Clinical trial NCT02532998: A Study to Assess the Pharmacodynamic Effect of Single Doses of AZD9977 in Healthy Male Subjects
Official title: A Phase I, Randomized, Single-Blind, Crossover Study to Assess the Pharmacodynamics of AZD9977 Following Single-Dose Administration to Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pharmacodynamics
Healthy Subjects
Keywords: Pharmacodynamics
AZD9977
Safety
Tolerability
Pharmacokinetics
Eplerenone
Fludrocortisone
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2015-08-26
Enrollment: 40
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: This is a Phase I, Randomized, Single-Blind, Crossover Study to Assess the Pharmacodynamics of AZD9977 following Single-Dose administration to healthy male subjects

Detailed description: This study will be a phase I study to assess the pharmacodynamics of AZD9977 following single-dose administration to healthy male subjects. It is a single-blind (with regards to AZD9977 and AZD9977 Placebo), randomized, four-treatment, four-period crossover design, with a potential 5th and 6th randomized cross-over treatment period. In this study eplerenone is used as a positive control and fludrocortisone will be used as a challenge agent. In addition the safety, tolerability and pharmacokinetics will be assessed.

Eligibility criteria: 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. Male subjects must accept to comply with the restrictions for sexual activity provided to them.
4. 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.
5. Optional: Provision of signed and dated written informed consent for genetic research.

   Note: Participation in exploratory biomarker research is mandatory. If a subject declines 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.
6. Able to understand, read and speak the English language.

Exclusion criteria

1. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the potential subject at risk because of participation in the study, or influences the results or the potential subject's ability to participate in the study.
2. 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 significant illness, medical/surgical procedure, or trauma within 4 weeks of first dosing with investigational medicinal product (IMP).
4. Any clinically significant abnormalities in hematology, clinical chemistry or urinalysis results, as judged by the investigator.
5. Abnormal findings in vital signs, after 10 minutes resting in the supine position, defined as any of the following:

   * Systolic blood pressure (SBP) \< 90 mmHg or ≥ 140 mmHg
   * Diastolic blood pressure (DBP) \< 50 mmHg or ≥ 90 mmHg
   * Pulse \< 45 or \> 85 beats per minute (bpm)
6. Any clinically significant abnormalities on the 12-lead electrocardiogram (ECG), as judged by the investigator.
7. Any positive result at screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibodies.
8. Known or suspected history of drug abuse, as judged by the investigator.
9. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of first dosing. The period of exclusion begins 3 months after the final dose or one month after the last visit whichever is the longest.

   Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.
10. Plasma donation within one month of screening or any blood donation/blood loss \> 500 mL during the 3 months prior to screening.
11. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator 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 within the previous 3 months.
13. Positive screen for drugs of abuse, alcohol or cotinine at screening or for 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 first dosing.
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 2 weeks prior to first dosing, 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, as judged by the investigator.
17. Involvement of any AstraZeneca or study site employee or their close relatives.
18. Subjects who previously received AZD9977.
19. Judgment by the investigator 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. Known allergy to eplerenone or fludrocortisone or any of the constituents (including lactose, which is a constituent of Florinef™).
21. History of galactose intolerance.
22. Any infections or at risk of infection (surgery, trauma, or significant infection) within 90 days of screening, or history of skin abscesses within 90 days of screening.
23. Presence, history or family history of long QT syndrome, hypokalemia, hyperkalemia or Torsades de Pointes.
24. Serum potassium \< 3.5 mmol/L or ≥ 5.0 mmol/L at screening or for each admission to the study center.
25. Presence or history of active peptic ulcer.
26. History of any psychiatric disorder (including affective, psychotic, behavioral, irritability, anxiety, sleep disturbances and cognitive disorders) which required specialist psychiatric review.
27. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea and chocolate) as judged by the investigator.
28. Subjects who are vegans or have medical dietary restrictions (vegetarians may be included in the study).
29. Subjects who cannot communicate reliably with the investigator.
30. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
31. In addition, any of the following is regarded as a criterion for exclusion from the genetic research:

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

Primary outcomes:
measure: Pharmacodynamics of AZD9977 Assessed Per Sodium/Potassium Ratio in Urine in Eplerenone Treatment Versus a Combination Treatment of Eplerenone and AZD9977.
timeFrame: From 2 hours post dose to 8 hours post dose
Secondary outcomes:
measure: Observed Maximum Concentration (Cmax) of AZD9977
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) of AZD9977.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to t Hours After Dosing (AUC[0-t]) of AZD9977.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Time to Reach Maximum Concentration (Tmax) of AZD9977.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Terminal Half-life (t½λz) of AZD9977.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Apparent Clearance (CL/F) of AZD9977.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Apparent Volume of Distribution at Terminal Phase (Vz/F) of AZD9977.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Apparent Volume of Distribution at Terminal Phase (Vz/F) of Eplerenone.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Apparent Clearance (CL/F) of Eplerenone.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Terminal Half-life (t½λz) of Eplerenone.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Time to Reach Maximum Concentration (Tmax) of Eplerenone.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Observed Maximum Concentration (Cmax) of Eplerenone.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to t Hours After Dosing (AUC(0-t)) of Eplerenone.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) of Eplerenone.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Pharmacodynamics of AZD9977 Assessed Per Sodium/Potassium Ratio in Urine in AZD9977 Treatment With Placebo Versus Treatment With AZD9977.
timeFrame: From 2 hours post dose to 8 hours post dose
measure: Number of Participants With Clinically Significant Blood Pressure Values.
timeFrame: From screening to post-study visit, up to 10 weeks
measure: Number of Participants With Clinically Significant Pulse Rate.
timeFrame: From screening to post-study visit, up to 10 weeks
measure: Number of Participants With Clinically Significant Electrocardiogram.
timeFrame: From screening to post-study visit, up to 10 weeks
measure: Number of Participants With Clinically Significant Physical Examination Values.
timeFrame: From screening to post-study visit, up to 10 weeks
measure: Number of Participants With Clinically Significant Safety Laboratory Tests Values.
timeFrame: From screening to post-study visit, up to 10 weeks
measure: Pharmacodynamics of AZD9977 Assessed by Estimating the Fractional Sodium Excretion in Urine for Each Urine Collection Time Interval.
timeFrame: From 0 to 8 hours after dosing
measure: Pharmacodynamics of AZD9977 Assessed Per Total Sodium Excreted Cumulatively and During Each of the Urine Collection Intervals.
timeFrame: From 0 to 24 hours after dosing
measure: Pharmacodynamics of AZD9977 Assessed Per Fractional Potassium Excretion in Urine for Each Urine Collection Time Interval.
timeFrame: From 0 to 8 hours post dosing
measure: Pharmacodynamics of AZD9977 by Assessment of Total Potassium Excreted Cumulatively and During Each of the Urine Collection Intervals
timeFrame: From 0 to 24 hours after dosing
measure: Pharmacodynamics of AZD9977 Assessed Per Urine Production for Each Urine Collection Time Interval.
timeFrame: From 8 hours before dosing until 24 hours after dosing
measure: Pharmacodynamics of AZD9977 by Assessment of Total Urine Volume Excreted Cumulatively and During Each of the Urine Collection Intervals
timeFrame: From 8 hours before dosing until 24 hours after dosing
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: Research Site
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit London
name: Muna Albayaty, MBChB, MSc, MFPM
role: PRINCIPAL_INVESTIGATOR
References: