Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02714595
• Date of registration: 26/02/2016
• Prospective Registration: Yes
• Primary sponsor: Shionogi
• Public title: Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens CREDIBLE - CR
• Scientific title: A Multicenter, Randomized, Open-label Clinical Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens
• Date of first enrolment: September 7, 2016
• Target sample size: 152
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02714595
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 3

Countries of recruitment

Brazil, Colombia, Croatia, France, Germany, Greece, Guatemala, Israel, Italy, Japan, Korea, Republic of, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States

Contacts

• Name: Shionogi Clinical Trials Administrator Clinical Support Help Line
• Affiliation: Shionogi

Key inclusion & exclusion criteria

Inclusion Criteria:

- Patients with clinically documented infection (HAP/VAP/HCAP, cUTI, or BSI/sepsis)
caused by a Gram-negative pathogen with evidence of carbapenem resistance

- Patients who have been treated previously with an empiric antibiotic regiment 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 2
days of the empiric antibiotic regimen

- 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

- Patients meeting specific criteria for each infection site

Exclusion Criteria:

1. Patients who have a history of any moderate or severe hypersensitivity or allergic
reaction to any ß-lactam (Note: for ß-lactams, a history of a mild rash followed by
uneventful re-exposure is not a contraindication to enrollment)

2. Patients who need more than 3 systemic antibiotics as part of best available therapy
(BAT) for the treatment of the Gram-negative infection (patients with mixed
Gram-positive or anaerobic infections may receive appropriate concomitant narrow
spectrum antibiotics [eg, vancomycin, linezolid, metronidazole, clindamycin])

3. Patients with coinfection caused by invasive aspergillosis, mucormycosis or other
highly lethal mold

4. Patients who have central nervous system (CNS) infection (eg, meningitis, brain
abscess, shunt infection)

5. Patients with infection requiring > 3 weeks of antibiotic treatment (eg, bone and
joint infection, endocarditis)

6. Patients with cystic fibrosis or moderate to severe bronchiectasis

7. Patients in refractory septic shock defined as persistent hypotension despite adequate
fluid resuscitation or despite vasopressive therapy at the time of Randomization

8. Patients with severe neutropenia, ie, polymorphonuclear neutrophils (PMNs) < 100
cells/µL

9. Female patients who have a positive pregnancy test at Screening or who are lactating

10. Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 30

11. Patients who have received a potentially effective antibiotic regimen for the
carbapenem-resistant Gram-negative infection for a continuous duration of more than 24
hours in cUTI, or 36 hours in HAP/VAP/HCAP or BSI/sepsis during the 72 hours leading
to Randomization

12. 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

13. Patients who have received another investigational drug or device within 30 days prior
to study entry

14. Patients who have previously been randomized in this study or received S-649266

15. Patients receiving peritoneal dialysis

16. Patients meeting specific exclusion criteria for each infection site



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Complicated Urinary Tract Infection (cUTI)

Healthcare-associated Pneumonia (HCAP)

Ventilator Associated Pneumonia (VAP)

Bloodstream Infections (BSI)

Hospital Acquired Pneumonia (HAP)

Sepsis

Intervention(s)

Drug: Best Available Therapy

Drug: S-649266

Primary Outcome(s)

Clinical outcome per patient at test of cure (TOC) in patients with HAP/VAP/HCAP or BSI/sepsis [Time Frame: Test of cure, defined as 7 days after end of treatment (treatment duration is 7-14 days)]

Microbiologic outcome (for Gram-negative pathogen) per patient at TOC in patients with cUTI [Time Frame: 7 days after end of treatment (7-14 days)]

Secondary Outcome(s)

Microbiologic outcome (for Gram-negative pathogen) per pathogen at EOT, TOC, and FUP (cUTI) [Time Frame: End of treatment (7-14 days) and at 7 days (TOC) and 14 days after end of treatment (FUP)]

Participants with positive clinical and microbiologic outcome at EOT, TOC, and FUP [Time Frame: End of treatment (7-14 days), 7 days after end of treatment (TOC), and 14 days after end of treatment (FUP)]

Sequential Organ Failure Assessment (SOFA) score at EOT and TOC [Time Frame: End of treatment and 7 days after end of treatment]

Clinical outcome per patient at end of treatment (EOT) and follow-up (FUP)(HAP/VAP/HCAP or BSI/sepsis) [Time Frame: End of treatment (7-14 days) and 14 days after end of treatment (FUP)]

Clinical Pulmonary Infection Score (CPIS) at EOT and TOC (HAP/VAP/HCAP only) [Time Frame: End of treatment (7-14 days) and 7 days after end of treatment]

Microbiologic outcome (for Gram-negative pathogen) per patient at EOT, and FUP (cUTI) [Time Frame: End of treatment (7-14 days) and 14 days after end of treatment (FUP)]

Microbiologic outcome with documented carbapenem-resistant Gram-negative bacteremia (regardless of primary infection diagnosis) at EOT, TOC, and FUP [Time Frame: End of treatment (7-14 days) and at 7 days (TOC)and 14 days after end of treatment (FUP)]

Microbiologic outcome (for Gram-negative pathogen) per patient/pathogen at EOT, TOC, and follow-up (FUP) (HAP/VAP/HCAP or BSI/sepsis) [Time Frame: End of treatment, 7 days after end of treatment (TOC), and 14 days after end of treatment (FUP)]

Clinical outcome per pathogen at EOT, TOC and FUP (HAP/VAP/HCAP or BSI/sepsis) [Time Frame: End of treatment (7-14 days), 7 days after end of treatment (TOC), and 14 days after end of treatment (FUP)]

All-cause mortality at Day 14 and Day 28 for HAP/VAP/HCAP and BSI/sepsis [Time Frame: Day 14 and Day 28]

Clinical outcome per patient/pathogen at EOT, TOC and FUP (cUTI) [Time Frame: End of treatment (7-14 days), 7 days after end of treatment (TOC), and 14 days after end of treatment (FUP)]

Composite endpoint of survival and no change in antibiotic treatment due to either lack of therapeutic benefit or drug-related toxicity at TOC [Time Frame: 7 days after end of treatment (7-14 days)]

Survival time (HAP/VAP/HCAP, BSI/sepsis) [Time Frame: Up to 28 days after the end of treatment (7-14 days)]

Number of participants with adverse events [Time Frame: From Baseline to 28 days after end of treatment (7-14 days)]

Secondary ID(s)

2015-004703-23

1424R2131

Source(s) of Monetary Support

Please refer to primary and secondary sponsors