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

• ClinicalTrials.gov Identifier: NCT01285401
• Recruitment Status: Completed
• First Posted: January 28, 2011
• Results First Posted: July 11, 2016
• Last Update Posted: November 28, 2016
• Sponsor: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Relapsing-Remitting Multiple Sclerosis	Drug: VigantOL oil plus interferon beta-1a (Rebif); Drug: Placebo plus interferon beta-1a (Rebif); Biological: Interferon beta-1a (Rebif®) alone	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 260 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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®
• Study Start Date: February 2011
• Actual Primary Completion Date: April 2015
• Actual Study Completion Date: May 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: VigantOL® oil; 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); 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.
Placebo Comparator: Placebo; Placebo daily plus Rebif in subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L	Drug: Placebo plus interferon beta-1a (Rebif); Matching placebo daily, orally administered matched placebo for 48 weeks on top of Rebif 44 mcg tiw.
Experimental: Rebif; Rebif alone in subjects with 25-hydroxy-vitamin D plasma levels equal or higher than 150 nmol/L	Biological: Interferon beta-1a (Rebif®) alone; Rebif® 44 mcg tiw, sub-cutaneously alone.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Subjects With Disease Activity Free Status up to Week 48 [ Time Frame: 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 :

1. Percentage of Relapse-free Subjects at Week 48 [ Time Frame: 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.
2. Percentage of Subjects Free From Any Expanded Disability Status Scale (EDSS) Progression at Week 48 [ Time Frame: 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.
3. Number od Subjects With Confirmed EDSS Progression [ Time Frame: 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.
4. Cumulative Number of Relaxation Time 1 (T1) Gadolinium Enhancing Lesions at Week 48 [ Time Frame: 48 Weeks ]
5. Mean Number of Combined Unique Active (CUA) Lesions Per Subject Per Scan at Week 48 [ Time Frame: 48 Weeks ]
   CUA lesions was defined as new T1 (Gd enhancing) lesions, new Relaxation time 2 (T2) lesions, or enlarging T2 lesions.
6. Cumulative Number of New Combined Unique Active (CUA) Lesions at Week 48 [ Time Frame: 48 Weeks ]
   CUA lesions was defined as new T1 (Gd enhancing) lesions, new T2 lesions, or enlarging T2 lesions.
7. Mean Change From Baseline in the Total Volume of T2 Lesions at Week 48 (T2 Burden of Disease) [ Time Frame: Baseline, 48 Weeks ]
8. Percentage of Subjects Free From T1 Gadolinium Enhancing Lesions at Week 48 [ Time Frame: 48 Weeks ]
9. Percentage of Subjects Free From New T1 Hypointense Lesions (Black Holes) at Week 48 [ Time Frame: 48 Weeks ]
10. Percentage of New T1 Hypointense Lesions (Black Holes) at Week 48 Within the Subgroup of New or Enlarging Non-enhancing T2 Lesions [ Time Frame: 48 Weeks ]
11. Number of Subjects With Relapse [ Time Frame: 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.
12. Annualized Relapse Rate at Week 48 [ Time Frame: 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.
13. Total Number of Reported Relapses at All Time Points up to 48 Weeks [ Time Frame: 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.
14. Percentage of Subjects Treated With Glucocorticoids Due to Relapses [ Time Frame: 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.
15. Mean Change From Baseline in the Total Volume of T1 Hypo Intense Lesions at Week 48 [ Time Frame: Baseline, 48 Weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Austria

Research Site

Vienna, Austria

Denmark

Research Site

Esbjerg, Denmark

Research Site

Glostrup, Denmark

Research Site

Sønderborg, Denmark

Research Site

Vejle, Denmark

Research Site

Viborg, Denmark

Estonia

Research Site

Tallinn, Estonia

Finland

Research Site

Helsinki, Finland

Research Site

Turku, Finland

Germany

Research Site

Bad Neustadt / Saale, Germany

Research Site

Bamberg, Germany

Research Site

Berlin, Germany

Research Site

Erlangen, Germany

Research Site

Freiburg, Germany

Research Site

Hannover, Germany

Research Site

Köln, Germany

Research Site

Münster, Germany

Research Site

Regensburg, Germany

Research Site

Rostock, Germany

Italy

Research Site

Cefalu, Italy

Latvia

Research Site

Riga, Latvia

Lithuania

Research Site

Kaunas, Lithuania

Netherlands

Research Site

Amsterdam, Netherlands

Research Site

Gouda, Netherlands

Research Site

Nieuwegein, Netherlands

Research Site

Rotterdam, Netherlands

Research Site

Sittard, Netherlands

Norway

Research Site

Bergen, Norway

Research Site

Lørenskog, Norway

Research Site

Tromsø, Norway

Portugal

Research Site

Amadora, Portugal

Research Site

Lisboa, Portugal

Research Site

Porto, Portugal

Switzerland

Research Site

Bern, Switzerland

Research Site

Lausanne, Switzerland

Research Site

Lugano, Switzerland

Research Site

St. Gallen, Switzerland

Research Site

Zurich, Switzerland

Sponsors and Collaborators

Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Manolo Beelke, MD, PhD; WCT Worldwide Clinical Trials GER GmbH Germany
• Principal Investigator: Prof. Dr. Raymond Hupperts, MD; Dept of Neurology, Orbis Medical Center Sittard, Maastricht University, The Netherlands

More Information

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01285401
• Other Study ID Numbers: EMR 200136-532; 2010-020328-23 ( EudraCT Number )
• First Posted: January 28, 2011
• Results First Posted: July 11, 2016
• Last Update Posted: November 28, 2016
• Last Verified: October 2016

Keywords provided by Merck KGaA, Darmstadt, Germany:

Multiple Sclerosis; Rebif; VigantOL® oil; Vitamin D; Add-on treatment

Additional relevant MeSH terms:

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Interferons; Interferon-beta; Interferon beta-1a; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic