Primary:To investigate the efficacy of ocrelizumab compared with placebo in patients with primary progressive multiple sclerosis, as measured by thetime to onset of confirmed disability progression over the treatment period, defined as an increase…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy: Time to onset of of confirmed disability progression, defined as an
increase in Expanded Disability Status Scale (EDSS) score that is
sustained for at least 12 weeks
Secondary outcome
1. Time to confirmed disability progression, defined as an increase in EDSS
score that is sustained for at least 24 weeks
2. Change in timed 25-foot walk
3. Change in total volume of T2 lesions on magnetic resonance imaging (MRI)
scans of the brain
4. Safety and tolerability: Incidence of adverse events
Background summary
Primary Progressive Multiple Sclerosis (PPMS) is a rare form of Multiple
Sclerosis (MS), accounting for 10-15% of all cases of MS. It's a neurologically
disabling condition without a cure. To date, no therapies have shown
effectiveness in PPMS and none are registered for its treatment in global
region.
B cells are believed to contribute to the development of all subtypes of MS,
including PPMS. Removing select B-cells from circulation may beneficially
disrupt inflammatory processes that potentially involve processes promoting
chronic autoimmunity.
Ocrelizumab specifically depletes CD20+ B cells, making it an attractive agent
to test therapeutic potential in patients with PPMS within clinical studies.
Study objective
Primary:
To investigate the efficacy of ocrelizumab compared with placebo in patients
with primary progressive multiple sclerosis, as measured by the
time to onset of confirmed disability progression over the treatment period,
defined as an increase in EDSS that is sustained for at least 12
weeks, based on regularly scheduled visits.
Secondary:
To evaluate the efficacy of ocrelizumab compared with placebo, as reflected by
the following:
• The time to confirmed disability progression over the treatment period,
defined as an increase in EDSS that is sustained for at least 24 weeks
• The change in 25-foot timed walk from baseline to Week 120
• The change in total volume of T2 lesions on MRI scans of the brain from
baseline to week 120
• The percentage change in total brain volume as detected by brain MRI from
Week 24 to Week 120
• The change in SF 36 Health Survey version 2 (SF 36v2) Physical Component
Summary (PCS) score from baseline to Week 120
• To evaluate the safety and tolerability of ocrelizumab300 mg × 2 (over 24
week treatment cycles) in patients with primary progressive multiple sclerosis
as compared with placebo
Exploratory (clinical):
• The proportion of patients with confirmed 12-week disability progression at
Week 120
• The change in EDSS score (mean change and area under the curve [AUC]) from
baseline to Weeks 48, 96, and 120
• The change in Multiple Sclerosis Functional Composite Scale (MSFCS) score
from baseline to Weeks 48, 96, and 120
• The time to confirmed disability progression over the treatment period,
defined as an increase in EDSS that is sustained for at least 12 weeks (0.5 or
1, same criteria as for the primary endpoint time to 12-week CDP) or a 20%
increase in 25-foot timed walk that is sustained for at least
12 weeks, or a 20% increase in the 9-hole peg test that is sustained for at
least 12 weeks
• The time to sustained 20 percent increase in 25 foot timed walk and 9-hole
peg test
• The proportion of patients with a 20 percent increase in 25 foot timed walk
time
• The proportion of patients with a 20 percent increase in 9-hole peg test time
• The change in Paced Auditory Serial Addition
Open Label Extension Phase
• To evaluate the long-term safety of ocrelizumab treatment during the Open
Label Extension (OLE) phase of the study.
• To evaluate the long-term effects of ocrelizumab on clinical and MRI
parameters of disease activity and progression during the OLE phase of the
study.
For Imaging, Patient-Reported Outcomes and Biomarkers Exploratory Objectives,
please refer to the study protocol
Study design
Multicentre, randomized, parallel group, double-blind, placebo controlled
study.
Intervention
A total of 630 primary progressive MS patients will be enrolled and assigned
(2:1 randomization) to either an ocrelizumab arm or a placebo arm, stratified
by age and region.
Ocrelizumab will be administered as a dual i.v. infusions of 300 mg x2 (on Days
1 and 15) for the first treatment cycle followed by single i.v. infusions of
600 mg every 24 weeks. Patients randomized to the placebo group will receive
placebo of ocrelizumab.
Study burden and risks
- Infusion Reaction Risk with Ocrelizumab:fever, chills/rigors, muscle pain,
headache, skin rash, fatigue, nausea, vomiting, abnormally low blood pressure,
flu-like symptoms, difficulty breathing or shortness of breath.
- Infection Risk with Ocrelizumab: Symptoms that could be due to an infection
are e.g. fever, chills, sore throat, coughing up phlegm, loin/kidney pain, pain
upon urination, feeling weak, giddy or generally very unwell.
- Other Risks with Ocrelizumab: When you receive ocrelizumab, there is a small
chance that your immune system might develop antibodies against the drug. If
you develop these special antibodies, they may cause side effects such as
rashes, they may affect your body*s ability to respond to ocrelizumab and may
stop ocrelizumab from working and increase the chances of infusion reactions.
It may also affect your body*s ability to respond to other drugs of similar
type.
- Worsening MS: Since this study will have a long duration for the treatment
period, some individuals with PPMS treated with placebo as well as ocrelizumab
can be expected to experience a worsening of their symptoms that can lead to
disability.
- Magnetic Resonance Imaging: The contrast agent may cause temporary nausea (a
feeling of being sick to your stomach) or headache. Itching, a rash, or a drop
in blood pressure are also possible.
- Blood Draws: The risks of drawing blood from a vein include discomfort at the
site of the needle stick, possible bruising and swelling around the site of the
needle stick, rarely an infection, and uncommonly feeling faint from the
procedure.
- Lumbar Puncture: This procedure could cause discomfort and may result in
bruising, stiffness, and, rarely, infection. You may experience a headache, and
there is a small chance of bleeding, infection, or injury to a nerve.
Grenzacherstrasse 12
Basel 4070
CH
Grenzacherstrasse 12
Basel 4070
CH
Listed location countries
Age
Inclusion criteria
- Adult patients, Ages 18-55 years inclusive
- Primary Progressive Multiple Sclerosis (according to revised McDonald
criteria)
- Expanded Disability Status Scale (EDSS) 3.0 to 6.5 points
- Disease duration from the onset of MS symptoms:
a. less than 15 years in patients with an EDSS at screening > 5.0
b. less than 10 years in patients with an EDSS at screening <= 5.0
- Sexually active female and male patients of reproductive potential must use:
Female: two methods of contraception throughout the trial, including the
active treatment phase AND for 48 weeks after the last dose of ocrelizumab, or
until their B-cells have repleted, whichever is longer.
Male: two methods of contraception throughout trial, including the active
treatment phase AND for 24 weeks after the last dose of ocrelizumab.
Exclusion criteria
- History of relapsing remitting multiple sclerosis, secondary progressive, or
progressive relapsing multiple sclerosis at screening
- Contraindications for Magnetic Resonance Imaging (MRI)
- Known presence of other neurologic disorders
- Known active infection or history of or presence of recurrent or chronic
infection
- History of cancer, including solid tumors and hematological malignancies
(except for basal cell, in situ squamous cell carcinomas of the skin and in
situ carcinoma of the cervix that have been excised and resolved)
- Previous treatment with B-cell targeted therapies (e.g. rituximab,
ocrelizumab, atacicept, belimumab, or ofatumumab)
- Any previous treatment with lymphocyte trafficking blockers, with
alemtuzumab, anti-CD4, cladribine, cyclophosphamide, mitoxantrone,
azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body
irradiation, or bone marrow transplantation
- Any concomitant disease that may require chronic treatment with systemic
corticosteroids or immunosuppressants during the course of the study;
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 | EUCTR2010-020338-25-NL |
| ClinicalTrials.gov | NCT01194570 |
| CCMO | NL33418.078.10 |