Safety Study of Intravenous Ertapenem in Combination With Zidebactam (WCK 6777)

Study Overview
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Brief Summary
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This is a Phase 1, single center study to investigate the safety, tolerability, and pharmacokinetics (PK) of three dose-level groups of WCK 6777 (ERT and ZID combination), and two dose-level groups of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male and female subjects aged 18 to 45 years old (both inclusive). Seven treatment cohorts will be evaluated in this study. WCK 6777 will be evaluated in three cohorts - Cohorts 1, 4 and 7- of 8 subjects each (6 study drug combinations and 2 placebos); ERT will be evaluated alone in two cohorts - Cohorts 2 and 5- of 8 subject each (6 ERT and 2 placebos); and ZID will be evaluated in two cohorts, Cohorts 3 and 6, of 6 subjects each (all ZID). The study will be placebo-controlled and double-blinded in all cohorts except Cohorts 3 and 6. No placebo subjects are included in standalone ZID cohorts, since adequate safety data for higher doses of ZID alone in comparison with placebo are available from completed Phase 1 studies of WCK 5107 (ZID) alone and the ZID-only arms of WCK 5222 (cefepime + ZID) studies. The primary objective is to assess the safety and tolerability of three dose-escalating regimens of WCK 6777 ( ERT and ZID combination) and two-dose escalating regimens of standalone ERT or ZID following single daily doses for 7 days in healthy adult subjects.

Detailed Description
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This is a Phase 1, single center study to investigate the safety, tolerability, and pharmacokinetics (PK) of three dose-level groups of WCK 6777 (ERT and ZID combination), and two dose-level groups of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male and female subjects aged 18 to 45 years old (both inclusive). Seven treatment cohorts will be evaluated in this study. WCK 6777 will be evaluated in three cohorts - Cohorts 1, 4 and 7- of 8 subjects each (6 study drug combinations and 2 placebos); ERT will be evaluated alone in two cohorts - Cohorts 2 and 5- of 8 subject each (6 ERT and 2 placebos); and ZID will be evaluated in two cohorts, Cohorts 3 and 6, of 6 subjects each (all ZID). The study will be placebo-controlled and double-blinded in all cohorts except Cohorts 3 and 6. No placebo subjects are included in standalone ZID cohorts, since adequate safety data for higher doses of ZID alone in comparison with placebo are available from completed Phase 1 studies of WCK 5107 (ZID) alone and the ZID-only arms of WCK 5222 (cefepime + ZID) studies. In each cohort, either study drugs alone or their combination will be administered by a single intravenous infusion (IV) of 100 mL daily for 7 consecutive days in Cohort 1 or 250 mL daily for 7 consecutive days in Cohorts 2 to 7. For each treatment cohort, however, the dose will be progressively escalated from 1 g/daily to 2 g/daily and to 3 g/daily, and the duration of infusion time increased from 30 min to 1 h and to 2 h over the course of the study. In Cohort 1, WCK 6777 2 g (ERT 1 g/daily combined with ZID 1 g/daily) will be administered in 30 (±5) minutes (min); in Cohort 2 (ERT 2 g/daily), Cohort 3 (ZID 2 g/daily), and Cohort 4 (WCK 6777 4 g [ERT 2 g/daily combined with ZID 2 g/daily]) the study drug(s) will be administered in 60 (±10) min, and in Cohort 5 (ERT 3 g/daily), Cohort 6 (ZID 3 g daily) and Cohort 7 (WCK 6777 6 g [ERT 3 g/daily combined with ZID 3 g/daily]), the study drug(s) will be administered in 120 (±10) min. The primary objective is to assess the safety and tolerability of three dose-escalating regimens of WCK 6777 ( ERT and ZID combination) and two-dose escalating regimens of standalone ERT or ZID following single daily doses for 7 days in healthy adult subjects. The secondary objective is to characterize the PK profiles in plasma (total & free) and in urine of three dose-escalating regimens of WCK 6777 (ERT and ZID combination) and two dose-escalating regimens of standalone ERT or ZID following a single initial dose on Day 1 and after single daily doses for 7 days in healthy adult subjects.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenous Ertapenem in Combination With Zidebactam (WCK 6777) In Healthy Adult Subjects

Conditions
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Bacterial Infection

Intervention / Treatment
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* Drug: Ertapenem
* Other: Placebo
* Drug: WCK 6777
* Drug: Zidebactam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide a signed and dated written informed consent and agrees to comply with the study procedures and length of confinement to the research site. Be able to understand and willing to comply with study procedures, restrictions, and requirements, as determined by the Site Principal Investigator (PI) or authorized clinician(s) (listed on FDA Form 1572). Adults 18 to 45 years of age inclusive, including non-pregnant, non-lactating females. Have suitable veins for cannulation or repeated venipuncture. Be in good general health at the time of enrollment. Note 1: Determined by medical history (MH), medication use, physical examination (PE), vital signs (VS), clinical laboratory tests including estimated creatinine clearance (CLCR) > / = 80 mL/min by the Cockcroft-Gault method, and 12-lead Electrocardiogram (ECG) within reference ranges at Screening and Day-1. Note 2: Exceptions to Blood Pressure (BP), Heart Rate (HR) and laboratory test values being with normal ranges are: Subjects with baseline HR > / = 45 to 50 Beats per Minute (bpm) may be accepted if otherwise healthy adults with known history of asymptomatic bradycardia. Subjects with baseline Systolic Blood Pressure (SBP) up to 140 Millimeters of Mercury (mmHg) and Diastolic Blood Pressure (DBP) up to 90 mmHg may be accepted if otherwise healthy. A laboratory value that is Grade 1 will be allowed if not considered to be clinically significant by the investigator, with the exception of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), total and direct bilirubin, Blood Urea Nitrogen (BUN), serum creatinine, Creatinine Clearance (CLcr), and urine protein. Sexually active females must be of non-childbearing potential or must use a highly effective method of birth control from screening to 30 days following the last dose of study product. Note 1: A female is considered of childbearing potential unless post-menopausal (defined as history of > / = 1 year of spontaneous amenorrhea and a Follicle-Stimulating Hormone (FSH) level >40 IU/L), or permanently surgically sterilized. Note 2: Highly effective contraceptive methods include: (a) surgical sterilization methods, such as tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful tubal obliteration (e.g., Essure(R)) with documented radiological confirmation test at least 90 days after the procedure, or (b) long-acting reversible contraception, such as progestin-releasing subdermal implants, copper intrauterine devices (IUDs), levonorgestrel-releasing IUDs. Note 3: A subject who is not sexually active and abstains from sexual intercourse can be enrolled and abstinence documented. Sexually active males must be vasectomized or agree to use barrier contraception and not donate sperm from first dose of study product until 30 days following the last dose. Note 1: Barrier contraception includes use of condom with spermicide. Note 2: A subject who is not sexually active and abstains from sexual intercourse can be enrolled and abstinence documented. Subjects must be willing to avoid excessive physical exercise within 48 h prior to dosing until discharge from the CTU on Day 8, and 24 h before the last visit (Day 11 +3 days). No history of acute febrile or infectious illness for at least 7 days prior to the administration of study drug(s). Exclusion Criteria: Known history of a clinically significant food or drug allergy/hypersensitivity including known allergy/hypersensitivity to Ertapenem (ERT), any ß-lactam drugs or other related drugs. Current seasonal allergies with ongoing symptoms for more than a week prior to dosing requiring glucocorticoids and/or frequent use of antihistamines for treatment. Any history of a chronic condition including renal failure that may increase risk to subject or interfere with endpoint assessment, or any unstable chronic disease. Note 1: Unstable chronic disease is defined by need for frequent medical interventions that lead to a change in medications and/or required hospitalization, surgery or an invasive procedure or emergency department/urgent care visit, as determined by the Site PI. Note 2: Any chronic disease, that has been diagnosed within 90 days of screening is excluded. History of any psychiatric condition that has required hospitalization in the last 12 months or subject is considered psychologically unstable by the investigator. History of any clinically significant (CS) disease or disorder, medical/surgical procedure, or trauma within 4 weeks prior to initiation of administration of study product(s). History of Clostridium difficile induced diarrhea within 1 year before screening Known history of past or current epilepsy or seizure disorders, excluding febrile seizures of childhood. Prior exposure to Zidebactam (ZID). Use of any prohibited prescription or non-prescription medication within 14 days prior to the first dose of study drug(s) as described in Section 6.6 Use of any investigational drug product within 30 days or 5 half-lives (whichever is longer) before investigational product administration in this study. Planned participation in a clinical research study that requires treatment with a study drug, blood draws or other invasive assessments during the study period (screening until final visit). Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 30 days before signing informed consent or planned donation prior to completion of this trial. Positive serum pregnancy test for women at screening and urine pregnancy test at check-in. Positive urine alcohol test or urine drug screen test at screening or check-in (Day -1). Positive test for HIV antibodies, hepatitis B-virus surface antigen (HBsAg), or anti-hepatitis C-virus antibodies (anti-HCV) at screening. History of > / = 10 pack-years smoking in the 5-year period before screening, or positive urine cotinine screen at check-in. Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing tobacco, nicotine patch. Note 2: Positive urine cotinine at screening is allowed if negative at check-in (Day -1). History of binge drinking or heavy drinking of alcohol at any time in the 6 months before study product administration. Note 1: Binge drinking is defined as 5 or more drinks during single occasion if male, or 4 or more if female. Note 2: Heavy drinking of alcohol is defined as consumption of more than 15 units of alcohol per week if male, or more than 8 units if female.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>WCK 6777 (Ertapenem 1 g combined with Zidebactam 1 g) or placebo administered by 100 ml of intravenous infusion (IV) for 30 (±5) minutes once daily for 7 days. N= 8 | Drug: Ertapenem<br>* A 1-beta methyl-carbapenem that is structurally related to beta-lactam antibiotics<br>Other: Placebo<br>* Placebo<br>Drug: WCK 6777<br>* A combination of ertapenem (ERT) and zidebactam (ZID)<br>Drug: Zidebactam<br>* A betaß-lactamase inhibitor and betaß-lactam enhancer from the diazabicyclooctane (DBO) class<br>|
| Experimental: Cohort 2<br>Ertapenem 2 g or placebo administered by 250 ml of intravenous infusion (IV) for 1 hour once daily for 7 days. N=8 | Drug: Ertapenem<br>* A 1-beta methyl-carbapenem that is structurally related to beta-lactam antibiotics<br>Other: Placebo<br>* Placebo<br>|
| Experimental: Cohort 3<br>Zidebactam 2 g administered by 250 ml of intravenous infusion (IV) for 1 hour,once daily,for 7 days. N=6 | Drug: Zidebactam<br>* A betaß-lactamase inhibitor and betaß-lactam enhancer from the diazabicyclooctane (DBO) class<br>|
| Experimental: Cohort 4<br>WCK 6777 (Ertapenem 2 g combined with Zidebactam 2 g) or placebo administered by 250 ml of intravenous infusion (IV) for 1 hour, once daily, for 7 days. N=8 | Drug: Ertapenem<br>* A 1-beta methyl-carbapenem that is structurally related to beta-lactam antibiotics<br>Other: Placebo<br>* Placebo<br>Drug: WCK 6777<br>* A combination of ertapenem (ERT) and zidebactam (ZID)<br>Drug: Zidebactam<br>* A betaß-lactamase inhibitor and betaß-lactam enhancer from the diazabicyclooctane (DBO) class<br>|
| Experimental: Cohort 5<br>Ertapenem 3 g or placebo administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=8 | Drug: Ertapenem<br>* A 1-beta methyl-carbapenem that is structurally related to beta-lactam antibiotics<br>Other: Placebo<br>* Placebo<br>|
| Experimental: Cohort 6<br>Zidebactam 3 g administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=6 | Drug: Zidebactam<br>* A betaß-lactamase inhibitor and betaß-lactam enhancer from the diazabicyclooctane (DBO) class<br>|
| Experimental: Cohort 7<br>WCK 6777 (Ertapenem 3 g combined with Zidebactam 3 g) or placebo administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=8 | Drug: Ertapenem<br>* A 1-beta methyl-carbapenem that is structurally related to beta-lactam antibiotics<br>Other: Placebo<br>* Placebo<br>Drug: WCK 6777<br>* A combination of ertapenem (ERT) and zidebactam (ZID)<br>Drug: Zidebactam<br>* A betaß-lactamase inhibitor and betaß-lactam enhancer from the diazabicyclooctane (DBO) class<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (AEs) |  | Day 1 through Day 11 | 
| Incidence of treatment-emergent serious adverse events (SAEs) |  | Day 1 through Day 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calculated exposure in plasma for Ertapenem (ERT) |  | Day 1 through Day 8 | 
| Calculated exposure in plasma for Zidebactam (ZID) |  | Day 1 through Day 8 | 
| Calculated exposure in urine for Ertapenem (ERT) |  | Day 1 through Day 8 | 
| Calculated exposure in urine for Zidebactam (ZID) |  | Day 1 through Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Double-blind, Intravenous Ertapenem, Phase 1, Safety, Zidebactam (WCK 6777)