A Single Oral Dose Study to Evaluate Four Different Formulations of AZD9977 and the Effect of Food in Healthy Male Subjects

NCT03450759 | Completed Phase 1

• 1 other identifier: D6401C00002
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate pharmacokinetics (PK) of four different formulations with different release profiles of AZD9977 (PART A) in the fasted state, and one of the formulation will be selected for further development (Part B). In Part B, the influence of food on the PK of AZD9977 will be evaluated

Conditions

Healthy Volunteers

Keywords

Heart failure.; Mineralocorticoid receptor modulator.; Heart failure with preserved ejection fraction (HFpEF).

Outcome Measures

Primary Outcomes (9)

• Relative bioavailability (Frel) of AZD9977 capsule, ER (fast rate) and ER (Int. rate) capsules versus AZD9977 oral suspension (reference): Area under plasma concentration-time curve from time zero to infinity (AUC)

  To assess Frel by assessments of PK parameters AUC after administration of single oral dose of AZD9977 capsule and ER (fast rate and Int. rate) capsules by comparison with AZD9977 oral suspension (reference).

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

• Relative bioavailability (Frel) of AZD9977 capsule, ER (fast rate) and ER (Int. rate) capsules versus AZD9977 oral suspension (reference): Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast)

  To assess Frel by assessments of PK parameters AUClast after administration of single oral dose of AZD9977 capsule and ER (fast rate and Int. rate) capsules by comparison with AZD9977 oral suspension (reference).

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

• Relative bioavailability (Frel) of AZD9977 capsule, ER (fast rate) and ER (Int. rate) capsules versus AZD9977 oral suspension (reference): Area under the plasma concentration-time curve from time zero to time 24 hours (AUC[0-24])

  To assess Frel by assessments of PK parameters AUC\[0-24\] after administration of single oral dose of AZD9977 capsule and ER (fast rate and Int. rate) capsules by comparison with AZD9977 oral suspension (reference).

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

• Relative bioavailability (Frel) of AZD9977 capsule, ER (fast rate) and ER (Int. rate) capsules versus AZD9977 oral suspension (reference): Maximum observed plasma concentration (Cmax )

  To assess Frel by assessments of PK parameters Cmax after administration of single oral dose of AZD9977 capsule and ER (fast rate and Int. rate) capsules by comparison with AZD9977 oral suspension (reference).

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

• Plasma PK parameter: Area under plasma concentration-time curve from time zero to infinity (AUC)

  To assess AUC after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

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

  To assess AUClast after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

• Plasma PK parameter: Maximum observed plasma concentration (Cmax)

  To assess Cmax after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

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

  To assess AUC(0-24) after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).

  Dosing sessions: Part A: Days 1, 3, 5 and 7

• The Effect of food on the PK of one of the solid formultaion evaluated in Part A under fasting and fed conditions in Part B

  To evaluate the influence of food by comparing AUC and Cmax under fasting and fed conditions for one of the solid formulations evaluated in Part A.

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

Secondary Outcomes (34)

• Plasma PK parameter: Plasma concentration 24 hours post-dose (C4)

  Dosing sessions: Part A and Part B - Day 1 (24 hours post-dose)

• Plasma PK parameter: Time to reach maximum observed plasma concentration (tmax)

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

• Plasma PK parameter: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz )

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

• Plasma PK parameter: Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (MRT)

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

• Plasma PK parameter: Terminal elimination rate constant (λz)

  Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1

Study Arms (4)

Treatment sequence 1

EXPERIMENTAL

In Part A, randomized subjects will receive orally single dose of all treatments in fasted condition in the following sequence: AZD9977 oral suspension (reference) AZD9977 capsule AZD9977 ER capsule (fast rate) AZD9977 ER capsule (Int. rate)

Drug: AZD9977 Oral suspension (reference); Drug: AZD9977 capsule; Drug: AZD9977 ER capsule (fastvrate); Drug: AZD9977 ER capsule (Int. rate)

Treatment sequence 2

EXPERIMENTAL

In Part A, randomized subjects will receive orally single dose of all treatments in fasted condition in the following sequence: AZD9977 capsule AZD9977 ER capsule (fast rate) AZD9977 ER capsule (Int. rate) AZD9977 oral suspension (reference)

Drug: AZD9977 Oral suspension (reference); Drug: AZD9977 capsule; Drug: AZD9977 ER capsule (fastvrate); Drug: AZD9977 ER capsule (Int. rate)

Treatment sequence 3

EXPERIMENTAL

In Part A, randomized subjects will receive orally single dose of all treatments in fasted condition in the following sequence: AZD9977 ER capsule (fast rate) AZD9977 ER capsule (Int. rate) AZD9977 Oral suspension (reference) AZD9977 capsule

Drug: AZD9977 Oral suspension (reference); Drug: AZD9977 capsule; Drug: AZD9977 ER capsule (fastvrate); Drug: AZD9977 ER capsule (Int. rate)

Treatment sequence 4

EXPERIMENTAL

In Part A, randomized subjects will receive orally single dose of all treatments in fasted condition in the following sequence: AZD9977 ER capsule (Int. rate) AZD9977 Oral suspension (reference) AZD9977 capsule AZD9977 ER capsule (fast rate)

Drug: AZD9977 Oral suspension (reference); Drug: AZD9977 capsule; Drug: AZD9977 ER capsule (fastvrate); Drug: AZD9977 ER capsule (Int. rate)

Interventions

AZD9977 Oral suspension (reference) DRUG

Randomized subjects will receive single oral dose of AZD9977 oral suspension 15 mg/mL on Days 1, 3, 5 and 7 in Part A.

Treatment sequence 1; Treatment sequence 2; Treatment sequence 3; Treatment sequence 4

AZD9977 capsule DRUG

Randomized subjects will receive single oral dose of AZD9977 capsule 65 mg on Days 1, 3, 5 and 7 in Part A.

Treatment sequence 1; Treatment sequence 2; Treatment sequence 3; Treatment sequence 4

AZD9977 ER capsule (fastvrate) DRUG

Randomized subjects will receive single oral dose of AZD9977 ER capsule (fast rate) 65 mg on Days 1, 3, 5 and 7 in Part A.

Treatment sequence 1; Treatment sequence 2; Treatment sequence 3; Treatment sequence 4

AZD9977 ER capsule (Int. rate) DRUG

Randomized subjects will receive single oral dose of AZD9977 ER capsule (Int rate) 65 mg on Days 1, 3, 5 and 7 in Part A.

Treatment sequence 1; Treatment sequence 2; Treatment sequence 3; Treatment sequence 4

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.
• Healthy male subjects aged 18 to 50 years with suitable veins for cannulation or repeated venipuncture.
• 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.
• Provision of signed, written and dated informed consent for optional genetic research. If a subject decline to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol.
• Subject judged likely to complete and agree to eat a specified high-fat, high-calorie standardized FDA breakfast.

You may not qualify if:

• 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 (GI), 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 specified below and as judged by the PI at screening and on admission: Systolic blood pressure (SBP) \< 90 mmHg or \> 140 mmHg; Diastolic blood pressure (DBP) \< 50 mmHg or \> 90 mmHg; Heart rate (HR) \< 45 or \> 90 beats per minute (bpm)
• Any clinically significant abnormalities on 12-lead 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 last 12 months, 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, cotinine or alcohol at screening or on each 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 IMP.
• 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 IMP or longer if the medication has a long half-life.
• Known or suspected history of alcohol or drug abuse or excessive intake of alcohol in the last 12 months as judged by the PI.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

London, HA1 3UJ, United Kingdom

Location

MeSH Terms

Conditions

Heart Failure

Interventions

AZD9977

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2018
• First Posted: March 1, 2018
• Study Start: March 28, 2018
• Primary Completion: June 6, 2018
• Study Completion: June 6, 2018
• Last Updated: June 15, 2018

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)