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Simvastatin in Secondary Progressive Multiple Sclerosis (MS-OPT)

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ClinicalTrials.gov Identifier: NCT03896217
Recruitment Status : Not yet recruiting
First Posted : March 29, 2019
Last Update Posted : March 29, 2019
Sponsor:
Collaborator:
MS Society
Information provided by (Responsible Party):
University College, London

Brief Summary:

Multiple sclerosis (MS) is a neurological condition which is a common cause of disability in young people. It is thought to be an autoimmune condition, where the body's immune system begins to attack itself. The cause of MS is unknown but is thought to be a mix of genetic and environmental factors. There are treatments available for early stages of MS, but the later stage known as Secondary Progressive MS (SPMS) has no current treatment.

Statins are a safe treatment traditionally used to reduce cholesterol levels. However, statins also have other effects which could reduce the progression of SPMS, such as effects on the immune system and circulation. A recent study (Chataway et al., 2014) showed that treatment with high-dose simvastatin, a type of statin, reduced the progression of SPMS but no effect on the immune system was seen. It is possible that simvastatin does not treat the immune system but improves how the blood and blood vessels in the brain work in this disease.

The purpose of the clinical trial is to test how Simvastatin (80mg/day) may slow down disease progression in people living with SPMS compared to placebo (dummy pill). Participants will receive either Simvastatin or placebo and will be asked to take 2 tablets daily, for up to 17 weeks.


Condition or disease Intervention/treatment Phase
Secondary Progressive Multiple Sclerosis Drug: Simvastatin Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomised, Placebo-controlled Single-site Study of High Dose Simvastatin Treatment for Secondary Progressive Multiple Sclerosis: Impact on Vascular Perfusion and Oxidative Damage
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Simvastatin

Arm Intervention/treatment
Active Comparator: Simvastatin
Simvastatin is part of the pharmacotherapeutic group of HMG-CoA reductase inhibitors (ATC-Code: C10A A01). Simvastatin is licensed within the EU for hypercholesterolemia and cardiovascular prevention but for this trial its use will be outside its licensed indication. Oral Simvastatin will be taken 40mg daily (one tablet in the evening) for 4 weeks and then at week 4 up titrated to 80mg daily (two tablets in the evening.
Drug: Simvastatin
Simvastatin 40mg for first 4 weeks and 80mg (if tolerated) thereafter up to 17 weeks
Other Name: ATC-Code: C10A A01

Placebo Comparator: Placebo
Matched Placebo (one tablet in the evening) for 4 weeks and then at week 4 up titrated to two tablets daily in the evening.
Drug: Simvastatin
Simvastatin 40mg for first 4 weeks and 80mg (if tolerated) thereafter up to 17 weeks
Other Name: ATC-Code: C10A A01




Primary Outcome Measures :
  1. Effect on cerebral blood flow [ Time Frame: Over 20 weeks ]
    compared between patients on simvastatin or placebo using multiple linear regressions. ASL is an MRI method that allows non-invasive measurement of CBF using inversion of arterial water spins as a tracer.The aim is to explore whether subtlechangesinCBFoccur over time between placebo and simvastatin treated patients, including potential waning of the effects of the drug over time.


Secondary Outcome Measures :
  1. MRI: glutamate levels [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    To explore whether statin treatment reduces glutamate levels. These will be measured applying an advanced MRI technique called spectroscopy which detects biochemical changes in the brain.

  2. AOSLO measurements of blood flow [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    To establish if Adaptive Optics Scanning Laser Ophthalmoscope (AOSLO) measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment.

  3. MRI: ASL measurements of blood flow [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    To establish whether Arterial Spin Labelling (ASL) measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment. The cerebral arterial hemodynamic measure bolus arrival time will be measured, as the time from labeling of blood in feeding arteries to its first arrival in the capillary network of the voxel of interest. This will be supported by a questionnaire investigating factors that influence brain perfusion (related to lifestyle and health, mental state, personality and cognition and use of caffeine and recreational drugs) to improve the accuracy and to facilitate the interpretation of perfusion-derived parameters.

  4. MRI: brain atrophy [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    To explore whether statin reduce the rate of brain atrophy, including grey matter volumes, on MRI (excluding the effect of pseudo-atrophy, which is a temporary response to the drug rather than an actual loss of tissue). The MRI images will be analysed using softwares developed at UCL to quantify the amount of brain tissue loss over time.

  5. Clinical Outcome: EDSS [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Clinician observed expanded disability status score (EDSS) is a method of quantifying disability in MS and records changes in disability over time. The EDSS scale ranges from 0 (no disability) to 10 (death due to MS) in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist and encompasses pyramidal, cerebellar, brainstem, sensory, bowel/bladder function in addition to visual, cerebral and other functions. Changes in score (including no changes) will be recorded to determine progression of disability.

  6. Clinical Outcomes: MSFC: 25 foot timed walk [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Multiple Sclerosis Function Composite (MSFC) includes the 25 foot timed foot walk (25TFW), which involves marking a 25-foot distance in an unobstructed hallway; an assistive device (if needed) may be used by the participant and recorded. Their speed is then timed up to a time limit of 3 mins in both directions. Changes in scores will be recorded over the time-points described.

  7. Clinical Outcomes: MSFC: 9 hole peg test [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Multiple Sclerosis Function Composite (MSFC) includes the 9 hole peg test (9HPT). The 9-HPT is a quantitative measure of upper extremity (arm and hand) function. Both the dominant and non-dominant hands are tested twice (two consecutive trials of the dominant hand, followed immediately by two consecutive trials of the non-dominant hand). It is important that the 9-HPT be administered on a solid table (not a rolling hospital bedside table) and that the 9-HPT apparatus be anchored (e.g., with Dycem). The pegs are selected one at a time, using one hand only, and put into the holes as quickly as possible in any order until all the holes are filled. Then, without pausing, the pegs are removed one at a time and returned to the container. This is timed and recorded at the time-points described.

  8. Clinical Outcomes: MSIS-29v2 questionnaires. [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Patient reported multiple sclerosis impact scale version 2 (MSIS-29v2) is a self-administered questionnaire covering 29 items that asks to what degree MS has impacted the person physically and mentally over the past two weeks.

  9. Clinical Outcomes: MSWSv2 questionnaires. [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Patient reported Multiple Sclerosis Walking Score version 2 (MSWSv2) is a 12 item self-administered questionnaire that measures walking performance over the previous two weeks. Each items is summed to generate a total score which is then transformed to a scale ranging from 0 to 100. Higher scores indicate greater impact on walking. Changes in scores will be recorded over the time-points described.

  10. Health Economic outcomes: EQ5D5L [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    The EuroQol Health Related Quality of Life (EQ5d5L) is a five-item questionnaire that assesses mobility, self-care, pain/discomfort, anxiety/depression and a person's usual activities. It incorporates an additional visual analogue scale (VAS) which enables a calculation of quality of life years (QALY) so health economic analyses can be performed. Each item of the EQ5D5L is responded to on a scale as follows: no problems, slight problems, moderate problems, severe problems and extreme problems. Changes in scores will be recorded over the time-points described.

  11. Exploratory outcomes: immune parameters, and biomarkers. [ Time Frame: At Day 0 (Baseline), Week 4, Week 16 and Week 20 ]
    Blood samples from these patients will be taken at baseline and at weeks 4, 16 and 20 to investigate the effect of statins on vascular leakage and free radical damage. Biomarkers will be determined as follows: (i) For RNA/DNA oxidative damage serum levels of 8-hydroxyguanosine (8-OHG)/8-hydroxydeoxyguanosine (8-OHdG); (ii) Protein oxidative damage will be determined by assaying plasma proteins for nitrotyrosine and carbonyl content; and (iii) Detection of lipid oxidative damage by assaying for the advanced lipid peroxidation end products 4-hydroxynonenal (4-HNE or HNE), malondialdehyde (MDA), 8-iso-prostaglandin F2α and thiobarbituric acid reactive substances (TBARS) (Miller et al., 2012).

  12. Frontal executive functioning: FAB [ Time Frame: At Day 0 and Week 20 ]

    Frontal Assessment Battery (FAB). The FAB is a brief tool that can be used at the bedside or in a clinic setting to assist in discriminating between dementias with a frontal dysexecutive phenotype and Dementia of Alzheimer‟s Type (DAT).

    The FAB has validity in distinguishing Fronto-temporal type dementia from DAT in mildly demented patients (MMSE > 24). Total score is from a maximum of 18, higher scores indicating better performance. Changes in scores will be recorded over the time-points described.


  13. SDMT [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Symbol Digit Modalities Test (SDMT) is measure of cognitive impairment. The subject is asked to match single digits to symbols using a key as a guide that pairs the numbers to the symbols. They are presented with a page headed by a key that pairs the single digits 1-9 with nine symbols and they then write or orally report their responses in a scoring form. It can be administered in oral and written form and is timed and guided by a trained examiner ie. suitably qualified member of the research team. Changes in scores will be recorded over the time-points described.

  14. Retinal Vessel Oxygen Saturation [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Oxygen saturation of retinal vessels will be measured using the Oxymap T1. The device measures oxygen saturation quickly and non-invasively by taking two simultaneous images of the retina using two different wavelengths to determine the amount of oxygen bound haemoglobin in the blood.

  15. Retinal Vessel Density [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Density of retinal vessels will be measured using optical coherence tomography angiography (OCTA). OCTA is a method of retinal imaging which is non-invasive and involves the patient holding their head still and staring at a dim light while imaging takes place.

  16. Inner retinal thickness [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    Inner retinal thickness will be measured using optical coherence tomography (OCT). OCT is a method of retinal imaging which is non-invasive and involves the patient holding their head still and staring at a dim light while imaging takes place.

  17. MRI: Neurite density and orientation dispersion imaging [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    To assess changes in axonal parameters, such as fiber orientation dispersion and axonal densities occurring over time using NODDI, an advanced MRI technique that reflects the microstructural complexity of dendrites and axons in vivo.

  18. MRI: Number of new or enlarging T2 lesions [ Time Frame: At Day 0 (Baseline), Week 16 and Week 20 ]
    To assess whether patients develop new lesions or pre-existing lesions enlarge over time as surrogate markers for the inflammatory process.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have a confirmed diagnosis of multiple sclerosis according to revised Mc Donald criteria and have entered the secondary progressive stage. (Polman et al., 2011, Lublin, 2014) 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 on the EDSS or clinical documentation of increasing disability.
  2. EDSS 4.0 - 6.5 (inclusive).
  3. Male and Females aged 18 to 65
  4. Females of childbearing potential and males with partners who are of childbearing age must be willing to use an effective method of contraception (Double barrier method of birth control or True abstinence) from the time consent is signed until 6 weeks after treatment discontinuation and inform the trial team if pregnancy occurs. For the purpose of clarity, True abstinence is when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence, withdrawal, spermicides only or lactational amenorrhoea method for the duration of a trial, are not acceptable methods of contraception.
  5. Females of childbearing potential have a negative pregnancy test within 7 days prior to being registered/randomised. Participants are considered not of child bearing potential if they are surgically sterile (i.e. they 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. Willing and able to provide written informed consent
  8. Willing to ingest gelatine (placebo will contain this). Participants must therefore be informed sensitive to personal beliefs e.g. faith, diet.

Exclusion criteria

  1. Unable to give informed consent.
  2. Primary progressive MS.
  3. Those that have experienced a relapse or have been treated with steroids (both i.v. and oral) for multiple sclerosis relapse within 3 months of the screening visit. These patients may undergo a further screening visit once the 3 month window has expired and may be included if no steroid treatment has been administered in the intervening period. Patients on steroids for another medical condition may enter as long as the steroid prescription is not for multiple sclerosis (relapse/ progression).
  4. Patient is already taking or is anticipated to be taking a statin or lomitapide for cholesterol control.
  5. Any medications that unfavourably interact with statins as per Spc recommendations e.g.: fibrates, nicotinic acid, cyclosporin, azole anti-fungal preparations, macrolideantibiotics, protease inhibitors, nefazodone, verapamil, amiodarone, large amounts of grapefruit juice or alcohol abuse within 6 months.
  6. The use of immunosuppressants (e.g. azathioprine, methotrexate, cyclosporin) or disease modifying treatments (avonex, rebif, betaferon, glatiramer, dimethyl fumerate, fingolimod) within the previous 6 months.
  7. The use of mitoxantrone if treated within the last 12 months.
  8. Patient has received treatment with alemtuzumab.
  9. Use of other experimental disease modifying treatment (including research in an investigational medicinal product) within 6 months of baseline visit
  10. Active Hepatic disease or known severe renal failure (creatinine clearance <30ml/min)
  11. Screening levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatine kinase (CK) are three times the upper limit of normal patients.
  12. If the patient reports any ophthalmic conditions such as glaucoma, ocular trauma or degenerative eye disease
  13. Patient unable to tolerate or unsuitable to have baseline MRI scan (e.g. metal implants, heart pacemaker) or MRI scan not of adequate quality for analysis (e.g. too much movement artefact).
  14. Females who are pregnant, planning pregnancy or breastfeeding.
  15. Allergies to IMP active substance or to any excipients of IMP and placebo or other conditions that contraindicate use of galactose (eg. Hereditary galactose intolerance, Lactase deficiency, glucose-galactose malabsorption).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03896217


Contacts
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Contact: Rosa Cortese, MD 02076792000 r.cortese@ucl.ac.uk

Locations
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United Kingdom
Department of Neuroinflammation, UCL Institute of Neurology Not yet recruiting
London, United Kingdom, WC1B 5EH
Contact: Rosa Cortese, MD         
Sponsors and Collaborators
University College, London
MS Society
Investigators
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Principal Investigator: Richard Nicholas, MD UCL

Publications:

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03896217     History of Changes
Other Study ID Numbers: 16/0730 & 2017-003008-30
First Posted: March 29, 2019    Key Record Dates
Last Update Posted: March 29, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No identifiable patient information will be supplied to other researchers external to the organisation.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University College, London:
Multiple sclerosis

Additional relevant MeSH terms:
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Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Chronic Progressive
Neoplasm Metastasis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Neoplastic Processes
Neoplasms
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors