Switching off leakage and inflammation in small brain blood vessels
| ISRCTN | ISRCTN15483452 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15483452 |
| Secondary identifying numbers | CPMS 39159 |
- Submission date
- 24/09/2018
- Registration date
- 01/10/2018
- Last edited
- 18/04/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Background and study aims
Cerebral small vessel disease (abnormalities related to small blood vessels in the brain) is a major cause of stroke and dementia in the UK. The causes of progression of the disease are not completely understood. Recently leakiness of the blood brain barrier has been proposed as a mechanism, which itself may cause inflammation of the brain. If we can understand what causes progression of the disease it may be possible to target treatments to reduce these processes and, therefore, progression. A previous study showed that differences between patients and healthy people can be detected in both blood brain barrier leakiness and neuroinflammation (inflammation of the nervous tissue). The aim of this study is to assess whether minocycline, an antibiotic which has been shown to inhibit the processes that cause inflammation and leakiness in animals, can have the same effect in humans.
Who can participate?
Patients aged 18 years and over with small vessel disease
What does the study involve?
Participants are randomly allocated to be treated with either minocycline or a placebo (dummy drug). MRI and PET imaging is performed before treatment starts and after three months and the amount of leakiness and inflammation is measured to see whether they differ between the groups. MRI images are also acquired after 12 months to see if the treatment has reduced the accrual of damage to the brain. Cognitive tests are also performed at the start of the study and after 12 months.
What are the possible benefits and risks of participating?
There is no direct benefit to participants, but it will provide useful information on the role of inflammation in small vessel disease, and how this can be influenced by the use of minocycline.
Where is the study run from?
Addenbrooke’s Hospital (UK)
When is the study starting and how long is it expected to run for?
March 2018 to June 2023
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Mrs Laurence Loubiere
lhl31@medschl.cam.ac.uk
Contact information
Mrs Laurence Loubiere
Scientific
Scientific
Stroke Research group, Dept of Clinical Neurosciences
R3, Box 83, Cambridge Biomedical Campus
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 (0)1223 217695 |
|---|---|
| lhl31@medschl.cam.ac.uk |
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | MINocyclinE to Reduce inflammation and blood brain barrier leakage in small Vessel diseAse (MINERVA) - A treatment trial |
| Study acronym | MINERVA |
| Study objectives | Cerebral small vessel disease (SVD) is a major cause of stroke and dementia in the UK. The causes of progression of the disease are not completely understood. Recently leakiness of the blood brain barrier has been proposed as a mechanism, which itself may cause inflammation of the brain. If we can understand what causes progression of the disease it may be possible to target treatments to reduce these processes and, therefore, progression. Our previous observational study showed that we can detect differences between SVD patients and controls in both blood brain barrier leakiness and neuroinflammation. This double-blind randomised controlled trial will assess whether a drug, minocycline, an antibiotic, which has been shown to inhibit the processes that cause inflammation and leakiness in animals, can have the same effect in man. |
| Ethics approval(s) | Approved 15/10/2018, NRES Committee East of England Cambridge Central (Royal Standard Place, Nottingham, NG1 6FS; +44 (0)207 104 8107/+44 (0)207 104 8234; nrescommittee.eastofengland-cambridgecentral@nhs.net), ref: 18/EE/0237 |
| Health condition(s) or problem(s) studied | Cerebral small vessel disease |
| Intervention | Current intervention as of 21/11/2019: This project is a double blind randomised clinical trial which uses MRI and PET imaging at baseline and three months to study blood brain barrier permeability and neuroinflammation and how it is affected by minocycline. The trialists will recruit 44 small vessel disease subjects split equally two treatment arms, minocycline and placebo taken orally at 100 mg bd of minocycline and an equivalent placebo. They will undergo conventional and gadolinium contrast agent enhanced MRI, PET imaging with [11C]PK11195, cognitive assessment, clinical assessment and phlebotomy at baseline and again at three months. The MHRA have reviewed the protocol and classified the study as a non-CTIMP. This is because minocycline is a well-recognised drug which is being used in this context as an experimental probe to reduce inflammation and blood brain barrier permeability. In more detail all subjects will undergo at baseline: 1. Screening. During routine clinical care consultations patients will be approached by their consultant if they are felt to be appropriate for the project. The suitability of participants will be assessed against the inclusion and exclusion criteria. Those who are eligible will be provided with a participant information sheet and the study will be explained by a trained researcher.The participant will then be asked to consent to participate in the study by completing a consent form. They will be given a copy of the consent and PIS to take away. 2. Blood collection. All participants who have not had their renal function measured will have a blood sample taken to calculate their renal function. If this is below an acceptable level (an eGFR =<59 ml/min/1.73m2) they will not be able to be a part of the study. 3. Cognitive and clinical assessment. All subjects who are eligible and who have consented will be asked to attend the clinic at Addenbrooke's for cognitive testing and clinical assessment. This will include collection of demographic data as well as cardiovascular risk factors and medical history as well as an estimate of disability. Cognitive assessment consists of a battery of tests that will provide information about the subject's cognitive ability including memory and attention tests as well as questionnaires about their mood and their fatigue experienced. These tests will take up to 90 minutes. 4. MRI and PET imaging. Subjects will undergo MRI and PET scanning at the same time using a dual-modality PET/MR scanner. The MRI protocol will include conventional MRI sequences as well as contrast enhanced MRI which is used to determine the permeability of the blood brain barrier. This will involve the insertion of a canula to allow the administration of the contrast agent during the MRI scan. The PET scan will involve the administration of a radioactive ligand [11C]PK11195 immediately prior to the scan. Scanning will take approximately 90 minutes. 5. During the fitting of the canula blood samples will be taken to perform serum analysis for endothelial dysfunction and inflammatory markers. 6. Randomisation, subjects will be assigned at random, using an online randomisation tool, to one of the two treatment arms. 7. Treatment. The subjects will then take the assigned treatment for three months 8. Follow-up testing and imaging. Three months after the first scan participants will be asked back to repeat the scanning to investigate change in this over the study period. The scanning will again last 90 minutes and further blood samples will be taken at this point. 9. Follow-up testing and imaging. A further follow-up scan will be performed after 12 months. This will comprise of non-contrast MRI only and take around 35 minutes. Cognitive testing will also be repeated at this time-point. Previous intervention: This project is a double blind randomised clinical trial which uses MRI and PET imaging at baseline and three months to study blood brain barrier permeability and neuroinflammation and how it is affected by minocycline. The trialists will recruit 44 small vessel disease subjects split equally two treatment arms, minocycline and placebo taken orally at 100mg bd of minocycline and an equivalent placebo. They will undergo conventional and gadolinium contrast agent enhanced MRI, PET imaging with [11C]PK11195, cognitive assessment, clinical assessment and phlebotomy at baseline and again at three months. The MHRA have reviewed the protocol and classified the study as a non-CTIMP. This is because minocycline is a well-recognised drug which is being used in this context as an experimental probe to reduce inflammation and blood brain barrier permeability. In more detail all subjects will undergo at baseline: 1. Screening. During routine clinical care consultations patients will be approached by their consultant if they are felt to be appropriate for the project. The suitability of participants will be assessed against the inclusion and exclusion criteria. Those who are eligible will be provided with a participant information sheet and the study will be explained by a trained researcher.The participant will then be asked to consent to participate in the study by completing a consent form. They will be given a copy of the consent and PIS to take away. 2. Blood collection. All participants who have not had their renal function measured will have a blood sample taken to calculate their renal function. If this is below an acceptable level (an eGFR =<59 ml/min/1.73m2) they will not be able to be a part of the study. 3. Cognitive and clinical assessment. All subjects who are eligible and who have consented will be asked to attend the clinic at Addenbrooke's for cognitive testing and clinical assessment. This will include collection of demographic data as well as cardiovascular risk factors and medical history as well as an estimate of disability. Cognitive assessment consists of a battery of tests that will provide information about the subject's cognitive ability including an estimate of their pre-morbid IQ. These tests will take up to 90 minutes. 4. MRI and PET imaging. Subjects will undergo MRI and PET scanning at the same time using a dual-modality PET/MR scanner. The MRI protocol will include conventional MRI sequences as well as contrast enhanced MRI which is used to determine the permeability of the blood brain barrier. This will involve the insertion of a canula to allow the administration of the contrast agent during the MRI scan. The PET scan will involve the administration of a radioactive ligand [11C]PK11195 immediately prior to the scan. Scanning will take approximately 90 minutes. 5. During the fitting of the canula blood samples will be taken to perform serum analysis for endothelial dysfunction and inflammatory markers. 6. Randomisation, subjects will be assigned at random, using an online randomisation tool, to one of the two treatment arms. 7. Treatment. The subjects will then take the assigned treatment for three months 8. Follow-up testing and imaging. Three months after the first scan participants will be asked back to repeat the cognitive testing and the scanning to investigate change in these over the study period. Both the testing and scanning will again last 90 minutes and further blood samples will be taken at this point. 9. Follow-up testing and imaging. A further follow-up scan will be performed after 12 months. This will comprise of non-contrast MRI only and take around 35 minutes. Cognitive testing will also be repeated at this time-point. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Minocycline |
| Primary outcome measure | The co-primary endpoints are: 1. Blood brain barrier permeability (white matter permeability) measured using MRI at baseline and 3 months 2. Microglial activation ([11C]-PK11195 binding) measured using PET of ‘hot-spots’ of binding in the white matter at baseline and 3 months |
| Secondary outcome measures | Current secondary outcome measures as of 25/02/2019: 1. Volume of tissue with abnormal BBB permeability and/or neuro-inflammation at baseline and 3 months 2. Blood endothelial and inflammatory markers (CRP, ICAM1, MMP9, thrombomodulin) at baseline and 3 months 3. Cognitive outcome measures at baseline and 12 months: 3.1. Working Memory (WM), measured using digit span 3.2. Episodic (Long Term) Memory (LTM), measured using logical memory I & II and visual reproduction I & II from the WMS-IV battery 3.3. Processing Speed (PS), measured using digit symbol substitution, B-MIPB speed of information processing task, and the grooved pegboard task 3.4. Executive Function (EF), measured using trail-making test (part B), single letter (FAS) verbal fluency, and the Wisconsin card sort test 3.5 Mood assessment (Apathy and Depression) measured using the Geriatric Depression Scale (Long Form, GDS-30) Previous secondary outcome measures: 1. Volume of tissue with abnormal BBB permeability and/or neuro-inflammation at baseline and 3 months 2. Blood endothelial and inflammatory markers (CRP, ICAM1, MMP9, thrombomodulin) at baseline and 3 months 3. Cognitive outcome measures at baseline, 3 months and 12 months: 3.1. Working Memory (WM), measured using digit span 3.2. Episodic (Long Term) Memory (LTM), measured using logical memory I & II and visual reproduction I & II from the WMS-IV battery 3.3. Processing Speed (PS), measured using digit symbol substitution, B-MIPB speed of information processing task, and the grooved pegboard task 3.4. Executive Function (EF), measured using trail-making test (part B), single letter (FAS) verbal fluency, and the Wisconsin card sort test |
| Overall study start date | 26/03/2018 |
| Completion date | 30/06/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Planned Sample Size: 44; UK Sample Size: 44 |
| Total final enrolment | 48 |
| Key inclusion criteria | 1. Clinical evidence of cerebral small vessel disease as evidenced by one or more of; 1.1. A lacunar stroke syndrome (e.g., pure motor stroke, pure sensory stroke, sensorimotor stroke or ataxic hemiparesis, or clumsy hand dysarthria syndrome) with a corresponding acute lacunar infarct on diffusion weighted imaging (DWI) for cases imaged (clinically) within 3 weeks of stroke or an anatomically compatible lacunar infarct on FLAIR/T1 MRI for cases imaged later after stroke (<=1.5 cm diameter) 1.2. Symptoms of cognitive impairment 1.3. Gait apraxia 2. Confluent white matter hyper-intensities on T2 weighted MRI 3. If a past history of stroke at least 3 months after last stroke to exclude BBB changes secondary to acute infarction |
| Key exclusion criteria | Current exclusion criteria as of 21/11/2019: 1. Unable/unwilling to consent 2. MMSE <21 (for consent issues) 3. Age <18 years 4. Lacunar infarcts >1.5 cm – as many of these are striatocapsular infarcts caused by embolism 5. Evidence of cortical stroke 6. Any stroke cause other than SVD including: 6.1. Cardioembolic source 6.2. Carotid or vertebral stenosis > 50% measured on NASCET criteria 7. Estimated glomerular filtration rate (eGFR) =<59 ml/min/1.73m2 within past 3 months. Estimated GFR will be calculated using the Modification of Diet in Renal Disease (MDRD) equation: 186 x (Creatinine / 88.4)1.154 x (Age) - 0.203 x (0.742 if female) x (1.210 if black) 8. Contraindications to taking part in MRI study, e.g., pacemaker 9. Inability to lie still in the PET/MR scanner for up to 75 minutes 10. Women who are of childbearing age, pregnant or breastfeeding 11. Meeting exclusions related to minocycline consumption, in particular: 11.1. Allergic to minocycline hydrochloride or other similar antibiotics 11.2. Have had complete kidney failure 11.3. Suffer from myasthenia gravis, have impaired liver or kidney function or have systemic lupus erythematosus (SLE) 11.4. Suffer from increased pressure in the skull 11.5. Are sensitive to sunlight or artificial light (e.g. sunbeds) 12. Taking medication contra-indicated to minocycline Previous exclusion criteria: 1. Unable/unwilling to consent 2. MMSE <21 (for consent issues) 3. Age <18 years 4. Lacunar infarcts >1.5 cm – as many of these are striatocapsular infarcts caused by embolism 5. Evidence of cortical stroke 6. Any stroke cause other than SVD including: 6.1. Cardioembolic source 6.2. Carotid or vertebral stenosis >50% measured on NASCET criteria 7. Estimated glomerular filtration rate (eGFR) =<59 ml/min/1.73m2 within past 3 months. Estimated GFR will be calculated using the Modification of Diet in Renal Disease (MDRD) equation: 186 x (Creatinine / 88.4)1.154x (Age) - 0.203 x (0.742 if female) x (1.210 if black) 8. Contraindications to taking part in MRI study, e.g., pacemaker 9. Inability to lie still in the PET/MR scanner for up to 75 minutes 10. Women who are of childbearing age, pregnant or breastfeeding 11. Meeting exclusions related to minocycline consumption, in particular: 12. Allergic to minocycline hydrochloride, other similar antibiotics 13. Have had complete kidney failure 14. Suffer from myasthenia gravis, have impaired liver or kidney function, Have systemic lupus erythematosus (SLE) 15. Suffer from increased pressure in the skull 16. Are sensitive to sunlight or artificial light (e.g. sunbeds) 17. Taking medication contra-indicated to minocycline |
| Date of first enrolment | 29/04/2019 |
| Date of final enrolment | 15/06/2022 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Addenbrooke’s Hospital
Hills Rd
Cambridge
CB2 0QQ
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Sponsor information
Cambridge University Hospitals NHS Foundation Trust
Hospital/treatment centre
Hospital/treatment centre
Addenbrooke's Hospital
Hills Rd
Cambridge
CB2 0QQ
England
United Kingdom
| Phone | +44 (0)1223 217418 |
|---|---|
| research@addenbrookes.nhs.uk | |
"ROR" |
https://ror.org/04v54gj93 |
Funders
Funder type
Research council
Medical Research Council; Grant Codes: MR/N026896/1
Government organisation / National government
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/11/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 17/05/2022 | 29/11/2022 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 17/04/2024 | 18/04/2024 | Yes | No |
Editorial Notes
18/04/2024: Publication reference added.
01/11/2023: The total final enrolment was added.
29/11/2022: Recruitment for this study resumed in July 2020 and the following changes have been made:
1. The recruitment end date has been changed from 31/12/2021 to 15/06/2022.
2. The overall trial end date has been changed from 31/12/2022 to 30/06/2023 and the plain English summary was updated accordingly.
3. The intention to publish date has been changed from 01/03/2023 to 30/11/2023.
4. Publication reference added.
17/04/2020: Due to current public health guidance, recruitment for this study has been paused.
21/11/2019: The following changes have been made:
1. The ethics approval information has been updated.
2. The intervention has been changed.
3. The participant exclusion criteria have been changed.
4. The scientific contact's telephone number has been updated.
28/03/2019: The condition has been changed from "Specialty: Stroke, Primary sub-specialty: Experimental Medicine; Health Category: Neurological, Stroke" to "Cerebral small vessel disease" following a request from the NIHR.
25/02/2019: The following changes have been made:
1. The scientific title has been changed from "Can we switch off blood brain barrier leakage and inflammation in cerebral small vessel disease? A treatment trial" to "MINocyclinE to Reduce inflammation and blood brain barrier leakage in small Vessel diseAse (MINERVA) - A treatment trial".
2. The trial acronym has been added.
3. The secondary outcome measures have been changed.
4. The plain English summary has been updated to reflect the changes to the secondary outcome measures .
5. The recruitment start date has been changed from 01/01/2019 to 29/04/2019.
