Clinical trial NCT03435276: Multiple-ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD9977 in Healthy Male Subjects
Official title: A Phase 1, Randomized, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD9977 Following Multiple-Ascending Dose Administration in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Heart failure.
Oral selective mineralocorticoid receptor modulator.
Heart failure with preserved ejection fraction (HFpEF).
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2018-02-19
Enrollment: 27
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: This is a phase 1, randomized, single-blind, placebo-controlled, single center, multiple-ascending dose sequential-group design study conducted on 45 healthy male subjects to investigate the safety, tolerability, pharmacokinetics (PK) of AZD9977, time to reach steady state, the degree of accumulation and the time dependency of the PK. The study consists of three visits:

* A screening period (maximum 28 days)
* A treatment period (subjects will be resident from 2 days before first dose of investigation medicinal product (IMP) (Day -2) until at least 36 after last dose of IMP and will be discharged on Day 9) and
* A follow-up visit within 5 to 7 days after last dose of IMP. This study consists of 3 Cohorts (9 subjects each). Based on the safety review committee (SRC) requirement, 2 additional cohorts may be added either to repeat a dose level or additional dose steps, if required. In each cohort, subjects will be randomized to receive AZD9977 (6 subjects) and placebo (3 subjects) oral suspension twice daily. The dose of AZD9977 in Cohort 1 will be 50 mg as starting dose and in Cohort 2 and 3 at provisional dose 150 mg and 300 mg, respectively. Each subject will receive a total of 14 oral doses of AZD9977 or placebo. Each subject will receive a single dose of IMP in the morning of Day 1 and Day 8 and twice daily doses on Day 2 to Day 7.

On Day 1 and Day 8, subjects will be fasted for 10 hours before dosing until 4 hours after dosing when lunch will be served. On Day 2 to Day 6, subjects will be fasted for 10 hours before dosing until 1 hour after dosing when breakfast will be served. On Day 7, subjects will be fasted for 10 hours before dosing and until after the completion of the oral glucose tolerance test (OGTT) when breakfast will be served. For the evening dose of IMP (Days 2 to Day 7), subjects will be fasted for 2 hours before dosing until 1 hour after dosing. On all days, subjects will be allowed to drink freely until 1 hour before dosing to prevent dehydration before each morning and evening dose and water consumption could be resumed 1 hour after dosing.

Dosing for each ascending dose cohort will proceed with 2 subjects in a sentinel cohort, such that 1 subject will be randomized to receive placebo and 1 subject will be randomized to receive AZD9977. The safety data from the sentinel subjects up to 72 hours post first dose will be reviewed by the principal investigator (PI) before the remaining subjects in the cohort are dosed. Following review of data from the study, the SRC may decide to adjust the length of the stay at the study site and the timing and number of assessments and/or blood samples for subsequent cohorts. The time window between the single dose and start of repeated dosing may also be adjusted. The duration of the study is approximately 6 weeks

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated, written informed consent before any study specific procedures.
2. Healthy male subject aged 18 to 50 years (inclusive) 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 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.

Exclusion Criteria:

1. 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.
2. History/presence of gastrointestinal, hepatic/renal disease/any other condition known to interfere with absorption, distribution, metabolism/excretion of drugs.
3. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the 1st administration of the IMP.
4. 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%.
5. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody \& human immunodeficiency virus (HIV).
6. 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).
7. 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.
8. Known or suspected history of drug abuse in the last 12 months before the Screening Visit as judged by the Investigator.
9. Current smokers/those who have smoked/used nicotine products (including e-cigarettes) within last 3 months before the Screening Visit.
10. History of alcohol abuse in the last 12 months before the Screening Visit/current excessive intake of alcohol as judged by the Investigator.
11. Positive screen for drugs of abuse, alcohol/cotinine (nicotine) at the Screening Visit/admission.
12. 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.
13. Excessive intake of caffeine-containing drinks/food (e.g., coffee, tea, chocolate,) as judged by the Investigator.
14. Use of drugs with enzyme inducing properties like St John's Wort within 3 weeks before the 1st administration of the IMP.
15. Use of any prescribed/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 before the first administration of the IMP or longer if the medication has a long half-life.
16. Plasma donation within 1 month of the Screening Visit or any blood donation/blood loss \> 500 mL during the 3 months before the Screening Visit.
17. Has received another new chemical/non-chemical entity (a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The exclusion period 3 months after the final dose/1 month after the last visit whichever is the longest.
18. Subjects who have previously received AZD9977.
19. Involvement of any Astra Zeneca or study site employee or their close relatives.
20. Judgment by the Investigator that the subject should not participate in the study if they have any ongoing/recent (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.
21. Subjects who cannot communicate reliably with the Investigator.
22. Vulnerable subjects (kept in detention, protected adults under guardianship, trusteeship or committed to an institution by governmental or juridical order).
23. Previous bone marrow transplant.
24. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

Primary outcomes:
measure: Number of subjects with adverse events (AEs) due to AZD9977
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Systolic blood pressure [SBP]
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Diastolic blood pressure [DBP]
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Pulse rate
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments of urine volume
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Number of participants with abnormal findings in Twelve-lead (12-Lead) electrocardiograms (ECGs) (safety ECGs and 12-lead continuous digital ECG [dECG])
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Number of participants with abnormal cardiac telemetry
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Number of participants with abnormal physical examination findings
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Hematology - Differential count
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Hematology - Hematocrit (HCT) and Reticulocyte absolute count
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Hematology - Hemoglobin (Hb)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Hematology - Mean corpuscular hemoglobin (MCH)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Hematology - Mean corpuscular hemoglobin concentration (MCHC)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Hematology - Mean corpuscular volume (MCV)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Hematology - Platelets
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Hematology - Blood cells count
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Albumin
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - C reactive protein (CRP)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Creatine kinase (CK)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Creatinine
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Glucose (fasting)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Calcium, potassium, phosphate and sodium
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Urea and Uric acid
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Liver enzymes
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Bilirubin
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Steroid
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Luteinizing hormone (LH)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Sex hormone binding globulin (SHBG)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Testosterone
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Aldosterone
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Hemoglobin A1c (HbA1c)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - High-sensitivity troponin T
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - N-terminal pro-brain natriuretic peptide (NT-proBNP)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Serum Clinical chemistry - Follicle-stimulating hormone (FSH)
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Clinical Urinalysis - Protein
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Clinical Urinalysis - Blood
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Clinical Urinalysis - Glucose
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Clinical Urinalysis - Uric acid
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Clinical Urinalysis - Creatinine
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
measure: Laboratory assessments: Urinalysis - Urinary Electrolytes
timeFrame: From baseline up to follow-up (5 to 7 days post last dose)
Secondary outcomes:
measure: Plasma PK parameter: Observed maximum plasma concentration (Cmax)
timeFrame: 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)
measure: Plasma PK parameter: Time to reach maximum concentration (tmax)
timeFrame: 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)
measure: Plasma PK parameter: Terminal half-life (t1/2λz)
timeFrame: 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)
measure: Plasma PK parameter: Terminal rate constant (λz)
timeFrame: 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)
measure: Plasma PK parameter: Area under the plasma concentration-time curve in the dosing interval (AUCτ)
timeFrame: 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)
measure: Plasma PK parameter: Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUClast)
timeFrame: Treatment period:Day 1and Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)
measure: Plasma PK parameter: Apparent volume of distribution for parent drug at terminal phase (Vz/F)
timeFrame: 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)
measure: Plasma PK parameter: Apparent clearance for parent drug (CL/F)
timeFrame: 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)
measure: Plasma PK parameter: Dose normalized AUCτ (AUCτ/D)
timeFrame: 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)
measure: Plasma PK parameter: Dose normalized Cmax (Cmax/D)
timeFrame: 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)
measure: Plasma PK parameter: Mean Residence Time (MRT)
timeFrame: 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)
measure: Plasma PK parameter: Area under the concentration-time curve from time zero extrapolated to infinity (AUC)
timeFrame: Treatment period:Day 1 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)
measure: Plasma PK parameter: Dose normalized AUC (AUC/D)
timeFrame: Treatment period:Day 1 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)
measure: Plasma PK parameter: Dose normalized AUClast (AUClast/D)
timeFrame: Treatment period:Day 1 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)
measure: Plasma PK parameter: Observed concentration at the end of the dosing interval (Cmin)
timeFrame: Treatment period: Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)
measure: Plasma PK parameter: Accumulation ratio for AUCτ (Rac AUCτ)
timeFrame: Treatment period: Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)
measure: Plasma PK parameter: Accumulation ratio for AUCτ (Rac Cmax)
timeFrame: Treatment period: Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)
measure: Plasma PK parameter: Temporal change (TCP)
timeFrame: Treatment period: Day 8 (Pre-dose & 20 min, 40 min, 1, 2, 4, 6, 8, 10, 12, 16, & 20 hours post-dose)
measure: Urine PK parameter: Renal clearance (CLR)
timeFrame: Treatment period: Day 8 (Pre-dose and 0-4, 4-8 and 8-12 hours post-dose)
measure: Urine PK parameter: Amount of analyte excreted into the urine from time t1 to t2 (Ae[t1-t2])
timeFrame: Treatment period: Day 8 (Pre-dose and 0-4, 4-8 and 8-12 hours post-dose)
measure: Urine PK parameter: Percentage Fraction of dose excreted in urine from time t1 to t2 (fe[t1-t2]%)
timeFrame: Treatment period: Day 8 (Pre-dose and 0-4, 4-8 and 8-12 hours post-dose)
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: Research Site
Study officials:
References: