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

NCT03126695 | Completed Phase 1

• 1 other identifier: D5136C00011
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Sickle Cell Disease

Keywords

Abnormal hemoglobin (called hemoglobin S or sickle hemoglobin) in the red blood cells; Thrombotic cardiovascular events; Acute coronary syndrome; P2Y12 platelet inhibitor; Brilinta

Outcome Measures

Primary Outcomes (2)

• Maximum observed plasma concentration (Cmax)

  * 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)

  * 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 Outcomes (16)

• Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(0-t))

  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).

  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).

  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).

  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).

  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

Study Arms (4)

Treatment Sequence 1 (ADBC)

EXPERIMENTAL

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

Drug: Ticagrelor granule; Drug: Ticagrelor pediatric tablets; Drug: Ticagrelor pediatric tablets suspended in water; Drug: Ticagrelor immediate release (IR) tablets (Commercial tablet)

Treatment Sequence 2 (BACD)

EXPERIMENTAL

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

Drug: Ticagrelor granule; Drug: Ticagrelor pediatric tablets; Drug: Ticagrelor pediatric tablets suspended in water; Drug: Ticagrelor immediate release (IR) tablets (Commercial tablet)

Treatment Sequence 3 (CBDA)

EXPERIMENTAL

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

Drug: Ticagrelor granule; Drug: Ticagrelor pediatric tablets; Drug: Ticagrelor pediatric tablets suspended in water; Drug: Ticagrelor immediate release (IR) tablets (Commercial tablet)

Treatment Sequence 4 (DCAB)

ACTIVE COMPARATOR

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

Drug: Ticagrelor granule; Drug: Ticagrelor pediatric tablets; Drug: Ticagrelor pediatric tablets suspended in water; Drug: Ticagrelor immediate release (IR) tablets (Commercial tablet)

Interventions

Ticagrelor granule DRUG

A P2Y12 receptor inhibitor provided as granule for suspension.

Treatment Sequence 1 (ADBC); Treatment Sequence 2 (BACD); Treatment Sequence 3 (CBDA); Treatment Sequence 4 (DCAB)

Ticagrelor pediatric tablets DRUG

A P2Y12 receptor inhibitor provided as pediatric tablets to be swallowed whole.

Treatment Sequence 1 (ADBC); Treatment Sequence 2 (BACD); Treatment Sequence 3 (CBDA); Treatment Sequence 4 (DCAB)

Ticagrelor pediatric tablets suspended in water DRUG

A P2Y12 receptor inhibitor provided as pediatric tablets suspended in water.

Treatment Sequence 1 (ADBC); Treatment Sequence 2 (BACD); Treatment Sequence 3 (CBDA); Treatment Sequence 4 (DCAB)

Ticagrelor immediate release (IR) tablets (Commercial tablet) DRUG

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

Also known as: Brilinta

Treatment Sequence 1 (ADBC); Treatment Sequence 2 (BACD); Treatment Sequence 3 (CBDA); Treatment Sequence 4 (DCAB)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Gender Eligibility Details: Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated written informed consent prior to any study specific procedures.
• Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.
• 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.
• 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.
• Able to understand, read and speak the German language.

You may not qualify if:

• 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.
• History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
• 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.
• Any clinically significant abnormal findings in vital signs at Screening or Day -1 of Treatment Period 1, as judged by the Investigator.
• Any clinically significant abnormalities on 12-lead ECG at Screening, as judged by the Investigator.
• 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.
• 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.
• \. Current smokers or those who have smoked or used nicotine products within the previous 3 months.
• \. 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.
• \. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
• \. 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.
• \. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol, as judged by the Investigator.
• \. Involvement of any AstraZeneca or Clinical Unit employee or their close relatives.
• \. 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.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Berlin, 14050, Germany

Location

Related Publications (1)

• Niazi M, Wissmar J, Berggren AR, Karlsson C, Johanson P. Development Strategy and Relative Bioavailability of a Pediatric Tablet Formulation of Ticagrelor. Clin Drug Investig. 2019 Aug;39(8):765-773. doi: 10.1007/s40261-019-00800-w.

  PMID: 31140114 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell; Sickle Cell Trait; Acute Coronary Syndrome

Interventions

Excipients; Water; Ticagrelor; Tablets

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Pharmaceutical Vehicles; Pharmaceutic Aids; Pharmaceutical Preparations; Specialty Uses of Chemicals; Chemical Actions and Uses; Hydroxides; Alkalies; Inorganic Chemicals; Anions; Ions; Electrolytes; Oxides; Oxygen Compounds; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Dosage Forms

Study Officials

• Rainard Fuhr, Dr. med.

  PAREXEL Early Phase Clinical Unit Berlin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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 Record Dates

• First Submitted: April 20, 2017
• First Posted: April 24, 2017
• Study Start: May 12, 2017
• Primary Completion: July 24, 2017
• Study Completion: July 24, 2017
• Last Updated: August 2, 2017

Record last verified: 2017-07

Locations

DE (1)