Simvastatin in Secondary Progressive Multiple Sclerosis

• Register: EUCTR
• Last refreshed on: 7 September 2020
• Main ID: EUCTR2017-003008-30-GB
• Date of registration: 17/05/2018
• Prospective Registration: Yes
• Primary sponsor: University College London
• Public title: Simvastatin in Secondary Progressive Multiple Sclerosis
• Scientific 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 - MS-OPT Version 1.3 dated 23/05/18
• Date of first enrolment: 01/07/2020
• Target sample size: 40
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003008-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom

Contacts

• Name: David Wilkie
• Affiliation: University College London

• Name: David Wilkie
• Affiliation: University College London

Key inclusion & exclusion criteria

Inclusion criteria:
The following inclusion criteria must be met (answer yes) when assessing patient’s eligibility onto the trial:
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.

References:
Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72 Suppl 1:1-5

Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302


Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 35
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

Exclusion criteria:
Patients presenting with any of the following exclusion criteria (i.e. answers yes) at screening will not be eligible to proceed with the trial:
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)



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Multiple Sclerosis (Secondary Progressive)
MedDRA version: 20.0 Level: HLT Classification code 10052785 Term: Multiple sclerosis acute and progressive System Organ Class: 100000004852

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Trade Name: Simvastatin 40 mg film-coated tablets
Product Name: Simvastatin 40 mg film-coated tablets
Product Code: Not applicable
Pharmaceutical Form: Tablet
INN or Proposed INN: Simvastatin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): To establish whether simvastatin has an effect on cerebral blood flow in SPMS up to 22 weeks using arterial spin labelling MRI.

Timepoint(s) of evaluation of this end point: Up to Week 17 weeks on treatment

Main Objective: Primary: Cerebral arterial hemodynamics

To establish whether simvastatin has an effect on cerebral blood flow (CBF) in SPMS measured at baseline, 16 and 20 weeks using arterial spin labelling (ASL) MRI.

We expect ASL to be able to detect subtle changes in CBF at baseline, 16 and 20 weeks comparing placebo to simvastatin treated patients.

Secondary Objective: • To establish whether ASL measurements of blood flow are useful correlates for CBF measurement on and off treatment. This will be supported by a questionnaire investigating factors that influence brain perfusion.
• To explore whether statin treatment reduces glutamate levels in the brain as measured by MRI. In MS, high glutamate levels have been shown to have a neurotoxic effect.
• To explore whether statin reduce the rate of brain atrophy on MRI (excluding the effect of pseudo-atrophy, which is a temporary response to the drug rather than an actual loss of tissue).
• To examine the effects of simvastatin treatment on clinical measures, including
Expanded disability status score (EDSS) which 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.
Multiple Sclerosis Functional Composite (MSFC) comprises quantitative

Secondary Outcome(s)

Secondary end point(s): • To establish whether ASL and AOSLO measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment. This will be supported by a questionnaire investigating factors that influence brain perfusion.
• To explore whether statin treatment reduces glutamate levels as measured by MRI
• To examine for evidence of pseudo-atrophy on MRI
• To examine the clinical effect of simvastatin treatment as reported by the clinician (EDSS, MSFC inc. 9HPT, 25FTW and PASAT) and patient reported outcome measures (MSIS-29v2, and MSWSv2).
• Frontal executive functioning will be assessed using the Frontal Assessment Battery (FAB).
• To collect health economic data (EQ5D5L) to inform future phase III trials
• Investigate the effect statins may have on retinal parameters such as blood flow, oxygen saturation, structure of vascular plexuses, neuronal structure and retinal layer thicknesses.

Timepoint(s) of evaluation of this end point: It is expected that data analyses will commence when the last participant leaves the study. Recruitment is expected to take up to 1 year from January 2018 and data analyses will continue until June 2019.

Secondary ID(s)

16/0730

Source(s) of Monetary Support

MS Society

Multiple Sclerosis Trials Collaboration

Ethics review

Status: Approved
Approval date: 01/07/2020
Contact: