E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Blood stream Infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB) including XDR-AB, CRE and XDR-PA |
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E.1.1.1 | Medical condition in easily understood language |
Blood stream infection and/or pneumonia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004031 |
E.1.2 | Term | Bacterial infection due to other gram-negative organisms |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10035701 |
E.1.2 | Term | Pneumonia gram-negative bacterial NOS |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064977 |
E.1.2 | Term | Acinetobacter bacteremia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051190 |
E.1.2 | Term | Pneumonia Pseudomonas aeruginosa |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10035679 |
E.1.2 | Term | Pneumonia due to Escherichia coli (E. Coli) |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054280 |
E.1.2 | Term | Escherichia coli bacteraemia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021860 |
E.1.2 | Term | Infection Pseudomonas aeruginosa |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023456 |
E.1.2 | Term | Klebsiella pneumonia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058883 |
E.1.2 | Term | Klebsiella bacteremia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10054218 |
E.1.2 | Term | Enterobacter pneumonia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058884 |
E.1.2 | Term | Enterobacter bacteremia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
Determine whether the treatment regimen of colistin combined with a carbapenem (imipenem or meropenem) is associated with a decreased risk for all-cause mortality during the 30 day post-enrollment period compared to colistin alone for subjects with bloodstream infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB).
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E.2.2 | Secondary objectives of the trial |
Determine what treatment regimen (colistin monotherapy or colistin combined a carbapenem (imipenem or meropenem) is more likely to reduce the frequency of emergence of colistin resistance among XDR-GNB isolates during therapy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Hospitalized Adults (> 18 years to 95 years of age), at one of the study sites. • Diagnosis of BSI and/or pneumonia (refer to Section 5.2.3 for definitions), due to a preliminary result of gram-negative non-lactose fermenter that is oxidase negative; ; or E. coli, Klebsiella spp. or Enterobacter spp. that are suspected to be CRE based on a screening test result (meropenem, imipenem, doripenem or ertapenem MIC>1 ug/ml); or result of a rapid molecular test performed indicating presence of A. baumannii, E. coli, Klebsiella spp., Enterobacter spp. or P. aeruginosa; or a final result of XDR-A. baumannii; carbapenem-resistant Enterobacteriaceae; or XDR- P. aeruginosa (refer to List of Abbreviations and Definition Section for pathogen definitions) and/or patients with suspected BSI and/or pneumonia and who have had a prior history (within last 6 months) of XDR-GNB that was susceptible to colistin. o If final results do not indicate that the pathogen is an XDR-GNB, according to study definitions, and alternative treatment options are identified, the patient would be eligible for the study if the patient is allergic to non-carbapenem beta-lactam treatment options.Patients are also eligible for inclusion if they have pneumonia or BSI due to Pseudomonas aeruginosa that, while “susceptible” to a beta-lactam option by current in vitro breakpoint definitions, the isolate is not considered to be treatable by the prescribing physician due to inability to achieve adequate clinical efficacy and/or pharmacokinetic/pharmacodynamic targets using standard approved dosages of these beta-lactam antimicrobials. For the purposes of this study, patients would be eligible if they have an infection due to a strain of Pseudomonas aeruginosa with a cefepime MIC of 8 mcg/ml; or imipenem/meropenem/doripenem MIC of 2 mcg/mL or aztreonam MIC of 8mcg/mL; where the treating physician does not feel that treatment with these agents would be adequate or optimal to treat this type of Pseudomonas aeruginosa strain. Recent literature suggests that current CLSI breakpoints may not be appropriate126,127. o In addition, if the pathogen is A. baumannii that is susceptible to ampicillin/sulbactam and the treating physician feels that ampicillin/sulbactam is not appropriate therapy, then the patient would be eligible for the trial, as the role and optimal dose of ampicillin/sulbactam remains uncertain for the treatment of invasive A. baumannii infections. Patients are also eligible at sites where the clinical microbiology laboratory does not differentiate between A. baumannii and non-baumannii Acinetobacter, because it is assumed that all XDR Acinetobacter are XDR A. baumannii. o Patients can also be included if they have isolates that are susceptible to ceftolazane-tazobactam and/or ceftazidime-avibactam and/or antimicrobials approved by the FDA after 1/1/2017. • Patients with polymicrobial respiratory or blood infections, including XDR-GNB and one or more pathogens, will be included in the study, as long as the XDR-GNB is determined to be a true pathogen (AB, CRE or PA). Other pathogens will be treated with antimicrobial agents as determined by the treating physician. • If more than one XDR-GNB study pathogens is identified as a study pathogen causing BSI and/or pneumonia, then the first study pathogen recovered will be considered as the primary study pathogen. If more than one study pathogen is recovered from the same culture, then the infection will be categorized as being caused by multiple study pathogens. • Patients with a life expectancy of > 24 hours • Signed written informed consent and HIPAA Authorization (if applicable) form For Assaf Harofeh Medical Center ICF exception refer to SOP #7 in the MOP.
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E.4 | Principal exclusion criteria |
• Female patients who are pregnant • Female patients who are nursing • Patients who are prisoners • Patients who are less than 18 years of age or greater than or equal to 96 years of age • Patients with neutropenia (WBC<500 cells/mm3) • The presence of any of the following known clinical syndromes involving XDR-GNB as a study pathogen which necessitate durations of antimicrobial therapies greater than 14 days: endocarditis, osteomyelitis, prosthetic joint infections, meningitis and/or other central nervous system infections. • Patients receiving valproic acid (with or without a known seizure disorder). • Patients who received 72 hours or more of polymyxin treatment (excluding inhaled and topical formulations) within 96 hours of enrollment. • Patients who have end-stage renal disease requiring hemodialysis are not excluded from the study but will be excluded from evaluation pertaining to nephrotoxicity in the per protocol population. • Patients with known Type 1 or other severe drug allergy to either of the study drugs or to β-lactams. o If patients with β-lactam allergy have previously received carbapenems safely then they would not be excluded.
No exclusions were made based upon gender or demographic preferences. Children <18 years of age were excluded from the study as they have not frequently developed infections due to XDR-GNB at study hospitals and the PK/PD of study drugs would have been different in this population
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E.5 End points |
E.5.1 | Primary end point(s) |
All-cause mortality 28-30 days after study enrollment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Clinical failure at the end of therapy as defined by the following: • Clinical failure • BSI: One or more positive blood cultures (of the study pathogen) obtained after day 5 of enrollment Death after 48 hours of enrollment but prior to End of Treatment (EOT) Clinical instability or clinical worsening during the trial requiring rescue antimicrobial drug therapy for treatment of the study pathogen • Pneumonia: Death after 48 hours of enrollment but prior to End of Treatment (EOT) Lack of improvement in PaO2/FiO2 at End of Treatment (EOT) Clinical instability or clinical worsening during the trial requiring rescue antimicrobial drug therapy for treatment of the study pathogen
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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 | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Bulgaria |
Greece |
Israel |
Italy |
Taiwan |
Thailand |
United States |
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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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Once the enrollment goal of 444 subjects has been met. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |