Clinical Trials Register

Summary
EudraCT Number:	2013-004412-22
Sponsor's Protocol Code Number:	U-2013-007
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-10-29
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2013-004412-22

A.3

Full title of the trial

TRIAL OF CAFFEINE TO ALLEVIATE DYSPNEA RELATED TO TICAGRELOR
(TROCADERO)

A double-blinded, placebo-controlled, randomized, multicenter,
development phase II study

Studie för att undersöka om koffein kan lindra andfåddhet orsakad av ticagrelor (TROCADERO)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to examine whether caffeine can relieve breathlessness caused by ticagrelor (TROCADERO)

Studie för att undersöka om koffein kan lindra andfåddhet orsakad av ticagrelor (TROCADERO)

A.3.2

Name or abbreviated title of the trial where available

TROCADERO

A.4.1

Sponsor's protocol code number

U-2013-007

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	UCR Uppsala Clinical Research Center
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UCR
B.5.2	Functional name of contact point	Academic Research Organization
B.5.3	Address:
B.5.3.1	Street Address	Dag Hammarskjölds v 14b
B.5.3.2	Town/ city	Uppsala
B.5.3.3	Post code	752 37
B.5.3.4	Country	Sweden
B.5.4	Telephone number	0046018611 9500
B.5.6	E-mail	stefan.james@ucr.uu.se

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Koffein Recip
D.2.1.1.2	Name of the Marketing Authorisation holder	Recip AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Koffein Receip
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Caffeine
D.3.9.1	CAS number	58-08-2
D.3.9.3	Other descriptive name	CAFFEINE
D.3.9.4	EV Substance Code	SUB13146MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Dyspnea

Andnöd/andfåddhet

E.1.1.1

Medical condition in easily understood language

Dyspnea

Andnöd/andfåddhet

E.1.1.2

Therapeutic area

Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10013963
E.1.2	Term	Dyspnea
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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).

Testa hypotesen att koffein, jämfört med placebo, lindrar ticagrelor associerade dyspnée, som bedöms av den visuell analog skala (VAS) och ytan under kurvan (AUC VAS).

E.2.2

Secondary objectives of the trial

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

• undersöka om koffein är associerad med en skillnad i dyspné jämfört med placebo, bedömt med en 7-gradig Likertskala (frågeformulär) vid slutet av studiebehandling
• bedöma om koffein administration förändrar plasmakoncentrationer av ticagrelor eller dess metabolit, AR-C124910XX
• undersöka om det finns ett samband mellan plasmanivåer av ticagrelor (och dess metabolit) och grad av dyspné
• bedöma om koffein förändrar trombocytfunktionen av pågående ticagrelorbehandlingen

E.2.3

Trial contains a sub-study

E.3

Principal 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

E.4

Principal exclusion criteria

•Chronic obstructive pulmonary disease, asthma or other known pulmonary disease requiring daily medical therapy
•Obstructive sleep apnea syndrome requiring therapy
•Ongoing signs and symptoms of heart failure*, or evidence of moderately to severely reduced LV function
•Renal failure, GFR <30 or on dialysis
•Pregnancy or lactation
•Known allergy to ticagrelor, or caffeine, or known intolerance of caffeine.
•Ongoing treatment with any of the following: quinolone antibiotics, fluvoxamine, phenylpropanolamine, carbamazepine, clozapine, lithium, NSAIDs; or any drug containing theophylline or caffeine.
•Any condition that seriously increases the risk of non-compliance or loss of follow-up

E.5 End points

E.5.1

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

For every patient at visit 3 and for the study after last patients last visit.

E.5.2

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.

E.5.2.1

Timepoint(s) of evaluation of this end point

For every patient at visit 3 and for the study after last patients last visit.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

216

F.4.2.2

In the whole clinical trial

500

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

No plans of continuation of study medication is planned.

Ingen medicinering med studiedrog är planerad efter studieavslut.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-12-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-22

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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