| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Carotid artery stenting (CAS) is treatment for atherosclerotic carotid stenosis. The main adverse events are thromboembolic brain infarcts during the procedure. Ticagrelor, a novel reversible inhibitor of the platelet adenosine diphosphate receptor P2Y12, was superior to clopidogrel as add-on to aspirin in preventing stent thrombosis and clinical adverse events during stenting of the coronary artery. Therefore, ticagrelor may be superior to clopidogrel in preventing brain infarcts during CAS. |
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| E.1.1.1 | Medical condition in easily understood language |
| Stent treatment reopens carotid arteries narrowed down by atherosclerosis. This study tests medication against blood clots to prevent strokes during carotid artery stenting. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to demonstrate efficacy of ticagrelor, by testing the hypothesis that ticagrelor (given at a loading dose of 180 mg prior to the procedure and maintained at 90 mg twice daily for 28-32 days thereafter) is superior to clopidogrel (given at a loading dose of 300 mg prior to the procedure and maintained at 75 mg once daily for 28-32 days thereafter) as add-on therapy to aspirin (75-100 mg once daily) in preventing the occurrence of ischaemic brain infarcts in patients treated with carotid artery stenting. Brain infarcts will be detected on magnetic resonance Imaging (MRI). |
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| E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives are to compare the following outcomes between the two treatment groups:
(1) the number and total volume of ischaemic brain infarcts detected on MRI:
(2) any brain haemorrhages detected on MRI;
(3) clinical safety outcome events including: stroke, myocardial infarction, major bleeding, and cardiovascular death.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Written informed consent as documented by signature from the patient;
- Men or women ≥40 years of age;
- Moderate (50-69% narrowing of the artery according to the measuring method used in the NASCET trial) or severe (70-99%) stenosis of the extracranial internal carotid artery caused by atherosclerosis;
- Symptomatic carotid stenosis (any transient or permanent symptoms caused by focal ischaemia in the vascular territory supplied by the carotid artery in the past 180 days, including ischaemic stroke, TIA, amaurosis fugax or ischaemic retinal infarct), as long as the patient is clinically stable and able to walk unassisted (mRS ≤3) at the time of randomisation; or asymptomatic carotid stenosis (no ischaemic symptoms in the past 180 days);
- Stenosis amenable for treatment by CAS according to routine clinical work-up (degree of stenosis and suitability of vascular anatomy for CAS must be documented on vascular imaging within 90 days before the screening visit);
- CAS scheduled to take place within 1-3 days of randomisation. |
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| E.4 | Principal exclusion criteria |
- Inability or unwillingness of the patient to understand and/or comply with study procedures and/or follow-up, e.g. due to language problems, psychological disorders, dementia, etc.;
- Women who are pregnant or breast feeding, or who intend to become pregnant during the course of the study. Women of childbearing age must take a blood pregnancy test to be eligible for the study;
- Lack of safe contraception, defined as: Female Participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the Investigator in individual cases. Female Participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential;
- Acute ischaemic stroke with symptom onset in the previous 24 hours before randomisation;
- Fresh thrombus in the relevant carotid artery;
- Patient clinically unstable at the time of randomisation (includes worsening in NIH Stroke Scale of >2 points over the previous 24 hours);
- Patient unable to walk unassisted at the time of randomisation (score on the modified Rankin Scale >3);
- Patients with known bleeding diathesis or coagulation disorder (e.g., thrombotic-thrombocytopenic purpura);
- Any active pathological bleed;
- Severe thrombocytopenia (platelet count <50’000/uL);
- History of previous symptomatic intracranial haemorrhage at any time (asymptomatic microbleeds do not qualify)
- History of gastrointestinal bleed within the past 6 months;
- Any contraindication to non-contrast MRI, including but not limited to:
-- cardiac pacemaker incompatible with MRI;
-- metal implants incompatible with MRI;
-- claustrophobia;
- Contraindications to ticagrelor, clopidogrel, or aspirin, or to any of their excipients, including known hypersensitivity or allergy;
- Increased risk of bradycardic events (e.g., patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree atrioventricular (AV) block, or history of bradycardia-related syncope;
- Need for medication not permitted during treatment period:
-- Antithrombotic therapy other than Study Medication or permitted concomitant medication including:
--- Antiplatelet therapy (other than Aspirin 75-100 mg daily), e.g.: open-label clopidogrel or ticagrelor; GPIIb/IIIa inhibitors, ticlopidine, prasugrel, dipyridamole, ozagrel, cilostazol;
--- Therapeutic-dose anticoagulation (other than unfractioned heparin at the start of the CAS procedure), e.g.: phenprocoumon, warfarin, oral thrombin and factor Xa inhibitors, bivalirudin, hirudin, argatroban, unfractionated and low molecular weight heparins;
--- Receipt of any intravenous or intra-arterial thrombolysis or mechanical thrombectomy within 24 hours prior to randomisation. If a patient requires intravenous or intra-arterial thrombolytic therapy during the treatment period, the Study Medication must be discontinued for at least 24 hours;
-- Strong cytochrome P450 3A (CYP3A) inhibitors leading to substantial increases in ticagrelor plasma levels: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir; or consumption of more than 1 litre of grapefruit juice daily;
-- Strong CYP3A inducers leading to substantial decreases in ticagrelor plasma levels: rifampicin, rifabutin, phenytoin, carbamazepine, and phenobarbital;
-- CYP3A substrates with narrow therapeutic indices which may be substantially increased by co-administration of ticagrelor: cyclosporine, quinidine, simvastatin at doses >40 mg daily or lovastatin at doses >40 mg daily. (Co-administration of ticagrelor with simvastatin increases simvastatin Cmax by 81% and AUC by 56% and increases simvastatin acid Cmax by 64% and AUC by 52% with some individual increases equal to 2- to 3-fold. Ticagrelor may have similar effect on lovastatin, but is not expected to have a clinically meaningful effect on other statins including atorvastatin and rosuvastatin);
-- Anticipated requirement for long-term (>7 days) non-steroidal anti-inflammatory drugs (NSAIDs; short-term treatment with NSAIDs up to 7 days is allowed during the treatment period at the investigator’s discretion);
- Need for any cardio-vascular surgery or cardio-vascular intervention other than the index CAS procedure for which the patient was randomised, or need for any other invasive procedure which requires halting of Study Medication within the next 30 days after randomisation;
- History of major surgery within the past 30 days;
- Moderate or severe hepatic impairment;
- Renal impairment requiring dialysis;
- Known or suspected non-compliance, drug or alcohol abuse. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the presence of at least one new ischaemic brain lesion on the second MRI scan done 1-3 days after carotid artery stenting (CAS) or on the third MRI scan done 28-32 days after CAS, which had not been present on the first MRI scan done 1-3 days before CAS.
New ischaemic brain lesions are defined as areas with ≥2 mm diameter in the brain parenchyma with hyperintense signal on DWI sequences, with hypointense or isointense signal at the corresponding location on apparent diffusion coefficient (ADC) maps. In addition, a lesion with a hyperintense signal on fluid-attenuated inversion recovery (FLAIR) sequences on the MRI scan 28-32 days after CAS will be counted as a new ischaemic lesion if it was not present on the pre-procedural scan and if it cannot be attributed to a more likely cause other than ischaemia.
Ischaemic brain lesions will be categorised as symptomatic if a rapid onset of a new focal neurological deficit attributable to the lesion(s) is present (in this case the event will be defined as an ischaemic stroke according to the definition in section 5.4.1.1); or silent if causing no focal neurological deficit.
The rationale for the choice of highly sensitive MRI-based efficacy and safety outcome measures is to investigate benefits and risks of ticagrelor for the indication at study in a relatively small population.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy endpoint will be assessed on MRI 1-3 days and 28-32 days after carotid artery stenting (CAS). |
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| E.5.2 | Secondary end point(s) |
Secondary imaging based efficacy endpoints are: (1) the total number of new ischaemic brain lesions on MRI after CAS; and (2) the total volume of new ischaemic brain lesions on MRI after CAS, defined as the sum of all volumes of separate DWI lesions.
The imaging based safety outcome is the presence of at least one new haemorrhagic brain lesion on the second MRI scan done 1-3 days after CAS or on the third MRI scan done 28-32 days after CAS, which had not been present on the first MRI scan done 1-3 days before the procedure. Haemorrhagic brain lesions are defined as areas with ≥2 mm diameter in the brain parenchyma with hypointense signal on susceptility-weighted (SWI) sequences which are not caused by calcification, iron deposition, or flow voids from cortical vessels; if SWI sequences are unavailable at a participating Study Site, T2 gradient echo sequences (T2*) may be used instead. Haemorrhagic brain lesions will be sub-classified as symptomatic if a rapid onset of a new focal neurological deficit attributable to the lesion(s) is present (in this case the event will be defined as an haemorrhagic stroke according to the definition above); or silent if causing no focal neurological deficit.
Clinical safety endpoints are stroke, myocardial infarction, major bleeding (including fatal, life-threatening or other major bleeding) or cardiovascular death, as well as all-cause death occurring between randomisation and study closure. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Imaging based secondary efficacy and safety endpoints will be assessed on MRI 1-3 days and 28-32 days after carotid artery stenting (CAS).
Clinical safety endpoints and adverse events will be assessed in Study Visits scheduled as follows: 1-3 days before scheduled CAS, 1-3 days after CAS, and 28-32 days after CAS. Additional Safety Visits will be scheduled as soon as possible in case of occurrence of any pre-specified clinical safety outcome Event or any Serious Adverse Event. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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