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

Phase 2

Completed

Conditions: Relapsing-Remitting Multiple Sclerosis

Interventions: Drug: Placebo plus interferon beta-1a (Rebif)
Biological: Interferon beta-1a (Rebif®) alone
Drug: VigantOL oil plus interferon beta-1a (Rebif)

Registration Number: NCT01285401

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 260

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo plus interferon beta-1a (Rebif)	Placebo daily plus Rebif in subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L
Rebif	Interferon beta-1a (Rebif®) alone	Rebif alone in subjects with 25-hydroxy-vitamin D plasma levels equal or higher than 150 nmol/L
VigantOL® oil	VigantOL oil plus interferon beta-1a (Rebif)	VigantOL oil plus Rebif in subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L

Primary Outcome Measures

Name	Time	Method
Percentage of Subjects With Disease Activity Free Status up to Week 48	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.

Secondary Outcome Measures

Name	Time	Method
Mean Number of Combined Unique Active (CUA) Lesions Per Subject Per Scan at Week 48	48 Weeks	CUA lesions was defined as new T1 (Gd enhancing) lesions, new Relaxation time 2 (T2) lesions, or enlarging T2 lesions.
Cumulative Number of New Combined Unique Active (CUA) Lesions at Week 48	48 Weeks	CUA lesions was defined as new T1 (Gd enhancing) lesions, new T2 lesions, or enlarging T2 lesions.
Percentage of Relapse-free Subjects at Week 48	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.
Percentage of Subjects Free From T1 Gadolinium Enhancing Lesions at Week 48	48 Weeks
Number od Subjects With Confirmed EDSS Progression	Baseline upto 48 Weeks	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.
Cumulative Number of Relaxation Time 1 (T1) Gadolinium Enhancing Lesions 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
Total Number of Reported Relapses at All Time Points up to 48 Weeks	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.
Percentage of Subjects Free From Any Expanded Disability Status Scale (EDSS) Progression at Week 48	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.
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 New T1 Hypointense Lesions (Black Holes) at Week 48	48 Weeks
Annualized Relapse Rate at Week 48	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.
Mean Change From Baseline in the Total Volume of T1 Hypo Intense Lesions at Week 48	Baseline, 48 Weeks
Number of Subjects With Relapse	Baseline upto 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.
Percentage of Subjects Treated With Glucocorticoids Due to Relapses	Baseline upto 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.