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

Heart Failure Clinical Trial

Official title:

An Open-label, Randomized, Four-way Crossover Single Oral Dose Study Comparing the Pharmacokinetics 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03804645
• Other study ID #: D6401C00006
• Status: Completed
• Phase: Phase 1
• Start date: February 5, 2019
• Est. completion date: April 16, 2019

Study information

• Verified date: April 2021
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This study will be a randomized, open-label, single-centre crossover study in healthy male subjects. The study is divided into 2 parts, Part A and Part B. The subjects will participate in both Part A and Part B. Part A will be a 4-way cross-over study comparing the PK of AZD9977 as a reference capsule and 2 different capsule formulations and a tablet formulation under fasting conditions. - Treatment A: Reference, AZD9977 capsule - Treatment B: AZD9977 HDL capsule - Treatment C: AZD9977 ODL capsule - Treatment D: AZD9977 tablet In Part B, based on the interim results in Part A, 1 of the formulations will be selected and evaluated at the 300 mg dose level under fed conditions. The same formulation will also be evaluated under fasting conditions at a lower dose level (50 mg). The first dose tested in Part B will be the 50 mg (fasted) dose, followed by the 300 mg (fed) dose. In Part A, subjects will be resident from 1 day before dosing (Day -1 of Treatment Period 1) with AZD9977 until 48 hours post-final-dose (Day 3 of Treatment Period 4). Subjects will return to the unit for Part B at least 48 hours (and up to 5 weeks) after completion of Part A. In Part B, subjects will be resident from 1 day before dosing (Day -1 of Treatment Period 1) with AZD9977 until 48 hours post-final-dose (Day 3 of Treatment Period 2). Subjects will return to the unit for a final study visit 5-7 days post-last-dose for a Follow up Visit. Each subject will be involved in the study for approximately 12 weeks (including approximately 4 to 5 weeks for the interim analysis). Twelve subjects will initially be randomized to ensure at least 8 and 6 evaluable subjects at the end of the last treatment period for Part A and Part B respectively.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: April 16, 2019
• Est. primary completion date: April 16, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.

2. Agree to use the methods of contraception.

3. Healthy male subjects aged 18 to 50 years, inclusive, with suitable veins for cannulation or repeated venipuncture at screening.

4. 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.

5. Subject judged at screening likely to complete and agree to eat a specified high fat standardized Food and Drug Administration (FDA) breakfast.

Exclusion Criteria:

1. 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.

2. History or presence of 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. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the PI, including: 4.1. Serum potassium > 5.0 mmol/L.

5. Any clinically significant abnormal findings in vital signs, as judged by the PI, including: 5.1. 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.

6. Any clinically significant abnormalities on 12-lead echocardiogram (ECG), as judged by the PI.

7. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.

8. Known or suspected history of drug abuse in the 12 months prior to screening, as judged by the PI.

9. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of AZD9977 in this study. The period of exclusion begins 3 months after the final dose or one month after the last visit whichever is the longest. Note: subjects consented and screened, but not randomized in this study or a previous Phase 1 study, are not excluded.

10. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.

11. 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.

12. Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 3 months prior to screening.

13. Positive screen for drugs of abuse, alcohol or cotinine at screening or on admission to the study center.

14. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of AZD9977.

15. 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 the first administration of AZD9977 or longer if the medication has a long half life.

16. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol in the 12 months prior to screening as judged by the PI.

17. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.

18. Subjects who have previously received AZD9977.

19. Judgment by the PI that the subject 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.

20. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Treatment A
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.
• Treatment B
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.
• Treatment C
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.
• Treatment D
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.

Locations

Country	Name	City	State
United Kingdom	Research Site	Harrow

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Number of subjects with Adverse events (AEs)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal blood pressure (BP)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects. Blood pressure includes both systolic and diastolic BP.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal pulse rate	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal findings in Real-Time Electrocardiogram (Cardiac Telemetry)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From Day-1 to follow-up (Week 12)
Secondary	Number of subjects with abnormal findings in 12-lead safety Electrocardiogram (ECG)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal findings in physical examination	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects. The complete physical examinations will include the general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: absolute count of Basophils, Eosinophils, Monocytes, Neutrophils, Lymphocytes and Reticulocytes; Platelets and White blood cell (WBC) count	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Hematology- Red blood cell (RBC) count	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Hematology- Hemoglobin (Hb)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Hematology- Hematocrit (HCT)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Hematology- Mean corpuscular volume (MCV)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Hematology- Mean corpuscular hemoglobin (MCH)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Hematology- Mean corpuscular hemoglobin concentration (MCHC)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry-Sodium	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry-Potassium	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Urea	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Creatinine	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Albumin	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Calcium	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Phosphate	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Glucose (fasting)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- C-reactive protein (CRP)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Alkaline phosphatase (ALP)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Alanine aminotransferase (ALT)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Aspartate aminotransferase (AST)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Gamma glutamyl transpeptidase (GGT)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Total Bilirubin (TBL)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Unconjugated bilirubin	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- High-sensitivity troponin T (hsTnT)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- Creatine kinase	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Serum Clinical Chemistry- N-terminal-pro-brain natriuretic peptide (NT-proBNP)	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Urinalysis-Glucose	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects.	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Urinalysis-Blood	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects. Microscopy will also be assessed if positive for blood): RBC count, WBC count, Casts (Cellular, Granular, Hyaline)	From screening (Day -28) to follow-up (Week 12)
Secondary	Number of subjects with abnormal laboratory assessments: Urinalysis-Protein	To assess the safety and tolerability of AZD9977 following oral administration in healthy male subjects. Microscopy will also be assessed if positive for protein): RBC count, WBC count, Casts (Cellular, Granular, Hyaline)	From screening (Day -28) to follow-up (Week 12)

External Links

•   Study Information posted to AstraZeneca Cinical Trials Webiste