole and meropenem±colistin at the Test of Cure visit in key sub populations - To assess the per-subject microbiological response to aztreonam-avibactam ±metronidazole and meropenem±colistin at the Test of Cure visit - To assess 28-day all-cause mortality - To evaluate the pharmacokinetics of aztreonam and avibactam in subjects with serious infections and to characterize the relationship between exposure and clinical and microbiological response for aztreonam-avibactam± metronidazole utilization (listings to be provided in the Clinical Study Report, analysis to be reported outside of the Clinical Study Report)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject must be ≥18 years of age. 2. Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative has been informed of all pertinent aspects of the study.If a subject is unable to consent for themselves at Screening, the subject’s legally acceptable representative may provide written consent, in accordance with the country-specific regulations. Those subjects who are unconscious or considered by the Investigator clinically unable to consent at Screening and who are entered into the study by the consent of a legally acceptable representative should provide their own written informed consent for continuing to participate in the study as soon as possible on recovery, as applicable in accordance with local regulations. 3. Subjects must have a confirmed diagnosis of HAP/VAP, or presumed diagnosis of cIAI requiring administration of IV antibacterial treatment 4. Female subjects of nonchildbearing potential must meet at least 1 of the following criteria: a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state; b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; c. Have medically confirmed ovarian failure. 5. Female subject of childbearing potential must have a negative serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL. 6. Subject must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
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E.4 | Principal exclusion criteria |
1. Subject has an APACHE II score >30. 2. At Screening the subject is found to have/or strongly suspected to have an infection caused by a Gram-negative species not expected to respond to either ATM-AVI and/or MER (eg, Acinetobacter baumannii), or an infection caused by only Gram-positive species. The subject is allowed to participate in the study if the Investigator considers that the species is a colonizer which does not warrant specific treatment. 3. Subject has received more than one day (>24 hours) of any systemic antibiotic within the 48 hours prior to randomization. This is inclusive of all doses of any systemic antibiotic initiated in this time period (but not counting overlapping periods of antibiotics), eg, a subject who receives 4 doses of an 8 hourly regimen with the last dose given just before randomization is calculated as 32 hours of prior antibiotic. 4. Subject has a history of serious allergy such as anaphylaxis, angioedema and bronchospasm, hypersensitivity or any serious reactions to any systemic antibacterial which is allowed per protocol including ATM, carbapenem, monobactam or other β-lactam antibiotics, AVI, colistimethate or polymixin B, nitroimidazoles or MTZ, vancomycin, linezolid, daptomycin, aminoglycosides (eg, amikacin, gentamicin, tobramycin), or any of the excipients of the respective (investigational) medicinal products to be administered during the study. 5. Subject is unlikely to respond to up to 14 days of study treatment.
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects with clinical cure at Test of Cure visit in the Intent-To-Treat and Clinically Evaluable analysis sets (Note: For non-United States countries, the Intent To Treat and Clinically Evaluable are considered co-primary analysis sets) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Test of Cure visit on Day 28 (±3 days) |
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E.5.2 | Secondary end point(s) |
- Proportion of subjects with clinical cure at the Test of Cure visit in the microbiological Intent-To-Treat and microbiologically Evaluable analysis sets - Proportion of subjects with clinical cure at the Test of Cure visit by infection type in the Intent-To-Treat and Clinically Evaluable analysis sets - Proportion of subjects with clinical cure at the Test of Cure visit for subjects with metallo-β-lactamase-positive pathogens in the microbiological Intent-To-Treat and microbiologically evaluable analysis sets - Proportion of subjects with a favorable per-subject microbiological response at the Test of Cure visit in the microbiological Intent-To-Treat and microbiologically evaluable analysis sets. - Proportion of subjects who died on or before 28 days from randomization in the Intent-To-Treat and microbiological Intent-To-Treat analysis sets - Pharmacokinetics of aztreonam and avibactam in subjects in the population pharmacokinetic analysis set - Pharmacokinetic/pharmacodynamic relationship between exposure and clinical and microbiological response for aztreonam-avibactam±metronidazole in the population pharmacokinetic analysis set
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Test of Cure visit on Day 28 (±3 days) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Chile |
China |
India |
Israel |
Korea, Republic of |
Malaysia |
Mexico |
Peru |
Philippines |
South Africa |
Taiwan |
Thailand |
United States |
Viet Nam |
Bulgaria |
Romania |
Spain |
Czechia |
Greece |
Italy |
Croatia |
Hungary |
Russian Federation |
Turkey |
Ukraine |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial in a Member State of the European Union is defined as the time at which it is deemed that a sufficient number of subjects have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application in the Member State. End of trial in all other participating countries is defined as last subject last visit (LSLV).
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 18 |