E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP)/healthcare-associated pneumonia (HCAP) or bloodstream infections/sepsis (BSI/sepsis) caused by carbapenem-resistant Gram-negative pathogens.
Complicated urinary tract infection (cUTI) caused by carbapenem-resistant Gram-negative pathogens. |
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E.1.1.1 | Medical condition in easily understood language |
Severe infections caused by Carbapenem-resistant Gram-negative pathogens. |
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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 | 10076918 |
E.1.2 | Term | Hospital acquired 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 | SOC |
E.1.2 | Classification code | 10021881 |
E.1.2 | Term | Infections and infestations |
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 | 10065153 |
E.1.2 | Term | Ventilator associated 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 | HLT |
E.1.2 | Classification code | 10046577 |
E.1.2 | Term | Urinary tract infections |
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 |
●To assess, at test of cure (TOC), the clinical outcome of treatment with S-649266 or best available therapy (BAT) in adult patients with either hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP)/healthcare-associated pneumonia (HCAP) or bloodstream infections/sepsis (BSI/sepsis) caused by carbapenem-resistant Gram-negative pathogens
●To assess, at TOC, the microbiologic outcome of treatment with S-649266 or BAT in adult patients with complicated urinary tract infection (cUTI) caused by carbapenem-resistant Gram-negative pathogens |
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E.2.2 | Secondary objectives of the trial |
Safety of S-649266
Clinical outcome of treatment with S-649266 or BAT in patients with HAP/VAP/HCAP or BSI/sepsis and cUTI (TOC/EOT)
Microbiologic outcome of treatment with S-649266 or BAT in patients with either HAP/VAP/HCAP or BSI/sepsis, with cUTI and with bacteremia (EOT/TOC/FU)
Composite clinical and microbiologic outcome of treatment with S-649266 or BAT in patients with cUTI
All-cause mortality at Day 14 and Day 28 in patients with HAP/VAP/HCAP and BSI/sepsis
Relationship between the PD parameter %Tf >MIC based on plasma drug concentrations at steady state and the clinical and microbiologic outcomes of treatment with S-649266 in patients with HAP/VAP/HCAP, cUTI, or BSI/sepsis
Resource utilization required for the treatment of the study qualifying infection
Compare S-649266 with BAT in patients with HAP/VAP/HCAP, cUTI, BSI/sepsis based on the composite endpoint of survival and no change in antibiotic treatment due to lack of therapeutic benefit or drug-related toxicity |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General Inclusion Criteria:
Patients who fulfill the following criteria at Screening will be included in the study:
1. Hospitalized male and female patients, 18 years or older at the time of signing informed consent
2. Patients who have provided written informed consent or their informed consent was provided by legal guardian (Note: Country specific rules and local Ethics Committee approval for legal guardian informed consent will determine whether or not and how a patient unable to comprehend or sign the informed consent is allowed to be enrolled in the study)
3. Patients with clinically documented infection (HAP/VAP/HCAP, cUTI, or BSI/sepsis) caused by a Gram-negative pathogen with evidence of carbapenem resistance
4. Patients who have been treated previously with an empiric antibiotic regimen and failed treatment, both clinically and microbiologically, are eligible for the study, if they have an identified carbapenem-resistant, Gram-negative pathogen which has either been shown to be nonsusceptible in vitro to each of the antibiotic(s) of the empiric antibiotic regimen or been grown from a culture performed after at least two days of the empiric antibiotic regimen
5. Patient is male (no contraception required) or female and meets one of the following criteria:
•Surgically sterile by hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy or tubal ligation for the purpose of contraception for at least 6 weeks with appropriate documentation of such surgery
•Postmenopausal (defined as older than 45 years of age with cessation of regular menstrual periods for 6 months and confirmed by a follicle-stimulating hormone level of > 40 mIU/ml, or amenorrhea for at least 12 months)
•Of childbearing potential and using combined (estrogen and progestogen) or progestogen-only hormonal contraception associated with inhibition of ovulation (including oral, intravaginal, injectable, implantable, and transdermal contraceptives), or an intrauterine device (IUD), or intrauterine hormone-releasing system (IUS) for the entire duration of the study
•Of childbearing potential and practice abstinence as a preferred and usual lifestyle, and agrees to continue practicing abstinence from screening and for the entire duration of the study
•Of childbearing potential, whose sole heterosexual partner has been successfully vasectomized and agrees to not have other heterosexual partners for the entire duration of the study
6. Patients meeting specific inclusion criteria for each infection site |
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E.4 | Principal exclusion criteria |
General Exclusion Criteria:
Patients who meet any of the following criteria at Screening will be excluded from the study:
1.Patients who have a history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment)
2.Patients with severe neutropenia, ie, polymorphonuclear neutrophils (PMNs) < 100 cells/µL
3.Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 30
4.Patients with any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of the study data
5.Patients meeting specific exclusion criteria for each infection site |
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E.5 End points |
E.5.1 | Primary end point(s) |
●Clinical outcome per patient at TOC in patients with HAP/VAP/HCAP or BSI/sepsis
●Microbiologic outcome (for Gram-negative pathogen) per patient at TOC in patients with cUTI |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Test of cure (TOC) - EOT + 7 days |
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E.5.2 | Secondary end point(s) |
●Clinical outcome per patient at EOT (HAP/VAP/HCAP or BSI/sepsis)
●Clinical outcome per pathogen at EOT, and TOC (HAP/VAP/HCAP or BSI/sepsis)
●Clinical outcome per patient/pathogen at EOT, and TOC (cUTI)
●Microbiologic outcome (for Gram-negative pathogen) per patient/pathogen at EOT, TOC, and FUP (HAP/VAP/HCAP or BSI/sepsis)
●Microbiologic outcome (for Gram-negative pathogen) per patient at EOT, and FUP (cUTI)
●Microbiologic outcome (for Gram-negative pathogen) per pathogen at EOT, TOC, and FUP (cUTI)
●Microbiologic outcome with documented carbapenem-resistant Gram-negative bacteremia (regardless of primary infection diagnosis) at EOT, TOC, and FUP
●Composite clinical and microbiologic outcome at EOT, and TOC (cUTI only)
●All-cause mortality at Day 14 and Day 28 for HAP/VAP/HCAP and BSI/sepsis
●Composite endpoint of survival and no change in antibiotic treatment due to either lack of therapeutic benefit or drug-related toxicity at TOC
●Survival time (HAP/VAP/HCAP, BSI/sepsis)
●CPIS parameters at EOT and TOC (HAP/VAP/HCAP only)
●SOFA Score at EOT, and TOC |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of treatment (EOT) - Last day of study therapy
Test of cure (TOC) - EOT + 7 days
Follow-up (FUP) - EOT + 14 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 | Yes |
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 | 56 |
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 |
Croatia |
France |
Germany |
Greece |
Guatemala |
Israel |
Italy |
Japan |
Korea, Republic of |
Spain |
Taiwan |
Thailand |
Turkey |
United Kingdom |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 6 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 13 |