Primary objective: To assess the efficacy of Vigantol oil versus placebo as add-on therapy in subjects with relapsing-RemittingMultiple sclerosis receiving treatment with Rebif.Secondary objective:To assess changes on clinical parametersto assess…
ID
Source
Brief title
Condition
- Central nervous system infections and inflammations
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is a composite endpoint of MRI and clinical variables:
the primary MRI endpoint is the mean change from baseline in the total volume
of T2 lesions at week 48
the primary clinical endpoint is the proportion or relapse free subject at week
96
(at randomization, subjects may be stratified according to (1=most important)
1. BMI
2. Gender
3. number of relapses in the past two years
Secondary outcome
Relapses:
-proportion of relapse-free subjects at week 48
-time to first documented relapse
-annualized relapse rate at week 48 and 96
-total of number of reported relapses at all time points
-requirement for treatment with glucocorticoids due to relapses (during 96
weeks)
EDSS:
-proportions of subject with stable EDSS at week 48 and 96
-time to 24 week sustained disability progression on EDSS
-proportions of subjects with 24 weeks sustained disability progression on EDSS
at week 48 an d96
MRI:
-Mean number of new T1 gadolinium enhancing lesions per subject per scan at
Week 48 and week 96
-Cumulative number of T1 gadolinium enhancing lesions at Week 48 and week 96
-Mean number of new CU lesions per subject per scan at Week 48 and week 96
-Cumulative number of new combined unique CU lesions at Week 48 and week 96
-Mean number of new T2 lesions per subject per scan at Week 48 and week 96
-Cumulative number of new T2 lesions at Week 48 and week 96
-Mean change from baseline in the total volume of T2 lesions at Week 48 and
Week 96 (T2 Burden of disease) [mm3].
-Proportion of subjects free from T1 gadolinium enhancing lesions at week 48
and week 96
-Proportion of subjects free from T1 lesions at week 48 and week 96
-Percentage of new T1 lesions at week 48 and 96 within the subgroup of new
non-enhancing T2 lesions
Other Efficacy endpoints:
-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 and 96
-Change in cognitive function at week 48 and 96 with respect to baseline as
measured by Symbol Digit Test.
-Proportion of T1 gadolinium-enhancing lesions at SD1 that transform into black
holes at Weeks 48 and 96.
-Percent Brain Volume Change (PBVC) at Weeks 48 and 96 with respect to baseline
and at Week 96 with respect to week 48
Background summary
Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the
central nervous system (CNS) and is one of the most common causes of
neurological disability in young adults. It characterized by multi focal
recurrent events of neurological symptoms and signs, with variable recovery.
The exact cause of multiple sclerosis is unknown, although an autoimmune
process has been implicated.
There are four clinical forms of MS, primary progressive,
progressive-relapsing, secondary progressive and relapsing-remitting.
Pathalogy change occurs in MS and include blood-brain barriere breakdown with
edema, leukocyte infiltration with cytokine release, demyelination, and axonal
transection.
It affects up to 2.5 million people worldwide.
Study objective
Primary objective:
To assess the efficacy of Vigantol oil versus placebo as add-on therapy in
subjects with relapsing-RemittingMultiple sclerosis receiving treatment with
Rebif.
Secondary objective:
To assess changes on clinical parameters
to assess changes in MRI parameters
To investigate the safety profile upp to the end of the treatment Period (week
96)
To explore pharmacogenetics/pharmacogenomics (PGx) biomarkers and to evalute
whether ther is a possible relationship to Vigantol oil traetment outcomes
Study design
The study consists of a screening visit, a baseline visit (SD1), a treatment
period with 9 subsequent visits and a follow-up visit.
The treatment period has a duration of 96 weeks and will consist of three arms:
Treatment Group 1: Vigantol ® oil 7.000 IU/d (175 *g/d) for 4 weeks followed by
14.000 IU/d (350 *g/d) for 92 weeks on top of Rebif® 44 *g tiw in subjects with
25-hydroxy-vitamin D plasma levels below 150 nmol/L (174 subjects)
Treatment Group 2: Matching placebo daily on top of Rebif® 44 *g tiw in
subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L (174 subjects)
Treatment Group 3: Subjects with 25-hydroxy-vitamin D plasma levels equal or
higher than 150 nmol/L will continue administration of Rebif® 44 *g tiw without
add-on therapy
Two parallel populations will be recruited, one with 25-hydroxy-vitamin D
plasma levels equal or higher than 150 nmol/L, and one with 25-hydroxy-vitamin
D plasma levels lower than 150 nmol/L.
Randomization will be done only for subjects with 25-hydroxy-vitamin D plasma
levels lower than 150 nmol/L by means of IVRS. These subjects will randomly be
assigned to Vigantol® oil (Treatment Group 1) and placebo treatment (Treatment
Group 2) in a 1:1 ratio on top of the preexisting treatment with Rebif®.
Subjects with 25-hydroxy-vitamin D plasma levels equal or higher than 150
nmol/L will be assigned automatically by means of IVRS to Treatment Group 3.
Recruitment will be concluded once the requested number of subjects for the
Treatment Groups 1 and 2 are included in the study.
The analyses planned for Treatment Group 3 will be limited to the number of
subjects assigned to this group during the recruitment period needed for
Treatment Groups 1 and 2.
During the whole treatment period efficacy and safety will be evaluated by
means of anti-inflammatory and neurodegenerative effects assessed by MRI
parameters and clinical outcomes, safety, and tolerability of Vigantol® oil at
the dose of 7.000 IU/d (175 *g/d) for 4 weeks followed by 14.000 IU/d (350 *g/
d) for 92 weeks in combination with Rebif® compared to placebo in combination
with Rebif® in subjects with RRMS according to the revised McDonald criteria
for the diagnosis of Multiple Sclerosis from 2005.
Intervention
Additional treatment with Vitamin D (Vigantol-oil)
Study burden and risks
(From the Patient information form:)
As with any drug, Vigantol® oil can also have side effects. Generally speaking,
Vigantol® oil is well tolerated Studies have been conducted to see to what
extent vitamin D supplementation, such as Vigantol®, affects blood pressure or
cholesterol, but to date no effects have been reported. Long-term treatment
with high doses of vitamin D has proven to cause high calcium concentrations in
the blood. Very high calcium concentrations may be connected with reduced
appetite, nausea, vomiting, fatigue, increased urine production, joint pain,
bone decalcification (with an increased risk of bone fractures), general loss
of strength and disorientation. At the vitamin D dose you receive in this
trial, it is very unlikely that you will receive calcium concentrations leading
to any of the symptoms listed.
The vitamin D dose you receive in connection with participation in this trial
may be up to 14 times higher than the dose you would take for a vitamin D
deficiency. Earlier studies suggest that the dose may have favourable effects
in the treatment of multiple sclerosis. In another, recent trial, a dose was
tested that was even higher than the dose you receive in this trial; namely 20
times higher than the dose you would take for a vitamin D deficiency. Data from
this trial do not indicate patient risks associated with such a high dose. In
total, about 320 ml blood will be taken throughout the clinical trial. The
pricking of a vein does not generally entail any risks. In rare cases, bleeding
in the surrounding tissue, a very rare inflammation of the vein or thrombosis
(formation of blood clots) may occur, or in rare cases a nerve may be affected.
MRI scan:
MRI is generally regarded as very safe imaging. In an MRI, no ionising
radiation is released and to date no notable side effects have been recorded
for the magnetic fields and radio waves used on the human body. The contrast
fluid gadolinium most used has proven to be safe, but may have the following,
short-term side effects: headache, irritation at the insertion site, nausea,
vomiting, dizziness, rash and a numb or tingling sensation in hands and feet.
MRI must, however, not be used for people with metal objects in their bodies,
such as:
* Patients with a pacemaker, hearing implants (inner ear or cochlea) or
implanted spinal cord stimulator
* Patients with a metal object (metal splinter) in the eye, inner ear implants
or an aneurysm clip in the brain (because the magnetic field may displace the
metal).
* Patients with metal objects in their back (such as screws and plates) may
undergo an MRI scan, but the resolution of the scan is often seriously
disturbed by the metal object and the backbone is not reproduced properly.
There are other conditions that may prevent the making of an MRI scan, such as
pregnancy and/or the presence of other kinds of metal in your body. Patients
with claustrophobia (i.e. people who are afraid in small spaces) may possibly
be unable to cope with an MRI scan, although more open scanners are now
available. A sedative may also simplify undergoing the test.
If you are allergic to gadolinium or do not want to undergo an MRI for other
reasons, you should notify your study doctor.
The further investigations do not entail any health risks for you.
9, Chemin des Mines
1202 Geneva
CH
9, Chemin des Mines
1202 Geneva
CH
Listed location countries
Age
Inclusion criteria
1. Males and females between 18 and 50 years of age
2. Diagnosis of a relapsing- remitting form of MS, according to teh revised Mc Donald criteria.
3. Brain and / or spinal MRI with findings typical of MS
4. A first clinical occuring within 5 years prior to screening
5. Disease activity by;
At least one MS lesion within the 12 months prior to Screening
One or more Gd-enhancing MRI lesions within the 12 months prior to Screening
EDSS score <<= 4.0 at Screening.
7. Currently and for the first time treated with interferon-beta-la (tiw) s.c., and having received this treatment for a minimum of 90 days and for not longer than 12 months before baseline visit ( including titration period).
8. Willingness and ability to comply with the protocol for the duration of the trial.
9. Written informed consent given prior to any trial-related procedures not part of the normal medical practice.
Exclusion criteria
10. Pregnancy and lactation period
11. Any disease other than MS that could better explain signs and symptoms.
12. Complete transvere meylitis or bilateral optic neuritis.
13. Currently receiving or use at any time of monoclonal antibodies, mitoxantrone, cytotoxic or immunosupressive therapy (excluding systemic steroids and adrenocortocotrophic hormone [ ACTH], B cell modulating therapies (e.g. RituxiMab or BelimuMab), total lymphoid irradiation or bone marrow transplantation.
14. Use of any cytokine or anti-cytokine therapy, intravenous immunoglobulin, plasmapheresis, or any investigational drug or experimental procedure within 12 months prior to Screening.
15. use of oral or systemic corticosteroids or ACTH
16. Have experienced a relapse within 30 days before the SDI visit
17. Have abnormalities of Vitamin D related hormonal system other than low dietary intake or decreased sun exposure, e.e. primary hyperparathyroidism or granulomatous disorder.
18. Have an urine calcium/ creatinine (mmol.mmol) ratio grater than 1.0 or hypercalcaemia (11 mg/100cc (5.5 mEq./l.)
19. Are taking medication that influence Vitamin D metabolism other than corticosteroids, e.g., phenytoin, barbiturates, thiszide diuretcs and cardiac glycosides
20. Have a conditions with increase susceptibilty to to hypercalcaemia, e.g., known arrhythmia or heart disease , treatment with Digilis, or Hydrochlorothiazide and those who suffer from nephroliathiasis.
21. Have inadequate liver function, defined by alanine aminotransferase (ALT) 3 times upper limit of normal (ULN), aspartate sminotransferase (AST) 3 times upper limit of normal (ULN) or alkanine phosphatase > 2.5 times ULN, or total bilirubin > 1.5 times ULN, if assiciated with any elevation of ALT or alkanine phosphatase
22. Moderate to servere renal impairment (estimate of glomurlar filtration rate [GFR] <50 mL/min/1.73 m2 [ based on creatinine clearance according to Cockcroft-Gault aquation])
23. Inadequate bone marrow reserve, defined by a WBC count <0,50 times the lower limit of normal.
24. History or presence of serious or acute heart disease such as controlled cardiac dysrhythmia or arrthythmia, uncontrolled cardiac dysrhythmia or arrthythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure ( NYHA class 3 or 4).
25. History or presence of severe depression, history of suicide attempt, or current suicidal ideation.
26. Epilepsy or seizures not adequately controlled by treatment.
27. Current or past (within the last 2 years) alcohol or drug abuse.
28. Any major medical or psychiatric illness (such as psychosis, bipolar disorder)
that in the opinionof the investigator could create undue risk to the subject or could affect adherence with the trial protocol.
29. known contra-indication to treatment with vitam D (according to SPC)
30. Known hypersentivity to IFN or its excipient(s) (according to SPC).
31. Known hypersentivity to gadolinium.
32. any other condition that would prevent the subject from undergoing an MRI scan
33. Signs and sympoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such.
34. Positive HIV, hepatitis C, or hepatitis B (HBsAg and HBc antibody) serology (test perfomed at screening).
35. Legal incapacity or limited legal capacity.
36. Another current autoimmune disease, except diabetes.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-020328-23-NL |
| CCMO | NL33417.096.10 |