Clinical Trials Register

Summary
EudraCT Number:	2017-003008-30
Sponsor's Protocol Code Number:	16/0730
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-05-17
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-003008-30

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Simvastatin in Secondary Progressive Multiple Sclerosis

A.3.2

Name or abbreviated title of the trial where available

MS-OPT Version 1.3 dated 23/05/18

A.4.1

Sponsor's protocol code number

16/0730

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University College London
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MS Society
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Multiple Sclerosis Trials Collaboration
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University College London
B.5.2	Functional name of contact point	David Wilkie
B.5.3	Address:
B.5.3.1	Street Address	Department of Neuroinflammation
B.5.3.2	Town/ city	UCL Institute of Neurology
B.5.3.3	Post code	WC1B 5EH
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02083830675
B.5.5	Fax number	02083830584
B.5.6	E-mail	davidwilkie@nhs.net

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Simvastatin 40 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Simvastatin 40 mg film-coated tablets
D.3.2	Product code	Not applicable
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Simvastatin
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Multiple Sclerosis (Secondary Progressive)

E.1.1.1

Medical condition in easily understood language

Multiple sclerosis (MS), an autoimmune condition affecting the central nervous system, is the most common cause of disability in young adults and affects over 2.3 million people worldwide.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10052785
E.1.2	Term	Multiple sclerosis acute and progressive
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

• 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

E.2.3

Trial contains a sub-study

E.3

Principal 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

E.4

Principal 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)

E.5 End points

E.5.1

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to Week 17 weeks on treatment

E.5.2

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.

E.5.2.1

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.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Effect of the drug on vascular perfusion in the CNS

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Information not present in EudraCT

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

As per section A69-2. In addition, consistent with protocol:
"The end of trial is defined as the date of the last participant finishing trial involvement. This is not defined as finishing treatment but the last day of follow-up."

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1