Topic: Neurological
Conditions
Interventions
440 patients will be randomised equally (1:1:1:1) between the three active treatments and placebo to give 110 per treatment arm. The primary analysis will be intention-to-treat (ITT) on the whole stud
Sponsors
University College London (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 24/05/2016: 1. Confirmed diagnosis of SPMS. Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Progression can be evident from either an increase of at least one point in EDSS or clinical documentation of increasing disability in patients notes 2. EDSS 4.0-6.5 3. Aged 25 to 65 inclusive 4. Women and men with partners of childbearing potential must be using an appropriate method of contraception to avoid any unlikely teratogenic effects of the 3 drugs from time of consent, to 6 weeks after treatment inclusive 5. Women must have a negative pregnancy test within 7 days prior to the baseline visit unless not of child bearing potential (e.g. have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy or they are postmenopausal) 6. Willing and able to comply with the trial protocol (e.g. can tolerate MRI and fulfils the requirements for MRI, e.g. not fitted with pacemakers or permanent hearing aids) ability to understand and complete questionnaires 7. Written informed consent Previous inclusion criteria: 1. Confirmed diagnosis of SPMS at randomisation 2. Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Progression can be evident from either an increase of at least one point in EDSS or clinical documentation of increasing disability 3. EDSS 4.0-6.5 4. Aged 25 to 65 5. Men or Women of childbearing age must be using an appropriate method of contraception to avoid any unlikely teratogenic effects of the 3 drugs from time of consent and 6 weeks after treatment 6. Females have a negative pregnancy test within 7 days prior to being enrolled (baseline visit) unless not of child bearing potential eg have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy or they are postmenopausal 7. Willing and able to comply with the trial protocol and have the ability to understand and complete questionnaires 8. Willing and able to give full written informed consent 9. Able to undertake MRI
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 24/05/2016: 1. Pregnancy or breast feeding females 2. Baseline MRI scan not of adequate quality for analysis (e.g. too much movement artefact) 3. Significant organ co-morbidity (e.g. malignancy or renal or hepatic failure) 4. Relapse within 3 months of baseline visit 5. Patients who have been treated with iv or oral steroids for an MS relapse/progression within 3 months of baseline visit (these patients can undergo future screening visits once the 3 month window has expired) , patients on steroids for another medical condition may enter as long as the steroid prescription is not for multiple sclerosis (relapse/ progression) 6. Use of Simvastatin at 80mg dose within 3 months of baseline visit (lower doses of Simvastatin and other statins are permissible) 7. Commencement of fampridine within 6 months of baseline visit 8. Use of immunosupressants (e.g. azathioprine, methotrexate, cyclosporine) or first generation disease modifying treatments (ß-interferons, glatiramer) within 6 months of baseline visit 9. Use of fingolimod/fumarate/teriflunomide/laquinomod/or other experimental disease modifying treatment (including research in an investigational medicinal product) within 12 months of baseline visit 10. Use of mitoxantrone/natalizumab/alemtuzumab/daclizumab if treated within 12 months of baseline visit 11. Primary progressive MS 12. Relapsing-remitting MS 13. Known hypersensitivity to the active substances and their excipients to any of the active drugs for this trial 14. Use of an SSRI within 6 months of the baseline visit 15. Current use of tamoxifen 16. Current use of herbal treatments containing St. John’s Wort 17. Patients with a history of bleeding disorders or currently on anticoagulants 18. Use of monoamine oxidase inhibitors, phenytoin, L-tryptophan and/or neuroleptic drugs within 6 months of the baseline visit 19. Use of: lithium, chlorpropamide, triamterene, spironolactone, within 6 months of the baseline visit 20. Current use of potassium supplements 21. Significant signs of depression 22. Bipolar disorder 23. A Beck Depression Index score of 19 or higher 24. Epilepsy/seizures 25. Receiving or previously received Electroconvulsive therapy treatment 26. Glaucoma 27. Routine screening blood values (LFT) >/ 3 x upper limit of normal (ULN) of site reference ranges (AST/ALT, bilirubin, ?GT) 28. Potassium 5.5mmol/l 29. Sodium 130µmol/l 31. WBCs <3x109/l 32. Lymphocytes <0.8 x 109/l 33. Neutrophil count <1.0 x109 /l 34. Platelet count <90 x109 /l 35. Haemoglobin <80g/l Previous exclusion criteria: 1. Pregnancy or breast feeding females 2. Patients unable to tolerate baseline MRI scan or scan not of adequate quality for analysis (eg too much movement artefact) 3. Patients fitted with pacemakers or permanent hearing aids
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| MRI-derived Percentage Brain Volume Change (PBVC); Timepoint(s): Baseline, 96 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| MRI: Count of new and enlarging T2 lesions Pseudoatrophy: To specifically examine for this, a baseline scan will be acquired 24 weeks after the start of treatment. Clinical: 1. Expanded Disability Status Scale (EDSS) 2. Timed 25 Foot Walk (T25FW) 3. 9 Hole Peg Test (9HPT) 4. Paced Auditory Serial Addition Test (PASAT) 5. MS Functional Composite score comprising of the following: 5.1. Timed 25 Foot Walk (T25FW) 5.2. 9 Hole Peg Test (9HPT) 5.3. Paced Auditory Serial Addition Test (PASAT) 6. Symbol Digit Modalities Test (SDMT) 7. Sloan Low contrast visual acuity (SLCVA) 8. Relapse rate 9. Multiple Sclerosis Impact Scale v2 (MSIS29v2) 10. Multiple Sclerosis Walking Scale v2 (MSWSv2) 11. Brief Pain Inventory (BPI) 12. Numerical Pain Rating Score (NPRS) 13. Neurological Fatigue Index (NFI) 14. Health economics (EQ-5D) Exploratory Mechanistic Endpoints MRI: 1. Proportion of new T2 lesions at 24 weeks being persistently T1 hypointense at 96 weeks 2. Change in brain grey matter volume 3. MR spectroscopy (MRS) 4. MR magnetisation transfer ratio (MTR) 5. Cervical cord imaging CSF: measurement of CSF neurofilament levels. OCT: measurement of retinal nerve fibre layer (RNFL) and retinal nerve ganglion cell and inner plexiform layer (RGC+IPL). | — |
Countries
United Kingdom
Outcome results
None listed