Cannabinoid Use in Progressive Inflammatory brain Disease
Lead Research Organisation:
University of Plymouth
Department Name: Sch of Biomedical & Biological Sciences
Abstract
We plan to evaluate whether a cannabis-based medicine (delta 9-THC) has an effect on slowing accumulation of disability in progressive multiple sclerosis (MS) over three years. MS is the commonest cause of disability in young adults and the majority of people affected eventually develop a progressive form of the condition, thought to be due to destruction of nerve cells.
MS treatments can be divided into those aimed at relieving symptoms and those that may alter the course of the condition. Unfortunately, few medicines are effective in MS, and none have been shown to have any effect in the later stages of progressive disease. The recent Cannabinoids in MS (CAMS) study investigated the effects of cannabis–based medicines on muscle stiffness (spasticity) in MS over a fifteen week period, with an option for participants to continue study medication for up to a year. Although the study did not demonstrate any effects on spasticity after fifteen weeks as measured by independent assessors, there was evidence that patients felt that the cannabis medicines helped many symptoms and the study did provide preliminary evidence to suggest that delta 9-THC may reduce accumulation of disability in the longer-term. In addition, new scientific evidence has emerged to suggest that some constituents of cannabis may help nerve cells to survive (neuroprotection). It is therefore possible that this medication may not only help treat symptoms of MS, but may also alter the course of the condition and be neuroprotective.
The CAMS study also highlighted the limitations of measuring the effects of treatments in chronic disease, especially the differences between patient experience and independent assessment e.g. by a doctor. In our new study we will use both old and new ways of assessing the effects of cannabis-based medicines and will continue to develop measurement methods from the patient perspective. This should lead to more effective ways of assessing new treatments in the future.
MS treatments can be divided into those aimed at relieving symptoms and those that may alter the course of the condition. Unfortunately, few medicines are effective in MS, and none have been shown to have any effect in the later stages of progressive disease. The recent Cannabinoids in MS (CAMS) study investigated the effects of cannabis–based medicines on muscle stiffness (spasticity) in MS over a fifteen week period, with an option for participants to continue study medication for up to a year. Although the study did not demonstrate any effects on spasticity after fifteen weeks as measured by independent assessors, there was evidence that patients felt that the cannabis medicines helped many symptoms and the study did provide preliminary evidence to suggest that delta 9-THC may reduce accumulation of disability in the longer-term. In addition, new scientific evidence has emerged to suggest that some constituents of cannabis may help nerve cells to survive (neuroprotection). It is therefore possible that this medication may not only help treat symptoms of MS, but may also alter the course of the condition and be neuroprotective.
The CAMS study also highlighted the limitations of measuring the effects of treatments in chronic disease, especially the differences between patient experience and independent assessment e.g. by a doctor. In our new study we will use both old and new ways of assessing the effects of cannabis-based medicines and will continue to develop measurement methods from the patient perspective. This should lead to more effective ways of assessing new treatments in the future.
Technical Summary
Multiple Sclerosis (MS) is the commonest cause of neurological disability in young adults, with a prevalence of around 1 in 800 in most of the UK. Treatments for MS can broadly be divided into symptomatic (such as muscle relaxants and bladder treatments) and so-called disease modifying, most of which are immunomodulatory. The majority of people with MS will ultimately develop more progressive disease, thought to be due to neuronal degeneration. There is now considerable interest in treatments that may be neuroprotective, of which none are available at present.
The recent Cannabinoids in MS (CAMS) study focused on testing symptomatic benefit from cannabinoids over a 15-week period. Participants were included on the basis of having relatively stable MS in the six months prior to study recruitment, and of the 630 who received treatment, 95% had progressive disease. Following the main trial period, patients were offered the opportunity to continue medication in a blinded fashion for up to 12 months, with continuing three-monthly assessments. The primary outcome measure assessed spasticity using the Ashworth scale. No treatment effect was found during the main study, although patients felt that active medication was much more helpful than placebo in alleviating some of their distressing symptoms.
During the course of the study, experimental evidence was emerging to suggest that cannabinoids may have a neuroprotective action. The results of the follow-up study show significant effects on spasticity scores in the tetrahydrocannabinol (delta9-THC) arm, but not the cannabis extract arm. There is also some evidence for an effect on some measures of disability. The proposed study will therefore test whether cannabinoids have a neuroprotective action in progressive MS, building on the success of the CAMS study. In the course of delivering this study we will also continue the important process of developing methodology of clinical trials in chronic disease.
Five hundred patients with progressive MS and EDSS score 4.0-6.5 (walking affected by disease, but still able to walk with aids if necessary) will be randomised to either oral delta9-THC capsules or matched placebo. There will be a 2:1 active: placebo ratio. Recruitment will occur over 18 months, and patients will be followed up for three years on treatment. There will be two primary outcome measures: the physician-based EDSS (overall proportion of patients deteriorating, confirmed at two consecutive six monthly visits), and the patient-based MSIS-29 (overall mean change from baseline to end of study).
The recent Cannabinoids in MS (CAMS) study focused on testing symptomatic benefit from cannabinoids over a 15-week period. Participants were included on the basis of having relatively stable MS in the six months prior to study recruitment, and of the 630 who received treatment, 95% had progressive disease. Following the main trial period, patients were offered the opportunity to continue medication in a blinded fashion for up to 12 months, with continuing three-monthly assessments. The primary outcome measure assessed spasticity using the Ashworth scale. No treatment effect was found during the main study, although patients felt that active medication was much more helpful than placebo in alleviating some of their distressing symptoms.
During the course of the study, experimental evidence was emerging to suggest that cannabinoids may have a neuroprotective action. The results of the follow-up study show significant effects on spasticity scores in the tetrahydrocannabinol (delta9-THC) arm, but not the cannabis extract arm. There is also some evidence for an effect on some measures of disability. The proposed study will therefore test whether cannabinoids have a neuroprotective action in progressive MS, building on the success of the CAMS study. In the course of delivering this study we will also continue the important process of developing methodology of clinical trials in chronic disease.
Five hundred patients with progressive MS and EDSS score 4.0-6.5 (walking affected by disease, but still able to walk with aids if necessary) will be randomised to either oral delta9-THC capsules or matched placebo. There will be a 2:1 active: placebo ratio. Recruitment will occur over 18 months, and patients will be followed up for three years on treatment. There will be two primary outcome measures: the physician-based EDSS (overall proportion of patients deteriorating, confirmed at two consecutive six monthly visits), and the patient-based MSIS-29 (overall mean change from baseline to end of study).
Organisations
- University of Plymouth, United Kingdom (Lead Research Organisation)
- University College London, United Kingdom (Collaboration)
- University Hospitals of Leicester NHS, United Kingdom (Collaboration)
- University Hospitals Birmingham NHS Foundation Trust, Birmingham (Collaboration)
- Gloucestershire Royal Hospital (Collaboration)
- Frenchay Hospital, United Kingdom (Collaboration)
- Hertford County Hospital (Collaboration)
- Imperial College Healthcare NHS Trust (Collaboration)
- Norfolk and Norwich University Hospital (Collaboration)
- NHS Ayrshire and Arran (Collaboration)
- Royal Cornwall Hospitals NHS Trust (Collaboration)
- University Hospital of North Staffordshire NHS Trust (Collaboration)
- Royal Berkshire NHS Foundation Trust, United Kingdom (Collaboration)
- Royal Hallamshire Hospital, United Kingdom (Collaboration)
- Western General Hospital (Collaboration)
- University Hospital Coventry NHS Trust, United Kingdom (Collaboration)
- Royal Victoria Infirmary (Collaboration)
- John Radcliffe Hospital, United Kingdom (Collaboration)
- Aberdeen Royal Infirmary, United Kingdom (Collaboration)
- Barts Health NHS Trust, London (Collaboration)
- Salford Royal NHS Foundation Trust, Greater Manchester (Collaboration)
- Royal Preston Hospital (Collaboration)
- Queen's Medical Centre (Collaboration)
- Poole Hospital NHS Foundation Trust, Pool (Collaboration)
- Birmingham Community Healthcare NHS Trust (Collaboration)
- Musgrove Park Hospital (Collaboration)
- Addenbrooke's Hospital (Collaboration)
- University Hospital of Wales (Collaboration)
Publications
Zajicek J
(2013)
Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial.
in The Lancet. Neurology
| Description | MS clinical research network |
| Organisation | Aberdeen Royal Infirmary |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Addenbrooke's Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Barts Health NHS Trust |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Birmingham Community Healthcare NHS Trust |
| Department | West Midlands Rehabilitation Centre |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Frenchay Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Gloucestershire Royal Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Hertford County Hospital |
| Department | Neurology Department |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Imperial College Healthcare NHS Trust |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | John Radcliffe Hospital |
| Department | Department of Clinical Neurology |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Leicester General Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Musgrove Park Hospital |
| Department | Neurology Department |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | NHS Ayrshire and Arran |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Norfolk and Norwich University Hospital |
| Department | Neurology Department |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Poole Hospital NHS Foundation Trust |
| Department | Portland Ward |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Queen's Medical Centre |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Royal Berkshire NHS Foundation Trust |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Royal Cornwall Hospitals NHS Trust |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Royal Hallamshire Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Royal Preston Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Royal Victoria Infirmary |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Salford Royal NHS Foundation Trust |
| Department | Department of Neurology |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | University College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | University Hospital of North Staffordshire NHS Trust |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | University Hospital of Wales |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | University Hospitals Birmingham NHS Foundation Trust |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | University Hospitals Coventry and Warwickshire NHS Trust |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |
| Description | MS clinical research network |
| Organisation | Western General Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Designed and obtained funding for multicentre clinical trial. |
| Collaborator Contribution | Recruited participants to clinical trial. |
| Impact | Successful completion of multicentre study. |