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

NCT05645757 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 21-0013
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Bacterial Infection

Keywords

Double-blind; Intravenous Ertapenem; Phase 1; Safety; Zidebactam (WCK 6777)

Outcome Measures

Primary Outcomes (10)

• Number of Participants With Treatment-Emergent Adverse Events

  Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). Number of participants with a TEAE are summarized by dose group and by MedDRA System Organ Class (SOC).

  Day 1 through Day 11

• Number of Treatment-Emergent Adverse Events Reported

  Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). Number of TEAEs reported are summarized by dose group and MedDRA System Organ Class (SOC)..

  Day 1 through Day 11

• Number of Participants With Treatment-Emergent Adverse Events Related to Study Product

  Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). TEAEs are assessed by the investigator to determine relationship to the study drug. Number of participants with a related TEAE are summarized by dose group and by MedDRA System Organ Class (SOC).

  Day 1 through Day 11

• Number of Serious Adverse Events Reported

  Serious AEs (SAEs) meet one or more of the following criteria: death, life-threatening AEs, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, substantial disruption of the ability to conduct normal life function, congenital anomaly/birth defect, or important medical events that may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. SAEs are listed.

  Day 1 through Day 11

• Number of Participants With Abnormal Chemistry Laboratory Toxicity Results

  Parameters and thresholds include alanine aminotransferase =33 (female (F) 19Y), =30 (F \>19) or =47 U/L (male (M) =19Y); albumin =3.5 g/dL; alkaline phosphatase =129 (F 19Y), =126 (F =49Y), =170 (M 19Y) or =131 U/L (M =49Y); aspartate aminotransferase =33 (19Y) or =41 U/L (20-49Y); bilirubin =1.2 (19Y) or =1.3 mg/dL (\>19Y); calcium =8.8 (4-19Y), =8.5 (20-49Y), =10.5 (4-19Y), =10.3 (F 20-49Y) or =10.4 mg/dL (M 20-49Y); carbon dioxide =19 or =33 mmol/L; creatinine =0.97 (F 18-29Y), =0.98 (F 30-39Y), =1.00 (F 40-49Y), =1.25 (M 18-29Y), =1.27 (M 30-39Y) or =1.30 mg/dL (M 40-49Y); direct bilirubin =0.3 mg/dL; glucose =64 or =100 mg/dL; potassium =3.7 (19Y), =3.4 (\>19Y), = 5.2 (19Y) or = 5.4 mmol/L (\>19Y); protein =6.2 (19Y) or =6.0 g/dL (\>19Y); sodium =134 or =147 mmol/L; and urea nitrogen =21 (19Y) or =26 mg/dL (\>19Y). All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.

  Day 1 through Day 11

• Number of Participants With Abnormal Hematology Laboratory Toxicity Results

  Parameters and thresholds include basophils =201 x106/L (\>6Y); eosinophils =501 x106/L (\>6Y); hemoglobin =11.4 (female (F) 18Y), =11.6 (F \>18Y), =11.9 (male (M) 18Y) or =13.1 g/dL (M \>18Y); leukocytes =4.4 (18Y), =3.7 (\>18Y), =13.1 (18Y) or =10.9 x109/L (\>18Y); lymphocytes =1199 (18Y) or =849 x106/L (\>18Y); monocytes =901 (18Y) or =951 x106/L (\>18Y); neutrophils =1799 (18Y) or =1499 x106/L (\>18Y); and platelets \<140 x109/L. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.

  Day 1 through Day 11

• Number of Participants With Abnormal Coagulation Laboratory Toxicity Results

  Parameters and thresholds include activated partial thromboplastin time \>32 s, prothrombin intl. normalized ratio \>1.1 (ratio), and prothrombin time \>11.5 s. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.

  Day 1 through Day 11

• Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results

  Parameters and thresholds include dipstick measurements of glucose =1+, leukocyte esterase =1+, occult blood =1+, protein =1+ and urinalysis with microscopy results of at least a few bacteria, red blood cells (RBC) =3 per high-powered field (HPF), and white blood cells (WBC) =6 per HPF. If dipstick results were abnormal, urinalysis with microscopy was performed. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.

  Day 1 through Day 11

• Number of Participants With Abnormal Electrocardiogram (ECG) Toxicity Results

  The only ECG parameters graded were PR interval with a threshold of =211 msec and QTcF interval with a threshold of =471 msec (female) or =451 msec (male) or an increase of =30 msec above baseline. ECG values after dosing were considered as TEAEs if they met toxicity grading criteria.

  Day 8 and Day 11

• Number of Participants With Abnormal Vital Signs (VS)

  VS parameters and thresholds include diastolic blood pressure =90 mmHg, oral temperature =37.3 °C, pulse =49 or =101 beats/min, respiratory rate =21 breaths/min, and systolic blood pressure =88 or =131 mmHg. VS could be repeated up to twice more at rest and within at least 5 minutes of each other. The following rules were used to determine which vital sign measurement to use for analysis if repeat measurements occurred: 1. If the first replicate was normal, it was used. 2. If the first and second replicates were both abnormal, the replicate with the higher severity was used. 3. If the first replicate was abnormal, the second replicate was normal, and the third replicate was not performed, the first replicate was used. 4. If the first replicate was abnormal and the second and third replicates were normal, the second replicate was used. 5. If the first and third replicates were abnormal and the second replicate was normal, the abnormal replicate with the higher severity was used.

  Day 1 through Day 11

Secondary Outcomes (42)

• Maximum Observed Concentration (Cmax) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma

  =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion

• Minimum Observed Concentration (Cmin) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma

  =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion

• Predicted Concentration at the End of the Dosing Interval (Ctau) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma

  =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion

• Dose-Normalized Maximum Observed Concentration (Cmax/Dose) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma

  =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion

• Time of Maximum Concentration (Tmax) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma

  =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion

Study Arms (7)

Cohort 1

EXPERIMENTAL

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; Other: Placebo; Drug: WCK 6777; Drug: Zidebactam

Cohort 2

EXPERIMENTAL

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; Other: Placebo

Cohort 3

EXPERIMENTAL

Zidebactam 2 g administered by 250 ml of intravenous infusion (IV) for 1 hour,once daily,for 7 days. N=6

Drug: Zidebactam

Cohort 4

EXPERIMENTAL

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; Other: Placebo; Drug: WCK 6777; Drug: Zidebactam

Cohort 5

EXPERIMENTAL

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; Other: Placebo

Cohort 6

EXPERIMENTAL

Zidebactam 3 g administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=6

Drug: Zidebactam

Cohort 7

EXPERIMENTAL

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; Other: Placebo; Drug: WCK 6777; Drug: Zidebactam

Interventions

Ertapenem DRUG

A 1-beta methyl-carbapenem that is structurally related to beta-lactam antibiotics

Cohort 1; Cohort 2; Cohort 4; Cohort 5; Cohort 7

Placebo OTHER

Placebo

Cohort 1; Cohort 2; Cohort 4; Cohort 5; Cohort 7

WCK 6777 DRUG

A combination of ertapenem (ERT) and zidebactam (ZID)

Cohort 1; Cohort 4; Cohort 7

Zidebactam DRUG

A betaß-lactamase inhibitor and betaß-lactam enhancer from the diazabicyclooctane (DBO) class

Cohort 1; Cohort 3; Cohort 4; Cohort 6; Cohort 7

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

Altasciences Inc - Kansas City

Overland Park, Kansas, 66212, United States

Location

MeSH Terms

Conditions

Bacterial Infections

Interventions

Ertapenem; zidebactam

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: George Saviolakis
• Organization: DynPort Vaccine Company, a GDIT Company

George.Saviolakis@gdit.com

301-835-4101

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All investigative site personnel, study volunteers, DMID, Wockhardt and DVC personnel will remain blinded through database lock, with the exception of an unblinded pharmacist/verifier at the research site, an unblinded SDCC biostatistician, and a DMID/CMS manager responsible for PK sample storage.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2022
• First Posted: December 9, 2022
• Study Start: April 19, 2023
• Primary Completion: November 3, 2023
• Study Completion: November 3, 2023
• Last Updated: January 20, 2025
• Results First Posted: December 5, 2024

Record last verified: 2022-09-22

Locations

US (1)