Clinical trial NCT03303924: Study to Determine and Compare Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam in Healthy Subjects
Official title: A Phase I Study to Determine and Compare Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Intravenous ETX2514 and Sulbactam Administered to Healthy Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Pharmacokinetic
Bronchoalveolar Lavage
Epithelial Lining Fluid
Alveolar Macrophage
Gram-negative bacterium
Acinetobacter baumannii
Lead sponsor: Entasis Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Clinartis
First posted: 2017-10-06
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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

Detailed description: Blood samples for determining plasma concentrations of ETX2514 and sulbactam will be collected within 5 minutes prior to and at 1.0, 2.0, 2.5, 2.95, 3.05, 3.25, 3.5, 4.0, 5.0 and 6.0 hours after start of the third dose (last dose) administered on Day 2.

Each subject will undergo one standardized bronchoscopy with bronchoalveolar lavage (BAL) in the outpatient bronchoscopy suite at 1.0, 2.5, 3.25, 4.0, or 6.0 hours after start of the infusion of the third dose of ETX2514 and sulbactam (6 subjects per timepoint) on Day 2.

Safety will be assessed throughout the study by adverse event monitoring, clinical laboratory tests, ECG, physical examination, and vital sign monitoring.

Eligibility criteria: Inclusion Criteria:

1. Healthy male or female subject, between 18 and 55 years of age (both inclusive) at the time of screening.
2. Body mass index (BMI) ≥ 18.0 kg/m2 and ≤ 32.0 kg/m2 and weight between 55.0 and 100.0 kg (both inclusive).
3. Be in general good health without clinically significant medical history as judged by the Principal Investigator.
4. Provide voluntary written informed consent prior to any study procedures and is willing and able to comply with the prescribed treatment protocol and evaluations.
5. Non-tobacco/nicotine-containing product users for a minimum of 6 months prior to screening.
6. 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.
7. 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.
8. 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.
9. 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):

   1. Bilateral tubal ligation
   2. Hysterectomy
   3. Hysterectomy with unilateral or bilateral oophorectomy
   4. Bilateral oophorectomy.

Exclusion Criteria:

1. History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antimicrobial (e.g., penicillin, cephalosporin, sulbactam or carbapenem)
2. History or presence of significant oncologic, cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease.
3. Calculated creatinine clearance less than 60 mL/min (Cockcroft-Gault method) at screening or confinement.
4. Positive alcohol breath test or urine drug screen test at screening or confinement.
5. Positive testing for HIV, Hepatitis B or Hepatitis C.
6. History or presence of alcohol or drug abuse within the 2 years prior to screening.
7. 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.
8. History of allergic or other serious adverse reactions to lidocaine or amide anesthetic agents.
9. Clinically significant pulmonary or any other disease that prevents a subject from undergoing bronchoscopy with pulmonary lavage.
10. Spirometry results showing an forced expiratory volume at one second (FEV1) \<80% of predicted.
11. Use of probenecid within 30 days before confinement.
12. 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.
13. Engagement in strenuous activity within 96 hours of confinement (Day 1) until discharge.
14. History of seizures, head injury or meningitis (e.g., epilepsy).
15. History of bleeding disorders.
16. History or evidence of difficulty in donating blood.
17. Use of any prescription medication (with the exception of hormonal contraceptives or hormone replacement therapy for females) within 14 days prior to confinement.
18. Blood donation/plasma donation or significant blood loss (i.e., \>500 mL) within 60 days prior to screening.
19. Participation in another investigational drug or device study or treated with an investigational drug within 30 days or five half-lives (whichever is longer) prior to screening.
20. Females who are pregnant or lactating.
21. Surgery within the past three months prior to screening determined by the investigator to be clinically relevant.
22. Any acute illness including clinically significant infection within 30 days prior to screening.
23. Subjects who have any of the following abnormalities on laboratory values at screening or prior confinement including:

    1. White blood cell count \< 3,000/mm3, hemoglobin \< 11g/dL.
    2. Absolute neutrophil count \<1,200/mm3, platelet count \<120,000/mm3.
24. Unwillingness or inability to comply with the study protocol for any other reason.
25. Use of caffeine or xanthine containing products, Seville oranges (sour), grapefruit or grapefruit juice within 48 hours prior to study drug dosing.
26. Any other condition or prior therapy, which, in the opinion of the Principal Investigator, would make the subject unsuitable for this study.

Primary outcomes:
measure: Mean maximum observed drug concentration (Cmax) in blood
timeFrame: 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
measure: Mean Cmax in epithelial lining fluid (ELF)
timeFrame: 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
measure: Mean area under the curve (AUC) 0-6h in blood
timeFrame: 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
measure: Mean terminal half-life (t1/2) in blood
timeFrame: 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
measure: Mean volume of distribution in the terminal elimination phase (Vdss) in blood
timeFrame: 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
measure: Mean clearance (CL) in blood
timeFrame: 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
measure: Ratio of AUC 0-6 for ELF to the corresponding AUC0-6 Plasma
timeFrame: 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:
measure: Number of participants with any non serious adverse event (AE)
timeFrame: Day 1-14
measure: Number of participants with any serious adverse event (SAE)
timeFrame: Day 1- 14
measure: Change from Baseline in electrocardiogram (ECG) parameters at the indicated time points
timeFrame: Day 1, 2, and 4
measure: Change from baseline in vital signs at the indicated time points
timeFrame: Days 1, 2,and 4
measure: Number of participants with abnormal, clinical significant hematology and chemistry laboratory values at the indicated time points
timeFrame: Day 1-14
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Pulmonary Associates, PA
state: Arizona
Study officials:
References:
citation: 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.