Supplementation of VigantOL® Oil Versus Placebo as Add-on in Patients With Relapsing Remitting Multiple Sclerosis Receiving Rebif® Treatment

Study Overview
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Brief Summary
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The drug being tested is called VigantOL® oil - a very effective form of Vitamin D hormone supplement (cholecalciferol). Low levels of Vitamin D have been described to be associated with a higher risk of developing Multiple Sclerosis (MS), and it is known that up to 90% of patients with Multiple Sclerosis have Vitamin D deficiency. Rebif® is known to be an effective treatment for slowing down the progression of MS. The purpose of this research trial is to evaluate if VigantOL® oil on top of Rebif® has any benefit on the progression of MS compared to Rebif® and placebo. Disease activity will be assessed by clinical examination and Magnetic Resonance Imaging (MRI). The planned study treatment duration for each study participant is 48 weeks, and the study consists of a total of 8 visits. Study participants who are already passed Week 48 at the time of approval of Protocol Amendment 5 will have a study duration of 96 weeks and a total of 12 visits. During the study, the participant will undergo physical examination, neurological assessments, safety assessments, blood tests and urinalysis (including pregnancy tests).

Official Title
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A Three Arm, Randomized, Double Blind, Placebo Controlled, Multicenter, Phase II Study to Evaluate the Efficacy of Vigantol® Oil as Add on Therapy in Subjects With Relapsing Remitting Multiple Sclerosis Receiving Treatment With 44mg Tiw of Rebif®

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: VigantOL oil plus interferon beta-1a (Rebif)
* Drug: Placebo plus interferon beta-1a (Rebif)
* Biological: Interferon beta-1a (Rebif®) alone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of a relapsing-remitting form of MS Brain and/or spinal MRI with findings typical of MS A first clinical event prior to Screening. Disease activity Expanded Disability Status Scale (EDSS) score of less than, or equal to 4.0 at Screening. Currently treated with interferon-beta-1a 44mg (tiw) sc Willingness and ability to comply with the protocol Written informed consent Exclusion Criteria: Pregnancy and lactation period Any disease other than MS that could better explain signs and symptoms. Complete transverse myelitis or bilateral optic neuritis. Currently receiving or use at any time of monoclonal antibodies, mitoxantrone, cytotoxic or immunosuppressive therapy (excluding systemic steroids and adrenocorticotrophic hormone [ACTH]), B cell modulating therapies (e.g. RituxiMab or BelimuMab), total lymphoid irradiation or bone marrow transplantation. Use of any cytokine other than interferon or anti-cytokine therapy, intravenous immunoglobulin, plasmapheresis, or any investigational drug or experimental procedure Use of oral or systemic corticosteroids or ACTH Have abnormalities of Vitamin D related hormonal system other than low dietary intake or decreased sun exposure, i.e. primary hyperparathyroidism or granulomatous disorders. Have an urine calcium/creatinine (mmol/mmol) ratio greater than 1.0 or hypercalcaemia Are taking medications that influence Vitamin D metabolism other than corticosteroids, e.g., phenytoin, barbiturates, thiazide diuretics and cardiac glycosides. Are taking more than 1000 IU (25 µg) of Vitamin D supplement daily. Have conditions with increased susceptibility to hypercalcaemia, e.g., known arrhythmia or heart disease, treatment with Digitalis, or Hydrochlorothiazide and those who suffer from nephrolithiasis. Have inadequate liver function Moderate to severe renal impairment Inadequate bone marrow reserve History or presence of serious or acute heart disease such as uncontrolled cardiac dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure (NYHA class 3 or 4). History or presence of severe depression, history of suicide attempt, or current suicidal ideation. Epilepsy or seizures not adequately controlled by treatment. Current or past alcohol or drug abuse. Any major medical or psychiatric illness (such as psychosis, bipolar disorder) that in the opinion of the Investigator could create undue risk to the subject or could affect adherence with the trial protocol. Known contra-indication to treatment with vitamin D Known hypersensitivity to interferon or its excipient(s) Known hypersensitivity to gadolinium. Any other condition that would prevent the subject from undergoing an MRI scan. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such. Positive HIV, hepatitis C, or hepatitis B (HBsAg and HBc antibody) serology (test performed at screening). Legal incapacity or limited legal capacity. Another current autoimmune disease, except diabetes. Have experienced a relapse within 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VigantOL® oil<br>VigantOL oil plus Rebif in subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L | Drug: VigantOL oil plus interferon beta-1a (Rebif)<br>* VigantOL oil 6,670 International Units per day (IU/d) (167 microgram per day [mcg/day]), was administered orally for 4 weeks followed by 14,007 IU/d (350 mcg/d) administered orally for 44 weeks on top of Rebif 44mcg three times per week (tiw) administered subcutaneously.<br>|
| Placebo Comparator: Placebo<br>Placebo daily plus Rebif in subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L | Drug: Placebo plus interferon beta-1a (Rebif)<br>* Matching placebo daily, orally administered matched placebo for 48 weeks on top of Rebif 44 mcg tiw.<br>|
| Experimental: Rebif<br>Rebif alone in subjects with 25-hydroxy-vitamin D plasma levels equal or higher than 150 nmol/L | Biological: Interferon beta-1a (Rebif®) alone<br>* Rebif® 44 mcg tiw, sub-cutaneously alone.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Disease Activity Free Status up to Week 48 | Disease activity free status was defined as absence of any of the clinical and imaging parameters related to the assessment of disease activity; no relapses, no expanded disability status scale (EDSS) progression and no new gadolinium (Gd)-enhancing or relaxation time 2 (T2) magnetic resonance imaging (MRI) lesions. | Up to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Relapse-free Subjects at Week 48 | A relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition. | Week 48 | 
| Percentage of Subjects Free From Any Expanded Disability Status Scale (EDSS) Progression at Week 48 | EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A confirmed EDSS progression was defined EDSS greater than or equal to 1.0 point confirmed during a visit performed 6 months later. An EDSS progression was defined as an increase of the EDSS score of at least 1.0 point compared to baseline (SD1) for subjects with a baseline EDSS ≤ 4.0. For subjects with an EDSS score of 0 at baseline (SD1), EDSS progression was defined as an increase of at least 1.5 points. A confirmed EDSS progression was defined as an EDSS progression confirmed after 24 weeks. | Week 48 | 
| Number od Subjects With Confirmed EDSS Progression | EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A confirmed EDSS progression was defined EDSS greater than or equal to 1.0 point confirmed during a visit performed 6 months later. An EDSS progression was defined as an increase of the EDSS score of at least 1.0 point compared to baseline (SD1) for subjects with a baseline EDSS ≤ 4.0. For subjects with an EDSS score of 0 at baseline (SD1), EDSS progression was defined as an increase of at least 1.5 points. A confirmed EDSS progression was defined as an EDSS progression confirmed after 24 weeks. | Baseline upto 48 Weeks | 
| Cumulative Number of Relaxation Time 1 (T1) Gadolinium Enhancing Lesions at Week 48 |  | 48 Weeks | 
| Mean Number of Combined Unique Active (CUA) Lesions Per Subject Per Scan at Week 48 | CUA lesions was defined as new T1 (Gd enhancing) lesions, new Relaxation time 2 (T2) lesions, or enlarging T2 lesions. | 48 Weeks | 
| Cumulative Number of New Combined Unique Active (CUA) Lesions at Week 48 | CUA lesions was defined as new T1 (Gd enhancing) lesions, new T2 lesions, or enlarging T2 lesions. | 48 Weeks | 
| Mean Change From Baseline in the Total Volume of T2 Lesions at Week 48 (T2 Burden of Disease) |  | Baseline, 48 Weeks | 
| Percentage of Subjects Free From T1 Gadolinium Enhancing Lesions at Week 48 |  | 48 Weeks | 
| Percentage of Subjects Free From New T1 Hypointense Lesions (Black Holes) at Week 48 |  | 48 Weeks | 
| Percentage of New T1 Hypointense Lesions (Black Holes) at Week 48 Within the Subgroup of New or Enlarging Non-enhancing T2 Lesions |  | 48 Weeks | 
| Number of Subjects With Relapse | Relapse was defined as neurological abnormality, either newly appearing or re-appearing, with abnormality specified by both as neurological abnormality separated by at least 30 days from onset of a preceding MS attack and Neurological abnormality lasting for at least 24 hours, absence of fever or known infection greater than 37.5 degree centigrade /99.5 degree fahrenheit , objective neurological impairment, correlating with the subject's reported symptoms, defined as either increase in at least one of the functional systems of the EDSS or increase of the total EDSS score and occurrence of paraesthesia, fatigue, mental symptoms, and/or vegetative symptoms without any additional symptom will not be classified as an MS attack. | Baseline upto 48 weeks | 
| Annualized Relapse Rate at Week 48 | Relapse was defined as neurological abnormality, either newly appearing or re-appearing, with abnormality specified by both as neurological abnormality separated by at least 30 days from onset of a preceding MS attack and Neurological abnormality lasting for at least 24 hours, absence of fever or known infection greater than 37.5 degree centigrade /99.5 degree fahrenheit , objective neurological impairment, correlating with the subject's reported symptoms, defined as either increase in at least one of the functional systems of the EDSS or increase of the total EDSS score and occurrence of paraesthesia, fatigue, mental symptoms, and/or vegetative symptoms without any additional symptom will not be classified as an MS attack. | 48 weeks | 
| Total Number of Reported Relapses at All Time Points up to 48 Weeks | Relapse was defined as neurological abnormality, either newly appearing or re-appearing, with abnormality specified by both as neurological abnormality separated by at least 30 days from onset of a preceding MS attack and Neurological abnormality lasting for at least 24 hours, absence of fever or known infection greater than 37.5 degree centigrade /99.5 degree fahrenheit , objective neurological impairment, correlating with the subject's reported symptoms, defined as either increase in at least one of the functional systems of the EDSS or increase of the total EDSS score and occurrence of paraesthesia, fatigue, mental symptoms, and/or vegetative symptoms without any additional symptom will not be classified as an MS attack. | 48 weeks | 
| Percentage of Subjects Treated With Glucocorticoids Due to Relapses | Relapse was defined as neurological abnormality, either newly appearing or re-appearing, with abnormality specified by both as neurological abnormality separated by at least 30 days from onset of a preceding MS attack and Neurological abnormality lasting for at least 24 hours, absence of fever or known infection greater than 37.5 degree centigrade /99.5 degree fahrenheit , objective neurological impairment, correlating with the subject's reported symptoms, defined as either increase in at least one of the functional systems of the EDSS or increase of the total EDSS score and occurrence of paraesthesia, fatigue, mental symptoms, and/or vegetative symptoms without any additional symptom will not be classified as an MS attack. | Baseline upto 48 weeks | 
| Mean Change From Baseline in the Total Volume of T1 Hypo Intense Lesions at Week 48 |  | Baseline, 48 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Rebif, VigantOL® oil, Vitamin D, Add-on treatment