TRIAL OF CAFFEINE TO ALLEVIATE DYSPNEA RELATED TO TICAGRELOR

INTERVENTION: Trade Name: Koffein Recip Product Name: Koffein Receip Pharmaceutical Form: Capsule INN or Proposed INN: Caffeine CAS Number: 58‐08‐2 Other descriptive name: CAFFEINE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Dyspnea ; MedDRA version: 17.1 Level: LLT Classification code 10013963 Term: Dyspnea System Organ Class: 100000004855 Therapeutic area: Body processes [G] ‐ Circulatory and Respiratory Physiological Phenomena [G09] SECONDARY OUTCOME: Secondary end point(s): At the end of treatment visit, patients will be asked to indicate if there has been a change in the dyspnea symptoms during study treatment, as compared with their condition prior to starting the study drug. A 7‐point Likert scale will be used for this purpose. Timepoint(s) of evaluation of this end point: For every patient at visit 3 and for the study after last patients last visit. INCLUSION CRITERIA: •Age = 18 years •Acute coronary syndrome within the last 3 months with ongoing ticagrelor treatment •Stabilized clinical condition with no plans of additional revascularization •Dyspnea with onset after start of ticagrelor treatment •Willingness to abstain from caffeine intake (e.g. coffee, tea, cola‐type beverages and energy drinks; other foods, nutritional supplements or medications containing caffeine) for the duration of the study •Provision of signed informed consent form Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 450 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 50 PRIMARY OUTCOME: Main Objective: To test the hypothesis that caffeine, compared with placebo, alleviates ticagrelor‐associated dyspnea, assessed by the visual analog scale area under the curve (VAS AUC). Primary end point(s): The primary endpoint is dyspnea, assessed by the visual analog scale area under the curve.; Patient diary: Patients are provided with a diary, which contains:; •Written instructions on how to fill in the VAS scale correctly; •VAS scales for each day of 7‐10 days of treatment (or in case of the run‐in period, for up to 7 days of run‐in); •Drug accountability questions; •Information regarding the next Study visit; •Contact information; ; MEASUREMENT AND REPORTING OF THE VAS SCORE; Endpoint description: In the diary, patients are each day asked to mark the degree of dyspnea on a visual analog scale, a vertical line measuring 100 mm, with the statement “I am as breathless as I have ever been” on the bottom, indicating a score of 0; and the statement “I am not breathless at all” at the top, indicating a score of 100. The distance from the bottom to the patient’s indication is measured in millimeters by the investigator/study nurse, and reported in the eCRF as the VAS score. Higher score thus indicates better breathing. Patients are asked to fill out the VAS form at the time of the evening dose of ticagrelor each day during the study. ; A ruler graded in millimeters will be used. It is made sure that the zero is aligned at the lower edge of the VAS line, and the upper edge of the line is aligned with 100 mm (=10 cm) on the ruler. The point where the patient’s indication crosses the line is read, and measured in millimeters from the bottom of the line. This is the VAS score. For each time point, the following is entered into the eCRF:; •Date; •VAS score; •If the patient has missed indicating VAS one day, ND is entered instead of the VAS score at that date; If possible, the same person at each site should preferably perform VAS measurements. The result is recorded, in millimeters, directly in the eCRF. ; ; PRIMARY SAFETY ENDPOINT: HIGH ON‐TREATMENT PLATELET REACTIVITY; At visit 2 and visit 3 (before and after ticagrelor maintenance dose) platelet reactivity will be tested by the VerifyNow® P2Y12 assay. The primary safety endpoint will be HTPR, defined as a PRU value of =230 at visit 3, test 1.; Secondary Objective: Secondary objectives are:; •To investigate if caffeine is associated with a difference in dyspnea as compared with placebo, assessed with a 7‐point Likert scale at the end of study treatment. See Appendix 4; •To assess if caffeine administration alters plasma concentrations of ticagrelor or its metabolite, AR‐C124910XX; •To investigate if there is a correlation between plasma levels of ticagrelor (and its metabolite) and grade of dyspnea.; •To assess if caffeine alters platelet function in the setting of ongoing ticagrelor treatment; Timepoint(s) of evaluation of this end point: For every patient at visit 3 and for the study after last patients last visit.