Study to Determine and Compare Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam in Healthy Subjects

NCT03303924 | Completed Phase 1 FDA Drug

• 1 other identifier: CS2514-2017-0001
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1, multiple dose, open-label pharmacokinetic study conducted in healthy adult male and female subjects to determine and compare plasma, epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations of ETX2514 and sulbactam in healthy adult subjects after intravenous infusion of ETX2514 1.0 g given concurrently with intravenous sulbactam 1.0 g, administered every 6 hours with each infused over 3 hours, for 3 consecutive doses

Conditions

Healthy

Keywords

Pharmacokinetic; Bronchoalveolar Lavage; Epithelial Lining Fluid; Alveolar Macrophage; Gram-negative bacterium; Acinetobacter baumannii

Outcome Measures

Primary Outcomes (7)

• Mean maximum observed drug concentration (Cmax) in blood

  Venous blood will be collected for ETX2514SUL pharmacokinetic (PK) analysis predose and after the 3 dose. The 3rd dose of ETX2514 and sulbactam will be administered on Day 2

  Predose, 1,2,2,5, 2.95, 3.05, 3.25, 3.5, 4, 5, and 6 hours after the start of the third dose (last dose) on Day 2

• Mean Cmax in epithelial lining fluid (ELF)

  Bronchoalveolar lavage fluid will be collected for ETX2514SUL PK at 1, 2.5, 3.25, 4, or 6 hours.

  Predose, 1,2,2,5, 2.95, 3.05, 3.25, 3.5, 4, 5, and 6 hours after the start of the third dose (last dose) on Day 2

• Mean area under the curve (AUC) 0-6h in blood

  AUC0-6h defined as the area under the concentration versus time curve from time zero to 6 hours postdose. Venous blood will be collected for ETX2514SUL pharmacokinetic (PK) analysis predose and after the 3 dose. The 3rd dose of ETX2514 and sulbactam will be administered on Day 2

  Predose, 1,2,2,5, 2.95, 3.05, 3.25, 3.5, 4, 5, and 6 hours after the start of the third dose (last dose) on Day 2

• Mean terminal half-life (t1/2) in blood

  Venous blood will be collected for ETX2514SUL pharmacokinetic (PK) analysis predose and after the 3 dose. The 3rd dose of ETX2514 and sulbactam will be administered on Day 2

  Predose, 1,2,2,5, 2.95, 3.05, 3.25, 3.5, 4, 5, and 6 hours after the start of the third dose (last dose) on Day 2

• Mean volume of distribution in the terminal elimination phase (Vdss) in blood

  Venous blood will be collected for ETX2514SUL pharmacokinetic (PK) analysis predose and after the 3 dose. The 3rd dose of ETX2514 and sulbactam will be administered on Day 2 .

  Predose, 1,2,2,5, 2.95, 3.05, 3.25, 3.5, 4, 5, and 6 hours after the start of the third dose (last dose) on Day 2

• Mean clearance (CL) in blood

  Venous blood will be collected for ETX2514SUL pharmacokinetic (PK) analysis predose, and 1,2,2,5, 2.95, 3.05, 3.25, 3.5, 4, 5, and 6 hours after the start of the third (last) dose.

  Predose, 1,2,2,5, 2.95, 3.05, 3.25, 3.5, 4, 5, and 6 hours after the start of the third dose (last dose) on Day 2

• Ratio of AUC 0-6 for ELF to the corresponding AUC0-6 Plasma

  defined as the area under the concentration versus time curve from time zero to 6 hours. Venous blood will be collected for ETX2514SUL pharmacokinetic (PK) analysis predose and after the 3 dose. The 3rd dose of ETX2514 and sulbactam will be administered on Day 2. Bronchoalveolar lavage fluid will be collected for ETX2514SUL PK at 1, 2.5, 3.25, 4, or 6 hours after the 3 dose (last dose) on Day 2.

  Predose, 1,2,2,5, 2.95, 3.05, 3.25, 3.5, 4, 5, and 6 hours after the start of the third dose (last dose) on Day 2

Secondary Outcomes (5)

• Number of participants with any non serious adverse event (AE)

  Day 1-14

• Number of participants with any serious adverse event (SAE)

  Day 1- 14

• Change from Baseline in electrocardiogram (ECG) parameters at the indicated time points

  Day 1, 2, and 4

• Change from baseline in vital signs at the indicated time points

  Days 1, 2,and 4

• Number of participants with abnormal, clinical significant hematology and chemistry laboratory values at the indicated time points

  Day 1-14

Study Arms (1)

ETX2514 and sulbactam

EXPERIMENTAL

Healthy male and female subjects, non-smoking, will receive multiple doses of ETX2514 1.0 g and sulbactam 1 g via intravenous (IV) infusion every 6 hours with each dose of medication infused over 3 hours.

Drug: ETX2514 and sulbactam

Interventions

ETX2514 and sulbactam DRUG

Each subject will receive three doses of of ETX2514 1.0 g and sulbactam 1.0 g via intravenous (IV) infusion administered every 6 hours with each drug infused over 3 hours

ETX2514 and sulbactam

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male or female subject, between 18 and 55 years of age (both inclusive) at the time of screening.
• Body mass index (BMI) ≥ 18.0 kg/m2 and ≤ 32.0 kg/m2 and weight between 55.0 and 100.0 kg (both inclusive).
• Be in general good health without clinically significant medical history as judged by the Principal Investigator.
• Provide voluntary written informed consent prior to any study procedures and is willing and able to comply with the prescribed treatment protocol and evaluations.
• Non-tobacco/nicotine-containing product users for a minimum of 6 months prior to screening.
• Clinical laboratory values within the normal limits as defined by the clinical laboratory, unless the Principal or sub-Investigator decides that out-of-range values are not clinically significant.
• If male, agree to be sexually abstinent or agree to use two approved methods of contraception when engaging in sexual activity from screening until 90 days following the last administration of the study drug, and to not donate sperm during same time period. In the event that the sexual partner is surgically sterile, contraception is not necessary.
• Female subjects of child bearing potential must agree to practice two highly effective methods of birth control (as determined by the Investigator; one of the methods must be a barrier technique) from Screening until 30 days after the last dose of study drug.
• Postmenopausal females (defined as 12 months spontaneous amenorrhea) with serum follicle stimulating hormone levels ≥ 40 mlU/mL or females who have undergone one of the following sterilization procedures at least 6 months prior to screening (and is documented):
• Bilateral tubal ligation
• Hysterectomy
• Hysterectomy with unilateral or bilateral oophorectomy
• Bilateral oophorectomy.

You may not qualify if:

• History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antimicrobial (e.g., penicillin, cephalosporin, sulbactam or carbapenem)
• History or presence of significant oncologic, cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease.
• Calculated creatinine clearance less than 60 mL/min (Cockcroft-Gault method) at screening or confinement.
• Positive alcohol breath test or urine drug screen test at screening or confinement.
• Positive testing for HIV, Hepatitis B or Hepatitis C.
• History or presence of alcohol or drug abuse within the 2 years prior to screening.
• Excessive intake of alcohol, defined as an average daily intake of greater than three units, or an average weekly intake of greater than 21 units (one unit is equivalent to 1 can or bottle (12 oz) of beer, or 1 measure (1.5 oz) of spirits, or 1 glass (5 oz) of wine) in the last 6 months prior to screening.
• History of allergic or other serious adverse reactions to lidocaine or amide anesthetic agents.
• Clinically significant pulmonary or any other disease that prevents a subject from undergoing bronchoscopy with pulmonary lavage.
• Spirometry results showing an forced expiratory volume at one second (FEV1) \<80% of predicted.
• Use of probenecid within 30 days before confinement.
• Use of medication, except for acetaminophen which is allowed up to 3 days before confinement. Multivitamins and vitamin C are allowed up to 7 days before confinement (Day 1). All other medication (including over the counter medication, health supplements, and herbal remedies such as St. John's Wort extract must have been stopped at least 14 days prior to confinement), unless agreed as non-clinically relevant by the Principal Investigator.
• Engagement in strenuous activity within 96 hours of confinement (Day 1) until discharge.
• History of seizures, head injury or meningitis (e.g., epilepsy).
• History of bleeding disorders.

Sponsors & Collaborators

• Entasis Therapeutics: lead
• Clinartis: collaborator

Study Sites (1)

Pulmonary Associates, PA

Phoenix, Arizona, 85006, United States

Location

Related Publications (1)

• Rodvold KA, Gotfried MH, Isaacs RD, O'Donnell JP, Stone E. Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam following Intravenous Administration of ETX2514SUL to Healthy Adult Subjects. Antimicrob Agents Chemother. 2018 Oct 24;62(11):e01089-18. doi: 10.1128/AAC.01089-18. Print 2018 Nov.

  PMID: 30126953 DERIVED

MeSH Terms

Interventions

durlobactam; Sulbactam

Intervention Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 22, 2017
• First Posted: October 6, 2017
• Study Start: August 21, 2017
• Primary Completion: October 17, 2017
• Study Completion: October 26, 2017
• Last Updated: November 9, 2017

Record last verified: 2017-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)