A Study of the Effect of Epinephrine on Platelet Reactivity in Subjects Treated With Ticagrelor

NCT03441412 | Completed Phase 1

• 1 other identifier: EudraCT 2017-003111-18
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The study is an experimental observational study in ten healthy volunteers. Based on an in vitro study, it is hypothesize that a low dose epinephrine infusion will improve platelet function in healthy volunteers who have received ticagrelor. Volunteers fulfilling all of the inclusion and none of the exclusion criteria will be included. Enrollment will be continued until the required sample size is achieved (10 subjects). Once informed consent is obtained, screening data will be collected to determine each subject's eligibility for study participation. The total expected duration of subject participation is 18 days, from screening visit to end of follow-up. The active participation is 8h (study procedure 4 hours, observation period 4 hours).

Conditions

Healthy Volunteers

Outcome Measures

Primary Outcomes (1)

• Platelet aggregability, Area under the aggregation curve (AUC) for adenosine diphosphate (ADP)-induced platelet aggregation

  Area under the aggregation curve (AUC) for adenosine diphosphate (ADP)-induced platelet aggregation

  The primary outcome measure will be assessed at 7 time-points during 4 hours: before ticagrelor, 2 hours after ticagrelor, after each epinephrine infusion and after metoprolol injection.

Secondary Outcomes (16)

• Platelet aggregability, Area under the aggregation curve (AUC) for arachidonic acid-aggregation.

  The secondary outcome measures will be assessed at 7 time-points during 4 hours: before ticagrelor, 2 hours after ticagrelor, after each epinephrine infusion and after metoprolol injection.

• Platelet aggregability, AUC for thrombin receptor activating peptide (TRAP)-induced aggregation.

  The secondary outcome measures will be assessed at 7 time-points during 4 hours: before ticagrelor, 2 hours after ticagrelor, after each epinephrine infusion and after metoprolol injection.

• Platelet activation, Median fluorescence of platelets expressing PAC-1 (name of an antibody), unstimulated

  The secondary outcome measures will be assessed at 7 time-points during 4 hours: before ticagrelor, 2 hours after ticagrelor, after each epinephrine infusion and after metoprolol injection.

• Platelet activation, Percentage of platelets expressing PAC-1, unstimulated

  The secondary outcome measures will be assessed at 7 time-points during 4 hours: before ticagrelor, 2 hours after ticagrelor, after each epinephrine infusion and after metoprolol injection.

• Platelet activation, Median fluorescence of platelets expressing PAC-1, ADP-induced

  The secondary outcome measures will be assessed at 7 time-points during 4 hours: before ticagrelor, 2 hours after ticagrelor, after each epinephrine infusion and after metoprolol injection.

Study Arms (1)

Ticagrelor/Epinephrine/Metoprolol

EXPERIMENTAL

2 x 90 mg of ticagrelor will be administered orally to the subjects. Two hours after administration, the registrations and blood sampling are repeated after which an infusion of epinephrine diluted in glucose solution (5%) is started at a weight-adjusted rate of 0.01, 0.05, 0.10 and 0.15 μg kg-1 min-1. Each infusion will be maintained for 15 minutes. After the measurement at the highest dose of epinephrine, 5 mg metoprolol (Abcur, Haelsingborg , Sweden) will be given intravenously to the study subject and thereafter registrations and blood sampling will be repeated.

Drug: Ticagrelor 90mg; Drug: Epinephrine; Drug: Metoprolol

Interventions

Ticagrelor 90mg DRUG

2 x 90 mg of ticagrelor will be administered orally to the subjects. Two hours after administration, the registrations and blood sampling are repeated after which an infusion of epinephrine diluted in glucose solution (5%) is started at a weight-adjusted rate of 0.01, 0.05, 0.10 and 0.15 μg kg-1 min-1. Each infusion will be maintained for 15 minutes. After the measurement at the highest dose of epinephrine, 5 mg metoprolol (Abcur, Haelsingborg , Sweden) will be given intravenously to the study subject and thereafter registrations and blood sampling will be repeated.

Ticagrelor/Epinephrine/Metoprolol

Epinephrine DRUG

2 x 90 mg of ticagrelor will be administered orally to the subjects. Two hours after administration, the registrations and blood sampling are repeated after which an infusion of epinephrine diluted in glucose solution (5%) is started at a weight-adjusted rate of 0.01, 0.05, 0.10 and 0.15 μg kg-1 min-1. Each infusion will be maintained for 15 minutes. After the measurement at the highest dose of epinephrine, 5 mg metoprolol (Abcur, Haelsingborg , Sweden) will be given intravenously to the study subject and thereafter registrations and blood sampling will be repeated.

Ticagrelor/Epinephrine/Metoprolol

Metoprolol DRUG

2 x 90 mg of ticagrelor will be administered orally to the subjects. Two hours after administration, the registrations and blood sampling are repeated after which an infusion of epinephrine diluted in glucose solution (5%) is started at a weight-adjusted rate of 0.01, 0.05, 0.10 and 0.15 μg kg-1 min-1. Each infusion will be maintained for 15 minutes. After the measurement at the highest dose of epinephrine, 5 mg metoprolol (Abcur, Haelsingborg , Sweden) will be given intravenously to the study subject and thereafter registrations and blood sampling will be repeated.

Ticagrelor/Epinephrine/Metoprolol

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent,
• Males of age 18-40 years

You may not qualify if:

• Any chronic physical or mental disease or disorder
• Chronic medication of any kind
• Any occasional doses of the following substances at least one week before the investigation due to potential interactions with ticagrelor: ketoconazole, clarithromycin, nefazodone, ritonavir, atazanavir, rifampicin, fenitoin, carbamazepin, pentobarbital , cyclosporine, verapamil, diltiazem, kinidin, heparin, enoxaparin, acetylsalicylic acid, desmopressin, digoxin, beta-blockers (e.g. metoprolol, atenolol , bisoprolol) and selective serotonin reuptake inhibitors (SSRI) (e.g. paroxetine, sertraline, citalopram). In addition non-steroidal anti-inflammatory drugs (NSAIDS) should be avoided due to an increased risk of bleeding.
• Any occasional doses of the following substances at least one week before the investigation due to potential interactions with adrenalin: Beta-blockers ((e.g. metoprolol, atenolol , bisoprolol), tricyclic antidepressants (e.g protriptyline, maprotilin), digoxin and kinidin.
• Any occasional doses of the following substances at least one week before the investigation due to potential interactions with metoprolol: Calcium-antagonists (verapamil, diltiazem, nifedipine), anti-arrythmics (e.g disopyramide), insulin, tricyclic antidepressants (e.g protriptyline, maprotilin), barbiturates; fentiazins and nitroglycerine.
• Non-willingness to refrain from caffeine intake or nicotine use within 24 hours before start of treatment
• Simultaneous participation in any other clinical study
• Known drug abuse of any kind, or other condition that may render the subject more likely to be non-compliant to the protocol, as judged by the investigator
• Known intolerance or contraindication to ticagrelor, adrenaline or metoprolol
• Any disorder that may interfere with drug absorption
• Previous intracranial bleeding
• Any condition that in the opinion of the investigator may interfere with adherence to trial protocol

Sponsors & Collaborators

• Vastra Gotaland Region: lead
• Gothia Forum - Center for Clinical Trial: collaborator
• Uppsala University: collaborator

Study Sites (1)

gothia Forum CTC

Gothenburg, 41345, Sweden

Location

Related Publications (1)

• Singh S, Damen T, Nygren A, Shams Hakimi C, Ramstrom S, Dellborg M, Lindahl TL, Hesse C, Jeppsson A. Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy Volunteers. Thromb Haemost. 2019 May;119(5):735-743. doi: 10.1055/s-0039-1683461. Epub 2019 Feb 19.

  PMID: 30780166 DERIVED

MeSH Terms

Interventions

Ticagrelor; Epinephrine; Metoprolol

Intervention Hierarchy (Ancestors)

Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenoxypropanolamines; Propanolamines; Propanols

Study Officials

• Anders Jeppsson, MD,PhD,Prof

  Dep of Cardiothoracic Surgery,Sahlgrenska University Hospital,413 45 Gothenburg, Sweden

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: The study is an experimental observational study in ten healthy volunteers. Volunteers fulfilling all of the inclusion and none of the exclusion criteria will be included. Enrollment will be continued until the required sample size is achieved (10 subjects).

Study Record Dates

• First Submitted: February 5, 2018
• First Posted: February 22, 2018
• Study Start: February 28, 2018
• Primary Completion: March 28, 2018
• Study Completion: March 28, 2018
• Last Updated: May 11, 2018

Record last verified: 2018-05

Locations

SE (1)