E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing-Remitting Multiple Sclerosis |
|
E.1.1.1 | Medical condition in easily understood language |
Relapsing-Remitting Multiple Sclerosis |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of Vigantol® oil versus placebo as add-on therapy
in subjects with Relapsing-Remitting Multiple Sclerosis receiving
treatment with Rebif®. |
|
E.2.2 | Secondary objectives of the trial |
• To assess changes on clinical parameters.
• To assess changes in MRI parameters.
• To investigate the safety profile up to the end of the Treatment Period (Week48),
• To explore pharmacogenetics (PGx), gene expression and circulating biomarkers and to evaluate whether there is a possible relationship to Vigantol® oil treatment outcomes. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
•EDSS score of less than, or equal to 4.0 at Screening.
•Currently treated with interferon-beta-1a 44μg (tiw) sc
•Willingness and ability to comply with the protocol
•Written informed consent |
|
E.4 | Principal 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 experienced a relapse within 30 days before the SD1 visit
•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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• The proportion of subjects with DAF status at Week 48.
DAF status is defined as a condition described by the absence of all of the following conditions:
— Occurrence of relapse
— EDSS progression
— New MRI lesions:
• Gd-enhancing
• T2 lesions
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Proportion of Disease Activity Free subjects at week 48 |
|
E.5.2 | Secondary end point(s) |
•Proportion of relapse-free subjects at week 48
•Proportion of subjects free from any EDSS progression at week 48
•Time to confirmed EDSS progression
•Proportion of subjects free from confirmed EDSS progression at week 48
•Mean number of new T1 gadolinium-enhancing lesions per subject per scan at week 48
•Cumulative number of T1 gadolinium enhancing lesions at Week 48
•Cumulative number of new CUA lesions at week 48
•Mean number of CUA lesions per subject per scan at week 48
•Mean change from baseline in the total volume of T2 lesions at week 48 (T2 Burden of disease) [mm³]
•Proportion of subjects free from new T1-hypointense lesions (black holes) at week 48
•Change in cognitive function at weeks 24 and 48 with respect to baseline as measured by Symbol Digit Modalities Test
•Proportion of T1 gadolinium-enhancing lesions at Study Day 1 (SD1)
that transform into black holes at week 48
•Percent Brain Volume Change (PBVC) at week 48 with respect to baseline, and at week 96 with respect to week 48
•Change from baseline in MSFC composite score at Weeks 12, 24, 36, 48
•Time to first documented relapse
•Annualized relapse rate at Weeks 48
•Total number of reported relapses at all time points
•Proportion of subjects treated with glucocorticoids due to relapses (during 48 weeks)
•Proportion of subjects free from T1 gadolinium enhancing lesions at Week 48
•Percentage of new T1-hypointense lesions (black holes) at Weeks 48 within the subgroup of new or enlarging non-enhancing T2
lesions
•Mean change from baseline in total volume of T1 hypointense lesions at Week 48 (in mm³) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
As described in Section E.5.2 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Denmark |
Estonia |
Finland |
Germany |
Italy |
Latvia |
Lithuania |
Netherlands |
Norway |
Portugal |
Switzerland |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
For administrative and safety reporting purposes, the end of the trial will be defined as the date of the final clinical database lock after the last subject has completed the Week 48/96/Early Termination visit and the safety follow-up visit 12 weeks after, at Week 108. This provides for a single and conservative definition across all trial sites. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |