Clinical trial NCT03491748: A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK, the Measure of How the Human Body Processes a Substance) of ETX0282 When Administered Orally to Healthy Participants
Official title: A Phase 1, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral ETX0282 Administered in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Pharmacokinetics
ETX0282
Single Ascending Dose
Multiple Ascending Doses
ETX1317
Cefpodoxime Proxetil
Cefpodoxime
Enterobacteriaceae Infections
Lead sponsor: Entasis Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-04-09
Enrollment: 99
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 investigate the safety, tolerability, and pharmacokinetics (PK) of a single ascending dose (SAD) and multiple ascending doses (MAD) of oral ETX0282 when administered alone and in combination with cefpodoxime proxetil in healthy adult participants.

Detailed description: This Phase 1, single-center, double-blind, randomized, placebo-controlled study will be conducted to:

* Determine the safety and tolerability of oral ETX0282 when administered as a SAD and MAD to healthy participants;
* Determine the safety and tolerability of oral ETX0282 when administered as a single oral dose in combination with cefpodoxime proxetil to healthy participants;
* Characterize the PK in plasma and in urine of ETX0282 and ETX1317 following administration of single and multiple oral doses of ETX0282 in healthy participants; and
* Determine the PK profile in plasma and in urine of ETX0282 and ETX1317 and of cefpodoxime proxetil and cefpodoxime following administration of single oral doses of ETX0282 and cefpodoxime proxetil alone and when ETX0282 is co-administered with cefpodoxime proxetil at the same time as single oral doses in healthy participants.

Eligibility criteria: Inclusion Criteria:

* Aged 18 to 55 years (inclusive) for all participants except for those in Cohort 6 (in Part A); for Cohort 6, only participants aged ≥ 65 years will be enrolled.
* Be in general good health without 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) ≥18.0 kilograms per meters squared (kg/m\^2) and ≤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, hepatitis C virus antibody, and human immunodeficiency virus at Screening; and drugs of abuse, alcohol predose on Day -1
* Female participants must be of non-childbearing potential (postmenopausal or with evidence of tubal ligation) or using a medically acceptable (highly effective method) 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. Men should not donate sperm during the study or for 90 days after the final dose of study medication.

Exclusion Criteria:

* History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antimicrobial (e.g., penicillin or cephalosporin)
* History of hypersensitivity or severe allergic reaction of any type to medications, bee stings, food, or environmental factors. A severe allergic reaction is defined as any of the following: anaphylaxis, urticaria, or angioedema.
* 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 were at least 30 days between the last dose in a prior study and dose administration in 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
* Surgery within 30 days before study enrolment
* Unwillingness or inability to comply with the study protocol for any other reason

Primary outcomes:
measure: Number of participants with any non-serious adverse event
timeFrame: Up to 14 days after the last dose of study drug (Study Day [SD] 210)
measure: Number of participants with any serious adverse event
timeFrame: Up to 14 days after the last dose of study drug (SD 210)
measure: Number of participants with an adverse event of the indicated causality and severity
timeFrame: Up to 14 days after the last dose of study drug (SD 210)
measure: Part A: Number of participants with abnormal, clinically significant hematology, clinical chemistry, and urinalysis laboratory values at the indicated time points
timeFrame: Screening (Day -1) up to Day 15±2 (Follow-up)
measure: Part B: Number of participants with abnormal, clinically significant hematology, clinical chemistry, and urinalysis laboratory values at the indicated time points
timeFrame: Screening (Day -1; SD 44) up to Day 18±2 (SD 62±2; Follow-up)
measure: Part C: Number of participants with abnormal, clinically significant hematology, clinical chemistry, and urinalysis laboratory values at the indicated time points
timeFrame: Screening (Day -1; SD 91) up to Day 22±2 (SD 113±2; Follow-up)
measure: Part D: Number of participants with abnormal, clinically significant hematology, clinical chemistry, and urinalysis laboratory values at the indicated time points
timeFrame: Screening (Day -1; SD 142) up to Day 21±2 (SD 163±2; Follow-up)
measure: Part G: Number of participants with abnormal, clinically significant hematology, clinical chemistry, and urinalysis laboratory values at the indicated time points
timeFrame: Screening (Day -1; SD 192) up to Day 18±2 (SD 210±2; Follow-up)
measure: Part A: Number of participants with abnormal, clinically significant vital sign values at the indicated time points
timeFrame: Screening (Day -1) up to Day 15±2 (Follow-up)
measure: Part B: Number of participants with abnormal, clinically significant vital sign values at the indicated time points
timeFrame: Screening (Day -1; SD 44) up to Day 18±2 (SD 62±2; Follow-up)
measure: Part C: Number of participants with abnormal, clinically significant vital sign values at the indicated time points
timeFrame: Screening (Day -1; SD 91) up to Day 22±2 (SD 113±2; Follow-up)
measure: Part D: Number of participants with abnormal, clinically significant vital sign values at the indicated time points
timeFrame: Screening (Day -1; SD 142) up to Day 21±2 (SD 163±2; Follow-up)
measure: Part G: Number of participants with abnormal, clinically significant vital sign values at the indicated time points
timeFrame: Screening (Day -1; SD 192) up to Day 18±2 (SD 210±2; Follow-up)
measure: Part A: Number of participants with abnormal, clinically significant electrocardiogram values at the indicated time points
timeFrame: Screening (Day -1) up to Day 15±2 (Follow-up)
measure: Part B: Number of participants with abnormal, clinically significant electrocardiogram values at the indicated time points
timeFrame: Screening (Day -1; SD 44) up to Day 18±2 (SD 62±2; Follow-up)
measure: Part C: Number of participants with abnormal, clinically significant electrocardiogram values at the indicated time points
timeFrame: Screening (Day -1; SD 91) up to Day 22±2 (SD 113±2; Follow-up)
measure: Part D: Number of participants with abnormal, clinically significant electrocardiogram values at the indicated time points
timeFrame: Screening (Day -1; SD 142) up to Day 21±2 (SD 163±2; Follow-up)
measure: Part G: Number of participants with abnormal, clinically significant electrocardiogram values at the indicated time points
timeFrame: Screening (Day -1; SD 192) up to Day 18±2 (SD 210±2; Follow-up)
measure: Part A: Mean peak plasma concentration (Cmax) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean plasma concentration at time t (Ct) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean time to peak plasma concentration (Tmax) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean area under the concentration-time curve from time 0 to 24 hours (AUC0-24) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), and 24 (Day 2) hours postdose
measure: Part A: Mean area under the concentration-time curve from time 0 to the last time point evaluated (AUC0-t) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean area under the concentration-time curve from time 0 and extrapolated to infinity (AUC0-∞) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean elimination rate constant (Kel) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean elimination half-life (t½) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean clearance (CL) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean volume of distribution (Vdss) of ETX0282 and ETX1317 in blood in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean cumulative excretion of unchanged ETX0282 and ETX1317 in urine (Ae) in Cohorts 1 to 5
timeFrame: Prior to dosing (-6 to 0 hours; Day 1); 0 to 8 (Day 1), 8 to 24 (Day 2), 24 to 48 (Day 3), and 48 to 72 (Day 4) hours postdose
measure: Part A: Mean urinary clearance (CLR) of ETX0282 and ETX1317 in Cohorts 1 to 5
timeFrame: Prior to dosing (-6 to 0 hours; Day 1); 0 to 8 (Day 1), 8 to 24 (Day 2), 24 to 48 (Day 3), and 48 to 72 (Day 4) hours postdose
measure: Part A: Mean fraction of the administered dose of ETX0282 and ETX1317 that is excreted unchanged in the urine (fe) in Cohorts 1 to 5
timeFrame: Prior to dosing (-6 to 0 hours; Day 1); 0 to 8 (Day 1), 8 to 24 (Day 2), 24 to 48 (Day 3), and 48 to 72 (Day 4) hours postdose
measure: Part A: Mean dose proportionality of ETX0282 and ETX1317 in Cohorts 1 to 5
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part C: Mean Cmax of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean Ct of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean Tmax of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean AUC0-24 of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean AUC0-t of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean AUC0-∞ of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean AUC from time 0 to the end of the dosing period (AUC0-tau) of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean accumulation ratio (R0) of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean Kel of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean t½ of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean CL of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean Vdss of ETX0282 and ETX1317 in blood
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part C: Mean Ae of ETX0282 and ETX1317
timeFrame: Days 1-4 and 8-11 (SDs 92-95 and 99-102): prior to dosing (-6 to 0 hours; first and last doses) and at 0-8, 8-24, 24-48, and 48-72 hours post first and last dose
measure: Part C: Mean CLR of ETX0282 and ETX1317
timeFrame: Days 1-4 and 8-11 (SDs 92-95 and 99-102): prior to dosing (-6 to 0 hours; first and last doses) and at 0-8, 8-24, 24-48, and 48-72 hours post first and last dose
measure: Part C: Mean fe of ETX0282 and ETX1317
timeFrame: Days 1-4 and 8-11 (SDs 92-95 and 99-102): prior to dosing (-6 to 0 hours; first and last doses) and at 0-8, 8-24, 24-48, and 48-72 hours post first and last dose
measure: Part C: Mean dose proportionality of ETX0282 and ETX1317
timeFrame: Days 1-3, 5, and 8 (SDs 92-94, 96, and 99): predose (30 min); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours post first dose; at troughs of Days 3, 5, and 8 (SDs 94, 96, and 99); at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post last dose
measure: Part D: Mean Cmax of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Ct of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Tmax of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean AUC0-24 of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part D: Mean AUC0-t of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean AUC0-∞ of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Kel of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean t½ of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean CL of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Vdss of ETX0282 and ETX1317 in blood
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Ae of ETX0282 and ETX1317
timeFrame: Days 1-10 (SDs 143-152): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part D: Mean CLR of ETX0282 and ETX1317
timeFrame: Days 1-10 (SDs 143-152): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part D: Mean fe of ETX0282 and ETX1317
timeFrame: Days 1-10 (SDs 143-152): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part D: Mean dose proportionality of ETX0282 and ETX1317
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Cmax of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Ct of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Tmax of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean AUC0-24 of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part D: Mean AUC0-t of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean AUC0-∞ of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Kel of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean t½ of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean CL of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Vdss of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part D: Mean Ae of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part D: Mean CLR of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part D: Mean fe of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part D: Mean dose proportionality of cefpodoxime proxetil and cefpodoxime following administration of cefpodoxime proxetil as a single oral dose either alone or in combination with ETX0282
timeFrame: Days 1-10 (SDs 143-152): predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48, and 72 hours postdose
measure: Part G: Mean Cmax of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean Ct of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean Tmax of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean AUC0-24 of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean AUC0-t of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean AUC0-∞ of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean AUC0-tau of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean R0 of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean Kel of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean t½ of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean CL of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean Vdss of ETX0282 and ETX1317 in blood
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean Ae of ETX0282 and ETX1317
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean CLR of ETX0282 and ETX1317
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean fe of ETX0282 and ETX1317
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
measure: Part G: Mean dose proportionality of ETX0282 and ETX1317
timeFrame: Days 1 and 4 (SDs 193 and 196): 30 minutes predose; 0.25, 0.5, 0.75, 1, 1.5, 2 (predose prior to subsequent dose), 2.5, 3, 4 (predose prior to subsequent dose), 7, 8, 12, and 16 hours postdose. Days 2 and 5 (SDs 194 and 197): 24 hours postdose
Secondary outcomes:
measure: Number of elderly participants with any non-serious adverse event
timeFrame: Up to 14 days after the last dose of study drug (SD 210)
measure: Number of elderly participants with any serious adverse event
timeFrame: Up to 14 days after the last dose of study drug (SD 210)
measure: Number of elderly participants with an adverse event of the indicated causality and severity
timeFrame: Up to 14 days after the last dose of study drug (SD 210)
measure: Part A: Number of elderly participants with abnormal, clinically significant hematology, clinical chemistry, and urinalysis laboratory values at the indicated time points
timeFrame: Screening (Day -1); Days 2, 3, 4, 7, and 15±2 (Follow-up)
measure: Part A: Number of elderly participants with abnormal, clinically significant vital sign values at the indicated time points
timeFrame: Screening (Day -1); Days 2, 3, 4, 7, and 15±2 (Follow-up)
measure: Part A: Number of elderly participants with abnormal, clinically significant electrocardiogram values at the indicated time points
timeFrame: Screening (Day -1); Days 1-7; Day 15±2 (Follow-up)
measure: Number of participants who received concomitant medications
timeFrame: Up to 14 days after the last dose of study drug (SD 210)
measure: Part A: Mean Cmax of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean Ct of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean Tmax of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean AUC0-24 of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), and 24 (Day 2) hours postdose
measure: Part A: Mean AUC0-t of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean AUC0-∞ of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean Kel of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean t½ of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean CL of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean Vdss of ETX0282 and ETX1317 in blood of elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part A: Mean Ae of ETX0282 and ETX1317 for elderly participants (Cohort 6)
timeFrame: Prior to dosing (-6 to 0 hours; Day 1); 0 to 8 (Day 1), 8 to 24 (Day 2), 24 to 48 (Day 3), and 48 to 72 (Day 4) hours postdose
measure: Part A: Mean CLR of ETX0282 and ETX1317 in urine for elderly participants (Cohort 6)
timeFrame: Prior to dosing (-6 to 0 hours; Day 1); 0 to 8 (Day 1), 8 to 24 (Day 2), 24 to 48 (Day 3), and 48 to 72 (Day 4) hours postdose
measure: Part A: Mean fe of ETX0282 and ETX1317 for elderly participants (Cohort 6)
timeFrame: Prior to dosing (-6 to 0 hours; Day 1); 0 to 8 (Day 1), 8 to 24 (Day 2), 24 to 48 (Day 3), and 48 to 72 (Day 4) hours postdose
measure: Part A: Mean dose proportionality of ETX0282 and ETX1317 for elderly participants (Cohort 6)
timeFrame: Predose (0); 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (Day 1), 24 (Day 2), 48 (Day 3), and 72 (Day 4) hours postdose
measure: Part B: Mean Cmax of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean Ct of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean Tmax of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean AUC0-24 of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, and 24 hours postdose
measure: Part B: Mean AUC0-t of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean AUC0-∞ of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean Kel of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean t½ of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean CL of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean Vdss of ETX0282 and ETX1317 in blood
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
measure: Part B: Mean Ae of ETX0282 and ETX1317
timeFrame: Days 1-7 (SDs 45-51): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part B: Mean CLR of ETX0282 and ETX1317
timeFrame: Days 1-7 (SDs 45-51): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part B: Mean fe of ETX0282 and ETX1317
timeFrame: Days 1-7 (SDs 45-51): prior to dosing (-6 to 0 hours) and at 0-8, 8-24, 24-48, and 48-72 hours postdose
measure: Part B: Mean dose proportionality of ETX0282 and ETX1317
timeFrame: Days 1-7 (SDs 45-51): predose (0), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 16, 24, 48, and 72 hours postdose
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Nucleus Network
state: Victoria
Study officials:
References: