| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mutliple Sclerosis (Secondary Progressive) |
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| E.1.1.1 | Medical condition in easily understood language |
| Multiple Sclerosis (Secondary Progressive) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| 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 |
Secondary Progressive Multiple Sclerosis (SPMS) results from progressive nerve death or neuro-degeneration that causes accumulating and irreversible disability characterised by a range of devastating problems affecting walking, balance, vision, cognition, pain control, bladder and bowel function.
MS-SMART will test 3 leading drugs to determine if any are effective at slowing the rate of brain shrinkage compared to placebo. Brain volume loss will be measured using MRI brain scans, which will also advance our understanding of how the drugs are providing neuroprotection in SPMS patients. |
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| E.2.2 | Secondary objectives of the trial |
The clinical effects of neuroprotection will be measured by various clinician and patient reported outcomes and disability assessments.
Advanced MRI scans will be used to work out what are the anti-inflammatory and neuro-protective mechanisms of the drugs being tested.
Cerebrospinal fluid (CSF) neurofilament levels will be measured to assess neuroprotection.
Markers (substances in CSF, blood and urine samples) will also be looked at. In the future these markers may help us develop effective ways of predicting which people with secondary progressive Multiple Sclerosis are more likely to respond to the neuroprotective drugs under investigation in the MS-SMART study.
CSF lymphocyte phenotyping -
In addition the lymphocytes present in the CSF (which are collected automatically at the same time) will be purified, analysed and phenotyped. Techniques such as deep sequencing will be used to understand lymphocyte repertoires which will enable us to examine the current status of i |
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| 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 |
1. Advanced MRI Sub-Study, Protocol Appendices 1st June 2014
OBJECTIVES
Advanced MRI scans to investigate the anti-inflammatory and neuro-protective mechanisms of the drugs being tested.
The purpose of the sub-study is to acquire a number of additional MRI outcome measures in order to gain a deeper insight in to the pathological evolution of secondary progressive MS (by evaluating serial changes in the placebo arm) and to explore whether the imaging outcome measures are modified by any of the 3 active treatments (thereby providing insights in to therapeutic mechanisms). Data on the longitudinal sensitivity and clinical correlation of the imaging measures will also inform their utility as outcome measures for future trials in secondary progressive MS.
2. CSF Neurofilament Sub-study, Protocol Appendices 1st June 2014
OBJECTIVES
i. Does Amiloride, Riluzole and Fluoxetine prevent axonal damage in SPMS? The primary outcome will be the impact on CSF Neurofilament levels.
ii. Does Amiloride, Riluzole and Fluoxetine favorably affect the profile of other CSF biomarkers? In addition to CSF Neurofilament levels we proposed measuring putative markers of neuronal sprouting and synaptogenesis and gliosis; these include NCAM, GAP43 and GFAP. In addition, the effects of these drugs on a panel of inflammatory biomarkers will also be assessed.
In addition the lymphocytes present in the CSF (which are collected automatically at the same time) will be purified, analysed and phenotyped. Techniques such as deep sequencing will be used to understand lymphocyte repertoires which will enable us to examine the current status of immune activity, as well as to gain further understanding as to the aetiology of MS.
3. Optical Coherence Tomography Sub-Study, Protocol Appendices 1st June 2014
OBJECTIVES
To use OCT to measure retinal nerve fibre layer thickness and retinal ganglion cell layer thickness; to evaluate the sensitivity of OCT to detect on-going retinal neuroaxonal loss in secondary progressive MS, and whether such loss can be prevented by Amiloride, Fluoxetine or Riluzole.
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| E.3 | Principal inclusion criteria |
• 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
• EDSS 4.0-6.5
• Aged 25 to 65 inclusive
• Women and men with partners of childbearing potentialage 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
• 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)
• 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
• Written informed consent
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| E.4 | Principal exclusion criteria |
• Pregnancy or breast feeding females
• Baseline MRI scan not of adequate quality for analysis (e.g. too much movement artefact)
• Significant organ co-morbidity (e.g. malignancy or renal or hepatic failure)
• Relapse within 3 months of baseline visit
• •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 or progression)
Use of Simvastatin at 80mg dose within 3 months of baseline visit (lower doses of Simvastatin and other statins are permissible)
• Commencement of fampridine within 6 months of baseline visit
• Use of immunosupressants (e.g. azathioprine, methotrexate, cyclosporine) or first generation disease modifying treatments (β-interferons, glatiramer) within 6 months of baseline visit
• 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
• Use of mitoxantrone/natalizumab/alemtuzumab/daclizumab if treated within 12 months of baseline visit
• Primary progressive MS
• Relapsing-remitting MS
• Known hypersensitivity to the active substances and their excipients to any of the active drugs for this trial
• Use of an SSRI- within 6 months of the baseline visit
• Current use of tamoxifen
• Current use of herbal treatments containing St. John’s Wort
• Patients with a history of bleeding disorders or currently on anticoagulants
• Use of monoamine oxidase inhibitors, phenytoin, L-tryptophan) and/or neuroleptic drugs within 6 months of the baseline visit
• Use of: lithium, chlorpropamide, triamterene, spironolactone, within 6 months of the baseline visit
• Current use of potassium supplements
• Significant signs of depression
• Bipolar disorder
• A Beck Depression Index score of 19 or higher
• Epilepsy/seizures
• Receiving or previously received Electroconvulsive therapy ECT treatment
• Glaucoma
• Routine screening blood values (LFT) >/ 3 x upper limit of normal (ULN) of site reference ranges (AST/ALT, bilirubin, ˠGT)
• Potassium <2.8mmol/l or >5.5mmol/l
• Sodium <125mmol/l
• Creatinine >130µmol/l
• WBCs <3x109/l
• Lymphocytes <0.8 x 109/l
• Neutrophil count <1.0 x109 /l
• Platelet count <90 x109 /l
• Haemoglobin <8.0g/l
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Percentage Brain Volume Change (PBVC)
A decrease in brain volume is seen at all stages of Multiple Sclerosis, and especially in patients with Secondary Progressive MS. Brain atrophy will be measured as a percentage brain volume change using the registration-based SIENA technique.
PBVC measured using the SIENA technique has therefore been chosen as the primary outcome measure for our trial. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline, 24 weeks & 96 weeks |
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| E.5.2 | Secondary end point(s) |
Secondary Objectives -
•To establish that a multi-arm trial strategy is an efficient way of screening drugs in SPMS and can become the template for future work.
•To explore any anti-inflammatory drug activity using the count of new and enlarging T2 lesions.
•Examining for evidence of pseudo-atrophy (to ensure reliability of the primary outcome measure).
•To examine the clinical effect of neuroprotection as measured by clinician (EDSS, MSFC, SDMT, SLCVA, relapse rate) and patient reported outcome measures (MSIS29, MSWS, Pain [NPRS, NPS and BPI] and Fatigue (NFI).
•To collect basic health economic data (EQ-5D) to inform future phase III trials.
Mechanistic Objectives
•Persistent new T1 hypointense lesion count to assess neuroprotection in new lesions
•Grey matter volume change to assess cortical neuroprotection
•MR spectroscopy (MRS) to measure N-acetyl aspartate (reversal of neuronal mitochondrial dysfunction), myoinositol (prevention of glial cell inflammation) and glutamate (prevention of excitotoxicity)
•Magnetic Transfer Ratio (MTR) to evaluate myelination
•Composite MRI/disability scores to increase sensitivity and study interaction of treatment mechanisms.
•Quantification of Cerebrospinal fluid (CSF) neurofilament levels to measure neuroprotection.
CSF lymphocyte phenotyping
•Optical Coherence Tomography (OCT)-measured Retinal nerve Fibre Layer thickness as a measure of neuroprotection.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline, 24, 36, 48 and 96 weeks. |
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| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 3 |
| 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
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| Last visit of the last participant. |
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| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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