A Study to Assess the Amount of Drug Levels in Blood and Safety of AZD5718 Formulations in Healthy Volunteers

A Randomized, Single-dose, Open-label, Single-center, Crossover Study to Assess the Relative Bioavailability and Safety of Different Formulations of AZD5718 in Healthy Volunteers

The study is a randomized, single-dose, open-label, combined 2x2 dose and 3x3 dose crossover design in fixed sequence. In this study, the relative bioavailability of different formulations of AZD5718 will be assessed in healthy volunteers in order to compare the exposure of Formulations A to D to the AZD5718 film-coated tablet formulation. The overall treatment period will start with a 2-period, 2-dose treatment crossover, followed by a 3-period, 3-dose treatment crossover.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease (CAD)
• Intervention / Treatment: Drug: AZD5718 tablet, Formulation A; Drug: AZD5718 tablet, Formulation B; Drug: AZD5718 tablet, Formulation C; Drug: AZD5718 tablet, Formulation D; Drug: AZD5718 film-coated tablet, Reference treatment

Detailed Description

This study will be conducted at a single study center in Parexel Early Phase Clinical Unit London.

A total of 12 healthy male and female volunteers (of non-childbearing potential) will be randomized.

The study will comprise:

• A screening period of maximum 28 days
• Five treatment periods
• There will be a washout period of 3 to 6 days between dose administrations
• Follow-up visit, 5 to 7 days after last dose

Each volunteer will be involved in the study for between 7 and 9 weeks. The volunteers will be admitted to the Unit on the day before first dosing in Treatment Period 1 until at least 72 hours after last dosing in Treatment Period 5.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Harrow, United Kingdom, HA1 3UJ
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

For inclusion in the study volunteers should fulfill the following criteria:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male or female volunteers aged 18 to 55 years (inclusive at screening) with suitable veins for cannulation or repeated venipuncture.
• Males must be willing to use appropriate contraception methods.
• Females must have a negative pregnancy test at screening and on admission to the Clinical Unit (Day -1), must not be lactating and must be of non childbearing potential, confirmed at screening by fulfilling the criteria.
• Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.

Exclusion Criteria:

Volunteers will not enter the study if any of the following exclusion criteria are fulfilled:

• 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 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.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first dosing.

• Any clinically significant abnormalities in hematology, clinical chemistry, or urinalysis results, at screening or on admission to the Clinical Unit (Day -1), as judged by the Investigator, including:

  1. Alanine aminotransferase (ALT) >1.5 x upper limit of normal (ULN).
  2. Aspartate aminotransferase (AST) >1.5 x ULN.
  3. Total bilirubin (TBL) >1.5 x ULN.
  4. Gamma glutamyl transpeptidase (GGT) >1.5 x ULN. Out-of-range test may be repeated once for each visit at the discretion of the Investigator.
• Known or suspected Gilbert's syndrome.
• Any clinically significant abnormal findings in vital signs at screening or on admission to the Clinical Unit, as judged by the Investigator.
• Any clinically significant abnormalities on 12-lead ECG at screening, as judged by the Investigator.
• Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
• Known or suspected history of drug abuse, as judged by the Investigator.
• Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of first dosing in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.
• Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.
• 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 AZD5718.
• Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 3 months prior to screening.
• Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate) as judged by the Investigator.
• Positive screen for drugs of abuse or cotinine at screening or admission to the Clinical Unit or positive screen for alcohol on admission to the Clinical Unit.
• Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to first dosing.
• Use of any prescribed or non prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to first dosing or longer if the medication has a long half-life.
• Known or suspected history of alcohol or excessive alcohol intake, as judged by the Investigator.
• Involvement of any AstraZeneca, Parexel or study site employee or their close relatives.
• Volunteers who have previously received AZD5718.
• Judgement by the Investigator that the volunteers should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
• Vulnerable volunteers, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AZD5718 tablet, Treatment A; Volunteers will receive single doses of AZD5718 tablet, Formulation A under fasted conditions.	Drug: AZD5718 tablet, Formulation A; Volunteers will receive single doses of AZD5718 tablet, Formulation A under fasted conditions. The dose will be administered with 240 mL (8 fluid ounces) of non-carbonated water after an overnight fast of at least 10 hours.
EXPERIMENTAL: AZD5718 tablet, Treatment B; Volunteers will receive single doses of AZD5718 tablet, Formulation B under fasted conditions.	Drug: AZD5718 tablet, Formulation B; Volunteers will receive single doses of AZD5718 tablet, Formulation B under fasted conditions. The dose will be administered with 240 mL (8 fluid ounces) of non-carbonated water after an overnight fast of at least 10 hours.
EXPERIMENTAL: AZD5718 tablet, Treatment C; Volunteers will receive single doses of AZD5718 tablet, Formulation C under fasted conditions.	Drug: AZD5718 tablet, Formulation C; Volunteers will receive single doses of AZD5718 tablet, Formulation C under fasted conditions. The dose will be administered with 240 mL (8 fluid ounces) of non-carbonated water after an overnight fast of at least 10 hours.
EXPERIMENTAL: AZD5718 tablet, Treatment D; Volunteers will receive single doses of AZD5718 tablet, Formulation C under fasted conditions.	Drug: AZD5718 tablet, Formulation D; Volunteers will receive single doses of AZD5718 tablet, Formulation D under fasted conditions. The dose will be administered with 240 mL (8 fluid ounces) of non-carbonated water after an overnight fast of at least 10 hours.
ACTIVE_COMPARATOR: AZD5718 film-coated tablet; Volunteers will receive single doses of AZD5718 film-coated tablet, Reference treatment under fasted conditions.	Drug: AZD5718 film-coated tablet, Reference treatment; Volunteers will receive single doses of AZD5718 film-coated tablet, Reference treatment under fasted conditions. The dose will be administered with 240 mL (8 fluid ounces) of non-carbonated water after an overnight fast of at least 10 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration-time curve from zero to infinity (AUC)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Maximum observed plasma concentration (Cmax)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Drug concentration at 24 hours after dosing (C24)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Time to reach maximum observed plasma concentration (tmax)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2λz)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Terminal elimination rate constant (λz)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Apparent total body clearance of drug from plasma after extravascular administration (CL/F)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Dose normalized AUC (AUC/D)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Dose normalized AUClast (AUClast/D)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Dose normalized Cmax (Cmax/D)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose
Dose normalized C24 (C24/D)	To evaluate the relative bioavailability of different formulations of AZD5718 and compare with the formulation used in the ongoing Phase 2a clinical study (Reference treatment), in healthy volunteers	Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of volunteers with having adverse events and/or abnormal findings in vital signs and/or clinical laboratory assessments and/or physical examination and/or electrocardiogram (ECG) evaluation and/or body weight	To further assess the safety and tolerability of single doses of AZD5718 in healthy volunteers	From Screening up to 9 weeks

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Principal Investigator: Dr Pablo Forte Soto, Senior Clinical Research Physician, Parexel Early Phase Clinical Unit London

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 14, 2020
• Primary Completion (ACTUAL): March 9, 2020
• Study Completion (ACTUAL): March 9, 2020

Study Registration Dates

• First Submitted: December 23, 2019
• First Submitted That Met QC Criteria: December 23, 2019
• First Posted (ACTUAL): December 24, 2019

Study Record Updates

• Last Update Posted (ACTUAL): March 25, 2020
• Last Update Submitted That Met QC Criteria: March 24, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Safety; Relative Bioavailability; Crossover Study
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease
• Other Study ID Numbers: D7550C00008

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No