E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
cUTI, Complicated Urinary Tract Infection, cIAI, Complicated intra-abdominal infection |
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E.1.1.1 | Medical condition in easily understood language |
Urinary Tract Infection, abdominal infection |
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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 estimate the per-patient clinical response to ceftazidime-avibactam and best available therapy at TOC in the treatment of selected serious infections caused by ceftazidime-resistant Gram negative pathogens. |
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E.2.2 | Secondary objectives of the trial |
•To further evaluate the clinical response to CAZ-AVI and BAT at different visits and in patient subgroups (including entry diagnosis, pathogen, resistance mechanism, and previously failed treatment class)
•To estimate the microbiological response to CAZ-AVI and BAT in the treatment of selected serious infections caused by ceftazidime-resistant Gram-negative pathogens
•To evaluate the reasons for treatment change and/or discontinuation for CAZ-AVI and BAT
•To estimate the 28-day, all-cause mortality among patients treated with CAZ-AVI and BAT
•To evaluate the safety and tolerability profile of CAZ-AVI and BAT for the treatment of selected serious infections caused by ceftazidime-resistant Gram-negative pathogens
•To evaluate the pharmacokinetics (PK) of the individual components of CAZ-AVI in this population with selected serious infections, and to characterize the relationship between the PK and clinical and microbiological response for CAZ-AVI
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Patient must be ≥18 and ≤90 years of age
2.Female patients can participate if they are surgically sterile or
completed menopause or females capable of having children and agree not to attempt pregnancy while receiving IV study therapy and for a
period of 7 days after
3.Patient has a ceftazidime-resistant Gram negative pathogen that was
isolated from an appropriate culture within 5 days prior to study entry
(ie, within 5 days prior to Screening; the study-qualifying culture), which
was determined to be the causative agent of the entry infection |
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E.4 | Principal exclusion criteria |
1.Patient has an APACHE II score >30 (cIAI patients only)
2.Patient has an infection due to Gram negative pathogen that is unlikely
to respond to CAZ-AVI treatment (eg, Acinetobacter spp.,
Stenotrophomonas spp.)
3.Patient is receiving hemodialysis or peritoneal dialysis or had a renal
transplant Patient is immunocompromised
4.Patient has a rapidly progressive or terminal illness with a high risk of
mortality due to any cause, including acute hepatic failure, respiratory
failure or severe septic shock such that they are unlikely to survive the
4- to 5-week study period. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of patients with clinical cure at the Treatment of Cure visit in the microbiological modified intent to treat (mMITT) analysis set. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
7-10 days after last infusion |
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E.5.2 | Secondary end point(s) |
1)The proportion of patients with clinical cure in the microbiological modified intent to treat analysis set.
2)The proportion of patients with clinical cure in the extended microbiologically evaluable analysis set.
3)The proportion of patients with clinical cure by pathogen (eg, E. coli, Klebsiella spp., Pseudomonas aeruginosa) in the microbiological modified intent to treat analysis set.
4)The proportion of patients with clinical cure by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the microbiological modified intent to treat analysis set.
5)The proportion of patients with clinical cure by entry diagnosis (complicated intra-abdominal infection/complicated urinary tract infection) in the microbiological modified intent to treat analysis set.
6)The proportion of patients with clinical cure by pathogen (eg, E. coli, Klebsiella spp., Pseudomonas aeruginosa) in the extended microbiologically evaluable analysis set.
7)The proportion of patients with clinical sure by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the extended microbiologically evaluable analysis set.
8)The proportion of patients with clinical cure by entry diagnosis (complicated intra-abdominal infection/complicated urinary tract infection) in the extended microbiologically evaluable analysis set.
9)The proportion of patients with clinical cure by previously failed treatment class (eg, quinolone, β lactam/β lactamase inhibitor, third- or fourth generation cephalosporin, carbapenem), in the microbiological modified intent to treat analysis set.
10)The proportion of patients with clinical cure by previously failed treatment class (eg, quinolone, β lactam/β lactamase inhibitor, third- or fourth generation cephalosporin, carbapenem) in the extended microbiologically evaluable analysis set.
11)The proportion of patients with favorable per-pathogen microbiological response in the microbiological modified intent to treat analysis set.
12)The proportion of patients with favorable per-pathogen microbiological response in the extended microbiologically evaluable analysis set.
13)The proportion of patients with a favorable per-patient microbiological response in the microbiological modified intent to treat analysis set.
14)The proportion of patients with a favorable per-patient microbiological response in the extended microbiologically evaluable analysis set.
15)The proportion of patients with a favorable microbiological response by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the microbiological modified intent to treat analysis set.
16)The proportion of patients with a favorable microbiological response by resistance mechanism (eg, Klebsiella pneumoniae carbapenemase producer, Extended spectrum β lactamase producer) in the extended microbiologically evaluable analysis set.
17)The proportion of favorable per-pathogen microbiologic response by minimum inhibitory concentration in the microbiological modified intent to treat analysis set.
18)The proportion of favorable per-pathogen microbiologic response by minimum inhibitory concentration in the extended microbiologically evaluable analysis set.
19)The reasons for treatment change and/or discontinuation in the microbiological modified intent to treat analysis set.
20)The 28-day mortality rate in the modified intent to treat analysis set.
21)The 28-day mortality rate in the extended microbiologically evaluable analysis set.
22)The safety and tolerability by incidence and severity of adverse events and serious adverse events, vital signs, clinical laboratory tests, ECGs and physical exams.
23)Pharmacokinetics: maximum concentration (Cmax), minimum concentration, area under plasma concentration time curve at study state and elimination half-life.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1, 2, 10-14, 17, 18) Within 24 hours after last infusion of study therapy, 21-35 days after randomization and 28-32 days after randomization
3-9, At 7-10,15,16 days after last infusion of study therapy
(19) Study duration [Day 1 through last follow up visit (up to 35 days)]
(20, 21) At 28 days after randomization
(22)At study duration (from screening visit (Day-1) through last follow up visit (up to 35 days)]
(23) At anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug
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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 | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Australia |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
China |
Croatia |
Czech Republic |
France |
Germany |
Greece |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Peru |
Philippines |
Poland |
Romania |
Russian Federation |
South Africa |
Spain |
Taiwan |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |