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Evaluation of the Safety, Tolerability and Pharmacokinetics of Intravenous ETX2514 Administered in Healthy Subjects

Primary Purpose

Acinetobacter Baumannii Infection

Status

Completed

Phase

Phase 1

Locations

Australia

Study Type

Interventional

Intervention

ETX2514

Placebo

Sulbactam

Imipenem/Cilastatin

About this trial

This is an interventional treatment trial for Acinetobacter Baumannii Infection focused on measuring infection, gram-negative bacterium

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Aged 18 to 55 years (inclusive). In addition, 8 participants greater than or equal to 65 years of age will be enrolled.
Be in general good health without a clinically significant medical history
Provide voluntary written informed consent prior to any study procedures and are willing and able to comply with the prescribed treatment protocol and evaluations
Body mass index (BMI) greater than or equal to 18.0 kilograms (kg)/meters square (m^2) and less than or equal to 32.0 kg/m^2
Clinical laboratory values within the normal limits as defined by the clinical laboratory, unless the Principal Investigator decides that out-of-range values are not clinically significant
Negative screen for drugs of abuse, alcohol, hepatitis B surface antigen (HBS Ag), hepatitis C virus antibody (HCV Ab), and Human Immunodeficiency Virus (HIV) at screening; and drugs of abuse, alcohol pre dose on Day -1
Female participants must be of non-childbearing potential, or using a medically acceptable contraceptive regimen and must have a negative pregnancy test at Screening (serum) and on Day -1 (urine) prior to study drug dosing. Male participants must be surgically sterile, or using a medically acceptable contraceptive regimen.

Exclusion Criteria:

History of any moderate or severe hypersensitivity or allergic reaction to any beta-lactam antimicrobial (e.g., penicillin, cephalosporin, sulbactam, or carbapenem).
Use of prescription or over the counter medications within 7 days of Investigational Product administration, with the exception of contraceptive medications, paracetamol, oral non-steroidal anti-inflammatory agents, topical over the counter preparations, and routine vitamins (if they do not exceed an intake of 20 to 600 times the recommended daily dose), unless agreed as non-clinically relevant by the Principal Investigator and Sponsor
Participation in an investigational drug or device study within 30 days before study drug dosing, i.e., there was at least 30 days in between the last dose on a prior study and dose administration on this study
Current smoker, or difficulty abstaining from smoking for the duration of study confinement
History of major organ dysfunction
Infection or any serious underlying medical condition that would impair the participant from receiving study drug
History of excessive alcohol intake (more than 4 standard drinks daily, on average) or use of recreational drugs within the last 3 months
Standard donation of blood within 30 days of the study
Concomitant disease or condition, including laboratory abnormality, which could interfere with the conduct of the study, or which would, in the opinion of the investigator, pose an unacceptable risk to the participant in this study
Anticipated need for surgery or hospitalization during the study
Unwillingness or inability to comply with the study protocol for any other reason

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm 14

Arm 15

Arm Type

Experimental

Arm Label

Part A; Cohort 1: 0.25 g IV ETX2514/placebo

Part A; Cohort 2: 0.5 g IV ETX2514/placebo

Part A; Cohort 3: 1.0 g IV ETX2514/placebo

Part A; Cohort 4: 1.0 g IV ETX2514/placebo

Part A; Cohort 5: 2.0 g IV ETX2514/placebo

Part A; Cohort 6: 4.0 g IV ETX2514/placebo

Part A; Cohort 7: 8.0 g IV ETX2514/placebo

Part A; Cohort 8: 1.0 g IV ETX2514/placebo

Part B; Cohort 9: 0.25 g IV EXT2514/placebo

Part B; Cohort 10: 0.5 g IV EXT2514/placebo

Part B; Cohort 11: 1.0 g IV EXT2514/placebo

Part B; Cohort 12: 2.0 g IV EXT2514/placebo

Part C; Cohort 13: ETX2514/placebo with sulbactam

Part C; Cohort 14: ETX2514/placebo with SUL and/or IM/CIL

Part D; Cohort 15: ETX2514/placebo with SUL and/or IM/CIL

Arm Description

Part A of the study will explore the safety and tolerability of a single ascending dose (SAD) of intravenous (IV) ETX2514. Participants in Cohort 1, aged 18 to 55 years, will receive 0.25 grams (g) IV ETX2514/placebo infused over 3 hours.

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 2, aged 18 to 55 years, will receive 0.5 g IV ETX2514/placebo infused over 3 hours.

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 3, aged 18 to 55 years, will receive 1.0 g IV ETX2514/placebo infused over 3 hours.

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 4, aged 18 to 55 years, will receive 1.0 g IV ETX2514/placebo infused over 2 hours.

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 5, aged 18 to 55 years, will receive 2.0 g IV ETX2514/placebo infused over 3 hours.

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 5, aged 18 to 55 years, will receive 4.0 g IV ETX2514/placebo infused over 3 hours.

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 7, aged 18 to 55 years, will receive 8.0 g IV ETX2514/placebo infused over 3 hours.

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 8, aged 65 years or older, will receive 1.0 g IV ETX2514/placebo infused over 3 hours.

Part B of the study will explore the safety and tolerability of multiple ascending doses (MAD) of IV ETX2514. Participants in Cohort 9, aged 18 to 55 years, will receive 0.25 g IV EXT2514/placebo infused over 3 hours, every 6 hours (4 times a day) for 7 consecutive days, and then will receive 1 dose on Day 8.

Part B of the study will explore the safety and tolerability of MAD of IV ETX2514. Participants in Cohort 10, aged 18 to 55 years, will receive 0.5 g IV EXT2514/placebo infused over 3 hours, every 6 hours (4 times a day) for 7 consecutive days, and then will receive 1 dose on Day 8.

Part B of the study will explore the safety and tolerability of MAD of IV ETX2514. Participants in Cohort 11, aged 18 to 55 years, will receive 1.0 g IV EXT2514/placebo infused over 3 hours, every 6 hours (4 times a day) for 7 consecutive days, and then will receive 1 dose on Day 8.

Part B of the study will explore the safety and tolerability of MAD of IV ETX2514. Participants in Cohort 12, aged 18 to 55 years, will receive 2.0 g IV EXT2514/placebo infused over 3 hours, every 6 hours (4 times a day) for 7 consecutive days, and then will receive 1 dose on Day 8.

Part C of the study will explore the safety and tolerability of IV ETX2514 when administered as a single dose in combination with sulbactam (1.0 g) and/or imipenem/cilastatin (0.5 g) to healthy participants. On Day 1, participants will receive a single dose of 1.0 g IV ETX2514/placebo infused over 3 hours. On Day 3, participants will receive a single dose of 1.0 g IV sulbactam infused over 3 hours. On Day 5, participants will receive a single dose of 1.0 g IV ETX2514/placebo plus 1.0 g sulbactam infused over 3 hours at the same time. The actual Day 1 and Day 5 ETX2514 dose and infusion time will be determined based on PK and safety data from Part A.

Part C of the study will explore the safety and tolerability of IV ETX2514 when administered as a single dose in combination with sulbactam (SUL: 1.0 g) and/or imipenem/cilastatin (IM/CIL: 0.5 g) to healthy participants. On Day 1, participants will receive a single dose of 1.0 g IV ETX2514/placebo infused over 3 hours. On Day 3, participants will receive a single dose of 0.5 g IV imipenem/cilastatin infused over 30 minutes. On Day 5, participants will receive a single dose of 1.0 g IV ETX2514/placebo infused over 3 hours plus 0.5 g imipenem/cilastatin infused over 30 minutes initiated at the same time as ETX2514/placebo. On Day 8, participants will receive a single dose of 1.0 g IV ETX2514/placebo plus 1.0 g sulbactam infused over 3 hours at the same time plus 0.5 g imipenem/cilastatin infused over 30 minutes initiated at the same time as ETX2514/placebo. The actual Day 1, Day 5, and Day 8 ETX2514 dose and infusion time will be determined based on PK and safety data from Part A.

Part D of the study will explore the safety and tolerability of multiple doses of combined IV ETX2514/sulbactam (1.0 g)/imipenem/cilastatin (0.5 g) to healthy participants. Participants in Cohort 15 will receive 1.0 g IV ETX2514/placebo and 1.0 g IV sulbactam both infused over 3 hours and 0.5 g IV imipenem/cilastatin infused over 30 minutes every 6 hours (4 times a day) for 10 days and will receive 1 dose on Day 11. The actual ETX2514 dose and infusion time will be determined based on PK and safety data from Part C.

Outcomes

Primary Outcome Measures

Number of participants with any non-serious and any serious adverse event

Number of participants with an adverse event of the indicated causality and severity

Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part A

Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part B

Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part C

Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part D

Change from Baseline in vital signs at the indicated time points in Part A

Day 1: prior to infusion, and 1, 3, 6, and 12 hours post start of infusion. Day 2: 24 hours post start of infusion). Day 3: 48 hours post start of infusion

Change from Baseline in vital signs at the indicated time points in Part B

Days 1-8: 30 minutes prior to infusion and 3, 6, and 12 hours post start of infusion. Day 9: 24 hours post Day 8 start of infusion. Day 10: 48 hours post Day 8 start of infusion

Change from Baseline in vital signs at the indicated time points in Cohort 13 of Part C

Days 1, 3, and 5: 30 minutes prior to infusion and 3, 6, and 12 hours post start of infusion. Days 2, 4, and 6: 24 hours post start of infusion. Day 7: 48 hours post Day 5 start of infusion

Change from Baseline in vital signs at the indicated time points in Cohort 14 of Part C

Days 1, 3, 5, and 8: 30 minutes prior to infusion and 3, 6, and 12 hours post start of infusion. Days 2, 4, 6, and 9: 24 hours post start of infusion. Days 7 and 10: 48 hours post Day 5 and Day 8, respectively, start of infusion

Change from Baseline in vital signs at the indicated time points in Part D

Days 1-11: 30 minutes prior to infusion and 3, 6, and 12 hours post infusion

Change from Baseline in electrocardiogram parameters at the indicated time points in Parts A and B

Part A: Day 1: 150 minutes after start of infusion; Day 3: 48 hours after start of infusion. Part B: Days 1, 3, 5, and 7: 150 minutes after start of infusion; Day 10: 48 hours post Day 8 start of infusion

Change from Baseline in electrocardiogram parameters at the indicated time points in Cohort 13 in Part C

Days 1, 3, and 5: 150 minutes post start of infusion; Day 7: 48 hours post Day 5 start of infusion

Change from Baseline in electrocardiogram parameters at the indicated time points in Cohort 14 in Part C

Days 1, 3, 5, and 8: 150 minutes post start of infusion; Day 10: 48 hours post Day 8 start of infusion

Change from Baseline in electrocardiogram parameters at the indicated time points in Part D

Days 1, 3, 5, 7, 9, and 11: 150 minutes post start of infusion. Day 13: 48 hours post Day 11 start of infusion

Number of participants with an infusion site reaction

Mean peak plasma concentration (Cmax) and plasma concentration at time t (Ct) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Cmax and Ct in blood at the indicated time points in Cohort 4 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Cmax and Ct in blood at the indicated time points in Part B

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Days 2 and 4: 30 minutes prior to infusion of the second dose given on Days 2 and 4, respectively. Day 8: 30 minutes prior to infusion of the final dose, which is given on Day 8; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 9: 24 and 36 hours post start of infusion. Day 10: 48 hours post start of infusion

Mean Cmax and Ct in blood at the indicated time points in Cohort 13 in Part C

Day 1: 30 minutes prior to infusion of ETX2514/placebo; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion of ETX2514/placebo. Day 2: 24 and 36 hours post start of infusion of ETX2514/placebo. Day 3: immediately prior to start of infusion of sulbactam (48 hours); 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion of sulbactam. Day 4: 24 and 36 hours post start of infusion of sulbactam. Day 5: immediately prior to infusion to co-administer ETX2514/placebo and sulbactam (48 hours); 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion to co-administer ETX2514/placebo and sulbactam. Day 6: 24 and 36 hours post start of infusion to co-administer ETX2514/placebo and sulbactam. Day 7: 48 hours post start of infusion to co-administer ETX2514/placebo and sulbactam

Mean Cmax and Ct in blood at the indicated time points in Cohort 14 in Part C

ETX2514/placebo infusion: Day 1: 30 minutes prior to infusion (PTI); 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion (PSOI). Day 2: 24 and 36 PSOI. Imipenem (IM)/cilastatin (CIL) infusion: Day 3: immediately prior to start of infusion (48 hours); 30 minutes PSOI; 1, 2, 3, 4, 5, 6, 8, and 12 hours PSOI. Day 4: 24 and 36 hours PSOI. Co-administration of ETX2514/placebo and IM/CIL: Day 5: immediately prior to infusion (48 hours); 30 minutes PSOI; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours PSOI. Day 6: 24 and 36 hours PSOI. Day 7: 48 hours PSOI. Co-administration of ETX2514/placebo, sulbactam, and IM/CIL: Day 8: 30 minutes prior to infusion; 30 minutes PSOI; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 PSOI. Day 9: 24 and 36 hours PSOI. Day 10: 48 hours PSOI

Mean Cmax and Ct in blood at the indicated time points in Part D

Day 1: 30 minutes prior to infusion; 30 minutes post start of infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Days 2 and 4: 30 minutes prior to infusion of the second dose given on Days 2 and 4, respectively. Day 11: 30 minutes prior to infusion of the final dose given on Day 11; 30 minutes post start of infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 12: 24 and 36 hours post start of infusion. Day 13: 48 hours post start of infusion

Mean time to peak plasma concentration (Tmax) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Tmax in blood at the indicated time points in Cohort 4 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Tmax in blood at the indicated time points in Part B

Mean Tmax in blood at the indicated time points in Cohort 13 in Part C

Mean Tmax in blood at the indicated time points in Cohort 14 in Part C

Mean Tmax in blood at the indicated time points in Part D

Mean AUC from time 0 to 24 hours (AUC0-24), AUC from time 0 to the last time point evaluated (AUC0-t), and AUC from time 0 and extrapolated to infinity (AUC0-∞) in blood at the indicated time points in Cohorts 1-3 in Part A

AUC is defined as area under the concentration time curve. Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 4 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part B

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 13 in Part C

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 14 in Part C

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part D

Mean elimination rate constant (Kel) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Kel in blood at the indicated time points in Cohort 4 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Kel in blood at the indicated time points in Part B

Mean Kel in blood at the indicated time points in Cohort 13 in Part C

Mean Kel in blood at the indicated time points in Cohort 14 in Part C

Mean Kel in blood at the indicated time points in Part D

Mean elimination half-life (t1/2) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean t1/2 in blood at the indicated time points in Cohort 4 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean t1/2 in blood at the indicated time points in Part B

Mean t1/2 in blood at the indicated time points in Cohort 13 in Part C

Mean t1/2 in blood at the indicated time points in Cohort 14 in Part C

Mean t1/2 in blood at the indicated time points in Part D

Mean clearance in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean clearance in blood at the indicated time points in Cohort 4 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean clearance in urine at the indicated time points in Part A

-12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Mean clearance in blood at the indicated time points in Part B

Mean clearance in urine at the indicated time points in Part B

All days: -12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Mean clearance in blood at the indicated time points in Cohort 13 in Part C

Mean clearance in urine at the indicated time points in Cohort 13 in Part C

Day 1 to Day 3 (ETX2514/placebo): from -12 to 0 hours prior to start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion. Days 3-5 (sulbactam): 0-6, 6-12, 12-24, and 24-48 hours post start of infusion. Days 5-7 (infusion to co-administer ETX2514/placebo and sulbactam): 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Mean clearance in blood at the indicated time points in Cohort 14 in Part C

Mean clearance in urine at the indicated time points in Cohort 14 in Part C

Day 1 to Day 3 (ETX2514/placebo): from -12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion. Day 3 to Day 5 (imipenem/cilastatin): 0-6, 6-12, 12-24, and 24-48 hours post start of infusion. Day 5 to Day 7 (infusion to co-administer ETX2514/placebo and imipenem/cilastatin): 0-6, 6-12, 12-24, and 24-48 hours post start of infusion. Day 8 to Day 10 (infusion to co-administer ETX2514/placebo, sulbactam, and imipenem/cilastatin): from -12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Mean clearance in blood at the indicated time points in Part D

Mean clearance in urine at the indicated time points in Part D

Days 1-3: from -12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion. Days 11-13: from -12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Mean volume of distribution (VzVdss) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean VzVdss in blood at the indicated time points in Cohort 4 in Part A

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean VzVdss in blood at the indicated time points in Part B

Mean VzVdss in blood at the indicated time points in Cohort 13 in Part C

Mean VzVdss in blood at the indicated time points in Cohort 14 in Part C

Mean VzVdss in blood at the indicated time points in Part D

Mean cumulative excretion of unchanged drug in urine (Ae) at the indicated time points in Part A

-12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Mean Ae at the indicated time points in Part B

All days: -12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Mean Ae at the indicated time points in Cohort 13 in Part C

Mean Ae at the indicated time points in Cohort 14 in Part C

Mean Ae at the indicated time points in Part D

Secondary Outcome Measures

Number of elderly participants with any non-serious and any serious adverse event

Number of elderly participants with an adverse event of the indicated causality and severity

Number of participants with abnormal, clinically significant hematology and clinical chemistry parameters at the indicted time points in Part A for elderly participants

Change from Baseline in vital signs at the indicated time points in Part A for elderly participants

Day 1: prior to infusion, and 1, 3, 6, and 12 hours post start of infusion. Day 2: 24 hours post start of infusion). Day 3: 48 hours post start of infusion

Change from Baseline in electrocardiogram parameters at the indicated time points in Part A for elderly participants

Day 1: 30 minutes after start of infusion

Number of elderly participants with an infusion site reaction

Mean Cmax and Ct in blood at the indicated time points in Part A for elderly participants

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Tmax in blood at the indicated time points in Part A for elderly participants

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part A for elderly participants

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Kel in blood at the indicated time points in Part A for elderly participants

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean t1/2 in blood at the indicated time points in Part A for elderly participants

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean clearance in blood at the indicated time points in Part A for elderly participants

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean clearance in urine at the indicated time points in Part A for elderly participants

-12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Mean VzVdss in blood at the indicated time points in Part A for elderly participants

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Mean Ae at the indicated time points in Part A for elderly participants

-12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Number of elderly participants using concomitant medications

Full Information

NCT ID

NCT02971423

First Posted

October 21, 2016

Last Updated

June 1, 2017

Sponsor

Entasis Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT02971423

Brief Title

Evaluation of the Safety, Tolerability and Pharmacokinetics of Intravenous ETX2514 Administered in Healthy Subjects

Official Title

A Phase I, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Intravenous ETX2514 Administered in Healthy Subjects

Study Type

Interventional

2. Study Status

Record Verification Date

April 2017

Overall Recruitment Status

Completed

Study Start Date

October 2016 (Actual)

Primary Completion Date

June 1, 2017 (Actual)

Study Completion Date

June 1, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Entasis Therapeutics

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This research project is being conducted to look at the safety, tolerability, and pharmacokinetics (PK; how the human body processes a substance) of ETX2514 when given to healthy volunteers intravenously as a single dose, and when given as multiple intravenous doses for up to 8 consecutive days. As it is anticipated that ETX2514 could be used as a treatment for Acinetobacter baumannii (a type of bacteria) infections, this project will also look at whether ETX2514 will interact with the current treatments for these infections when they are administered at the same time.

Detailed Description

This Phase 1, single-center, randomized, double-blind, and placebo-controlled study investigates the safety, tolerability, and PK profile of single and multiple ascending doses of intravenous (IV) ETX2514 when administered intravenously alone and in combination with sulbactam and/or imipenem/cilastatin in healthy adult participants. The study will be conducted in four Parts: A, B, C, and D. Part A will explore the safety and tolerability of a single ascending dose (SAD) of IV ETX2514 over 8 cohorts. Part B will explore the safety and tolerability of multiple ascending doses (MAD) of IV ETX2514 over 4 cohorts. Part C will explore the safety and tolerability of IV ETX2514 when administered as a single dose in combination with sulbactam (1.0 gram [g]) and/or imipenem/cilastatin (0.5 g) to healthy participants over 2 cohorts. Part D will explore the safety and tolerability of multiple doses of combined IV ETX2514/sulbactam (1.0 g)/imipenem/cilastatin (0.5 g) to healthy participants.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acinetobacter Baumannii Infection

Keywords

infection, gram-negative bacterium

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

124 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part A; Cohort 1: 0.25 g IV ETX2514/placebo

Arm Type

Experimental

Arm Description

Arm Title

Part A; Cohort 2: 0.5 g IV ETX2514/placebo

Arm Type

Experimental

Arm Description

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 2, aged 18 to 55 years, will receive 0.5 g IV ETX2514/placebo infused over 3 hours.

Arm Title

Part A; Cohort 3: 1.0 g IV ETX2514/placebo

Arm Type

Experimental

Arm Description

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 3, aged 18 to 55 years, will receive 1.0 g IV ETX2514/placebo infused over 3 hours.

Arm Title

Part A; Cohort 4: 1.0 g IV ETX2514/placebo

Arm Type

Experimental

Arm Description

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 4, aged 18 to 55 years, will receive 1.0 g IV ETX2514/placebo infused over 2 hours.

Arm Title

Part A; Cohort 5: 2.0 g IV ETX2514/placebo

Arm Type

Experimental

Arm Description

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 5, aged 18 to 55 years, will receive 2.0 g IV ETX2514/placebo infused over 3 hours.

Arm Title

Part A; Cohort 6: 4.0 g IV ETX2514/placebo

Arm Type

Experimental

Arm Description

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 5, aged 18 to 55 years, will receive 4.0 g IV ETX2514/placebo infused over 3 hours.

Arm Title

Part A; Cohort 7: 8.0 g IV ETX2514/placebo

Arm Type

Experimental

Arm Description

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 7, aged 18 to 55 years, will receive 8.0 g IV ETX2514/placebo infused over 3 hours.

Arm Title

Part A; Cohort 8: 1.0 g IV ETX2514/placebo

Arm Type

Experimental

Arm Description

Part A of the study will explore the safety and tolerability of a SAD of IV ETX2514. Participants in Cohort 8, aged 65 years or older, will receive 1.0 g IV ETX2514/placebo infused over 3 hours.

Arm Title

Part B; Cohort 9: 0.25 g IV EXT2514/placebo

Arm Type

Experimental

Arm Description

Arm Title

Part B; Cohort 10: 0.5 g IV EXT2514/placebo

Arm Type

Experimental

Arm Description

Arm Title

Part B; Cohort 11: 1.0 g IV EXT2514/placebo

Arm Type

Experimental

Arm Description

Arm Title

Part B; Cohort 12: 2.0 g IV EXT2514/placebo

Arm Type

Experimental

Arm Description

Arm Title

Part C; Cohort 13: ETX2514/placebo with sulbactam

Arm Type

Experimental

Arm Description

Arm Title

Part C; Cohort 14: ETX2514/placebo with SUL and/or IM/CIL

Arm Type

Experimental

Arm Description

Arm Title

Part D; Cohort 15: ETX2514/placebo with SUL and/or IM/CIL

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

ETX2514

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

matching placebo infusion

Intervention Type

Drug

Intervention Name(s)

Sulbactam

Intervention Type

Drug

Intervention Name(s)

Imipenem/Cilastatin

Primary Outcome Measure Information:

Title

Number of participants with any non-serious and any serious adverse event

Time Frame

up to 14 days after the last infusion of study drug (Study Day 182)

Title

Number of participants with an adverse event of the indicated causality and severity

Time Frame

up to 14 days after the last infusion of study drug (Study Day 182)

Title

Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part A

Time Frame

Baseline (Day -1); Days 3, 5, 7, and 15 (Follow-up)

Title

Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part B

Time Frame

Baseline (Day -1; Study Day [SD] 37); Days 2, 3, 5, 7, and 10 (SDs 39, 40, 42, 44, and 47, respectively); Day 22 (SD 59; Follow-up)

Title

Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part C

Time Frame

Cohort 13: Baseline (Day -1; Study Day [SD] 80); Days 3, 4, and 7 (SDs 83, 84, and 87, respectively); Day 19 (SD 99; Follow-up). Cohort 14: Baseline; Days 3, 4, 7, and 10 (SDs 83, 84, 87, and 90, respectively); Day 22 (SD 102; Follow-up)

Title

Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part D

Time Frame

Baseline (Day -1; SD 122); Days 2, 3, 5, 7, 10, 11, and 13 (SDs 124, 125, 127, 129, 132, and 133, respectively); Day 25 (SD 147; Follow-up)

Title

Change from Baseline in vital signs at the indicated time points in Part A

Description

Day 1: prior to infusion, and 1, 3, 6, and 12 hours post start of infusion. Day 2: 24 hours post start of infusion). Day 3: 48 hours post start of infusion

Time Frame

Baseline (Day -1); Days 1-3; Day 5; Day 7; Day 15 (Follow-up)

Title

Change from Baseline in vital signs at the indicated time points in Part B

Description

Days 1-8: 30 minutes prior to infusion and 3, 6, and 12 hours post start of infusion. Day 9: 24 hours post Day 8 start of infusion. Day 10: 48 hours post Day 8 start of infusion

Time Frame

Baseline (Day -1; SD 37); Days 1-10 (SDs 38-47, respectively); Day 22 (SD 59; Follow-up)

Title

Change from Baseline in vital signs at the indicated time points in Cohort 13 of Part C

Description

Days 1, 3, and 5: 30 minutes prior to infusion and 3, 6, and 12 hours post start of infusion. Days 2, 4, and 6: 24 hours post start of infusion. Day 7: 48 hours post Day 5 start of infusion

Time Frame

Baseline (Day -1; SD 80); Days 1-7 (SDs 81-87, respectively); Day 19 (SD 99; Follow-up)

Title

Change from Baseline in vital signs at the indicated time points in Cohort 14 of Part C

Description

Time Frame

Baseline (Day -1; SD 80); Days 1-10 (SDs 81-90, respectively); Day 22 (SD 102; Follow-up)

Title

Change from Baseline in vital signs at the indicated time points in Part D

Description

Days 1-11: 30 minutes prior to infusion and 3, 6, and 12 hours post infusion

Time Frame

Baseline (SD 122); Days 1-13 (SDs 123-135, respectively); Day 25 (SD 147; Follow-up)

Title

Change from Baseline in electrocardiogram parameters at the indicated time points in Parts A and B

Description

Time Frame

Part A: Baseline (Day -1); Days 1 and 3; Follow-up visit (Day 15). Part B: Baseline (Day -1; SD 37); Days 1, 3, 5, 7, 10, and 22 (SDs 38, 40, 42, 44, 47, and 59, respectively)

Title

Change from Baseline in electrocardiogram parameters at the indicated time points in Cohort 13 in Part C

Description

Days 1, 3, and 5: 150 minutes post start of infusion; Day 7: 48 hours post Day 5 start of infusion

Time Frame

Baseline (Day -1; SD 80); Days 1, 3, 5, and 7 (SDs 81, 83, 85, and 87, respectively); Day 19 (SD 99; Follow-up)

Title

Change from Baseline in electrocardiogram parameters at the indicated time points in Cohort 14 in Part C

Description

Days 1, 3, 5, and 8: 150 minutes post start of infusion; Day 10: 48 hours post Day 8 start of infusion

Time Frame

Baseline (Day -1; SD 80); Days 1, 3, 5, 8, and 10 (SDs 81, 83, 85, 88, and 90, respectively); Day 22 (SD 102; Follow-up)

Title

Change from Baseline in electrocardiogram parameters at the indicated time points in Part D

Description

Days 1, 3, 5, 7, 9, and 11: 150 minutes post start of infusion. Day 13: 48 hours post Day 11 start of infusion

Time Frame

Baseline (SD 122); Days 1, 3, 5, 7, 9, and 11 (SDs 123, 125, 127, 129, 131, and 133, respectively); Day 13 (SD 135); Day 25 (SD 147; Follow-up)

Title

Number of participants with an infusion site reaction

Time Frame

up to 14 days after the last infusion of study drug (SD 182)

Title

Mean peak plasma concentration (Cmax) and plasma concentration at time t (Ct) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Cmax and Ct in blood at the indicated time points in Cohort 4 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Cmax and Ct in blood at the indicated time points in Part B

Description

Time Frame

Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)

Title

Mean Cmax and Ct in blood at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Days 1-7 (SDs 81-87, respectively)

Title

Mean Cmax and Ct in blood at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Days 1-10 (SDs 81-90, respectively)

Title

Mean Cmax and Ct in blood at the indicated time points in Part D

Description

Time Frame

Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)

Title

Mean time to peak plasma concentration (Tmax) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Tmax in blood at the indicated time points in Cohort 4 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Tmax in blood at the indicated time points in Part B

Description

Time Frame

Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)

Title

Mean Tmax in blood at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Days 1-7 (SDs 81-87, respectively)

Title

Mean Tmax in blood at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Days 1-10 (SDs 81-90, respectively)

Title

Mean Tmax in blood at the indicated time points in Part D

Description

Time Frame

Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)

Title

Description

Time Frame

Days 1-3

Title

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 4 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part B

Description

Time Frame

Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)

Title

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Days 1-7 (SDs 81-87, respectively)

Title

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Days 1-10 (SDs 81-90, respectively)

Title

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part D

Description

Time Frame

Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)

Title

Mean elimination rate constant (Kel) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Kel in blood at the indicated time points in Cohort 4 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Kel in blood at the indicated time points in Part B

Description

Time Frame

Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)

Title

Mean Kel in blood at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Days 1-7 (SDs 81-87, respectively)

Title

Mean Kel in blood at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Days 1-10 (SDs 81-90, respectively)

Title

Mean Kel in blood at the indicated time points in Part D

Description

Time Frame

Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)

Title

Mean elimination half-life (t1/2) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean t1/2 in blood at the indicated time points in Cohort 4 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean t1/2 in blood at the indicated time points in Part B

Description

Time Frame

Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)

Title

Mean t1/2 in blood at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Days 1-7 (SDs 81-87, respectively)

Title

Mean t1/2 in blood at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Days 1-10 (SDs 81-90, respectively)

Title

Mean t1/2 in blood at the indicated time points in Part D

Description

Time Frame

Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)

Title

Mean clearance in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean clearance in blood at the indicated time points in Cohort 4 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean clearance in urine at the indicated time points in Part A

Description

-12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Time Frame

Baseline (Day -1); Days 1-3

Title

Mean clearance in blood at the indicated time points in Part B

Description

Time Frame

Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)

Title

Mean clearance in urine at the indicated time points in Part B

Description

All days: -12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Time Frame

Baseline (Day -1; SD 37); Days 1-3 and 7-10 (SDs 38-40 and 44-47, respectively)

Title

Mean clearance in blood at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Days 1-7 (SDs 81-87, respectively)

Title

Mean clearance in urine at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Baseline (Day -1; SD 80); Days 1-7 (SDs 81-87, respectively)

Title

Mean clearance in blood at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Days 1-10 (SDs 81-90, respectively)

Title

Mean clearance in urine at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Baseline (Day -1; SD 80); Days 1-10 (SDs 81-90, respectively)

Title

Mean clearance in blood at the indicated time points in Part D

Description

Time Frame

Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)

Title

Mean clearance in urine at the indicated time points in Part D

Description

Time Frame

Baseline (Day -1; SD 123); Days 1-3 (SDs 124-126, respectively); Days 10-13 (SDs 133-136, respectively)

Title

Mean volume of distribution (VzVdss) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean VzVdss in blood at the indicated time points in Cohort 4 in Part A

Description

Day 1: 30 minutes prior to infusion; 1, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean VzVdss in blood at the indicated time points in Part B

Description

Time Frame

Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)

Title

Mean VzVdss in blood at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Days 1-7 (SDs 81-87, respectively)

Title

Mean VzVdss in blood at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Days 1-10 (SDs 81-90, respectively)

Title

Mean VzVdss in blood at the indicated time points in Part D

Description

Time Frame

Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)

Title

Mean cumulative excretion of unchanged drug in urine (Ae) at the indicated time points in Part A

Description

-12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Time Frame

Baseline (Day -1); Days 1-3

Title

Mean Ae at the indicated time points in Part B

Description

All days: -12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Time Frame

Baseline (Day -1; SD 37); Days 1-3 and 7-10 (SDs 38-40 and 44-47, respectively)

Title

Mean Ae at the indicated time points in Cohort 13 in Part C

Description

Time Frame

Baseline (Day -1; SD 80); Days 1-7 (SDs 81-87, respectively)

Title

Mean Ae at the indicated time points in Cohort 14 in Part C

Description

Time Frame

Baseline (Day -1; SD 80); Days 1-10 (SDs 81-90, respectively)

Title

Mean Ae at the indicated time points in Part D

Description

Time Frame

Baseline (Day -1; SD 123); Days 1-3 (SDs 124-126, respectively); Days 10-13 (SDs 133-136, respectively)

Secondary Outcome Measure Information:

Title

Number of elderly participants with any non-serious and any serious adverse event

Time Frame

up to Day 15

Title

Number of elderly participants with an adverse event of the indicated causality and severity

Time Frame

up to Day 15

Title

Number of participants with abnormal, clinically significant hematology and clinical chemistry parameters at the indicted time points in Part A for elderly participants

Time Frame

Baseline (Day -1); Days 3, 5, 7, and 15 (Follow-up)

Title

Change from Baseline in vital signs at the indicated time points in Part A for elderly participants

Description

Day 1: prior to infusion, and 1, 3, 6, and 12 hours post start of infusion. Day 2: 24 hours post start of infusion). Day 3: 48 hours post start of infusion

Time Frame

Baseline (Day -1); Days 1-3; Day 5; Day 7; Day 15 (Follow-up)

Title

Change from Baseline in electrocardiogram parameters at the indicated time points in Part A for elderly participants

Description

Day 1: 30 minutes after start of infusion

Time Frame

Baseline (Day -1); Day 1; Day 3; Follow-up visit (Day 15)

Title

Number of elderly participants with an infusion site reaction

Time Frame

up to Day 15

Title

Mean Cmax and Ct in blood at the indicated time points in Part A for elderly participants

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Tmax in blood at the indicated time points in Part A for elderly participants

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part A for elderly participants

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Kel in blood at the indicated time points in Part A for elderly participants

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean t1/2 in blood at the indicated time points in Part A for elderly participants

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean clearance in blood at the indicated time points in Part A for elderly participants

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean clearance in urine at the indicated time points in Part A for elderly participants

Description

-12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean VzVdss in blood at the indicated time points in Part A for elderly participants

Description

Day 1: 30 minutes prior to infusion; 1, 2, 3, 3.5, 4, 5, 6, 8, and 12 hours post start of infusion. Day 2: 24 and 36 hours post start of infusion; Day 3: 48 hours post start of infusion

Time Frame

Days 1-3

Title

Mean Ae at the indicated time points in Part A for elderly participants

Description

-12 to 0 hours prior to the start of infusion; 0-6, 6-12, 12-24, and 24-48 hours post start of infusion

Time Frame

Days 1-3

Title

Number of elderly participants using concomitant medications

Time Frame

up to Day 15

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Aged 18 to 55 years (inclusive). In addition, 8 participants greater than or equal to 65 years of age will be enrolled. Be in general good health without a clinically significant medical history Provide voluntary written informed consent prior to any study procedures and are willing and able to comply with the prescribed treatment protocol and evaluations Body mass index (BMI) greater than or equal to 18.0 kilograms (kg)/meters square (m^2) and less than or equal to 32.0 kg/m^2 Clinical laboratory values within the normal limits as defined by the clinical laboratory, unless the Principal Investigator decides that out-of-range values are not clinically significant Negative screen for drugs of abuse, alcohol, hepatitis B surface antigen (HBS Ag), hepatitis C virus antibody (HCV Ab), and Human Immunodeficiency Virus (HIV) at screening; and drugs of abuse, alcohol pre dose on Day -1 Female participants must be of non-childbearing potential, or using a medically acceptable contraceptive regimen and must have a negative pregnancy test at Screening (serum) and on Day -1 (urine) prior to study drug dosing. Male participants must be surgically sterile, or using a medically acceptable contraceptive regimen. Exclusion Criteria: History of any moderate or severe hypersensitivity or allergic reaction to any beta-lactam antimicrobial (e.g., penicillin, cephalosporin, sulbactam, or carbapenem). Use of prescription or over the counter medications within 7 days of Investigational Product administration, with the exception of contraceptive medications, paracetamol, oral non-steroidal anti-inflammatory agents, topical over the counter preparations, and routine vitamins (if they do not exceed an intake of 20 to 600 times the recommended daily dose), unless agreed as non-clinically relevant by the Principal Investigator and Sponsor Participation in an investigational drug or device study within 30 days before study drug dosing, i.e., there was at least 30 days in between the last dose on a prior study and dose administration on this study Current smoker, or difficulty abstaining from smoking for the duration of study confinement History of major organ dysfunction Infection or any serious underlying medical condition that would impair the participant from receiving study drug History of excessive alcohol intake (more than 4 standard drinks daily, on average) or use of recreational drugs within the last 3 months Standard donation of blood within 30 days of the study Concomitant disease or condition, including laboratory abnormality, which could interfere with the conduct of the study, or which would, in the opinion of the investigator, pose an unacceptable risk to the participant in this study Anticipated need for surgery or hospitalization during the study Unwillingness or inability to comply with the study protocol for any other reason

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jason Lickliter

Organizational Affiliation

Nucleus Network

Official's Role

Principal Investigator

Facility Information:

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

3004

Country

Australia

12. IPD Sharing Statement

Citations:

PubMed Identifier

32284380

Citation

Lickliter JD, Lawrence K, O'Donnell J, Isaacs R. Safety, Pharmacokinetics, and Drug-Drug Interaction Potential of Intravenous Durlobactam, a beta-Lactamase Inhibitor, in Healthy Subjects. Antimicrob Agents Chemother. 2020 Jun 23;64(7):e00071-20. doi: 10.1128/AAC.00071-20. Print 2020 Jun 23. Erratum In: Antimicrob Agents Chemother. 2023 Jun 15;67(6):e0047623.

Results Reference

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Evaluation of the Safety, Tolerability and Pharmacokinetics of Intravenous ETX2514 Administered in Healthy Subjects

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