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

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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:
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Tracking Information
First Submitted Date  ICMJE January 26, 2011
First Posted Date  ICMJE January 28, 2011
Results First Submitted Date  ICMJE May 31, 2016
Results First Posted Date  ICMJE July 11, 2016
Last Update Posted Date November 28, 2016
Study Start Date  ICMJE February 2011
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2016)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 26, 2011)
  • Mean change from baseline in the total volume of T2 lesions at week 48 [ Time Frame: 48 weeks ]
    The primary MRI endpoint is the mean change from baseline in the total volume of T2 lesions at Week 48.
  • Proportion of relapse-free subjects at week 96 [ Time Frame: 96 Weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2016)
  • 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.
  • 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.
  • 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.
  • Cumulative Number of Relaxation Time 1 (T1) Gadolinium Enhancing Lesions at Week 48 [ Time Frame: 48 Weeks ]
  • 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.
  • 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.
  • Mean Change From Baseline in the Total Volume of T2 Lesions at Week 48 (T2 Burden of Disease) [ Time Frame: Baseline, 48 Weeks ]
  • Percentage of Subjects Free From T1 Gadolinium Enhancing Lesions at Week 48 [ Time Frame: 48 Weeks ]
  • Percentage of Subjects Free From New T1 Hypointense Lesions (Black Holes) at Week 48 [ Time Frame: 48 Weeks ]
  • 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 ]
  • 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.
  • 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.
  • 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.
  • 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.
  • Mean Change From Baseline in the Total Volume of T1 Hypo Intense Lesions at Week 48 [ Time Frame: Baseline, 48 Weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2011)
  • Proportion of relapse-free subjects at week 48 [ Time Frame: 48 Weeks ]
  • Proportion of subjects with stable Expanded Disability Status Scale (EDSS) at week 48 [ Time Frame: 48 Weeks ]
  • Time to 24 weeks sustained disability progression on EDSS [ Time Frame: 48 Weeks ]
  • Proportion of subjects with 24 weeks sustained disability progression on EDSS at week 48 [ Time Frame: 48 Weeks ]
  • Mean number of new T1 gadolinium enhancing lesions per subject per scan at week 48 [ Time Frame: 48 Weeks ]
  • Cumulative number of T1 gadolinium enhancing lesions at Week 48 [ Time Frame: 48 Weeks ]
  • Mean number of new Combined Unique (CU) lesions per subject per scan at week 48 [ Time Frame: 48 Weeks ]
  • Cumulative number of new combined unique CU lesions at week 48 [ Time Frame: 48 Weeks ]
  • Mean number of new T2 lesions per subject per scan at week 48 [ Time Frame: 48 Weeks ]
  • Cumulative number of new T2 lesions at week 48 [ Time Frame: 48 Weeks ]
  • Mean change from baseline in the total volume of T2 lesions at week 48 (T2 Burden of disease) [mm3] [ Time Frame: 48 Weeks ]
    Total volume of T2 lesions will be assessed in mm³.
  • Proportion of subjects free from T1 gadolinium enhancing lesions at week 48 [ Time Frame: 48 Weeks ]
  • Proportion of subjects free from T1 lesions at week 48 [ Time Frame: 48 Weeks ]
  • Percentage of new T1 lesions at week 48 within the subgroup of new non-enhancing T2 lesions [ Time Frame: 48 Weeks ]
  • Proportion of subjects free from disease activity at 48 weeks [ Time Frame: 48 Weeks ]
    Proportion of subjects free from disease activity: relapse-free, free of sustained disability progression, no new Gd+ lesions and no active T2 lesions at week 48
  • Change in cognitive function at week 48 with respect to baseline as measured by Symbol Digit Test [ Time Frame: 48 Weeks ]
  • Proportion of T1 gadolinium-enhancing lesions at Study Day 1 (SD1) that transform into black holes at week 48 [ Time Frame: 48 Weeks ]
  • Percent Brain Volume Change (PBVC) at week 48 with respect to baseline [ Time Frame: 48 Weeks ]
  • Proportion of subjects with stable Expanded Disability Status Scale (EDSS) at week 96 [ Time Frame: 96 Weeks ]
  • Time to 24 weeks sustained disability progression on EDSS [ Time Frame: 96 Weeks ]
  • Proportion of subjects with 24 weeks sustained disability progression on EDSS at week 96 [ Time Frame: 96 Weeks ]
  • Mean number of new T1 gadolinium enhancing lesions per subject per scan at week 96 [ Time Frame: 96 Weeks ]
  • Cumulative number of T1 gadolinium enhancing lesions at week 96 [ Time Frame: 96 Weeks ]
  • Mean number of new Combined Unique (CU) lesions per subject per scan at week 96 [ Time Frame: 96 Weeks ]
  • Mean number of new T2 lesions per subject per scan at week 96 [ Time Frame: 96 Weeks ]
  • Cumulative number of new T2 lesions at week 96 [ Time Frame: 96 weeks ]
  • Mean change from baseline in the total volume of T2 lesions at week 96 (T2 Burden of disease) [mm3] [ Time Frame: 96 Weeks ]
    Total volume of T2 lesions will be assessed in mm³.
  • Proportion of subjects free from T1 gadolinium enhancing lesions at week 96 [ Time Frame: 96 Weeks ]
  • Proportion of subjects free from T1 lesions at week 96 [ Time Frame: 96 Weeks ]
  • Percentage of new T1 lesions at week 96 within the subgroup of new non-enhancing T2 lesions [ Time Frame: 96 Weeks ]
  • Proportion of subjects free from disease activity at 96 weeks [ Time Frame: 96 Weeks ]
    Proportion of subjects free from disease activity: relapse-free, free of sustained disability progression, no new Gd+ lesions and no active T2 lesions at week 96
  • Change in cognitive function at week 96 with respect to baseline as measured by Symbol Digit Test [ Time Frame: 96 Weeks ]
  • Proportion of T1 gadolinium-enhancing lesions at Study Day 1 (SD1) that transform into black holes at week 96 [ Time Frame: 96 Weeks ]
  • Percent Brain Volume Change (PBVC) at week 96 with respect to baseline [ Time Frame: 96 Weeks ]
  • Percent Brain Volume Change (PBVC) at week 96 with respect to week 48 [ Time Frame: 48 Weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Supplementation of VigantOL® Oil Versus Placebo as Add-on in Patients With Relapsing Remitting Multiple Sclerosis Receiving Rebif® Treatment
Official Title  ICMJE 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®
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Relapsing-Remitting Multiple Sclerosis
Intervention  ICMJE
  • 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.
  • Drug: Placebo plus interferon beta-1a (Rebif)
    Matching placebo daily, orally administered matched placebo for 48 weeks on top of Rebif 44 mcg tiw.
  • Biological: Interferon beta-1a (Rebif®) alone
    Rebif® 44 mcg tiw, sub-cutaneously alone.
Study Arms  ICMJE
  • Experimental: VigantOL® oil
    VigantOL oil plus Rebif in subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L
    Intervention: Drug: VigantOL oil plus interferon beta-1a (Rebif)
  • Placebo Comparator: Placebo
    Placebo daily plus Rebif in subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L
    Intervention: Drug: Placebo plus interferon beta-1a (Rebif)
  • Experimental: Rebif
    Rebif alone in subjects with 25-hydroxy-vitamin D plasma levels equal or higher than 150 nmol/L
    Intervention: Biological: Interferon beta-1a (Rebif®) alone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 31, 2016)
260
Original Estimated Enrollment  ICMJE
 (submitted: January 26, 2011)
348
Actual Study Completion Date  ICMJE May 2015
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Denmark,   Estonia,   Finland,   Germany,   Italy,   Latvia,   Lithuania,   Netherlands,   Norway,   Portugal,   Switzerland
Removed Location Countries Belgium,   Hungary
 
Administrative Information
NCT Number  ICMJE NCT01285401
Other Study ID Numbers  ICMJE EMR 200136-532
2010-020328-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Merck KGaA, Darmstadt, Germany
Study Sponsor  ICMJE Merck KGaA, Darmstadt, Germany
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Merck KGaA, Darmstadt, Germany
Verification Date October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP