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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01689207
First received: September 12, 2012
Last updated: September 6, 2016
Last verified: August 2016
  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:
  • Safety Profile - Number of Subjects With at Least 1 AE [ Time Frame: Informed consent (up to 28 days before first dose) to follow up period (max of 22 days after first dose for Part A, a max of 28 days after first dose in Part B, max 17 days in Part C) ] [ Designated as safety issue: No ]
    from screening visit (Day -28) to 3 to 7 days post treatment period 3 (up to Day 22) in Part A, 3 to 7 days after receiving the final dose on Day 11 (days 14 to 18) in Part B, and 3 to 7 days after receiving the final dose on Day 10 (days 13 to 17) in Part C.


Secondary Outcome Measures:
  • PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C [ Time Frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from zero extrapolated to infinity (AUC µg*h/mL) or AUC(0-last) in Part A on Day 1 after single infusion, area under the plasma concentration-time curve at steady state after multiple infusion (AUCss µg*h/mL).

  • PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C [ Time Frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C ] [ Designated as safety issue: No ]
    Terminal half-life (t1/2), on Day 1 after single infusion and at steady state after multiple infusion.

  • PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Time to Cmax (tmax)

  • PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C [ Time Frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C ] [ Designated as safety issue: No ]
    Maximum plasma concentration (Cmax µg/mL) on Day 1 after single infusion , maximum plasma concentration at steady state (Css,max µg/mL) after multiple infusion.

  • PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C [ Time Frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C ] [ Designated as safety issue: No ]
    Systemic clearence (CL) and renal clearance (CLr) on Day 1 after single infusion and at steady state after multiple infusion.

  • PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C [ Time Frame: 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C ] [ Designated as safety issue: No ]
    Volume of distribution at steady state (Vss).


Enrollment: 222
Study Start Date: September 2012
Study Completion Date: December 2014
Primary Completion Date: December 2014 (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 to 130 Years   (Adult, Senior)
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

Locations
United Kingdom
Research Site
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

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01689207     History of Changes
Other Study ID Numbers: D4910C00001 
Study First Received: September 12, 2012
Results First Received: December 14, 2015
Last Updated: September 6, 2016
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

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

Additional relevant MeSH terms:
Infection
Communicable Diseases
Bacterial Infections
Avibactam
Aztreonam
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on December 07, 2016