A phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial of Rebif New Formulation (44 mcg tiw and 44 mcg ow) in subjects at high risk of converting to Multiple Sclerosis

The Rebif new formulation RNF is a HSA-Free formulation and a new formulation
subcutaneous which will be test in a frequency of 3x per week and 1x per week
This formulation is well tolerated in a dosage of 44 mcg and the reported side
effects were consistent with the known to the safety profile of Rebif
Over the last years, various clinical trials have demonstrated that early
treatment of MS could be beneficial for the patient special for the time to
conversion to develop a progression.
Patients who have A clinically Isolated Syndrome (CIS) for MS e.g optic
neuritis, myelopathy or a brainstem syndrome is a isolated syndrome in the
central nervous system at a single site do not yet comply with a diagnosis of
MS.
They will undergo a period of time till the diagnosis MS as per McDonald
criteria is reached, unless there is a better parameter as a new MRI lesion or
a second attack implicating a different location
In order to invest the period to the definitive diagnosis of MS and possible
to delay this progression this trial has been prepared in which the two dosages
of RNF will be used compared to placebo
In addition to the procedures described in the main part all patients entering
the study 27025 who DO NOT suffer from conditions of the eye such as glaucoma,
hypoplasia of the optic nerve, macular hole, vitreomacular traction, diabetes,
other diseases of the optic nerve, which are not related to multiple sclerosis,
are proposed to undergo Optical Coherence Tomography (OCT), low contrast letter
acuity (Sloan chart) and Contrast Sensitivity (Pelli-Robson charts). In
addition to the aforementioned, subjects who suffer with severe myopia,
superior to 5 diopters, will be excluded from this substudy

The primary objective of the study is to evaluate the effect of Rebif New
Formulation 44 mcg (tiw and ow) versus placebo on the time to conversion to
McDonald MS in patients with a first clinical demyelinating event at high risk
of converting to MS.
The aim of these extra procedures for the OCT study is to investigate any
degeneration to the nerve fibres (axons) in the retina of the eye, following
the first attack suggestive of multiple sclerosis (MS) and at regular intervals
throughout the study, It also aims to examine the effect of Rebif® New
Formulation on nerve degeneration compared with placebo and to establish
whether there is any link between nerve degeneration and other MS related
assessments such as Magnetic Resonance Imagining (MRI) or the Neurological
assessments done by the Evaluating Physician

This study will be a randomised, double-blind, placebo-controlled, multicenter,
clinical trial comparing 2 dosage regimens of Rebif (Rebif New Formulation; 44
mcg tiw and ow) in a 1:1:1 randomisation of subjects with a single
demyelinating event at high risk of converting to a diagnosis of MS. When
subjects reach CDMS, they will be re-titrated to open-label treatment with
Rebif, 44 mcg tiw. The duration of study treatment will be a total 24 months
from randomisation except for subjects who do not convert to CDMS within the 24
months, who will be offered an additional 12-month open-label treatment period
with Rebif 44 mcg tiw.

Investigational Medicinal Product:
- Rebif New Formulation 44 mcg sc tiw.
- Rebif New Formulation 44 mcg sc ow (+ placebo twice weekly to ensure
appropriate blinding).
- Matching placebo sc tiw.
All patients will be titrated at the beginning of the study over 4 weeks. For
the first 2 weeks clip-on spacers for the syringes will be provided which will
ensure that patients receive 20% of the total dose; the following 2 weeks
clip-on spacers that will allow for 50% of the dose to be dispensed will be
provided. When subjects reached CDMS they will be re-titrated to 44 mcg tiw
For patients who have not converted to CDMS within the 24 months, an optional
12-month open-label extended treatment with RNF 44 mcg tiw will be offered.

The duration of the study is 24 months in which in total 11 visits will be
performed, in addition a option extended observation period of 12 months in
which 4 visits will be performed. When subjects during the study reach CDMS,
they will be re-titrated to open-label treatment with Rebif, 44 mcg tiw. The
first visit, screening visit will take 2-3 hours, the other visits will take 2
hours. During the study visits a MRI scan will be performed.
During the screening vsit there is an optional liquor sample (15ml) and a
Cervix MRI, during the study period an Optic Coherence Tomography (OCT) can be
requested at the sites that are selected by the sponsor. During the visit day1,
month 6, 12, 18 and 24 blood samples for the Immunological biomarkers can be
drawn. During visit day 1 and visit month 24 or early termination visit a blood
sample for pharmacogenetic analysis can be drawn, for this a separate patient
information and consent form is developed. In order to reduce the risks the
standard procedures which will be used for the used assessments, will be done
as clean and sterile as possible.it is recommended to telephone contact with
the subject within 10 days after SD1 to ensure compliance to study medication.
it is recommended to offer prophylaxis and treatment of flu like symptoms with
Iboprofen and/or paracetamol. The patients will be offered to use the Rebiject®
in order to be of help for the subcutaneous self injections. The patients will
receive the self injection instructions from the research nurse and there will
be guidance offered for the self injection procedures performed at their home .
Possible side effects of Rebif as described on page 15 of the protocol ( most
mentioned ) flu like symptoms, tiredness, skin reactions at the injection site,
( also reported) decrease of white blood cells, also decrease of red blood
cells as well as decrease of platelets.
Changes in liver enzyme Transaminase is reported (increase of value), in some
cases liver function disorders, in which jaundice and in two cases a liver
transplantation was requested. Most side effects are mild. Rebif can be of
influence on thyroid and course depression, there are also notifications for
miscarriages during the use of Rebif. Finally Rebif can course just as other
medications an allergic reaction. Possible side effect due to the misuse of the
Rebiject® can give blood extravasations. Possible side effects due to Blood
dawns are site located pain, blood extravasations and swelling, also possible
are a light feeling in the head, dizziness, and in some rare cases faint and/
or local infection.
Possible side effects of the liquor drawn are incidental headache after the
drawn, this will disappear after a few hours. Possible side effects of the MRI
assessments, during the MRI assessment Gadolinium will be added, this can give
a headache, disturbance on the injection site, disgusting, vomiting, dizziness,
irritation of the skin and e deaf feeling or itching of hands and feet*s. The
patients will be asked in advance if they are allergic to Gadolinium.
If the patient is suffering from a renal disease, the contrast dye that is
injected while the MRI scan is taken may be poorly tolerated and the following
possible signs and symptoms may occur: swelling and tightening of the skin;
difficulty extending the joints of arms, hands, legs, and feet; weakness,
reddened or darkened areas on the skin; burning or itching of the skin; and
deep bone pain in the hips and ribs. Gradual improvement of these effects may
occur over time if the renal function improves, but complete recovery has not
yet been reported. Therefore, it is important to advise the treating physician
if the patient is suffering from a renal (kidney) disease, as depending on the
severity of the illness, the patient may not be allowed to participate to this
study.
Female subjects must use a highly effective method of birth control as
explained by the Treating Doctor. A highly effective method of contraception is
defined as those which result in low failure rate (i.e. less than 1% per year
or 1 in every 100 per year) when used consistently and correctly such as
implants, injectables, combined oral contraceptive, some IUDs (Intra Uterine
Devices), sexual abstinence or vasectomised partner.
The following additional tests for the oCT substudy will be asked for 8x for
the participants,
Optical Coherence Tomography (OCT) is a relatively new, non-invasive test that
measures the thickness of the nerve fibres in the retina of the eye as they
enter the optic nerve. The test is very similar to having a photograph taken.
You will see a red background with a rotating gold circle. The test takes about
2 to 3 minutes per eye (4 to 6 minutes in total). OCT is completely painless
and non-invasive. There is no injection of any dye into the vein or into the
eye. No adverse events or side effects have been associated with OCT.
Low-contrast letter acuity (Sloan charts). You will be asked to read letters
from a chart. The letters on the chart get progressively smaller in size but
all of the letters on the chart are of the same contrast (darkness). Different
charts of varying contrast may be used. This test takes about 5 minutes per eye
(10 minutes in total).
Contrast sensitivity (Pelli-Robson charts). You will be asked to read out
letters from a chart. The letters on the chart decrease in contrast (darkness)
but not in size. The letters are arranged in groups of 3, successive groups of
3 letters decrease in contrast. This test takes about 5 minutes per eye (10
minutes in total).
Although there are no risks associated with any of the above tests, no direct
benefits can be promised from your participation in this additional testing,
other than contributing to scientific knowledge of Clinically Isolated Syndrome.
Smoking Habits. You will be asked about your previous smoking habits and your
smoking habits during the course of the study.