Evaluation of the Pharmacokinetics, Safety, and Tolerability of Intravenous ETX2514 and Sulbactam Administered Concurrently to Subjects With Various Degrees of Renal Impairment and Healthy Matched Control Subjects

NCT03310463 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: CS2514-2017-0002
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 3

Brief Summary

This research project is being conducted to look at the pharmacokinetics (PK; how the human body processes a substance), safety, and tolerability of a single dose of ETX2514 and sulbactam (ETX2514SUL) when concurrently administered by separate intravenous (IV) infusion in participants with various degrees of renal impairment (RI), in participants with end-stage renal disease (ESRD) who are on hemodialysis (HD), and in healthy matched control participants with normal renal function.

Conditions

Acinetobacter Baumannii Infection

Keywords

infection; gram-negative bacterium; renal impairment

Outcome Measures

Primary Outcomes (41)

• Mean maximum observed drug concentration (Cmax) in blood: Cohorts 1 and 2

  Venous blood will be collected for ETX2514SUL pharmacokinetic (PK) analyses.

  Days 1 to 3: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose")

• Mean Cmax in blood: Cohorts 3 and 4

  Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 4: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose")

• Mean Cmax in blood: Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines. Hemodialysis will be started approximately 1 hour after the end of infusion. If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session.

  Days 1 to 4. Period 1 (post-hemodialysis): predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Period 2 (pre-hemodialysis): approximately 4, 5, 6, and 7 hours after the start of infusion

• Mean time to reach the maximum concentration (tmax) in blood: Cohorts 1 and 2

  Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 3: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose")

• Mean tmax in blood: Cohorts 3 and 4

  Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 4: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose")

• Mean tmax in blood: Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines. Hemodialysis will be started approximately 1 hour after the end of infusion. If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session.

  Days 1 to 4. Period 1 (post-hemodialysis): predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Period 2 (pre-hemodialysis): approximately 4, 5, 6, and 7 hours after the start of infusion

• Mean AUC0-24 in blood: Cohorts 1 and 2

  AUC0-24 is defined as the area under the concentration versus time curve from time zero to 24 hours postdose. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 3: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose")

• Mean AUC0-48 in blood: Cohorts 1 and 2

  AUC0-48 is defined as the area under the concentration versus time curve from time zero to 48 hours postdose. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 3: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose")

• Mean AUC0-last in blood: Cohorts 1 and 2

  AUC0-last is defined as the area under the concentration versus time curve from time zero to the time of the last quantifiable concentration after dosing. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 3: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose")

• Mean AUC0-∞ in blood: Cohorts 1 and 2

  AUC0-∞ is defined as the area under the concentration versus time curve from time zero extrapolated to infinity. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 3: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose")

• Mean AUC0-24 in blood: Cohorts 3 and 4

  AUC0-24 is defined as the area under the concentration versus time curve from time zero to 24 hours postdose. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 4: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose")

• Mean AUC0-48 in blood: Cohorts 3 and 4

  AUC0-48 is defined as the area under the concentration versus time curve from time zero to 48 hours postdose. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 4: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose")

• Mean AUC0-60 in blood: Cohorts 3 and 4

  AUC0-60 is defined as the area under the concentration versus time curve from time zero to 60 hours. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 4: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose")

• Mean AUC0-last in blood: Cohorts 3 and 4

  AUC0-last is defined as the area under the concentration versus time curve from time zero to the time of the last quantifiable concentration after dosing. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 4: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose")

• Mean AUC0-∞ in blood: Cohorts 3 and 4

  AUC0-∞ is defined as the area under the concentration versus time curve from time zero extrapolated to infinity. Venous blood will be collected for ETX2514SUL PK analyses.

  Days 1 to 4: predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose")

• Mean AUC0-24 in blood: Cohort 5

  AUC0-24 is defined as the area under the concentration versus time curve from time zero to 24 hours postdose. Venous blood will be collected for ETX2514SUL PK analyses in Period 1. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines. Hemodialysis will be started approximately 1 hour after the end of infusion. If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session.

  Days 1 to 4. Periods 1 (post-hemodialysis): predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Period 2 (pre-hemodialysis): approximately 4, 5, 6, and 7 hours after the start of infusion

• Mean AUC0-48 in blood: Cohort 5

  AUC0-48 is defined as the area under the concentration versus time curve from time zero to 48 hours postdose. Venous blood will be collected for ETX2514SUL PK analyses in Period 1. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines. Hemodialysis will be started approximately 1 hour after the end of infusion. If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session.

  Days 1 to 4. Periods 1 (post-hemodialysis): predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Period 2 (pre-hemodialysis): approximately 4, 5, 6, and 7 hours after the start of infusion

• Mean AUC0-60 in blood: Cohort 5

  AUC0-60 is defined as the area under the concentration versus time curve from time zero to 60 hours postdose. Venous blood will be collected for ETX2514SUL PK analyses in Period 1. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines. Hemodialysis will be started approximately 1 hour after the end of infusion. If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session.

  Days 1 to 4. Periods 1 (post-hemodialysis): predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Period 2 (pre-hemodialysis): approximately 4, 5, 6, and 7 hours after the start of infusion

• Mean AUC0-last in blood: Cohort 5

  AUC0-last is defined as the area under the concentration versus time curve from time zero to the time of the last quantifiable concentration after dosing. Venous blood will be collected for ETX2514SUL PK analyses in Period 1. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines. Hemodialysis will be started approximately 1 hour after the end of infusion. If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session.

  Days 1 to 4. Periods 1 (post-hemodialysis): predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Period 2 (pre-hemodialysis): approximately 4, 5, 6, and 7 hours after the start of infusion

• Mean AUC0-∞ in blood: Cohort 5

  AUC0-∞ is defined as the area under the concentration versus time curve from time zero extrapolated to infinity. Venous blood will be collected for ETX2514SUL PK analyses in Period 1. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous. Hemodialysis will be started approximately 1 hour after the end of infusion. If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session.

  Days 1 to 4. Periods 1 (post-hemodialysis): predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Period 2 (pre-hemodialysis): approximately 4, 5, 6, and 7 hours after the start of infusion

• Mean terminal elimination rate constant (λz) in blood: Cohorts 1 and 2

  Venous blood will be collected for ETX2514SUL PK analyses at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose"). Infusion can begin at any time on Day 1; thus, 48 hours post infusion could fall on Day 3.

  Days 1 to 3

• Mean λz in blood: Cohorts 3 and 4

  Venous blood will be collected for ETX2514SUL PK analyses at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose"). Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Days 1 to 4

• Mean λz in blood: Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1 at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines at approximately 4, 5, 6, and 7 hours after the start of infusion (where hemodialysis will be started approximately 1 hour after the end of infusion). If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Periods 1 (post-hemodialysis) and 2 (pre-hemodialysis): Days 1 to 4

• Mean terminal half life (t1/2) in blood: Cohorts 1 and 2

  Venous blood will be collected for ETX2514SUL PK analyses at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose"). Infusion can begin at any time on Day 1; thus, 48 hours post infusion could fall on Day 3.

  Days 1 to 3

• Mean t1/2 in blood: Cohorts 3 and 4

  Venous blood will be collected for ETX2514SUL PK analyses at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose"). Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Days 1 to 4

• Mean t1/2 in blood: Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1 at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines at approximately 4, 5, 6, and 7 hours after the start of infusion (where hemodialysis will be started approximately 1 hour after the end of infusion). If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Periods 1 (post-hemodialysis) and 2 (pre-hemodialysis): Days 1 to 4

• Mean total clearance (CL) from blood: Cohorts 1 and 2

  Venous blood will be collected for ETX2514SUL PK analyses at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose"). Infusion can begin at any time on Day 1; thus, 48 hours post infusion could fall on Day 3.

  Days 1 to 3

• Mean CL from blood: Cohorts 3 and 4

  Venous blood will be collected for ETX2514SUL PK analyses at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose"). Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Days 1 to 4

• Mean CL in blood: Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1 at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines at approximately 4, 5, 6, and 7 hours after the start of infusion (where hemodialysis will be started approximately 1 hour after the end of infusion). If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Periods 1 (post-hemodialysis) and 2 (pre-hemodialysis): Days 1 to 4

• Mean volume of distribution in the terminal elimination phase (Vz) in blood: Cohorts 1 and 2

  Venous blood will be collected for ETX2514SUL PK analyses at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, and 48 hours after the start of infusion ("postdose"). Infusion can begin at any time on Day 1; thus, 48 hours post infusion could fall on Day 3.

  Days 1 to 3

• Mean Vz in blood: Cohorts 3 and 4

  Venous blood will be collected for ETX2514SUL PK analyses at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, and 60 hours after the start of infusion ("postdose"). Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Days 1 to 4

• Mean Vz in blood: Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1 at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines at approximately 4, 5, 6, and 7 hours after the start of infusion (where hemodialysis will be started approximately 1 hour after the end of infusion). If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Periods 1 (post-hemodialysis) and 2 (pre-hemodialysis): Days 1 to 4

• Mean cumulative amount of drug excreted in urine (Aeu): Cohorts 1 and 2

  Urine for ETX2514SUL PK analyses will be collected continuously from participants capable of producing urine at the following intervals: predose (a single void within 30 minutes prior to the start of infusion) and 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after the start of infusion. Infusion can begin at any time on Day 1; thus, 24 hours post infusion could fall on Day 2.

  Days 1 and 2

• Mean Aeu: Cohorts 3 and 4

  Urine for ETX2514SUL PK analyses will be collected continuously from participants capable of producing urine at the following intervals: predose (a single void within 30 minutes prior to the start of infusion), and 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 60 hours after the start of infusion. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Days 1 to 4

• Mean renal clearance (CLR): Cohorts 1 and 2

  Urine for ETX2514SUL PK analyses will be collected continuously from participants capable of producing urine at the following intervals: predose (a single void within 30 minutes prior to the start of infusion) and 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after the start of infusion. Infusion can begin at any time on Day 1; thus, 24 hours post infusion could fall on Day 2.

  Days 1 and 2

• Mean CLR: Cohorts 3 and 4

  Urine for ETX2514SUL PK analyses will be collected continuously from participants capable of producing urine at the following intervals: predose (a single void within 30 minutes prior to the start of infusion), and 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 60 hours after the start of infusion. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Days 1 to 4

• Mean fraction of the dose renally eliminated (Feu): Cohorts 1 and 2

  Urine for ETX2514SUL PK analyses will be collected continuously from participants capable of producing urine at the following intervals: predose (a single void within 30 minutes prior to the start of infusion) and 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after the start of infusion. Infusion can begin at any time on Day 1; thus, 24 hours post infusion could fall on Day 2.

  Days 1 and 2

• Mean Feu: Cohorts 3 and 4

  Urine for ETX2514SUL PK analyses will be collected continuously from participants capable of producing urine at the following intervals: predose (a single void within 30 minutes prior to the start of infusion), and 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, and 48 to 60 hours after the start of infusion. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Days 1 to 4

• Mean amount dialyzed (AHD): Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1 at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines at approximately 4, 5, 6, and 7 hours after the start of infusion (where hemodialysis will be started approximately 1 hour after the end of infusion). If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Periods 1 (post-hemodialysis) and 2 (pre-hemodialysis): Days 1 to 4

• Mean fraction of the dose removed by hemodialysis (FHD): Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1 at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines at approximately 4, 5, 6, and 7 hours after the start of infusion (where hemodialysis will be started approximately 1 hour after the end of infusion). If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Periods 1 (post-hemodialysis) and 2 (pre-hemodialysis): Days 1 to 4

• Estimated hemodialysis (HD) recovery clearance (CLD Recovery): Cohort 5

  Venous blood will be collected for ETX2514SUL PK analyses in Period 1 at predose, and 0.5, 1, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 60 hours after the start of infusion. Blood will be collected for ETX2514SUL PK analyses in Period 2 from arterial and venous lines at approximately 4, 5, 6, and 7 hours after the start of infusion (where hemodialysis will be started approximately 1 hour after the end of infusion). If the hemodialysis session takes longer than 7 hours after the start of infusion, a final sample will be collected at the end of the hemodialysis session. Infusion can begin at any time on Day 1; thus, 60 hours post infusion could fall on Day 4.

  Periods 1 (post-hemodialysis) and 2 (pre-hemodialysis): Days 1 to 4

Secondary Outcomes (7)

• Number of participants with any non-serious adverse event (AE)

  Cohorts 1 and 2: Days 1, 2, 3, and 7. Cohorts 3 and 4: Days 1, 2, 3, 4, and 7. Cohort 5: Period 1: Days 1, 2, 3, and 4; Washout. Period 2: Days -1, 2, 3, 4, and 7

• Number of participants with any serious adverse event (SAE)

  Cohorts 1 and 2: Days 1, 2, 3, and 7. Cohorts 3 and 4: Days 1, 2, 3, 4, and 7. Cohort 5: Period 1: Days 1, 2, 3, and 4; Washout. Period 2: Days -1, 2, 3, 4, and 7.

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

  Cohorts 1 and 2: Days 1, 2, 3, and 7. Cohorts 3 and 4: Days 1, 2, 3, 4, and 7. Cohort 5: Period 1: Days 1, 2, 3, and 4; Washout. Period 2: Days -1, 2, 3, 4, and 7

• Number of participants with abnormal, clinically significant physical examination findings at the indicated time points

  Cohorts 1 and 2: Screening; Days -1 and 7. Cohorts 3 and 4: Screening; Days -1 and 7. Cohort 5: Period 1: Screening; Day -1. Period 2: Day 7

• Number of participants with abnormal, clinically significant vital sign values at the indicated time points

  Cohorts 1 and 2: Screening; Days -1, 1, 2, 3, and 7. Cohorts 3 and 4: Screening; Days -1, 1, 2, 3, 4, and 7. Cohort 5: Period 1: Screening; Days -1, 1, 2, 3, and 4. Period 2: Days -1, 1, 2, 3, 4, and 7.

Study Arms (5)

Cohort 1, Normal Renal Function

EXPERIMENTAL

Healthy control participants matched to participants enrolled in Cohort 4 (creatinine clearance ≥90 milliliters per minute \[mL/min\] estimated by the Cockcroft-Gault equation) will receive ETX2514SUL as a single dose of up to 1000 milligrams (mg) ETX2514 and 1000 mg sulbactam given by concurrent 3-hour intravenous (IV) infusion.

Drug: ETX2514SUL

Cohort 2, Mild Renal Impairment

EXPERIMENTAL

Participants with mild renal impairment (estimated glomerular filtration rate \[eGFR\] ≥60 to \<90 mL/min/1.73 meters squared \[m\^2\] calculated by the Modified Diet in Renal Disease \[MDRD\] equation) will receive ETX2514SUL as a single dose of up to 1000 mg ETX2514 and 1000 mg sulbactam given by concurrent 3-hour IV infusion.

Drug: ETX2514SUL

Cohort 3, Moderate Renal Impairment

EXPERIMENTAL

Participants with moderate renal impairment (eGFR ≥30 to \<60 mL/min/1.73 m\^2 calculated by the MDRD equation) will receive ETX2514SUL as a single dose of up to 1000 mg ETX2514 and 1000 mg sulbactam given by concurrent 3-hour IV infusion.

Drug: ETX2514SUL

Cohort 4, Severe Renal Impairment

EXPERIMENTAL

Participants with severe renal impairment (eGFR \<30 mL/min/1.73 m\^2 calculated by the MDRD equation) and not on hemodialysis (HD) will receive ETX2514SUL as a single dose of up to 1000 mg ETX2514 and 1000 mg sulbactam given by concurrent 3-hour IV infusion.

Drug: ETX2514SUL

Cohort 5, ESRD on a Stable HD Regimen

EXPERIMENTAL

Participants with end-stage renal disease (ESRD) on a stable HD regimen (determined by medical history) will receive ETX2514SUL as a single dose of up to 1000 mg ETX2514 and 1000 mg sulbactam given by concurrent 3-hour IV infusion.

Drug: ETX2514SUL

Interventions

ETX2514SUL DRUG

Single dose of up to 1000 mg ETX2514 and 1000 mg sulbactam given by concurrent 3-hr IV infusion

Cohort 1, Normal Renal Function; Cohort 2, Mild Renal Impairment; Cohort 3, Moderate Renal Impairment; Cohort 4, Severe Renal Impairment; Cohort 5, ESRD on a Stable HD Regimen

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All Participants (Cohorts 1-5)
• Is capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements and study-related procedures
• Willing to be confined to the Clinical Research Unit for the entire duration required by the protocol, able to comply with all study-related requirements and able to adhere to study restrictions and visit schedules
• Male or female, between 18 and 75 years of age (inclusive) at the time of Screening
• Body mass index (BMI) between 18 and 40 kilograms per meters squared (kg/m\^2) (inclusive) at the time of Screening
• Female participants must:
• be non-pregnant and non-lactating;
• be either postmenopausal (defined as amenorrhea for ≥12 months with a confirmed follicle stimulating hormone \[FSH\] ≥40 milli International Units per milliliter \[mIU/mL\]), surgically sterile (defined as having undergone hysterectomy and/or bilateral oophorectomy), practice total abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence is not acceptable), or agree to use an appropriate method of birth control consistently throughout the study and continue to use this method for 30 days (or 5 half-lives, whichever is longer) after study drug administration;
• Hormonal contraception and double barrier methods of non-hormonal contraception are permitted in this study. Acceptable forms of contraception include the following:
• oral, implantable, transdermal, injectable, or intravaginal hormonal contraception used consistently for at least 1 month prior to Screening;
• intrauterine device;
• female condom with spermicide (cream, spray, gel, suppository, contraceptive sponge, or polymer film);
• contraceptive sponge with condom;
• diaphragm with spermicide (with or without a condom);
• cervical cap with spermicide (with or without a condom);

You may not qualify if:

• All Participants (Cohorts 1-5)
• Known sensitivity or idiosyncratic reaction to any compound present in ETX2514 or sulbactam, its related compounds, or any compound listed as being present in the study formulation
• Participants with a history of hypersensitivity or serious adverse reaction to β-lactam agents (penicillin, cephalosporin, carbapenem, or sulbactam)
• Pregnant (positive pregnancy test) or lactating women at Screening or Day -1. If serum human chorionic gonadotropin (hCG) pregnancy test results are indeterminate, follow-up testing should be performed to determine eligibility.
• All female participants will not be pregnant and will have a negative pregnancy test at Screening and Day -1, with the following exception: females receiving dialysis with an indeterminate pregnancy test result or persistently low hCG resulting in a false positive pregnancy test may be included in the study at the discretion of the Investigator and notification of the Sponsor. Postmenopausal participants with a result outside the post-menopausal range or an indeterminate pregnancy test will undergo additional testing for FSH to confirm postmenopausal status prior to study enrollment.
• Any clinically significant (CS) concomitant disease or condition (including treatment for such conditions) that, in the opinion of the Investigator, could either interfere with the study drug or pose an unacceptable risk to the participant
• Any other CS abnormalities in laboratory test results at Screening that would, in the opinion of the Investigator, increase the participant's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data
• Uncontrolled medical condition (treated or untreated) considered to be CS by the Investigator
• Treatment with another investigational drug or device study within 30 days (or 5 half-lives, whichever is longer) prior to study drug administration on Day 1
• Participant has taken probenecid within 30 days prior to study drug administration on Day 1
• Has experienced an illness that is considered by the Investigator to be CS within 2 weeks of study drug administration on Day 1
• Has donated or lost a significant volume (\>450 mL) of blood within 56 days or plasma within 7 days prior to Day -1
• Participated in strenuous exercise from 48 hours prior to Day -1 or during the study through the final end of study assessment
• Evidence of previous myocardial infarction (did not include ST segment changes associated with repolarization)
• Any conduction abnormality (including but not specific to atrioventricular block \[2nd degree or higher\], Wolff Parkinson White syndrome \[unless curative radio ablation therapy\])

Sponsors & Collaborators

• Entasis Therapeutics: lead

Study Sites (3)

DaVita Clinical Research

Lakewood, Colorado, 80228, United States

Location

University of Miami, Division of Clinical Pharmacology

Miami, Florida, 33136, United States

Location

Davita Clinical Research

Minneapolis, Minnesota, 55404, United States

Location

MeSH Terms

Conditions

Infections; Renal Insufficiency

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 25, 2017
• First Posted: October 16, 2017
• Study Start: October 3, 2017
• Primary Completion: May 25, 2018
• Study Completion: May 29, 2018
• Last Updated: June 14, 2018

Record last verified: 2018-06

Locations

US (3)