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

NCT ID: NCT02971423

Last Updated: 2017-06-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 124 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-31
• Study Completion Date: 2017-06-01

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.

Conditions

Acinetobacter Baumannii Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

Part C; Cohort 13: ETX2514/placebo with sulbactam

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

Sulbactam

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

Sulbactam

Intervention Type: DRUG

Imipenem/Cilastatin

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

ETX2514

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

matching placebo infusion

Sulbactam

Intervention Type: DRUG

Imipenem/Cilastatin

Intervention Type: DRUG

Interventions

ETX2514

Intervention Type: DRUG

Placebo

matching placebo infusion

Intervention Type: DRUG

Sulbactam

Intervention Type: DRUG

Imipenem/Cilastatin

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Entasis Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jason Lickliter

Role: PRINCIPAL_INVESTIGATOR

Nucleus Network

Locations

Melbourne, Victoria, Australia

Countries

Australia

References

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.

Reference Type: DERIVED

PMID: 32284380 (View on PubMed)

Other Identifiers

ACTRN12616000995471p

Identifier Type: REGISTRY

Identifier Source: secondary_id

CS2514-2016-0001

Identifier Type: -

Identifier Source: org_study_id