A Study to Compare if the Uptake of Ticagrelor in the Body Differs When Different Tablets Are Administered

August 1, 2017 updated by: AstraZeneca

An Open-label, Randomized, 4-period, 4-treatment, Cross-over, Single-center, Single-dose Study to Assess the Relative Bioavailability of Ticagrelor in Different Formulations in Healthy Adult Subjects

To evaluate the relative bioavailability of ticagrelor for the different formulations. A randomized cross-over design has been chosen to minimize the effects of between-subject variability and any period effects on the overall results.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This study will be an open-label, randomized, 4-period, 4-treatment, cross-over, single-center, single-dose study to assess the relative bioavailability of different formulations of ticagrelor in approximately 44 healthy adult subjects. Eligible subjects will be healthy male and female aged 18 to 55 years, with a body weight of 55 to 100 kg and a body mass index (BMI) of 18 to 30 kg/m2. Of the 44 randomized subjects, at least 36 evaluable subjects should be at the end of the last treatment period. Subjects will be randomized to 1 of 4 treatment sequences and will receive single oral doses of 4 different formulations of ticagrelor under fasted conditions. Subjects will fast for at least 10 hours prior to administration of Investigational Medicinal Products (IMPs). No fluids will be allowed apart from water which can be given until 1 hour prior to administration of the IMP and then from 2 hours after administration of the IMP. A meal can be given 4 hours after administration of the IMP.

Study Type

Interventional

Enrollment (Actual)

44

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Berlin, Germany, 14050
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 55 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Provision of signed and dated written informed consent prior to any study specific procedures.
  2. Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.
  3. Females must have a negative pregnancy test at Screening and on each admission to the Clinical Unit, must not be lactating and if of non child-bearing potential, confirmed at Screening by fulfilling one of the following criteria:

    - Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range (> 40 milli international units per milliliter (mIU/mL)). - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. - Childbearing potential and are sexually active must use 1 highly effective method of birth control in combination with a barrier method, from the time of IMP administration until 3 months after the last dose of IMP.

  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. Able to understand, read and speak the German 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 influence 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 the first administration of IMP.
  4. Any clinically significant abnormalities in hematology, clinical chemistry, coagulation or urinalysis results at Screening or Day -1 of Treatment Period 1, as judged by the Investigator.
  5. Any clinically significant abnormal findings in vital signs at Screening or Day -1 of Treatment Period 1, as judged by the Investigator.
  6. Any clinically significant abnormalities on 12-lead ECG at Screening, as judged by the Investigator.
  7. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (anti-HBcAb), hepatitis C antibodies (anti- HCV) and human immunodeficiency virus (HIV) antibodies.
  8. Has received a new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.
  9. Plasma donation within 1 month of Screening or any blood donation/loss more than 500 mL during the 3 months prior to Screening. 10. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to ticagrelor.

11. Current smokers or those who have smoked or used nicotine products within the previous 3 months.

12. Positive screen for drugs of abuse or cotinine (cotinine level above 500 ng/mL) at Screening or on each admission to the Clinical Unit or positive screen for alcohol on each admission to the Clinical Unit.

13. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.

14. 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 the first administration of IMP or longer if the medication has a long half-life.

15. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol, as judged by the Investigator.

16. Involvement of any AstraZeneca or Clinical Unit employee or their close relatives.

17. Judgment by the Investigator that the potential 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.

18. Consumption of poppy seeds within 7 days of first admission to the Clinical Unit.

19. History of hemophilia, von Willebrand's disease, lupus anticoagulant, or other diseases/syndromes that can either alter or increase the propensity for bleeding. 20. A personal history of vascular abnormalities including aneurysms; a personal history of severe hemorrhage, hematemesis, melena, hemoptysis, severe epistaxis, severe thrombocytopenia, intracranial hemorrhage; or rectal bleeding within 1 year prior to Screening; or history suggestive of peptic ulcer disease; or at the discretion of the Investigator.

21. History of a clinically significant non-traumatic bleed or clinically significant bleeding risk, as judged by the Investigator.

22. Use of aspirin, ibuprofen, NSAIDs, or any other drug known to increase the propensity for bleeding for 2 weeks before randomization. 23. Platelet count less than 150 x 109/L.

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment Sequence 1 (ADBC)

Subjects were randomized to treatment sequence ADBC:

On Day 1, following an overnight fast of at least 10 hours, each subject will receive single dose of the treatment assigned to that treatment period.

A =Ticagrelor granule for oral suspension equal to 90 mg. B = Ticagrelor pediatric tablets equal to 90 mg. C= Ticagrelor pediatric tablets suspended in water equal to 90 mg. D = Ticagrelor commercial IR (1 x 90 mg) tablet

A P2Y12 receptor inhibitor provided as granule for suspension.
A P2Y12 receptor inhibitor provided as pediatric tablets to be swallowed whole.
A P2Y12 receptor inhibitor provided as pediatric tablets suspended in water.
A P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (unstable angina, non-ST (S and T waves) elevation MI or ST elevation MI) and in patients with a history of MI
Other Names:
  • Brilinta
Experimental: Treatment Sequence 2 (BACD)

Subjects were randomized to treatment sequence BACD:

On Day 1, following an overnight fast of at least 10 hours, each subjects will receive single dose of the treatment assigned to that treatment period.

A =Ticagrelor granule for oral suspension equal to 90 mg. B = Ticagrelor pediatric tablets equal to 90 mg. C= Ticagrelor pediatric tablets suspended in water equal to 90 mg. D = Ticagrelor commercial IR (1 x 90 mg) tablet

A P2Y12 receptor inhibitor provided as granule for suspension.
A P2Y12 receptor inhibitor provided as pediatric tablets to be swallowed whole.
A P2Y12 receptor inhibitor provided as pediatric tablets suspended in water.
A P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (unstable angina, non-ST (S and T waves) elevation MI or ST elevation MI) and in patients with a history of MI
Other Names:
  • Brilinta
Experimental: Treatment Sequence 3 (CBDA)

Subjects were randomized to treatment sequence CBDA:

On Day 1, following an overnight fast of at least 10 hours, each subjects will receive single dose of the treatment assigned to that treatment period.

A =Ticagrelor granule for oral suspension equal to 90 mg. B = Ticagrelor pediatric tablets equal to 90 mg. C= Ticagrelor pediatric tablets suspended in water equal to 90 mg. D = Ticagrelor commercial IR (1 x 90 mg) tablet

A P2Y12 receptor inhibitor provided as granule for suspension.
A P2Y12 receptor inhibitor provided as pediatric tablets to be swallowed whole.
A P2Y12 receptor inhibitor provided as pediatric tablets suspended in water.
A P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (unstable angina, non-ST (S and T waves) elevation MI or ST elevation MI) and in patients with a history of MI
Other Names:
  • Brilinta
Active Comparator: Treatment Sequence 4 (DCAB)

Subjects were randomized to treatment sequence DCAB:

On Day 1, following an overnight fast of at least 10 hours, each subjects will receive single dose of the treatment assigned to that treatment period.

A =Ticagrelor granule for oral suspension equal to 90 mg. B = Ticagrelor pediatric tablets equal to 90 mg. C= Ticagrelor pediatric tablets suspended in water equal to 90 mg. D = Ticagrelor commercial IR (1 x 90 mg) tablet

A P2Y12 receptor inhibitor provided as granule for suspension.
A P2Y12 receptor inhibitor provided as pediatric tablets to be swallowed whole.
A P2Y12 receptor inhibitor provided as pediatric tablets suspended in water.
A P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (unstable angina, non-ST (S and T waves) elevation MI or ST elevation MI) and in patients with a history of MI
Other Names:
  • Brilinta

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum observed plasma concentration (Cmax)
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
  • To determine the relative bioavailability of ticagrelor granule for oral suspension and the pediatric ticagrelor tablet to the commercial ticagrelor tablet in healthy subjects.
  • To determine the relative bioavailability of ticagrelor pediatric tablet taken whole and the pediatric tablet dispersed in water to the granule for oral suspension in healthy subjects.
  • To evaluate the bioequivalence between the pediatric ticagrelor tablet taken whole and the pediatric ticagrelor tablet dispersed in water in healthy subjects.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Area under plasma concentration-time curve from zero to infinity (AUC)
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose.
  • To determine the relative bioavailability of ticagrelor granule for oral suspension and the pediatric ticagrelor tablet to the commercial ticagrelor tablet in healthy subjects.
  • To determine the relative bioavailability of ticagrelor pediatric tablet taken whole and the pediatric tablet dispersed in water to the granule for oral suspension in healthy subjects.
  • To evaluate the bioequivalence between the pediatric ticagrelor tablet taken whole and the pediatric ticagrelor tablet dispersed in water in healthy subjects.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(0-t))
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the pharmacokinetic (PK) profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Time to reach maximum observed plasma concentration, taken directly from the individual concentration-time curve (tmax).
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz).
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Terminal rate constant, estimated by log-linear regression of the terminal part of the concentration-time curve (λz).
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Apparent clearance, estimated as dose divided by AUC (ticagrelor only) (CL/F).
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Apparent volume of distribution at the terminal phase, estimated by dividing the apparent clearance (CL/F) by λz (ticagrelor only) (Vz/F).
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Ratio of metabolite Cmax to parent Cmax, adjusted for differences in molecular weights (MRCmax).
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Ratio of metabolite AUC(0-t) to parent AUC(0-t), adjusted for differences in molecular weights (MRAUC(0-t)).
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Ratio of metabolite AUC to parent AUC, adjusted for differences in molecular weights (MRAUC)
Time Frame: At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
To compare the PK profiles of ticagrelor and its active metabolite (AR-C124910XX) in healthy subjects when administered as granule for oral suspension, pediatric ticagrelor tablet, pediatric ticagrelor tablet suspended in water and commercial ticagrelor tablet.
At 0 hours (pre-dose) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose in each treatment period
Number of patients with Adverse Events (AEs)
Time Frame: From screening (day -28) until follow-up/early termination (ET) (Day 5 to Day 10 (after treatment Period 4/ET))
To assess the adverse events as a criteria of safety and tolerability variables.
From screening (day -28) until follow-up/early termination (ET) (Day 5 to Day 10 (after treatment Period 4/ET))
Vital sign (systolic and diastolic blood pressure [BP])
Time Frame: At screening (Day -28), admission (Day -1), treatment periods 1, 2, 3, 4 (Day 1 - 3) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
To assess the vital signs as a criteria of safety and tolerability variables.
At screening (Day -28), admission (Day -1), treatment periods 1, 2, 3, 4 (Day 1 - 3) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Vital sign (pulse rate)
Time Frame: At screening (Day -28), admission (Day -1), treatment periods 1, 2, 3, 4 (Day 1 - 3) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
To assess the vital signs as a criteria of safety and tolerability variables.
At screening (Day -28), admission (Day -1), treatment periods 1, 2, 3, 4 (Day 1 - 3) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Twelve-lead electrocardiograms (ECGs)
Time Frame: At screening (Day -28) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
To assess the cardiovascular system functioning as a criteria of safety and tolerability variables.
At screening (Day -28) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Physical examination
Time Frame: At screening (Day -28) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
To assess the physical examination as a criteria of safety and tolerability variables.
At screening (Day -28) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Laboratory assessments (hematology and clinical chemistry)
Time Frame: At screening (Day -28), admission (day -1) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
To assess the hematology and clinical chemistry as a criteria of safety and tolerability variables.
At screening (Day -28), admission (day -1) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
Laboratory assessments (Urinalysis (dipstick))
Time Frame: At screening (Day -28), admission (day -1) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))
To assess the urinalysis as a criteria of safety and tolerability variables.
At screening (Day -28), admission (day -1) and follow-up/ET (Day 5 to Day 10 (after treatment Period 4/ET))

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Collaborators

Investigators

  • Principal Investigator: Rainard Fuhr, Dr. med., Parexel Early Phase Clinical Unit Berlin

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 12, 2017

Primary Completion (Actual)

July 24, 2017

Study Completion (Actual)

July 24, 2017

Study Registration Dates

First Submitted

April 20, 2017

First Submitted That Met QC Criteria

April 20, 2017

First Posted (Actual)

April 24, 2017

Study Record Updates

Last Update Posted (Actual)

August 2, 2017

Last Update Submitted That Met QC Criteria

August 1, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Other Study ID Numbers

  • D5136C00011

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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