Multiple-ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD9977 in Healthy Male Subjects

NCT03435276 | Completed Phase 1

• 1 other identifier: D6401C00001
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

This is a randomized, single-blind, placebo-controlled study conducted on healthy male subjects at a single study center to assess the safety, tolerability and the pharmacokinetics of AZD9977 following multiple-ascending oral doses at steady state

Conditions

Healthy Volunteers

Keywords

Heart failure.; Oral selective mineralocorticoid receptor modulator.; Heart failure with preserved ejection fraction (HFpEF).

Outcome Measures

Primary Outcomes (40)

• Number of subjects with adverse events (AEs) due to AZD9977

  To assess AEs as variable of safety and tolerability after administration of multiple dose of AZD9977 oral suspension. 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 baseline up to follow-up (5 to 7 days post last dose)

• Systolic blood pressure [SBP]

  To measure SBP as variable of safety and tolerability after administration of multiple dose of AZD9977 oral suspension. SBP will be collected after the subject has rested in the supine position for at least 10 minutes.

  From baseline up to follow-up (5 to 7 days post last dose)

• Diastolic blood pressure [DBP]

  To measure DBP as variable of safety and tolerability after administration of multiple dose of AZD9977 oral suspension. DBP will be collected after the subject has rested in the supine position for at least 10 minutes.

  From baseline up to follow-up (5 to 7 days post last dose)

• Pulse rate

  To measure pulse as variable of safety and tolerability after administration of multiple dose of AZD9977 oral suspension. Pulse rate will be collected after the subject has rested in the supine position for at least 10 minutes.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments of urine volume

  To assess the urine volume as variable of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Number of participants with abnormal findings in Twelve-lead (12-Lead) electrocardiograms (ECGs) (safety ECGs and 12-lead continuous digital ECG [dECG])

  To assess any clinically significant abnormalities on cardiac electrophysiological parameters as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension. 12-lead safety ECG and dECG will be obtained after the participant rested in the supine position for at least 10 minutes. Safety ECG will be collected at the end of each dECG recording. Various dECG variables like time between 2 consecutive R waves on ECG (RR), ECG interval measured form onset of P wave to the onset of QRS complex (PR), ECG interval measured from onset of QRS complex to the J point (QRS) and ECG interval measured form onset of QRS complex to the end of the T wave (QT intervals) will be reported. Derived parameters like QT interval corrected for heart rate using Fridericia's formula (QTcF), heart rate (HR) and others, as applicable are also calculated.

  From baseline up to follow-up (5 to 7 days post last dose)

• Number of participants with abnormal cardiac telemetry

  To assess any clinically significant abnormalities in the cardiovascular system functioning as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension. A 2-lead real-time telemetry ECG will be used to assess the heart rate.

  From baseline up to follow-up (5 to 7 days post last dose)

• 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 multiple dose of AZD9977 oral suspension. Brief physical examination includes assessment of the general appearance, skin, cardiovascular system, respiratory and abdomen. Full physical examination includes 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 baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Hematology - Differential count

  To assess the differential white blood cell count (absolute count of basophils, eosinophils, lymphocytes, monocyets and neutrophils) as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Hematology - Hematocrit (HCT) and Reticulocyte absolute count

  To assess the HCT (red blood cells \[RBC\]) and reticulocyte absolute count (immature RBCs) as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Hematology - Hemoglobin (Hb)

  To assess the Hb as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH)

  To assess the MCH as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC)

  To assess the MCHC as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Hematology - Mean corpuscular volume (MCV)

  To assess the MCV as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Hematology - Platelets

  To assess platelets count as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Hematology - Blood cells count

  To assess RBC and white blood cells (WBC) count as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Albumin

  To assess the serum albumin level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - C reactive protein (CRP)

  To assess the serum CRP level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Creatine kinase (CK)

  To assess the serum CK level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Creatinine

  To assess the serum creatinine level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Glucose (fasting)

  To assess the serum fasting glucose level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Calcium, potassium, phosphate and sodium

  To assess the serum calcium, potassium, phosphate and sodium level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Urea and Uric acid

  To assess the serum urea and uric acid level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Liver enzymes

  To assess the serum Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Aspartate aminotransferase (AST) and Gamma glutamyl transpeptidase (GGT) level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Bilirubin

  To assess the serum bilirubin (total and unconjugated) level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Steroid

  To assess the serum cholesterol and triglycerides level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Luteinizing hormone (LH)

  To assess the serum LF level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Sex hormone binding globulin (SHBG)

  To assess the serum SHBG level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Testosterone

  To assess the serum testosterone level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Aldosterone

  To assess the serum aldosterone level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Hemoglobin A1c (HbA1c)

  To assess the serum HbA1c level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - High-sensitivity troponin T

  To assess the serum high-sensitivity troponin T level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - N-terminal pro-brain natriuretic peptide (NT-proBNP)

  To assess the serum NT-proBNP level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Serum Clinical chemistry - Follicle-stimulating hormone (FSH)

  To assess the serum FSH level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Clinical Urinalysis - Protein

  To assess the urine protein level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension. If urinalysis is positive for protein, a microscopy test will be performed to assess RBC, WBC, casts \[cellular, granular, hyaline\]).

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Clinical Urinalysis - Blood

  To assess the urine blood level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension. If urinalysis is positive for blood, a microscopy test will be performed to assess RBC, WBC, casts \[cellular, granular, hyaline\]).

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Clinical Urinalysis - Glucose

  To assess the urine glucose level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Clinical Urinalysis - Uric acid

  To assess the urine uric acid level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Clinical Urinalysis - Creatinine

  To assess the urine creatinine level as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

• Laboratory assessments: Urinalysis - Urinary Electrolytes

  To assess the urine electrolytes level (calcium, chloride, potassium and sodium) as variables of safety and tolerability after administration of multiple dose of AZD9977 oral suspension.

  From baseline up to follow-up (5 to 7 days post last dose)

Secondary Outcomes (21)

• Plasma PK parameter: Observed maximum plasma concentration (Cmax)

  Treatment period:Day 1 and Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)

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

  Treatment period:Day 1 and Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)

• Plasma PK parameter: Terminal half-life (t1/2λz)

  Treatment period:Day 1 and Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)

• Plasma PK parameter: Terminal rate constant (λz)

  Treatment period:Day 1 and Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)

• Plasma PK parameter: Area under the plasma concentration-time curve in the dosing interval (AUCτ)

  Treatment period:Day 1 and Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)

Study Arms (3)

Cohort 1

EXPERIMENTAL

Randomized subjects will receive AZD9977 50 mg or placebo oral suspension single dose on Day 1 and Day 8; twice daily dose Day 2 to Day 7

Drug: AZD9977; Other: Placebo

Cohort 2

EXPERIMENTAL

Randomized subjects will receive AZD9977 150 mg or placebo oral suspension single dose on Day 1 and Day 8; twice daily dose on Day 2 to Day 7

Drug: AZD9977; Other: Placebo

Cohort 3

EXPERIMENTAL

Randomized subjects will receive AZD9977 300 mg or placebo oral suspension single dose on Day 1 and Day 8; twice daily dose on Day 2 to Day 7

Drug: AZD9977; Other: Placebo

Interventions

AZD9977 DRUG

Randomized subjects will receive AZD9977 oral suspension at a dose of 50 mg in Cohort 1, 150 mg in Cohort 2 and 300 mg in Cohort 3

Cohort 1; Cohort 2; Cohort 3

Placebo OTHER

Randomized subjects will receive orally AZD9977 matched placebo in Cohorts 1, 2 and 3

Cohort 1; Cohort 2; Cohort 3

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 before any study specific procedures.
• Healthy male subject aged 18 to 50 years (inclusive) 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 and/or biomarker research. If a subject declines to participate in the genetic components 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.

You may not qualify if:

• History of any clinically important disease/disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study/influence the results/subject's ability to participate in the study.
• History/presence of gastrointestinal, hepatic/renal disease/any other condition known to interfere with absorption, distribution, metabolism/excretion of drugs.
• Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the 1st administration of the IMP.
• Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results at the Screening Visit and/or admission, as judged by the Investigator and specified below: Serum potassium \> 5.0 mmol/L; Hemoglobin A1c (HbA1c) \> 5.7%.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody \& human immunodeficiency virus (HIV).
• Abnormal vital signs, after 10 minutes supine rest at the Screening Visit and/or admission, defined as any of the following: Systolic BP \< 90 mmHg or \> 140 mmHg; Diastolic BP \< 50 mmHg or \> 90 mmHg; Heart rate \< 45 or \> 85 beats per minute (bpm).
• Any clinically important abnormalities in rhythm, conduction or morphology of the resting 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 CSP defined primary lead or LV hypertrophy at the Screening Visit or/and admission.
• Prolonged QT interval corrected for HR by Fridericia's formula (QTcF) \> 450 ms or shortened QTcF \< 340 ms or family history of long QT syndrome.
• PR (PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular preexcitation).
• PR (PQ) interval prolongation (\> 240 ms intermittent second (Wenckebach block while asleep is not exclusive) or 3rd degree atrioventricular (AV) block, or AV dissociation.
• Persistent/intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS \> 110 ms. Subjects with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of ventricular hypertrophy or pre-excitation.
• Known or suspected history of drug abuse in the last 12 months before the Screening Visit as judged by the Investigator.
• Current smokers/those who have smoked/used nicotine products (including e-cigarettes) within last 3 months before the Screening Visit.
• History of alcohol abuse in the last 12 months before the Screening Visit/current excessive intake of alcohol as judged by the Investigator.
• Positive screen for drugs of abuse, alcohol/cotinine (nicotine) at the Screening Visit/admission.

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 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. In the event of a medical emergency when management of a subject's condition requires knowledge of the trial medication, the treatment received may be revealed by personnel authorized by the PI. Reasons for breaking a code will be clearly explained and justified in ClinBase. The date on which the code was broken together with the identity of the person responsible will also be documented.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2018
• First Posted: February 19, 2018
• Study Start: February 27, 2018
• Primary Completion: June 13, 2018
• Study Completion: June 13, 2018
• Last Updated: June 21, 2018

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)