A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD9977 After Single Ascending Doses to Healthy Males

A Phase I, Randomized, Single-blind, Placebo-controlled Study to Access the Safety, Tolerability and Pharmacokinetics of AZD9977 Following Single Ascending Dose Administration to Healthy Male Subjects

This study will be a randomized, single-blind, placebo-controlled first-in-human study in healthy male subjects to assess the safety, tolerability and pharmacokinetics of single ascending doses of AZD9977. In Part B of this study the regional absorption of AZD9977 along the gastro-intestinal tract will be investigated using the IntelliCap® system in a non-randomized, open-label, fixed-sequence design. The study will be performed at a single study centre.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects; Pharmacokinetics; Tolerability; Safety
• Intervention / Treatment: Drug: AZD9977, oral suspension; Drug: Placebo, oral suspension; Drug: AZD9977, oral solution

Detailed Description

This study will be a randomized, single-blind, placebo-controlled first-in-human study in healthy male subjects to assess the safety, tolerability and pharmacokinetics of single ascending doses of AZD9977. In Part B of this study the regional absorption of AZD9977 along the gastro-intestinal tract will be investigated using the IntelliCap® system in a non-randomized, open-label, fixed-sequence design with oral solution as reference. The study will be performed at a single study centre.

• Study Type: Interventional
• Enrollment (Actual): 196
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Harrow, United Kingdom
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 have 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.

   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 GI, 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 dosing in Part A or the first dose of AZD9977 in Part B.
4. Any clinically significant abnormalities in hematology, clinical chemistry or urinalysis results, as judged by the investigator.
5. Any positive result at screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibodies.

6. 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 > 90 bpm
7. Any clinically important abnormalities in rhythm, conduction or morphology of the electrocardiogram (ECG) at screening or pre-dose, as considered by the investigator.
8. Prolonged QTcF > 450 ms or family history of long QT syndrome.
9. PR (PQ) interval shortening < 120 ms. PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation.

10. PR (PQ) interval prolongation > 240ms; intermittent second or third degree atrioventricular (AV) block, or AV dissociation.

    Wenckebach block while asleep is not exclusive.

11. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms.

    QRS > 110 ms but < 115 ms are acceptable if there is no evidence of ventricular hypertrophy or pre-excitation.

12. Serum potassium higher than 5.0 mmol/L at screening or admission to the study center (Day -1).
13. Known or suspected history of drug abuse as judged by the investigator.
14. Current smokers or those who have smoked or used nicotine products within the previous 3 months.
15. History of alcohol abuse or excessive intake of alcohol as judged by the investigator.
16. Positive screen for drugs of abuse, alcohol or cotinine at screening or admission to the study center.
17. 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.
18. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea and chocolate) as judged by the investigator.
19. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to dosing in Part A or the first dose of AZD9977 in Part B.
20. 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 dosing in Part A or the first dose of AZD9977 in Part B, or longer if the medication has a long half-life.
21. Plasma donation within one month of screening or any blood donation/blood loss > 500 mL during the 3 months prior to screening.

22. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of dosing in Part A or the first dose of AZD9977 in Part B in this study. 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.

23. Involvement of any AstraZeneca or study site employee or their close relatives.
24. 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.
25. Subjects who are vegans or have medical dietary restrictions (vegetarians may be included in the study).
26. Subjects who cannot communicate reliably with the investigator.

27. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

    In addition, any of the following is regarded as a criterion for exclusion from the genetic research:

28. Previous bone marrow transplant.

29. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

    Criteria applicable to Part B only:

30. Subjects with pacemakers or other implanted electro-medical devices.
31. Subjects with swallowing disorders.
32. Subjects with pre-planned MRI examination.
33. Subjects not willing to have an abdominal X-ray performed if the IntelliCap® capsule has not been retrieved within one week after ingestion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD9977 oral suspension, single doses; In Part A up to 10 cohorts with single ascending doses with AZD9977 as oral suspension. In Part B AZD9977 as oral suspension in IntelliCap® capsule	Drug: AZD9977, oral suspension; Single ascending doses of AZD9977 oral suspension (Part A) Single dose of AZD9977 oral suspension in IntelliCap® capsule in regional absorption part (Part B)
Placebo Comparator: Placebo, oral suspension, single doses; In Part A up to 10 cohorts with single doses with matching placebo to AZD9977	Drug: Placebo, oral suspension; Matching placebo
Experimental: AZD9977, oral solution, single dose; In Part B, of oral solution of AZD9977 will be used as reference	Drug: AZD9977, oral solution; AZD9977, single dose of oral solution in Part B as reference

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of AZD9977 by Assessing the Percentage of Participants With Adverse Events	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 45 days, i.e. from Screening to Follow-up
Safety and Tolerability of AZD9977 by Assessing Number of Participants With Clinically Significant Pulse Rate	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 45 days, i.e. from Screening to Follow-up
Safety and Tolerability of AZD9977 by Assessing Number of Participants With Clinically Significant Trends in 12-lead Electrocardiograms	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 45 days, i.e. from Screening to Follow-up
Safety and Tolerability of AZD9977 by Number of Participants With Clinically Significant Trends in Cardiac Telemetry	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 4 days, i.e. on the day before each dosing and for 24 hours after each dosing
Safety and Tolerability of AZD9977 by Assessing the Number of Subjects With Adverse Events	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 45 days, i.e. from Screening to Follow-up
Safety and Tolerability of AZD9977 by Assessing Number of Participants With Clinically Significant Changes in Blood Pressure	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 45 days, i.e. from Screening to Follow-up
Safety and Tolerability of AZD9977 by Assessing Number of Participants With Clinically Significant Changes in Hematology	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 45 days, i.e. from Screening to Follow-up
Safety and Tolerability of AZD9977 by Assessing Number of Participants With Clinically Significant Changes in Clinical Chemistry	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 45 days, i.e. from Screening to Follow-up
Safety and Tolerability of AZD9977 by Assessing Number of Participants With Clinically Significant Changes in Urinalysis	To assess the safety and tolerability of single ascending doses of AZD9977	For up to 45 days, i.e. from Screening to Follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Versus Time Curve (AUC) From Zero Extrapolated to Infinity.	To assess plasma pharmacokinetic parameters following single ascending doses of AZD977	Pre-dose and post-dose upto 48 hrs
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Analyte concentrationAUC(0-t)	To assess plasma pharmacokinetic parameters following single ascending doses of AZD977	Pre-dose and post-dose upto 48 hrs
Observed Maximum Concentration (Cmax)	To assess plasma pharmacokinetic parameters following single ascending doses of AZD977	Pre-dose and post-dose upto 48 hrs
Time to Maximum Observed Plasma Concentration (t Max)	To assess plasma pharmacokinetic parameters following single ascending doses of AZD977	Pre-dose and post-dose upto 48 hrs
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t1/2λz)	To assess plasma pharmacokinetic parameters following single ascending doses of AZD977	Pre-dose and post-dose upto 48 hrs
Apparent Clearance (CL/F)	To assess plasma pharmacokinetic parameters following single ascending doses of AZD977	Pre-dose and post-dose upto 48 hrs
Apparent Volume of Distribution (Vz/F)	To assess plasma pharmacokinetic parameters following single ascending doses of AZD977	Pre-dose and post-dose upto 48 hrs
Cumulative Amount of Unchanged Drug Excreted Into Urine [Ae (0-48)]	To assess urine pharmacokinetic parameters following single ascending doses of AZD9977	Pre-dose and post-dose upto 48 hrs
Fraction Excreted Unchanged in Urine[Fe (0-48)]	To assess percentage of the total drug excreted in the urine that was unchanged following single ascending doses of AZD9977	Pre-dose and post-dose upto 48 hrs
Renal Clearance of Drug From Plasma [CLR (0-48)]	To assess urine pharmacokinetic parameters following single ascending doses of AZD9977	Pre-dose and post-dose upto 48 hrs

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Muna Albayaty, Dr., PAREXEL Early Phase Clinical Unit London, Level 7, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, United Kingdom

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: June 18, 2015
• First Submitted That Met QC Criteria: June 25, 2015
• First Posted (Estimate): June 30, 2015

Study Record Updates

• Last Update Posted (Actual): April 28, 2017
• Last Update Submitted That Met QC Criteria: March 28, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Tolerability; First-in-human; Single Ascending Dose; Healthy male subjects; AZD9977; Regional absorption
• Other Study ID Numbers: D6400C00001; 2015-000877-11 (EudraCT Number)