| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| lacunar (small vessel) ischaemic stroke |
|
| E.1.1.1 | Medical condition in easily understood language |
| A type of stroke caused by damage to the small blood vessels of the brain |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10071043 |
| E.1.2 | Term | Basal ganglia stroke |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068644 |
| E.1.2 | Term | Brain stem stroke |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023987 |
| E.1.2 | Term | Late effects of cerebrovascular disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061256 |
| E.1.2 | Term | Ischaemic stroke |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10042244 |
| E.1.2 | Term | Stroke |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 objective of this trial is to find out whether a much larger scale study testing the effects of Cilostazol and ISMN on preventing brain damage from small vessel disease will be achievable in the future. We will assess how easy is it to identify suitable patients, how many of them are willing to take part in the study and how many stay on the study for the full 12 months. Feedback from participants on study procedures/burden will also inform any future studies. We will also collect information on how many patients have another stroke, experience difficulties in independent daily living or in thinking skills, and on drug safety such as bleeding. |
|
| E.2.2 | Secondary objectives of the trial |
1. Do patients stay on their allocated drug therapy for a year?
2. Are there any safety concerns with the drug therapies?
3. Have any of the drug therapies been effective?
4. A cost analysis on the different drug therapies will be carried out. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Clinical lacunar stroke syndrome.
2) Brain MRI scanning with MR including diffusion imaging wherever possible, and obtained soon after the presentation with stroke, shows either:
o a recent, relevant (in time and location) acute lacunar infarct on diffusion MR imaging
o or, if no visible acute lacunar infarct on diffusion MR imaging then there is no competing pathology as a cause for stroke (eg no acute cortical infarct, no acute intra-cerebral haemorrhage, no stroke mimic such as tumour, subdural haematoma)
o or, if only a CT brain scan is available, then there is a small relevant (in age and location) subcortical infarct, or if no infarct then there is no competing pathology as a cause for stroke (eg no acute cortical infarct, no acute intra-cerebral haemorrhage, no stroke mimic such as tumour, subdural haematoma)
3) Age > 30 years
4) Independent in activities of daily living (modified Rankin ≤2)
5) Capacity to give consent themselves
|
|
| E.4 | Principal exclusion criteria |
1) Other significant active neurological illness present since suffering stroke (e.g. recurrent seizures, multiple sclerosis, brain tumour). Well-controlled epilepsy present prior to the stroke, a single seizure at onset of the stroke or provoked seizure is not an exclusion.
2) Requiring assistance with activities of daily living (Modified Rankin ≥3)
3) Has been diagnosed as having dementia on formal clinical assessment
4) Active cardiac disease (atrial fibrillation, myocardial infarction in past 6 months, active angina, symptomatic cardiac failure)
5) Diagnosis of hypotension, defined as sitting systolic blood pressure less than 100mmHg.
6) Definite indication for (i.e. already prescribed) either trial medication, or definite contraindication to a trial drug as per SmPCSPCs - lactose intolerance is a contraindication to ISMN preparations which contain lactose monohydrate - (indication for or contraindication to one of the trial drugs still allows randomisation to the other trial drug)
7) Unable to swallow tablets
8) Bleeding tendency (e.g. known platelets<100, active peptic ulcer, history of intracranial haemorrhage such as subdural haematoma, subarachnoid haemorrhage, intracerebral haemorrhage, but not asymptomatic haemorrhagic transformation of infarction or a few microbleeds, taking anticoagulant medication)
9) Unlikely to comply with trial medication based on knowledge of past history, lifestyle
10) Planned surgery during the trial period including carotid endarterectomy. Note prior and apparently successful carotid endarterectomy (or other surgery) is not an exclusion criterion and patients who would otherwise be eligible but require endarterectomy first may be randomised after recovery from successful endarterectomy.
11) Other concurrent life threatening illness
12) Unlikely to be available for follow-up (eg moving outside or visitor to the area)
13) History of drug overdose or attempted suicide or significant active mental illness
14) Pregnant or breastfeeding women, women of childbearing age not taking contraception. Acceptable contraception in women of childbearing age is a “highly effective” contraceptive measure as defined by the Clinical Trials Facilitation Group (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) and includes combined (oestrogen and progesterone containing) or progesterone-only contraception associated with inhibition of ovulation, or intrauterine device or bilateral tubal occlusion. Contraception must be continued for up to 30 days after the end of the IMP dosing schedule.
15) Prohibited medications to either trial drug (see sections 4.5 of the appended SmPCSPCs and protocol section 6.6.3, plus no anticoagulant drugs); (prohibited medications to one of the trial drugs still allows randomisation to the other trial drug).
16) Renal impairment (creatinine clearance <25 ml/min)
17) Hepatic impairment
18) Current enrolment in another Clinical Trial of Investigational Medicinal Product (CTIMP); still in extended follow-up beyond the CTIMP primary outcome and no longer taking that trial’s IMP is not an exclusion to enrolment in LACI-2.
19) Unable to tolerate MRI or contraindication to MRI (Claustrophobia, Pacemaker)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To determine whether a prospective, randomised trial of cilostazol and ISMN in lacunar stroke is feasible in the UK. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Within 3 years of first randomised patient (recruitment period -18 months, follow-up for a further 12 months, followed by data analysis) |
|
| E.5.2 | Secondary end point(s) |
Tolerability - 75% of patients will adhere to trial medication, in at least half dose, at one year.
Safety - symptoms of systemic or intracranial bleeding, recurrent cerebral and systemic vascular events, and vascular and non-vascular causes of death will be collected. The risk of death, including fatal haemorrhage, will not differ significantly from 2% per year on trial drugs when given in addition to guideline drugs; and will not increase bleeding or ischaemic SVD lesions significantly on MRI.
Efficacy – individual event-rate data (stroke, TIA, myocardial ischaemia, cognitive impairment and dementia, will be collected. The combined rate of recurrent stroke, MI, death, cognitive impairment and dependency will be 40-50% at one year after enrolment in order to detect modest but clinically-important reductions in poor outcomes.
Health Economics – data to assess health economic impact will be gathered.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Within 3 years of first randomised patient |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability and cost effectiveness |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| one arm of the study involves no drug therapy |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The end of study is defined as the completion of analysis of the study data. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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