A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD9977 in Japanese Healthy Participants With Single and Multiple Ascending Dose Administration

NCT03801967 | Completed Phase 1 DMC

• 1 other identifier: D6401C00005
• Study Type: interventional
• Target: 28
• 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 safety, tolerability and pharmacokinetics (PK) of AZD9977, following oral administration of single and multiple ascending dose of AZD9977.

Conditions

Heart Failure

Keywords

Mineralocorticoid receptor; Heart failure with preserved ejection fraction; Safety; Pharmacokinetics; Single Ascending Dose; Multiple Ascending Dose

Outcome Measures

Primary Outcomes (46)

• Number of participants with adverse events (AEs)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants. Serious AEs will be recorded from the time of screening.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal blood pressure (BP)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants. Blood pressure includes both systolic and diastolic BP.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal supine pulse

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

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

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal findings in 12-lead safety Digital Electrocardiogram (dECG)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  At week 5 (Visit 2)

• Number of participants with abnormal findings in Real-Time ECG (Cardiac Telemetry)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  At week 5 (Visit 2)

• Number of participants with abnormal physical examination findings

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants. The complete physical examinations will include an assessment of the general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Hematology - absolute count of Basophils, Eosinophils, Monocytes, Neutrophils, Lymphocytes and Reticulocytes; Platelets and White blood cell (WBC) count

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assesments: Hematology - Mean corpuscular volume (MCV)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Hematology-Hematocrit (HCT)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Hematology - Hemoglobin (Hb)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Hematology - Red blood cell (RBC) count

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assesments: Heamtology - Mean corpuscular hemoglobin (MCH)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assssments : Hematology - Mean corpuscular hemoglobin concentration (MCHC)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Albumin

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Urea

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - C-reactive protein (CRP)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Alkaline phosphatase

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Alanine aminotransferase

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Aspartate aminotransferase

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Creatinine kinase

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Creatinine

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Uric acid

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Glucose (fasting)

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Gamma glutamyl transpeptidase

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Phosphate

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Total Bilirubin and Unconjugated bilirubin

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Potassium

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Sodium

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Cholesterol

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Luteinizing hormone

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Triglycerides

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Sex hormone binding globulin

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Follicle-stimulating hormone

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Testosterone

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Aldosterone

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Hemoglobin A1c

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - Electrolytes

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants. Electrolyte Measurements includes Bicarbonate, Calcium, Chloride, Potassium, Sodium

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Clinical Chemistry - High-sensitive-CRP

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  At Visit 2 (Week 5)

• Number of participants with abnormal laboratory assessments: High-sensitivity Troponin T

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: N-terminal pro-brain Natriuretic Peptide

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal urine volume

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  At Visit 2 (Week 5)

• Number of participants with abnormal laboratory assessments: Urinalysis - Glucose

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Urinalysis - Protein

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnormal laboratory assessments: Urinalysis - Blood

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants. Microscopy should be done (if positive for protein or blood): red blood cells (RBC), white blood cells (WBC), Casts (Cellular, Granular, Hyaline)

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

• Number of participants with abnorml laboratory assessments: Urinalysis - Urinary Electrolytes

  To investigate the safety and tolerability of AZD9977 following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants. Urinary Electrolytes: Calcium, Potassium, Chloride, Sodium, Creatinine and Uric acid.

  From screening (Day -28) till follow-up visit (Up to 6 weeks)

Secondary Outcomes (21)

• Plasma PK analysis: Area under curve (AUC)

  Day 1-2: Pre-dose and 0-4, 4-8, 8-12 and 12-24 hours post-dose and Day 9: Pre-dose and 0-4, 4-8 and 8-12 hours post-dose

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

  Day 1-2: Pre-dose and 0-4, 4-8, 8-12 and 12-24 hours post-dose and Day 9: Pre-dose and 0-4, 4-8 and 8-12 hours post-dose

• Plasma PK analysis: Time to reach peak or maximum observed concentration following drug administration (tmax)

  Day 1-2: Pre-dose and 0-4, 4-8, 8-12 and 12-24 hours post-dose and Day 9: Pre-dose and 0-4, 4-8 and 8-12 hours post-dose

• Plasma PK analysis: Observed concentration at the end of the dosing interval following drug administration (Cmin)

  Day 1-2: Pre-dose and 0-4, 4-8, 8-12 and 12-24 hours post-dose and Day 9: Pre-dose and 0-4, 4-8 and 8-12 hours post-dose

• Plasma PK analysis: Terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve following drug administration (λz)

  Day 1-2: Pre-dose and 0-4, 4-8, 8-12 and 12-24 hours post-dose and Day 9: Pre-dose and 0-4, 4-8 and 8-12 hours post-dose

Study Arms (2)

AZD9977

EXPERIMENTAL

Each participant will receive AZD9977 at the selected dose level on Day 1 and from Day 3 to 9, with single dose on Day 1 and Day 9 and twice a day (BID) dosing on Day 3 to Day 8. No dose will be given on Day 2.

Drug: AZD9977

Placebo

PLACEBO COMPARATOR

Each participant will receive placebo at the selected dose level on Day 1 and from Day 3 to 9, with single dose on Day 1 and Day 9 and twice a day (BID) dosing on Day 3 to Day 8. No dose will be given on Day 2.

Drug: Placebo

Interventions

AZD9977 DRUG

Randomized participants will receive oral dose of AZD9977.

AZD9977

Placebo DRUG

Randomized participants will receive oral dose of matching placebo.

Placebo

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 Japanese participants aged 18 to 50 years (inclusive) with suitable veins for cannulation or repeated venipuncture. A Japanese participant is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan.
• 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/biomarker research. If a participant decline to participate in the genetic and/or biomarker component of the study, there will be no penalty or loss of benefit to the participant. The participant will not be excluded from other aspects of the study described in this protocol.

You may not qualify if:

• History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant'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. 3. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
• \. Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results at the Screening Visit and/or admission.
• Serum potassium \> 5.0 mmol/L 4.2. Hemoglobin A1c (HbA1c) \> 5.7% 5. Any positive result on Screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
• \. Abnormal vital signs, after 10 minutes supine rest at the Screening Visit and/or admission 7. Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiography (ECG) and any clinically important abnormalities in the 12 Lead ECG as judged by the Investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or LV hypertrophy at the Screening Visit and/or admission.
• \. Known or suspected history of drug abuse in the last 12 months before the Screening Visit as judged by the Investigator.
• \. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the previous 3 months.
• \. History of alcohol abuse in the last 12 months before the Screening Visit or current excessive intake of alcohol as judged by the Investigator.
• \. Positive screen for drugs of abuse, alcohol or cotinine (nicotine) at Screening or admission.
• \. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD9977.
• \. Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate,) as judged by the Investigator.
• \. 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 nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega-dose 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.
• \. Plasma donation within 1 month of the Screening Visit or any blood donation/blood loss \> 500 mL during the 3 months prior to the Screening Visit.
• \. Participants who have previously received AZD9977. 19. Involvement of any Astra Zeneca or Clinical Unit employee or their close relatives.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Harrow, HA1 3UJ, United Kingdom

Location

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: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: This study is single-blind (in which the study center staff have to remain blinded during the clinical conduct of a given cohort) with regard to treatment (AZD9977 or placebo) at each dose level. AZD9977 and placebo will be matched for formulation, appearance, and amount.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Multiple ascending dose, placebo-controlled, single blind sequential group design

Study Record Dates

• First Submitted: December 12, 2018
• First Posted: January 14, 2019
• Study Start: January 24, 2019
• Primary Completion: May 2, 2019
• Study Completion: May 2, 2019
• Last Updated: May 10, 2019

Record last verified: 2019-05

Locations

GB (1)