A Study to Assess the Reaction of Body for Four Different Formulations of AZD9977 (Part A) and Influence of Food and Lower Dose of a Selected Formulation (Part B) in Healthy Male Subjects

NCT03804645 | Completed Phase 1 DMC

• 1 other identifier: D6401C00006
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

AZD9977 is an oral, selective mineralocorticoid receptor (MR) modulator. AZD9977 is a partial antagonist and partial agonist in reporter gene assays and has a different interaction pattern with the MR compared to eplerenone. This study will assess the pharmacokinetics (PK) of four different Formulations of AZD9977 (Part A) and influence of food and lower dose of a selected formulation (Part B) in healthy male subjects.

Conditions

Heart Failure

Keywords

Mineralocorticoid receptor; Heart failure with preserved ejection fraction; Safety; Pharmacokinetics; Influence of Food; Bioavailability

Outcome Measures

Primary Outcomes (10)

• Area under plasma concentration-time curve from time zero to infinity (AUC)

  To determine the relative bioavailability (Frel) and compare the plasma concentration time profile of 3 different formulations versus a reference capsule formulation of AZD9977 and to evaluate the influence of food by comparing AUC and Cmax under fasting and fed conditions for 1 of the formulations evaluated in Part A.

  At Dosing Session, For Part A (Days 1-3, 3-5, 5-7, 7-9) and For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast)

  To determine the relative bioavailability (Frel) and compare the plasma concentration time profile of 3 different formulations versus a reference capsule formulation of AZD9977 and to evaluate the PK of a lower dose of 1 of the formulations evaluated in Part A.

  At Dosing Session, For Part A (Days 1-3, 3-5, 5-7, 7-9) and For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Area under the plasma concentration-time curve from time zero to 24 hours [AUC(0-24)]

  To determine the relative bioavailability (Frel) and compare the plasma concentration time profile of 3 different formulations versus a reference capsule formulation of AZD9977 and to evaluate the PK of a lower dose of 1 of the formulations evaluated in Part A.

  At Dosing Session, For Part A (Days 1-3, 3-5, 5-7, 7-9) and For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Maximum observed plasma concentration (Cmax)

  To determine the relative bioavailability (Frel) and compare the plasma concentration time profile of 3 different formulations versus a reference capsule formulation of AZD9977 and to evaluate the influence of food by comparing AUC and Cmax under fasting and fed conditions for 1 of the formulations evaluated in Part A.

  At Dosing Session, For Part A (Days 1-3, 3-5, 5-7, 7-9) and For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Observed AZD9977 concentration at 24 hours (C24)

  To determine the relative bioavailability (Frel) and compare the plasma concentration time profile of 3 different formulations versus a reference capsule formulation of AZD9977 and to evaluate the PK of a lower dose of 1 of the formulations evaluated in Part A.

  At Dosing Session, For Part A (Days 1-3, 3-5, 5-7, 7-9) and For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Area under plasma concentration-time curve from time zero to infinity divided by dose (AUC/D)

  To evaluate the PK of a lower dose of 1 of the formulations evaluated in Part A.

  At Dosing Session, For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration divided by dose (AUClast/D)

  To evaluate the PK of a lower dose of 1 of the formulations evaluated in Part A

  At Dosing Session, For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Area under the plasma concentration-time curve from time zero to 24 hours divided by dose [AUC(0-24)/D]

  To evaluate the PK of a lower dose of 1 of the formulations evaluated in Part A

  At Dosing Session, For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Maximum observed plasma concentration divided by dose (Cmax/D)

  To evaluate the PK of a lower dose of 1 of the formulations evaluated in Part A

  At Dosing Session, For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

• Observed AZD9977 concentration at 24 hours divided by dose (C24/D)

  To evaluate the PK of a lower dose of 1 of the formulations evaluated in Part A

  At Dosing Session, For Part B (Days 1-2, 3-4): Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36 and 48 hours post dose of each treatment

Secondary Outcomes (34)

• Number of subjects with Adverse events (AEs)

  From screening (Day -28) to follow-up (Week 12)

• Number of subjects with abnormal blood pressure (BP)

  From screening (Day -28) to follow-up (Week 12)

• Number of subjects with abnormal pulse rate

  From screening (Day -28) to follow-up (Week 12)

• Number of subjects with abnormal findings in Real-Time Electrocardiogram (Cardiac Telemetry)

  From Day-1 to follow-up (Week 12)

• Number of subjects with abnormal findings in 12-lead safety Electrocardiogram (ECG)

  From screening (Day -28) to follow-up (Week 12)

Study Arms (5)

Cohort 1

EXPERIMENTAL

In Part A, each subject will receive AZD9977 as a single dose on 4 different occasions under fasting conditions, separated by at least 48 hours.

Drug: Treatment A; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D

Cohort 2

EXPERIMENTAL

In Part A, each subject will receive AZD9977 as a single dose on 4 different occasions under fasting conditions, separated by at least 48 hours.

Drug: Treatment A; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D

Cohort 3

EXPERIMENTAL

In Part A, each subject will receive AZD9977 as a single dose on 4 different occasions under fasting conditions, separated by at least 48 hours.

Drug: Treatment A; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D

Cohort 4

EXPERIMENTAL

In Part A, each subject will receive AZD9977 as a single dose on 4 different occasions under fasting conditions, separated by at least 48 hours.

Drug: Treatment A; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D

Cohort 5

EXPERIMENTAL

In Part B, each subject will receive one formulation from Part A chosen for further development, dose under fed conditions, followed by dose under fasted condition.

Drug: Treatment A; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D

Interventions

Treatment A DRUG

Each subject will receive single dose of AZD9977 capsule under fasting condition in Part A. If the formulation chosen for Part B, each subject will receive one dose under fed condition and another dose under fasted condition.

Also known as: AZD9977 capsule, reference

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

Treatment B DRUG

Each subject will receive single dose of AZD9977 HDL capsule under fasting condition in Part A. If the formulation chosen for Part B, each subject will receive one dose under fed condition and another dose under fasted condition.

Also known as: AZD9977 HDL capsule

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

Treatment C DRUG

Each subject will receive single dose of AZD9977 ODL capsule under fasting condition in Part A. If the formulation chosen for Part B, each subject will receive one dose under fed condition and other dose under fasted condition.

Also known as: AZD9977 ODL capsule

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

Treatment D DRUG

Each subject will receive single dose of AZD9977 tablet under fasting condition in Part A. If the formulation chosen for Part B, each subject will receive one dose under fed condition and another dose under fasted condition.

Also known as: AZD9977 tablet

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Agree to use the methods of contraception.
• Healthy male subjects aged 18 to 50 years, inclusive, with suitable veins for cannulation or repeated venipuncture at screening.
• 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 at screening.
• Subject judged at screening likely to complete and agree to eat a specified high fat standardized Food and Drug Administration (FDA) breakfast.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the principal investigator (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.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the PI, including:
• Serum potassium \> 5.0 mmol/L.
• Any clinically significant abnormal findings in vital signs, as judged by the PI, including:
• Systolic BP \< 90 mmHg or \> 140 mmHg. 5.2. Diastolic BP \< 50 mmHg or \> 90 mmHg. 5.3. Pulse rate \< 45 or \> 90 beats per minute.
• Any clinically significant abnormalities on 12-lead echocardiogram (ECG), as judged by the PI.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
• Known or suspected history of drug abuse in the 12 months prior to screening, as judged by the PI.
• 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 PI or history of hypersensitivity to drugs with a similar chemical structure or class to AZD9977.
• Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 3 months prior to screening.
• Positive screen for drugs of abuse, alcohol or cotinine at screening or on admission to the study center.
• Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of AZD9977.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Harrow, HA1 3UJ, United Kingdom

Location

Related Links

• Study Information posted to AstraZeneca Cinical Trials Webiste

MeSH Terms

Conditions

Heart Failure

Interventions

AZD9977

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Officials

• Pablo Forte Soto, MD, MSc, PhD

  Dr.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an open-label study.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: open-label, randomized, four-way crossover single oral dose

Study Record Dates

• First Submitted: January 14, 2019
• First Posted: January 15, 2019
• Study Start: February 5, 2019
• Primary Completion: April 16, 2019
• Study Completion: April 16, 2019
• Last Updated: April 19, 2021

Record last verified: 2021-04

Locations

GB (1)