To Investigate the Safety and Tolerability of Aztreonam-Avibactam (ATM-AVI)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01689207
First received: September 12, 2012
Last updated: July 1, 2014
Last verified: July 2014
  Purpose

This is a randomised, double-blind, 3-part study designed to investigate the safety and tolerability of ATM-AVI. The study aims to characterise the pharmacokinetics of ATM-AVI, when both drugs are administered alone (ATM or AVI) and in combination (ATM-AVI), following single administration, and following multiple administrations of ATM-AVI in healthy male and female (females of nonchildbearing potential) volunteers both young and elderly.


Condition Intervention Phase
Complicated Infection
Bacterial Infections
Drug: Avibactam (AVI)
Drug: Aztreonam (ATM)
Drug: combination of Aztreonam - Avibactam (ATM-AVI)
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: A Phase I, Randomised, Double-blind, 3-Part Study in Healthy Young and Elderly Subjects to Assess the Safety and Tolerability, and Investigate the Pharmacokinetics of Aztreonam and Avibactam Given Alone and in Combination (ATM-AVI)

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Part A: Safety profile in terms of adverse events, ECG, blood pressure, pulse, physical examination, body temperature, haematology, clinical chemistry, coagulation, urinalysis and Direct Coombs Test. [ Time Frame: Part A : up to 52 days ] [ Designated as safety issue: Yes ]
    from screening visit (Day -28) to 7 days post treatment period 3 (up to Day 22)

  • Part B: Safety profile in terms of adverse events, ECG, blood pressure, pulse, physical examination, body temperature, haematology, clinical chemistry, coagulation, urinalysis and Direct Coombs Test. [ Time Frame: PART B: up to 58 days ] [ Designated as safety issue: Yes ]
    from screening visit (Day -28) through follow up visit (up to Day 18)

  • Part C: Safety profile in terms of adverse events, ECG, blood pressure, pulse, physical examination, body temperature, haematology, clinical chemistry, coagulation, urinalysis and Direct Coombs Test. [ Time Frame: PART C: up to 56 days ] [ Designated as safety issue: Yes ]
    from screening visit (Day -28) through follow up visit (up to Day 17)


Secondary Outcome Measures:
  • Part A: PK- Plasma pharmacokinetic profile in terms of (see description) for ATM (alone) and AVI (alone) and ATM-AVI (combined) following single 1 hour IV infusions [ Time Frame: Day 1 of each crossover period: pre-dose, 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 5, 6, 8, 12 and 24 hours post dose ] [ Designated as safety issue: No ]
    Maximum plasma concentration (Cmax µg/mL), maximum plasma concentration at steady state (Css,max µg/mL), time to Cmax (tmax h), time to Css,max (tss,max h), minimum plasma concentration at the end of the dosing interval on Day 1 [C(6h)min h] and at steady state (Css,min h), time of last quantifiable plasma concentration (tlast h), area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration [AUC(0-t) µg.h/mL], from zero extrapolated to infinity (AUC µg.h/mL), during the dosing interval on Day 1 [AUC(0-6) µg.h/mL] and at steady state during the dosing interval [AUCss µg.h/mL].

  • Part A: PK- Plasma pharmacokinetic profile in terms of (see description) for ATM (alone) and AVI (alone) and ATM-AVI (combined) following single 1 hour IV infusions [ Time Frame: Day 1 of each crossover period: pre-dose, 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 5, 6, 8, 12 and 24 hours post dose ] [ Designated as safety issue: No ]
    Half-life (t1/2λz h),systemic plasma clearance (CL L/h), systemic plasma clearance at steady state (CLss L/h), volume of distribution at steady-state (Vss L), volume of distribution at the terminal phase (Vz L), mean residence time (MRT).

  • Part B: PK- Plasma pharmacokinetic profile in terms of (see description) for ATM-AVI following a single IV infusion on Day 1 and multiple IV infusions on Days 2-11 [ Time Frame: Day 1 and 11: pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.25,3.5, 3.75, 4, 4.5, 5, 6, 8, 12, and 24 hours.Day 4: pre dose, 1.5, 3, 4, 6 ] [ Designated as safety issue: No ]
    Maximum plasma concentration (Cmax µg/mL), maximum plasma concentration at steady state (Css,max µg/mL), time to Cmax (tmax h), time to Css,max (tss,max h), minimum plasma concentration at the end of the dosing interval on Day 1 [C(6h)min h] and at steady state (Css,min h), time of last quantifiable plasma concentration (tlast h), area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration [AUC(0-t) µg.h/mL], from zero extrapolated to infinity (AUC µg.h/mL), during the dosing interval on Day 1 [AUC(0-6) µg.h/mL] and at steady state during the dosing interval [AUCss µg.h/mL].

  • Part B: PK- Plasma pharmacokinetic profile in terms of (see description) for ATM-AVI following a single IV infusion on Day 1 and multiple IV infusions on Days 2-11 [ Time Frame: Day 1 and 11: pre-dose, 0.5, 1, 1.5, 2, 2.5, 3,3.25, 3.5,3.75,4,4.5, 5, 6, 8, 12, and 24 hours.Day 4:pre dose, 1.5,3,4,6 ] [ Designated as safety issue: No ]
    Half-life (t1/2λz h),systemic plasma clearance (CL L/h), systemic plasma clearance at steady state (CLss L/h), volume of distribution at steady-state (Vss L), volume of distribution at the terminal phase (Vz L), mean residence time (MRT), dose-normalized exposure parameters after single and multiple dose for AVI.

  • Part C: PK- Plasma pharmacokinetic profile in terms of (see description) for ATM-AVI following multiple IV infusions Days 1-10 [ Time Frame: Day 1 and 10: pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.25,3.5,3.75,4,4.5,3.5, 5, 6 hours. Day 4 and 7: pre dose, 1.5,3,4,6 ] [ Designated as safety issue: No ]
    Maximum plasma concentration (Cmax µg/mL), maximum plasma concentration at steady state (Css,max µg/mL), time to Cmax (tmax h), time to Css,max (tss,max h), minimum plasma concentration at the end of the dosing interval on Day 1 [C(6h)min h] and at steady state (Css,min h), time of last quantifiable plasma concentration (tlast h), area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration [AUC(0-t) µg.h/mL], from zero extrapolated to infinity (AUC µg.h/mL), during the dosing interval on Day 1 [AUC(0-6) µg.h/mL] and at steady state during the dosing interval [AUCss µg.h/mL].

  • Part C: PK- Plasma pharmacokinetic profile in terms of (see description) for ATM-AVI following multiple IV infusions Days 1-10 [ Time Frame: Day 1 and 10: pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.25,3.5,3.75,4,4.5, 5, 6 hours.Day 4 and 7:pre dose, 1.5,3,4.6 ] [ Designated as safety issue: No ]
    Half-life (t1/2λz h), systemic plasma clearance (CL L/h), systemic plasma clearance at steady state(CLss L/h), volume of distribution at steady-state (Vss L), volume of distribution at the terminal phase (Vz L), mean residence time (MRT).

  • Part A:To characterize the renal clearance of combination ATM-AVI using the following urine PK parameters (see description) [ Time Frame: Day 1 of each crossover period at pre-dose, during 0-2, 2-4, 4-6 6-8, 8-12 and 12-24h post-dose. ] [ Designated as safety issue: No ]
    Amount of drug excreted unchanged in urine from zero to time t (Ae(0-t) mg), fraction of dose excreted unchanged in urine (fe, % dose) and renal clearance (CLR L/h).

  • Part B: To characterize the renal clearance of combination ATM-AVI using the following urine PK parameters (see description) [ Time Frame: Day 1: pre-dose, during 0-6, 6-12 and 12-24h post-dose. Day 11: pre-dose and during 0-6 h post-dose ] [ Designated as safety issue: No ]
    Amount of drug excreted unchanged in urine from zero to time t (Ae(0-t) mg), fraction of dose excreted unchanged in urine (fe, % dose) and renal clearance (CLR L/h).

  • Part C: To characterize the renal clearance of combination ATM-AVI using the following urine PK parameters:(see description) [ Time Frame: Days 1 and 10: pre-dose, during 0-6h post-dose. ] [ Designated as safety issue: No ]
    Amount of drug excreted unchanged in urine from zero to time t (Ae(0-t) mg), fraction of dose excreted unchanged in urine (fe, % dose) and renal clearance (CLR L/h).


Estimated Enrollment: 103
Study Start Date: September 2012
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Drug: A
Avibactam (AVI)
Drug: Avibactam (AVI)
PART A: AVI IV infusion
Experimental: Drug: B
Aztreonam (ATM)
Drug: Aztreonam (ATM)
PART A: ATM IV infusion
Experimental: Drug: C
combination of Aztreonam-Avibactam (ATM-AVI)
Drug: combination of Aztreonam - Avibactam (ATM-AVI)
PART A: ATM-AVI IV infusion. PART B and C: ATM-AVI IV infusions.
Placebo Comparator: Drug: D
Matching Placebo
Drug: Placebo
PART A, PART B, PART C: matching placebo IV infusions

Detailed Description:

A Phase I, Randomised, Double-blind, 3-Part Study in Healthy Young and Elderly Subjects to Assess the Safety and Tolerability, and Investigate the Pharmacokinetics of Aztreonam and Avibactam given Alone and in Combination (ATM-AVI)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Provision of signed and dated, written informed consent prior to any study specific procedures
  • Healthy young male and female volunteers aged 18 to 45 years (inclusive) and healthy elderly volunteers aged 65 or older (Part C) with suitable veins for cannulation or repeated venipuncture
  • Have a body mass index (BMI) between 19 and 30 kg/m2
  • Be able to understand and willing to comply with study procedures, restrictions, and requirements, as judged by the PI

Exclusion Criteria:

  • History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study
  • History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs
  • Known history of severe allergy to betalactam and/or L-arginine
  • History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to ATM or AVI
  • Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks prior to the first administration of IP
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01689207

Contacts
Contact: Quintiles Drug Research Unit Call Centre 0800 634 1132 ClinicalTrialTransparency@astrazeneca.com

Locations
United Kingdom
Research Site Recruiting
London, United Kingdom
Sponsors and Collaborators
AstraZeneca
Investigators
Principal Investigator: Frans van den Berg, MD Hammersmith Medicines Research Cumberland Avenue Park Royal London NW10 7EW, England Telephone: +44 020 8961 4130 Fax: +44 020 8961 8665
  More Information

No publications provided

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01689207     History of Changes
Other Study ID Numbers: D4910C00001
Study First Received: September 12, 2012
Last Updated: July 1, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by AstraZeneca:
Phase I, Safety, tolerability, healthy.

Additional relevant MeSH terms:
Bacterial Infections
Communicable Diseases
Infection
Aztreonam
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 31, 2014