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

Healthy Volunteers Clinical Trial

Official title:

Low Dose EPInephrine to Improve Platelet Reactivity in TICagrelor-treated Subjects: A Proof of Concept Study in Healthy Volunteers (EPITIC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03441412
• Other study ID #: EudraCT 2017-003111-18
• Status: Completed
• Phase: Phase 1
• Start date: February 28, 2018
• Est. completion date: March 28, 2018

Study information

• Verified date: May 2018
• Source: Vastra Gotaland Region
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Description:

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).

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).

The study will include four visits in total, beginning with the written informed consent at the screening visit, followed by the study visit. A phone follow-up visit is conducted the day after the treatment and after 72h to ensure subject's well-being/ inquire if the subject have had any Adverse Event (AE).

On the treatment day, an arterial catheter for continuous invasive blood pressure registration and blood sample collection will be inserted in the radial artery. In addition, a catheter for drug administration will be inserted in the brachial vein. After baseline registration (blood pressure and pulse), blood sampling and assessment of dyspnea (Borg-scale), ticagrelor is administered orally to the subjects. Two hours after administration, the registrations and blood sampling (outcome samples) are repeated after which an infusion of epinephrine 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. At the end of each infusion period, registrations and blood sampling are repeated. The blood pressure may increase as a result of epinephrine infusion and metoprolol will therefore be administered to investigate if it affects platelet function. Hence, after the last measurement with the highest dose of epinephrine, 5 mg metoprolol (Abcur, Haelsingborg , Sweden) will be given intravenously and thereafter registrations and blood sampling will be repeated. The infusion is then stopped and the healthy volunteers are observed for 4 hours.

All study subjects will be contacted the day after treatment and three days after treatment and asked about their wellbeing/ if they have had any AEs.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: March 28, 2018
• Est. primary completion date: March 28, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

1. Signed informed consent,

2. Males of age 18-40 years

Exclusion Criteria:

1. Any chronic physical or mental disease or disorder

2. Chronic medication of any kind

3. 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.

4. 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.

5. 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.

6. Non-willingness to refrain from caffeine intake or nicotine use within 24 hours before start of treatment

7. Simultaneous participation in any other clinical study

8. 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

9. Known intolerance or contraindication to ticagrelor, adrenaline or metoprolol

10. Any disorder that may interfere with drug absorption

11. Previous intracranial bleeding

12. Any condition that in the opinion of the investigator may interfere with adherence to trial protocol

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• Ticagrelor 90mg
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.
• Epinephrine
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.
• Metoprolol
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.

Locations

Country	Name	City	State
Sweden	gothia Forum CTC	Gothenburg

Sponsors (3)

Lead Sponsor	Collaborator
Vastra Gotaland Region	Gothia Forum, Uppsala University

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Platelet aggregability, Area under the aggregation curve (AUC) for arachidonic acid-aggregation.	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.
Secondary	Platelet aggregability, AUC for thrombin receptor activating peptide (TRAP)-induced aggregation.	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.
Secondary	Platelet activation, Median fluorescence of platelets expressing PAC-1 (name of an antibody), unstimulated	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.
Secondary	Platelet activation, Percentage of platelets expressing PAC-1, unstimulated	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.
Secondary	Platelet activation, Median fluorescence of platelets expressing PAC-1, ADP-induced	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.
Secondary	Platelet activation, ADP-induced percentage of platelets expressing PAC-1, ADP-induced	ADP-induced percentage 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.
Secondary	Platelet activation, Median fluorescence of platelets expressing P-selectin, unstimulated	Median fluorescence of platelets expressing P-selectin, 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.
Secondary	Platelet activation, Percentage of platelets expressing P-selectin, unstimulated	Percentage of platelets expressing P-selectin, 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.
Secondary	Platelet activation, Median fluorescence of platelets expressing P-selectin, ADP-induced	Median fluorescence of platelets expressing P-selectin, 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.
Secondary	Platelet activation, Percentage of platelets expressing P-selectin, ADP-induced	Percentage of platelets expressing P-selectin, 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.
Secondary	Coagulation parameters, EXTEM (name of a thromboelastometric test) Clotting time	EXTEM (name of a thromboelastometric test) Clotting time	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.
Secondary	Coagulation parameters, EXTEM clot formation time	EXTEM clot formation time	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.
Secondary	Coagulation parameters, EXTEM maximum clot firmness	EXTEM maximum clot firmness	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.
Secondary	Coagulation parameters, EXTEM maximum clot elasticity	EXTEM maximum clot elasticity	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.
Secondary	Coagulation parameters, FIBTEM (name of a thromboelastometric test) Maximum clot firmness	FIBTEM (name of a thromboelastometric test) Maximum clot firmness	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.
Secondary	Coagulation parameters, FIBTEM maximum clot elasticity.	FIBTEM maximum clot elasticity.	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.