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Mass Balance Recovery, Pharmacokinetics and Metabolite Profile and Identification of [14C]AZD7594

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04002427
Recruitment Status : Completed
First Posted : June 28, 2019
Last Update Posted : July 25, 2019
Sponsor:
Collaborator:
Quotient Sciences
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE April 18, 2019
First Posted Date  ICMJE June 28, 2019
Last Update Posted Date July 25, 2019
Actual Study Start Date  ICMJE June 11, 2019
Actual Primary Completion Date July 5, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • AZD7594 excreted (Ae) [ Time Frame: Urine and faecal samples collected from pre-dose until 168 hours post-dose ]
    Assessment of total radioactivity by measuring AZD7594 excreted (Ae)
  • AZD7594 excreted and expressed as a percentage of the administered dose (Fe) [ Time Frame: Urine and faecal samples colected from pre-dose until 168 hours post-dose ]
    Assessment of total radioactivity by measuring AZD7594 excreted and expressed as a percentage of the administered dose (Fe)
  • Cumulative amount of AZD7594 excreted (CumAe) [ Time Frame: Urine and faecal samples collected from pre-dose until 168 hours post-dose ]
    Assessment of total radioactivity by measuring the cumulative amount of AZD7594 excreted (CumAe)
  • Cumulative amount of AZD7594 excreted and expressed as a percentage of the administered dose (CumFe) [ Time Frame: Urine and faecal samples collected from pre-dose until 168 hours post-dose ]
    Assessment of total radioactivity by measuring AZD7594 excreted and expressed as a percentage of the administered dose (CumFe)
  • Assessment of metabolites in plasma by liquid chromatography-radiochemical-detection and subsequent mass spectrometry [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry
  • Assessment of metabolites in faeces by liquid chromatography-radiochemical-detection and subsequent mass spectrometry [ Time Frame: Collection of faecal samples from pre-dose until 168 hours post-dose ]
    Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry
  • Assessment of metabolites in urine by liquid chromatography-radiochemical-detection and subsequent mass spectrometry [ Time Frame: Collection of urine samples from pre-dose until 168 hours post-dose ]
    Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • Determination of routes and rates of elimination of [14C]AZD7594 [ Time Frame: Collection of urine and faecal samples from pre-dose until 168 hours post-dose ]
    Assessment of total radioactivity by measuring AZD7594 excreted (Ae), cumulative recovery (Cumae), Ae as a percentage of the administered dose (Fe) and cumulative recovery expressed as a percentage of the dose (CumFe)
  • Determination of the chemical structure of the "major" metabolites of [14C]AZD7594 [ Time Frame: Collection of urine adn faeces samples from pre-dose until 168 hours post-dose ]
    Structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry
  • Evaluation of whole blood:plasma concentration ratios for total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Assessment of total radioactivity by measuring AZD7594 in blood and plasma
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Time from dosing at which Cmax was apparent (tmax)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The maximum observed plasma concentration (Cmax)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The area under the concentration-time curve from dosing to the last measurable concentration (AUClast)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The area under the concentration-time curve from dosing extrapolated to infinity (AUC0-inf)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The percentage of AUC extrapolated beyond the last measured time point (AUC%extr)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The terminal elimination rate constant calculated from the slope of the apparent elimination phase (λz)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The apparent terminal elimination half-life (t½)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Total clearance (CL)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Volume of distribution (Vz)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Volume of distribution at steady state (Vss)
  • Assessment of the IV PK of [14C]AZD7594 and total radioactivity [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Mean residence time (MRT)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The time from dosing at which Cmax was apparent (tmax)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The maximum observed plasma concentration (Cmax)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The area under the concentration-time curve from dosing to the last measurable concentration (AUClast)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The area under the concentration-time curve from dosing extrapolated to infinity (AUC0-inf)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The percentage of AUC extrapolated beyond the last measured time point(AUC%exre)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The terminal elimination rate constant calculated from the slope of the apparent elimination phase (λz)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    The apparent terminal elimination half-life (t½)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Apparent total clearance (CL/F)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Apparent volume of distribution (Vz/F)
  • Assessment of the inhaled PK of AZD7594 [ Time Frame: Collection of plasma samples from pre-dose until 168 hours post-dose ]
    Absolute bioavailability (F)
  • Number of adverse events (AE) [ Time Frame: AEs recorded from the time of informed consent until discharge from the study (168 hours post-dose) ]
    Safety and tolerability assessed through incidence of AE
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mass Balance Recovery, Pharmacokinetics and Metabolite Profile and Identification of [14C]AZD7594
Official Title  ICMJE A Phase I, Open-Label Study to Assess Mass Balance Recovery, Pharmacokinetics, Metabolite Profile & Metabolite Identification After Intravenous Microdose Administration of [14C]AZD7594 & Inhaled Administration of AZD7594 in Healthy Subjects
Brief Summary

AZD7594 is in clinical development for the treatment of asthma.

This is a single centre, open-label, single period study in 6 healthy subjects, to determine the mass balance recovery and generate samples to enable metabolite profiling and structural identification of AZD7594.

Each subject will receive a single inhaled 792 µg nominal dose (720 µg delivered dose) of AZD7594 followed by an IV dose of 30 µg [14C]AZD7594 containing not more than (NMT) 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 h infusion. The IV dose will be administered approximately 10 min after the inhaled dose. Subjects will remain resident in the clinical unit up to 168 h post dose (up to Day 8).

Detailed Description

This is a single centre, open-label, single period study in 6 healthy male and non-pregnant, non-lactating female subjects to determine the mass balance recovery after a single intravenous (IV) dose of [14C]AZD7594 and to generate samples to enable metabolite profiling and structural identification of AZD7594 in plasma, urine and faeces. It is planned to enrol 6 subjects to ensure data in at least 4 evaluable subjects. A subject will be considered evaluable if they have provided mass balance and PK samples for up to 48 h after drug administration.

Subjects will be screened for eligibility to participate in the study up to 28 days before dosing. Eligible subjects will be admitted to the clinical unit in the afternoon on the day before dosing (Day 1). Subjects will be dosed on the morning of Day 1 in the fasted state (8 h overnight fast). Before oral inhalation of AZD7594 using the Dry Powder Inhaler (DPI), all subjects must demonstrate their ability to use the DPI as intended. Subjects will receive training with an empty DPI at screening, Day -1 and pre-dose (optional) in accordance with study specific instructions. Each subject will receive a single inhaled 792 µg nominal dose (720 µg delivered dose) of AZD7594 followed by an IV dose of 30 µg [14C]AZD7594 containing 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 h infusion. The infusion of the IV dose will be started approximately 15 min after the inhaled dose. Subjects will remain resident in the clinical unit up to 168 h post dose (up to Day 8).

Whole blood, plasma, urine and faeces will be collected from pre-dose until discharge (168 h post-dose; Day 8). Any accidental sources of elimination (eg emesis) will be collected and sent to the mass balance laboratory for total radioactivity analysis.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Drug: Intravenous Infusion
    30 µg [14C]AZD7594 containing 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 hour infusion.
  • Drug: Inhaled dose
    A single inhalation on one occasion.
Study Arms  ICMJE Experimental: Only one study arm

[14C]AZD7594 Solution for Infusion 5 µg/mL (1.1 kBq/mL)

AZD7594 Inhalation Powder, SD3FL Inhaler

Interventions:
  • Drug: Intravenous Infusion
  • Drug: Inhaled dose
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 27, 2019)
6
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 5, 2019
Actual Primary Completion Date July 5, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Provision of signed and dated, written informed consent prior to any study specific procedures.
  2. Healthy male or non-pregnant, non-lactating female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture.
  3. Have a body mass index of 18.5 to 35.0 kg/m2, and weigh at least 50 kg and no more than 100 kg, as measured at screening.
  4. Must have regular bowel movements (ie, average stool production of ≥1 and ≤3 stools per day).
  5. Must be willing and able to communicate and participate in the whole study.
  6. Must agree to adhere to the contraception requirements defined in Section 9.4 of the protocol.
  7. Must demonstrate the ability to use the study inhalation device properly.

Exclusion Criteria:

  1. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the volunteer at risk because of participation in the study, or influence the results of the volunteer's ability to participate in the study.
  2. History or presence of clinically significant gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
  3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
  4. Subjects with Gilbert's syndrome or subjects with a history of cholecystectomy or gall stones.
  5. Subjects with pregnant partners
  6. Any confirmed clinically significant abnormalities in clinical chemistry, haematology or urinalysis as judged by the investigator.
  7. Any confirmed clinically significant abnormal findings in vital signs or 12-lead ECG as judged by the investigator.
  8. Any positive result at screening for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results.
  9. Has received any other new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose. Note: subjects consented and screened, but not randomised in this study or a previous Phase I study are not excluded.
  10. Plasma donation within 1 month of screening or any blood donation/loss of more than 500 mL of blood during the 3 months prior to screening.
  11. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7594 or the formulation excipients including lactose. Hay fever is allowed unless it is active.
  12. Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission.
  13. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
  14. Females of childbearing potential who are pregnant or lactating (all female subjects must have a negative urine pregnancy test and screening and admission). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle stimulating hormone [FSH] concentration ≥40 IU/L).
  15. Confirmed positive screen for drugs of abuse at screening or admission to the clinical unit or positive screen for alcohol at screening or admission to the clinical unit.
  16. Herbal preparations/medications are not allowed throughout the study. These herbal medications include, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Subjects should stop using these herbal medications 14 days prior to administration of AZD7594.
  17. Use of any prescribed or nonprescribed medication including antacids, H2 antagonists, PPI, analgesics (other than paracetamol/acetaminophen up to 4 g/day), vitamins and minerals during the 14 days prior to administration of AZD7594 or longer if the medication has a longer half-life (see Section 11.4 of the protocol). Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor's medical monitor.
  18. Known or suspected history of alcohol or drug abuse within the past 2 years or regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type)
  19. Subjects who are study site employees, or immediate family members of a study site or sponsor employee
  20. Subjects who have previously been enrolled in this study.
  21. Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 2017, shall participate in the study.
  22. Subjects who have been enrolled in an ADME study in the last 12 months
  23. Judgment by the investigator that the volunteer should not participate in the study if they have any ongoing or recent (ie during the screening period) minor medical complaints that may interfere with the interpretation of the study data or are considered unlikely to comply with the study procedures, restrictions and requirements.
  24. History of infantile bronchiolitis, a history of asthma, adverse reaction or allergy to the inhaled medication or any excipients
  25. Upper respiratory tract infection (excluding otitis media) within 14 days of the first study day, or lower respiratory tract infection within the last 3 months
  26. Subjects who are unable to demonstrate their ability to fulfil the physical demands of the study
  27. Failure to satisfy the investigator of fitness to participate for any other reason.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04002427
Other Study ID Numbers  ICMJE D3741C00010
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Quotient Sciences
Investigators  ICMJE
Principal Investigator: Sharan Sidhu, MBChB, BAO, MRCS, MFPM Quotient Sciences Limited (indemnified by
PRS Account AstraZeneca
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP