A 2-year Prospective Study to Assess Health-related Quality of Life in Subjects with Highly-Active Relapsing Multiple Sclerosis Treated with Mavenclad®

Protocol V1.0 3.1
Multiple sclerosis (MS) is a chronic, inflammatory, progressive, demyelinating
disease of the central nervous system and is the most common cause of serious
neurological disability in young adults (Przybek et al., 2015). The disease
course of MS is heterogeneous and unpredictable requiring chronic treatment and
regular medical monitoring by numerous methods such as for example, magnetic
resonance imaging (MRI) that was designed for the investigation, diagnosis and
management of subjects with MS (Oreja-Guevara e Paradig, 2015).
Some subjects experience a highly active disease course with rapid and early
disability often heralded by high relapse rates and early motor, cerebellar
and/or cognitive dysfunction (Hirst CL et al, 2008). Early initiation of
effective immunotherapy is considered to be important in this group of subjects
in order to prevent aggressive disease progression and severe disability
accumulation (Dubey D et al, 2016).

synopsis:

Primary:
• To assess the health related quality of life (HRQoL) through the MSQoL-54
scale in highly-active relapsing multiple sclerosis (RMS) subjects treated with
Mavenclad® for 2 years (24 months)
Secondary:
• To assess treatment satisfaction through the TSQM v1.4 questionnaire in
highly active relapsing multiple sclerosis subjects at 6 months of treatment
with Mavenclad®

Tertiary:
• To assess the safety and tolerability of Mavenclad®
• To assess the effect of Mavenclad® on the progression of disability,
cognition, relapse, and brain atrophy
• To establish correlations between clinical outcomes and health related
quality of life with treatment satisfaction

synopsis:

This will be an open label, single arm, exploratory, multicentre, 2-year Phase
IV study.

Subjects will attend visits for assessments at Baseline and at Months 6, 12,
18, and 24.

Subjects will attend visits for lymphocyte count as per mandatory monitoring at
screening, Baseline and at Months 2, 6, 12, 14, 18 and 24.

synopsis:

Mavenclad®, 3.5 mg/kg divided in 2 yearly treatment courses. Each course of
treatment consists of 2 treatment weeks, one at the beginning of the first
month and one at the beginning of the second month of the respective treatment
year. Each treatment week consists of 4 or 5 days on which a subject receives
10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body
weight.

What is expected of the patient:

• You should sign this informed consent form if you are willing to participate
in the study.
• We will collect some demographic information (age, sex and ethnicity), ask
you about your medical history, and check if you meet the entry criteria for
the study. You will also be asked how many relapses you have had in the
previous 12 months.
• You will have a physical examination and your vital signs (blood pressure,
heart rate and body temperature) will be measured.
• If you are a female of childbearing potential, you will have a urine
pregnancy test.
• You will be asked about what contraceptive methods you and your partner are
using.
• Blood samples will be collected for laboratory tests (lymphocyte (white blood
cell) count, Human Immunodeficiency Virus [HIV], hepatitis , tuberculosis [TB]
testing; and if you have no prior history of varicella (chicken pox), Varicella
Zoster Virus testing. Your doctor may recommend you are vaccinated against
varicella (less than 5% of patients will require this vaccine). You cannot take
Mavenclad® within at least 4 weeks after undergoing varicella zoster
vaccination. If you have any of these diseases, we will tell you. If you don*t
want to know, you cannot participate in this study.
• You will have a brain MRI scan. An MRI scan is an image of your body using
magnetic fields and radio waves.
• You will have the following test to assess how you are affected by your MS:
Expanded Disability Status Scale (EDSS)/Kurtzke Functional Scale (KFS). This is
a widely used method to assess disability in MS. The study doctor (or the
trained assessor) will assess you to see if your MS treatment makes you less or
more able to do certain things like moving, sensing, seeing, coordinating,
walking etc.
• All medications you are taking will be recorded.

Treatment and procedures
If you meet the requirements of this study and you wish to take part, you will
have the following tests and procedures or assessments in this study:
• Expanded Disability Status Scale (EDSS)/Kurtzke Functional Scale (KFS)
• Nine-hole peg test (9 HPT): The 9 HPT is a short test to look at the function
of your upper limbs (arms and hands).
• Timed 25-foot walk (T25-FW): The T25-FW is a test to look at your mobility /
leg function.
• Complete several questionnaires
• If you are a female of childbearing potential, you will have a urine
pregnancy test.
• Blood samples will be collected for laboratory tests (lymphocyte count).
Lymphocytes are a type of white blood cells which fight disease.
• Your weight will be measured and you will receive and take Mavenclad® at the
study center.
• You will be given a diary and asked to record any relapses of your MS
symptoms that you may experience.
• You will have a brain MRI.

Common Side Effects: (may affect more than 1 in 10 subjects)
• Lymphopenia:
The most important side effect is a reduction in the number of white blood
cells called lymphocytes (lymphopenia), which may be severe. Lymphopenia may
increase the risk of getting an infection.
• Shingles:
An infection commonly seen with Mavenclad® is shingles. Shingles can affect any
part of your body, including your face and eyes, although the chest and abdomen
(tummy) are the most common area where shingles develops. In some cases,
shingles may cause some early symptoms that develop a few days before the
painful shingles rash first appears. These early symptoms can include:
- Headache
- burning, tingling, numbness or itchiness of the skin in the affected area
- feeling of being generally unwell
- fever
Most people with shingles experience a localized "band" of severe pain and
blistered rash in the affected area. The affected area of skin will usually be
tender.
The shingles rash usually appears on one side of your body and develops on the
area of skin related to the affected nerve. Initially, the shingles rash
appears as red blotches on your skin before developing into itchy blisters. New
blisters may appear for up to a week, but a few days after appearing they
become yellowish in color, flatten and dry out.
If you notice any of the signs or symptoms described above, you should contact
your study doctor immediately. Your study doctor can prescribe medicine to
treat the infection and early treatment can lead to a less severe or shorter
course of the shingles.
• cold sore (oral herpes)
• rash
• hair loss
• reduction in the number of certain white blood cells (neutrophils)

Very rare side effects: (may affect up to 1 in 10,000 subjects)
• tuberculosis
Other potential risks
• Malignancies:
There has been no proven link between Mavenclad® treatment and cancer risk:
however, because of the way Mavenclad® works, a potential risk of cancer cannot
be excluded. Single events of cancer have been observed in patients who had
received Mavenclad® in clinical studies. You should undergo cancer screening as
per standard of care after taking Mavenclad®.
Side effects relating to procedures:
• Magnetic Resonance Imaging:
You will not be able to take part in this study if you have any of the
following: an artificial heart valve, pacemaker, metal plate, pin or other
metallic objects in your body (including gun shot or shrapnel).
You may become anxious from lying in a tight space without moving. The MRI scan
does not cause any pain and does not expose you to X-ray radiation.
During the MRI procedure, a contrast dye (gadolinium) may be administered
through a needle or intravenous catheter. Generally, the contrast dye is safe
to use, and will pass through and exit the body naturally with time. There may
be side effects which could be severe and life threatening (including symptoms
similar to allergic reactions and formation of excessive connective tissue in
the kidney). The more severe side effects may be more common if your kidney
function is not normal. You should tell the study doctor if you have a history
of abnormal kidney function. The contrast dye may also cause an allergic
reaction in some people. You should also tell the doctor if you know you are
allergic to contrast dye.
• Varicella vaccine:
Your doctor will discuss the potential effects with you if needed (vaccination
will be required for <5% of subjects).
• Blood samples:
You will need to have samples of blood taken during the study for laboratory
testing. Blood samples will be taken from a vein in your arm during the study.
You may experience temporary discomfort from this. The needle sticks may cause
local pain, bruising, swelling, lightheadedness, dizziness and rarely, fainting
and/or a possible infection from the needle stick. In very rare cases nerve
damage might occur.
The maximum amount of blood that will be taken on any day of the study is about
7.5ml.