Clinical trial NCT02971423: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acinetobacter Baumannii Infection
Keywords: infection
gram-negative bacterium
Lead sponsor: Entasis Therapeutics
Sponsor class: INDUSTRY
First posted: 2016-11-23
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of participants with any non-serious and any serious adverse event
timeFrame: up to 14 days after the last infusion of study drug (Study Day 182)
measure: Number of participants with an adverse event of the indicated causality and severity
timeFrame: up to 14 days after the last infusion of study drug (Study Day 182)
measure: Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part A
timeFrame: Baseline (Day -1); Days 3, 5, 7, and 15 (Follow-up)
measure: Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part B
timeFrame: 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)
measure: Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part C
timeFrame: 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)
measure: Number of participants with abnormal, clinically significant hematology and clinical chemistry laboratory values at the indicated time points in Part D
timeFrame: 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)
measure: Change from Baseline in vital signs at the indicated time points in Part A
timeFrame: Baseline (Day -1); Days 1-3; Day 5; Day 7; Day 15 (Follow-up)
measure: Change from Baseline in vital signs at the indicated time points in Part B
timeFrame: Baseline (Day -1; SD 37); Days 1-10 (SDs 38-47, respectively); Day 22 (SD 59; Follow-up)
measure: Change from Baseline in vital signs at the indicated time points in Cohort 13 of Part C
timeFrame: Baseline (Day -1; SD 80); Days 1-7 (SDs 81-87, respectively); Day 19 (SD 99; Follow-up)
measure: Change from Baseline in vital signs at the indicated time points in Cohort 14 of Part C
timeFrame: Baseline (Day -1; SD 80); Days 1-10 (SDs 81-90, respectively); Day 22 (SD 102; Follow-up)
measure: Change from Baseline in vital signs at the indicated time points in Part D
timeFrame: Baseline (SD 122); Days 1-13 (SDs 123-135, respectively); Day 25 (SD 147; Follow-up)
measure: Change from Baseline in electrocardiogram parameters at the indicated time points in Parts A and B
timeFrame: 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)
measure: Change from Baseline in electrocardiogram parameters at the indicated time points in Cohort 13 in Part C
timeFrame: Baseline (Day -1; SD 80); Days 1, 3, 5, and 7 (SDs 81, 83, 85, and 87, respectively); Day 19 (SD 99; Follow-up)
measure: Change from Baseline in electrocardiogram parameters at the indicated time points in Cohort 14 in Part C
timeFrame: 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)
measure: Change from Baseline in electrocardiogram parameters at the indicated time points in Part D
timeFrame: 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)
measure: Number of participants with an infusion site reaction
timeFrame: up to 14 days after the last infusion of study drug (SD 182)
measure: 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
timeFrame: Days 1-3
measure: Mean Cmax and Ct in blood at the indicated time points in Cohort 4 in Part A
timeFrame: Days 1-3
measure: Mean Cmax and Ct in blood at the indicated time points in Part B
timeFrame: Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)
measure: Mean Cmax and Ct in blood at the indicated time points in Cohort 13 in Part C
timeFrame: Days 1-7 (SDs 81-87, respectively)
measure: Mean Cmax and Ct in blood at the indicated time points in Cohort 14 in Part C
timeFrame: Days 1-10 (SDs 81-90, respectively)
measure: Mean Cmax and Ct in blood at the indicated time points in Part D
timeFrame: Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)
measure: Mean time to peak plasma concentration (Tmax) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A
timeFrame: Days 1-3
measure: Mean Tmax in blood at the indicated time points in Cohort 4 in Part A
timeFrame: Days 1-3
measure: Mean Tmax in blood at the indicated time points in Part B
timeFrame: Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)
measure: Mean Tmax in blood at the indicated time points in Cohort 13 in Part C
timeFrame: Days 1-7 (SDs 81-87, respectively)
measure: Mean Tmax in blood at the indicated time points in Cohort 14 in Part C
timeFrame: Days 1-10 (SDs 81-90, respectively)
measure: Mean Tmax in blood at the indicated time points in Part D
timeFrame: Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)
measure: 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
timeFrame: Days 1-3
measure: Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 4 in Part A
timeFrame: Days 1-3
measure: Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part B
timeFrame: Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)
measure: Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 13 in Part C
timeFrame: Days 1-7 (SDs 81-87, respectively)
measure: Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Cohort 14 in Part C
timeFrame: Days 1-10 (SDs 81-90, respectively)
measure: Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part D
timeFrame: Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)
measure: Mean elimination rate constant (Kel) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A
timeFrame: Days 1-3
measure: Mean Kel in blood at the indicated time points in Cohort 4 in Part A
timeFrame: Days 1-3
measure: Mean Kel in blood at the indicated time points in Part B
timeFrame: Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)
measure: Mean Kel in blood at the indicated time points in Cohort 13 in Part C
timeFrame: Days 1-7 (SDs 81-87, respectively)
measure: Mean Kel in blood at the indicated time points in Cohort 14 in Part C
timeFrame: Days 1-10 (SDs 81-90, respectively)
measure: Mean Kel in blood at the indicated time points in Part D
timeFrame: Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)
measure: Mean elimination half-life (t1/2) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A
timeFrame: Days 1-3
measure: Mean t1/2 in blood at the indicated time points in Cohort 4 in Part A
timeFrame: Days 1-3
measure: Mean t1/2 in blood at the indicated time points in Part B
timeFrame: Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)
measure: Mean t1/2 in blood at the indicated time points in Cohort 13 in Part C
timeFrame: Days 1-7 (SDs 81-87, respectively)
measure: Mean t1/2 in blood at the indicated time points in Cohort 14 in Part C
timeFrame: Days 1-10 (SDs 81-90, respectively)
measure: Mean t1/2 in blood at the indicated time points in Part D
timeFrame: Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)
measure: Mean clearance in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A
timeFrame: Days 1-3
measure: Mean clearance in blood at the indicated time points in Cohort 4 in Part A
timeFrame: Days 1-3
measure: Mean clearance in urine at the indicated time points in Part A
timeFrame: Baseline (Day -1); Days 1-3
measure: Mean clearance in blood at the indicated time points in Part B
timeFrame: Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)
measure: Mean clearance in urine at the indicated time points in Part B
timeFrame: Baseline (Day -1; SD 37); Days 1-3 and 7-10 (SDs 38-40 and 44-47, respectively)
measure: Mean clearance in blood at the indicated time points in Cohort 13 in Part C
timeFrame: Days 1-7 (SDs 81-87, respectively)
measure: Mean clearance in urine at the indicated time points in Cohort 13 in Part C
timeFrame: Baseline (Day -1; SD 80); Days 1-7 (SDs 81-87, respectively)
measure: Mean clearance in blood at the indicated time points in Cohort 14 in Part C
timeFrame: Days 1-10 (SDs 81-90, respectively)
measure: Mean clearance in urine at the indicated time points in Cohort 14 in Part C
timeFrame: Baseline (Day -1; SD 80); Days 1-10 (SDs 81-90, respectively)
measure: Mean clearance in blood at the indicated time points in Part D
timeFrame: Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)
measure: Mean clearance in urine at the indicated time points in Part D
timeFrame: Baseline (Day -1; SD 123); Days 1-3 (SDs 124-126, respectively); Days 10-13 (SDs 133-136, respectively)
measure: Mean volume of distribution (VzVdss) in blood at the indicated time points in Cohorts 1-3 and 5-8 in Part A
timeFrame: Days 1-3
measure: Mean VzVdss in blood at the indicated time points in Cohort 4 in Part A
timeFrame: Days 1-3
measure: Mean VzVdss in blood at the indicated time points in Part B
timeFrame: Days 1, 2, 4, 8, 9, and 10 (SDs 38, 39, 41, 45, 46, and 47, respectively)
measure: Mean VzVdss in blood at the indicated time points in Cohort 13 in Part C
timeFrame: Days 1-7 (SDs 81-87, respectively)
measure: Mean VzVdss in blood at the indicated time points in Cohort 14 in Part C
timeFrame: Days 1-10 (SDs 81-90, respectively)
measure: Mean VzVdss in blood at the indicated time points in Part D
timeFrame: Days 1, 2, 4, 11, 12, and 13 (SDs 124, 125, 127, 134, 135, and 136, respectively)
measure: Mean cumulative excretion of unchanged drug in urine (Ae) at the indicated time points in Part A
timeFrame: Baseline (Day -1); Days 1-3
measure: Mean Ae at the indicated time points in Part B
timeFrame: Baseline (Day -1; SD 37); Days 1-3 and 7-10 (SDs 38-40 and 44-47, respectively)
measure: Mean Ae at the indicated time points in Cohort 13 in Part C
timeFrame: Baseline (Day -1; SD 80); Days 1-7 (SDs 81-87, respectively)
measure: Mean Ae at the indicated time points in Cohort 14 in Part C
timeFrame: Baseline (Day -1; SD 80); Days 1-10 (SDs 81-90, respectively)
measure: Mean Ae at the indicated time points in Part D
timeFrame: Baseline (Day -1; SD 123); Days 1-3 (SDs 124-126, respectively); Days 10-13 (SDs 133-136, respectively)
Secondary outcomes:
measure: Number of elderly participants with any non-serious and any serious adverse event
timeFrame: up to Day 15
measure: Number of elderly participants with an adverse event of the indicated causality and severity
timeFrame: up to Day 15
measure: Number of participants with abnormal, clinically significant hematology and clinical chemistry parameters at the indicted time points in Part A for elderly participants
timeFrame: Baseline (Day -1); Days 3, 5, 7, and 15 (Follow-up)
measure: Change from Baseline in vital signs at the indicated time points in Part A for elderly participants
timeFrame: Baseline (Day -1); Days 1-3; Day 5; Day 7; Day 15 (Follow-up)
measure: Change from Baseline in electrocardiogram parameters at the indicated time points in Part A for elderly participants
timeFrame: Baseline (Day -1); Day 1; Day 3; Follow-up visit (Day 15)
measure: Number of elderly participants with an infusion site reaction
timeFrame: up to Day 15
measure: Mean Cmax and Ct in blood at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Mean Tmax in blood at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Mean AUC0-24, AUC0-t, and AUC0-∞ in blood at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Mean Kel in blood at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Mean t1/2 in blood at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Mean clearance in blood at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Mean clearance in urine at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Mean VzVdss in blood at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Mean Ae at the indicated time points in Part A for elderly participants
timeFrame: Days 1-3
measure: Number of elderly participants using concomitant medications
timeFrame: up to Day 15
Other outcomes:
Locations:
city: Melbourne
country: Australia
state: Victoria
Study officials:
affiliation: Nucleus Network
name: Jason Lickliter
role: PRINCIPAL_INVESTIGATOR
References:
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.