OraL Crushed and dIspersed Ticagrelor 180mg Compared to Whole Tablets of eQUal Dose in STEMI Patients unDergoing Primary PCI: a Pharmacokinetic/Pharmacodynamic Study (the LIQUID Study) (LIQUID)

OraL Crushed and dIspersed Ticagrelor 180mg Compared to Whole Tablets of eQUal Dose in STEMI Patients unDergoing Primary PCI: a Pharmacokinetic/Pharmacodynamic Study

This is a single-center, prospective, randomized, single-blind, investigator initiated, pharmacokinetic/pharmacodynamic study of parallel design.Patients with ST elevation myocardial infarction (symptom onset<12 hours), undergoing primary percutaneous coronary intervention, who are P2Y12 inhibitor naïve, will be randomized after informed consent, immediately after diagnostic coronary angiography, in a 1:1 ratio to either:

• Ticagrelor 180mg loading dose, in the form of 2 whole tablets administered per os in the supine position (standard administration)
• Ticagrelor 180mg loading dose, in the form of 2 tablets crushed and dispersed in purified water and administered per os with 1-minute-stay in a 60-70 degrees semi-upright sitting position Platelet reactivity assessment will be performed at randomization (Hour 0) and at 0.5, 1, 2, 4 and 6 hours after randomization, using the VerifyNow assay, in platelet reactivity units (PRU). The cutoff >208 PRU will be used for definition of high platelet reactivity (HPR). All platelet reactivity assessments will be performed by a physician blind to the actual treatment given. Additional blood samples will be collected at the same time points for pharmacokinetic analysis. These samples will be collected in vacuum tubes with lithium heparin and will be kept in ice until centrifugation (3000 rpm at 4°C for 10 min, within 30 min of sampling). The resultant plasma will be transferred into a plain polypropylene tube (screw cap) and stored at or below -20°C until analysed.

Study Overview

• Status: Completed
• Conditions: ST Elevation Myocardial Infarction
• Intervention / Treatment: Drug: Ticagrelor 180mg whole tablets; Drug: Ticagrelor 180mg crushed and dispersed

Detailed Description

Preparation of Ticagrelor liquid formulation:

Crushed and dispersed Ticagrelor 180mg for oral administration will be prepared as follows: two ticagrelor 90mg tablets are placed in a mortar and crushed for 60 s using a pestle. 20 mL of purified water will be added in the mortar and stirred for 60s. The liquid is transferred to a dosing cup and another 15 mL of purified water is added to the mortar and stirred, ensuring that all powder has been dispersed and none remained on the mortar and pestle. Again the liquid is transferred to the dosing cup. The same procedure is repeated with 15 ml of purified water.The total contents are stirred for another 30 s to ensure that all remaining tablet particles are dispersed.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Greece
  • Achaia
    • Patras, Achaia, Greece, 26500
      • Patras University Hospital Department of Cardiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years old
2. Patients with STEMI (onset of pain<12 hours) with indication for primary PCI
3. Informed consent obtained in writing

Exclusion Criteria:

Pregnancy/Breastfeeding

• Severe nausea or vomiting
• Treatment with a P2Y12 inhibitor within the previous 1 month
• Inability to give informed consent
• Hemodynamic instability
• Arrhythmias requiring cardioversion, temporary pacemaker insertion or intravenous antiarrhythmic agents
• Killip class ≥3
• Known hypersensitivity to ticagrelor
• History of gastrointestinal bleeding, genitourinary bleeding or other site abnormal bleeding within the previous 3 months.
• Other bleeding diathesis, or considered by investigator to be at high risk for bleeding
• Thombocytopenia (<100.000 / μL) at randomization
• Anaemia (Hct <30%) at randomization
• Polycytaemia (Hct > 52%) at randomization
• Periprocedural IIb/IIIa inhibitor administration
• Thrombolysis administration
• Recent (< 6 weeks) major surgery or trauma, including GABG.
• Concomitant oral or IV therapy with strong CY P3A inhibitors (ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazana vir, grapefruit juice N1 L/d), CYP3A substrates with narrow therapeutic indices (cyclosporine, quinidine), or strong CYP3A inducers (rifampin /rifampicin, phenytoin, carbamazepine).
• Patients considered by the investigator to be at increased risk of bradycardiac events.
• Dialysis required.
• Severe uncontrolled chronic obstructive pulmonary disease
• Known severe hepatic impairement

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Ticagrelor 180mg whole tablets; Ticagrelor 180mg loading dose, in the form of 2 whole tablets administered per os in the supine position (standard administration)	Drug: Ticagrelor 180mg whole tablets
EXPERIMENTAL: Ticagrelor 180mg crushed and dispersed; Ticagrelor 180mg in the form of 2 tablets crushed and dispersed in purified water administered per os with 1-minute-stay in a 60-70 degrees semi-upright sitting position	Drug: Ticagrelor 180mg crushed and dispersed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Ticagrelor's Cmax over 1 hour post ticagrelor administration	1 hour
Area under the ticagrelor plasma concentration versus time curve (AUC0-1) over 1 hour post ticagrelor administration	1 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet reactivity at 1 hour post randomization	Platelet reactivity assessment with the VerifyNow assay	1 hour
HPR rate at 1 hour post randomization	HPR rate at 1 hour post randomization between the two treatment arms	1 hour
Platelet reactivity at 2 hours post randomization	Platelet reactivity assessment with the VerifyNow assay	2 hours
HPR rate at 2 hours post randomization	HPR rate at 2 hours post randomization between the 2 treatment arms.	2 hours
AR-C124910XX Cmax over 1 hour post ticagrelor administration		1 hour
AR-C124910XX Cmax over 6 hours post ticagrelor administration		6 hours
Ticagrelor Cmax over 6 hours post ticagrelor administration		6 hours
Area under the AR-C124910XX plasma concentration versus time curve (AUC0-1) over 1 hour post ticagrelor administration		1 hour
Area under the AR-C124910XX plasma concentration versus time curve (AUC0-6) over 6 hours post ticagrelor administration		6 hours
Area under the Ticagrelor plasma concentration versus time curve (AUC0-6) over 6 hours post ticagrelor administration		6 hours
Time for the maximum plasma concentration (Tmax) of Ticagrelor over 6 hours post Ticagrelor administration		6 hours
Time for the maximum plasma concentration (Tmax) of AR-C124910XX over 6 hours post Ticagrelor administration		6 hours

Collaborators and Investigators

• Sponsor: University of Patras

Publications and helpful links

General Publications

• Alexopoulos D, Barampoutis N, Gkizas V, Vogiatzi C, Tsigkas G, Koutsogiannis N, Davlouros P, Hahalis G, Nylander S, Parodi G, Xanthopoulou I. Crushed Versus Integral Tablets of Ticagrelor in ST-Segment Elevation Myocardial Infarction Patients: A Randomized Pharmacokinetic/Pharmacodynamic Study. Clin Pharmacokinet. 2016 Mar;55(3):359-67. doi: 10.1007/s40262-015-0320-0.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (ACTUAL): January 1, 2015
• Study Completion (ACTUAL): January 1, 2015

Study Registration Dates

• First Submitted: January 23, 2014
• First Submitted That Met QC Criteria: January 24, 2014
• First Posted (ESTIMATE): January 27, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): January 27, 2015
• Last Update Submitted That Met QC Criteria: January 26, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: ST elevation myocardial infarction; ticagrelor; liquid formulation
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; ST Elevation Myocardial Infarction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor
• Other Study ID Numbers: LIQUID study