E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Ischaemic stroke or transient ischaemic attack (TIA) (ICD Classification Code I63.0-9 and G45.0-1) |
|
E.1.1.1 | Medical condition in easily understood language |
Stroke due to blood clots or mini strokes. |
|
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 | 21.1 |
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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10044390 |
E.1.2 | Term | Transient ischaemic attack |
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 |
1. To establish whether a two year course of allopurinol 300 mg twice daily reduces WMH progression after ischaemic stroke. |
|
E.2.2 | Secondary objectives of the trial |
1. To establish whether allopurinol reduces BP after ischaemic stroke. 2. To evaluate whether allopurinol reduces cognitive decline after ischaemic stroke. 3. To evaluate whether allopurinol reduces vascular event rate after ischaemic stroke.
Carotid plaque sub-analysis: 1. To establish whether allopurinol improves carotid plaque measures after ischaemic stroke.
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
XILO-FIST Cardiac Sub-study, Version 1. The objective of this sub-study is to establish whether allopurinol use reduces cardiac enlargement (left ventricular hypertrophy) in stroke survivors.
The cardiac sub study has been termination due to lack of recruitment with the agreement of the TSC.
A second sub study has been added.
XILO-FIST 7T MRI sub study: the objective of this study is to generate initial 7T MRI data in people with cerebral small vessel disease and better understand the pathophysiology of features of SVD. We will 1) assess the morphology of vessels and arteries in areas of small vessel disease markers compared to normal appearing brain tissue; 2)perform a comparative analysis of MRI data at 3T and 7T MRI findings, cognition and other clinical variables. |
|
E.3 | Principal inclusion criteria |
1. Ischaemic Stroke. 2. Age greater than 50 years. 3. Ischaemic lesion on brain imaging in relevant anatomical territory in patients with transient ischaemic attack. 4. Consent within one month of stroke.
Ischaemic stroke will be diagnosed by a stroke specialist and defined as a focal neurological event lasting more than 24 hours or symptoms lasting less than 24 hours with positive diffusion weighted imaging or a corresponding lesion on CT. This inclusion criterion will be verified by local investigators following image review and this will be recorded in the patient record and on the eCRF. |
|
E.4 | Principal exclusion criteria |
1. Modified Rankin scale score of 5 (at end of the possible enrolment window of one month after stroke). 2. Diagnosis of dementia (defined as a documented diagnosis or a screening IQCODE (Informant Questionnaire for Cognitive Decline in the Elderly) score of 3.6 or more). 3. Cognitive impairment deemed sufficient to compromise capacity to consent or to comply with the protocol (in the opinion of the local investigator). 4. Dependent on daily help from others for basic or instrumental activities of daily living prior to stroke (defined as assistance needed with toileting, walking or dressing). 5. Significant co-morbidity or frailty likely to cause death within 24 months or likely to make adherence to study protocol difficult for participant (in the opinion of the local investigator). 6. Contra-indication to or indication for administration of allopurinol (as detailed in Summary of Product Characteristics on the XILO-FIST web portal and in trial master file). 7. Concurrent azathioprine, 6-mercaptopurine therapy, other cytotoxic therapies, cyclosporin, theophylline and didanosine. 8. Significant hepatic impairment (defined as serum bilirubin, AST or ALT greater than three times upper limit of normal (ULN)). 9. Estimated Glomerular Filtration Rate < 30 mls/min 10. Contraindication to MRI scanning. 11. Women of childbearing potential. 12. Prisoners. 13. Active participation in another CTIMP or device trial or participation within the past month. 14. eGFR < 60 and of Korean, Han Chinese or Thai descent
Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries. A woman is also presumed to be infertile due to natural causes if she has been amenorrheic for greater than 12 months and has an FSH greater than 40 IU/L |
|
E.5 End points |
E.5.1 | Primary end point(s) |
WMH progression rate over 2 years, defined using the Rotterdam Progression Score.
As of March 2020 we will extend the maximum duration of treatment from 104 weeks to 130 weeks, this has been done in response to the temporary shutdown of face to face contact at many sites due to the COVID19 restrictions. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Brain MRI will be performed at baseline and 2 years using either 1.5T or 3T MRI. The Rotterdam progression score will be calculated between baseline and subsequent scans. MRI analysis will be performed centrally at the core laboratory (University of Glasgow). This will be performed as soon as possible following the 2 year MRI scan being performed. |
|
E.5.2 | Secondary end point(s) |
1) change in mean day-time systolic BP at 1 month. 2) change in mean day-time diastolic BP at 1 month 3) Schmidt’s Progression Score 4) WMH volume at 2 years 5) New brain infarction on MRI 6) Rotterdam Progression Score with those who die/become too ill to undergo 7) MRI being assigned the highest score 8) MoCA score 9) Change in mean day-time systolic BP at 2 years 10) Change in mean day-time diastolic BP at 2 years
The following outcomes are exploratory - Fazekas score - Scheltens scale score - Blood pressure variability - One month mean day-time systolic blood pressure - One month mean day-time diastolic blood pressure - Clinic blood pressure - Incident atrial fibrillation - Recurrent stroke - Recurrent MI, stroke or cardiac death - Hospitalisation for, or incident of heart failure - Incident dementia - Mortality - Animal naming test - Controlled work association test - Hopkins verbal learning test - Trail making test - Quality of life (EQ-5D, SS-QOL)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints will be evaluated at 2 years with the exception of clinic blood pressure (which will be assessed at 1 month, 2 years and as a mean on treatment level) and MoCA score which will be assessed at week 52 months.
As of March 2020 we will extend the maximum duration of treatment from 104 weeks to 130 weeks, this has been done in response to the temporary shutdown of face to face contact at many sites due to the COVID19 restrictions.
|
|
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 | No |
E.6.5 | Efficacy | No |
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) | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 12 |
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
|
For the purposes of regulatory requirements the end of the trial is defined as one month after the date of the last investigational visit for the last patient undergoing protocol treatment.
This is in order to ensure that we can quality assess and review the final MRI image before the end of the study. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 14 |