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

Healthy Volunteers Clinical Trial

Official title:

An Open-label, Randomized, Four-way Cross-over, Single Oral Dose Study Comparing the Pharmacokinetics of Four Different Formulations of AZD9977 (Part A) and Influence of Food (Part B) in Healthy Male Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03450759
• Other study ID #: D6401C00002
• Status: Completed
• Phase: Phase 1
• Start date: March 28, 2018
• Est. completion date: June 6, 2018

Study information

• Verified date: June 2018
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Description:

This study is a randomized, open-label, single-center study conducted on 12 healthy male subjects. This consists of three periods:

• Screening period (only prior to Day-1)

• Residential/treatment period (Part A and Part B)

• Follow-up period (5 to 7 days after-final dose)

The study is divided into 2 parts: Part A and B. The subjects will participate in both Part A and Part B. Part A will be a 4-way cross-over study to compare the PK of 3 different solid formulations with different release rates with an oral suspension of AZD9977 in fasting conditions. Subjects in Part A will receive the following treatments on Days 1, 3, 5 and 7:

• AZD9977 oral suspension 15 mg/mL (15 mg/mL = 195 mg) (reference)

• AZD9977 capsule, 65 mg (3 x 65 mg = 195 mg)

• AZD9977 extended release (ER) capsule, 65 mg, fast (3 x 65 mg = 195 mg)

• AZD9977 ER capsule, 65 mg, intermediate release (Int) (3 x 65 mg = 195 mg) Subjects will be resident from 1 day before Part A until at least 36 hours post last dosing in Part A. Subjects will return to the unit for Part B after completion of Part A. There will be a washout period of at least 2 days between the doses for a subject. Based on the results in Part A, one of the solid formulations will be selected and evaluated in fed conditions on Day of Part B. Subjects will return to the unit for a final study visit 5 to 7 days post- dose in Part B. Each subject will be involved in the study for approximately 9 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: June 6, 2018
• Est. primary completion date: June 6, 2018
• 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. Healthy male subjects aged 18 to 50 years with suitable veins for cannulation or repeated venipuncture.

3. 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.

4. 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.

5. Subject judged likely to complete and agree to eat a specified high-fat, high-calorie standardized FDA breakfast.

Exclusion Criteria:

1. 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.

2. 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.

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: Serum potassium > 5.0 mmol/L

5. 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)

6. Any clinically significant abnormalities on 12-lead 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 last 12 months, 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 IMP 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. 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, cotinine or alcohol at screening or on each 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 IMP.

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 IMP 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 last 12 months 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.

21. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection or previous bone marrow transplant.

22. Subjects with any special dietary restrictions such as subjects that are lactose intolerant or are vegetarians/vegans.

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• AZD9977 Oral suspension (reference)
Randomized subjects will receive single oral dose of AZD9977 oral suspension 15 mg/mL on Days 1, 3, 5 and 7 in Part A.
• AZD9977 capsule
Randomized subjects will receive single oral dose of AZD9977 capsule 65 mg on Days 1, 3, 5 and 7 in Part A.
• AZD9977 ER capsule (fastvrate)
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.
• AZD9977 ER capsule (Int. rate)
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.

Locations

Country	Name	City	State
United Kingdom	Research Site	London

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Plasma PK parameter: Plasma concentration 24 hours post-dose (C4)	To assess C24 after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	Dosing sessions: Part A and Part B - Day 1 (24 hours post-dose)
Secondary	Plasma PK parameter: Time to reach maximum observed plasma concentration (tmax)	To assess tmax 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
Secondary	Plasma PK parameter: Half-life associated with terminal slope (?z) of a semi-logarithmic concentration-time curve (t½?z )	To assess t½?z 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
Secondary	Plasma PK parameter: Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (MRT)	To assess MRT after administration of single oral dose of AZD9977 capsule, ER (fast rate and Int. rate) capsules and oral suspension (reference).	Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1
Secondary	Plasma PK parameter: Terminal elimination rate constant (?z)	To assess ?z after administration of single oral dose of AZD9977 capsule, ER (fast rate and Int. rate) capsules and oral suspension (reference).	Dosing sessions: Part A: Days 1, 3, 5 and 7; Part B: Day 1
Secondary	Plasma PK parameter: Apparent total body clearance of drug from plasma after extravascular administration AZD9977 (CL/F)	To assess CL/F 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
Secondary	Plasma PK parameter: Apparent volume of distribution during the terminal phase after extravascular administration AZD9977 (Vz/F)	To assess Vz/F 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
Secondary	Number of subjects with adverse events (AEs) due to AZD9977	To assess AEs as variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference). AEs will be collected from the start of screening throughout the treatment period up to and including the follow-up visit. Serious AEs will be recorded from the time of informed consent.	From screening up to follow-up (5 to 7 days after final dose)
Secondary	Vital sign: Blood pressure [BP]	To assess supine position systolic and diastolic BP as variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference). Both SBP and DBP will be collected after the subject has rested in the supine position for at least 5 minutes.	From screening up to follow-up (5 to 7 days after final dose)
Secondary	Vital sign: Pulse rate	To assess supine position pulse rate as variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference). Pulse rate will be collected after the subject has rested in the supine position for at least 5 minutes.	From screening up to follow-up (5 to 7 days after final dose)
Secondary	Number of participants with abnormal findings in Resting 12-lead Electrocardiogram (ECG)	To assess any clinically significant abnormalities in the cardiovascular system functioning using a 10-second 12-lead ECG as variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference). The specific type and nature of the abnormality will be documented in ClinBase. Clinically significant findings will also be documented on the AE page of the CRF if applicable.	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Number of participants with abnormal physical examination findings	To assess any clinically significant abnormal physical examination findings as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference). Brief physical examination includes assessment of the general appearance, skin, abdomen, cardiovascular system and respiratory. Full physical examination includes assessment of the general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Hematology - Blood cells count	To assess red blood cells ( RBC) and white blood cells (WBC) countas a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Hematology - Hemoglobin (Hb)	To assess Hb as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Hematology - Hematocrit (HCT) and Reticulocyte absolute count	To assess HCT (RBC) and reticulocyte absolute count (immature RBCs) as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Hematology - Mean corpuscular volume (MCV)	To assess MCV as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH)	To assess MCH as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC)	To assess MCHC as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Hematology - Differential count	To assess differential WBC count (absolute count of neutrophils, lymphocytes, monocyets, eosinophils and basophils) as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Hematology - Platelets	To assess platelets count as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - sodium, potassium, calcium and phosphate	To assess serum sodium, potassium, calcium and phosphate level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - Urea and Uric acid	To assess serum urea and uric acid level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - Creatinine	To assess serum creatinine level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - Albumin	To assess serum albumin level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - Glucose (fasting)	To assess serum fasting glucose level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - C-reactive protein (CRP)	To assess serum CRP level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - Liver enzymes	To assess serum Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Gamma glutamyl transpeptidase (GGT) level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - Bilirubin	To assess serum bilirubin (total and unconjugated) level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - High-sensitivity troponin T	To assess serum high-sensitivity troponin T level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - Creatine kinase	To assess serum creatine kinase level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Serum Clinical chemistry - N-terminal-pro-brain natriuretic peptide (NT-proBNP)	To assess serum NT-proBNP level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Clinical Urinalysis - Glucose	To assess urine glucose level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Clinical Urinalysis - Protein	To assess urine protein level as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference). If urinalysis is positive for protein, a microscopy test will be performed to assess RBC, WBC, casts [cellular, granular, hyaline]).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)
Secondary	Laboratory assessments: Clinical Urinalysis - Blood	To assess presence of blood in urine as a variable of safety and tolerability after administration of single oral dose of AZD9977 capsule, ER capsules (fast rate and Int. rate) and oral suspension (reference). If urinalysis is positive for blood, a microscopy test will be performed to assess RBC, WBC, casts [cellular, granular, hyaline]).	At screening, dosing sessions of Part A and Part B and follow-up (5 to 7 days after final dose)