A Study to Assess the Pharmacodynamic Effect of Single Doses of AZD9977 in Healthy Male Subjects

Healthy Subjects Clinical Trial

Official title:

A Phase I, Randomized, Single-Blind, Crossover Study to Assess the Pharmacodynamics of AZD9977 Following Single-Dose Administration to Healthy Male Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02532998
• Other study ID #: D6400C00004
• Secondary ID: 2015-002224-11
• Status: Completed
• Phase: Phase 1
• First received: August 24, 2015
• Last updated: December 22, 2015
• Start date: September 2015
• Est. completion date: December 2015

Study information

• Verified date: December 2015
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• 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. 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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Healthy Subjects
• Pharmacodynamics

Intervention

Drug:
• AZD9977 oral suspension
AZD9977 oral suspension, single dose
• AZD9977 placebo oral suspension
oral suspension, single dose
• Fludrocortisone, tablets
Loading dose of 0.5 mg and maintenance doses of 0.1 mg every second hour up to a total dose of 1.0 mg per treatment period (may be modified to up to 1.3 mg based on emerging data)
• Eplerenone, tablets
100 mg (2 x 50 mg tablets) single dose, may be modified based on emerging data (will not exceed 500 mg per treatment period)

Locations

Country	Name	City	State
United Kingdom	Research Site	Harrow

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacodynamics of AZD9977 by assessment of sodium/potassium ratio in urine after treatment with eplerenone in comparison with after treatment with a combination of eplerenone and AZD9977	Pharmacodynamics of AZD9977 after single dosing of AZD9977 with fludrocortisone both with and without eplerenone	From 2 hours post dose to 6 or 8 hours post dose, depending on the clearance of AZD9977 as determined in a prior study, during each of the 6 treatment periods. Total duration of the study will be up to 10 weeks	No
Secondary	Pharmacodynamics of AZD9977 by assessment of the sodium/potassium ratio in urine after treatment with AZD9977 placebo in comparison with after treatment with AZD9977	Pharmacodynamics of AZD9977 after single dosing of AZD9977 with fludrocortisone in comparison to AZD9977 placebo	From 2 hours post dose to 6 or 8 hours post dose, depending on the clearance of AZD9977 as determined in a prior study, during each of the 6 treatment periods. Total duration of the study will be up to 10 weeks	No
Secondary	Safety and tolerability of AZD9977 by assessment of the number of adverse events and the number of subjects with adverse events	To assess the safety and tolerability of single doses of AZD9977	From screening to post-study visit, up to 10 weeks	Yes
Secondary	Safety and tolerability of AZD9977 by assessment of blood pressure	To assess the safety and tolerability of single doses of AZD9977	From screening to post-study visit, up to 10 weeks	Yes
Secondary	Safety and tolerability of AZD9977 by assessment of pulse	To assess the safety and tolerability of single doses of AZD9977	From screening to post-study visit, up to 10 weeks	Yes
Secondary	Safety and tolerability of AZD9977 by assessment of electrocardiogram	To assess the safety and tolerability of single doses of AZD9977	From screening to post-study visit, up to 10 weeks	Yes
Secondary	Safety and tolerability of AZD9977 by assessment of physical examination	This is a composite 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 to post-study visit, up to 10 weeks	Yes
Secondary	Safety and tolerability of AZD9977 by assessment of safety laboratory tests	This is a composite of clinical chemistry, hematology and urinalysis	From screening to post-study visit, up to 10 weeks	Yes
Secondary	Pharmacodynamics of AZD9977 by assessment of fractional sodium excretion in urine for each urine collection time interval	Pharmacodynamics of AZD9977 after single dosing of AZD9977 with fludrocortisone and/or eplerenone	From 8 h before dosing until 24h after dosing	No
Secondary	Pharmacodynamics of AZD9977 by assessment of total sodium excreted cumulatively and during each of the urine collection intervals	Pharmacodynamics of AZD9977 after single dosing of AZD9977 with fludrocortisone and/or eplerenone	From 8 h before dosing until 24h after dosing	No
Secondary	Pharmacodynamics of AZD9977 by assessment of fractional potassium excretion in urine for each urine collection time interval	Pharmacodynamics of AZD9977 after single dosing of AZD9977 with fludrocortisone and/or eplerenone	From 8 h before dosing until 24h after dosing	No
Secondary	Pharmacodynamics of AZD9977 by assessment of urine production for each urine collection time interval	Pharmacodynamics of AZD9977 after single dosing of AZD9977 with fludrocortisone and/or eplerenone	From 8 h before dosing until 24h after dosing	No
Secondary	Pharmacodynamics of AZD9977 by assessment of total potassium excreted cumulatively and during each of the urine collection intervals	Pharmacodynamics of AZD9977 after single dosing of AZD9977 with fludrocortisone and/or eplerenone	From 8 h before dosing until 24h after dosing	No
Secondary	Pharmacodynamics of AZD9977 by assessment of total urine volume excreted cumulatively and during each of the urine collection intervals	Pharmacodynamics of AZD9977 after single dosing of AZD9977 with fludrocortisone and/or eplerenone	From 8 h before dosing until 24h after dosing	No