The primary objective of this study is to assess whether the efficacy of ocrelizumab given as two dose regimens of 600 mg (given as 300 mg infusions on days 1 and 15 and 600 mg infusion in the following cycles) or 400 mg (given as 200 mg infusions…
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Brief title
Condition
- Central nervous system infections and inflammations
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is annualized protocol-defined relapse rate at
two years (96 weeks). Protocol-defined relapse, is defined as the occurrence of
new or worsening neurological symptoms attributable to MS.
Secondary outcome
The key secondary objectives of this study are to evaluate whether the efficacy
of ocrelizumab is superior to Rebif®, as reflected by the
following measures:
* The time to onset of confirmed disability progression for at least 12 weeks
with the initial event of neurological worsening occurring
during the 96-week, double-blind, double-dummy, treatment period.
* The total number of new T1 Gd-enhancing lesions as detected by brain MRI at
Weeks 24, 48, and 96.
* The total number of new, and/or enlarging T2 hyperintense lesions as detected
by brain MRI at Weeks 24, 48, and 96.
* The proportion of patients who have confirmed disability improvement for at
least 12 weeks with the initial event of neurological improvement occurring
during the 96-week doubleblind, double-dummy treatment period.
* The time to onset of confirmed disability progression for at least 24 weeks,
with the initial event of neurological worsening occurring
during the 96-week, double-blind, double-dummy, treatment period.
* The total number of T1-hypo-intense lesions (Chronic Black Holes) at Weeks
24, 48, and 96.
* The change in Multiple Sclerosis Functional Composite Scale (MSFCS) score
from baseline to Week 96.
* The percentage change in brain volume as detected by brain MRI from Week 24
to Week 96.
* The change in SF-36 Physical Component Summary (PCS) Score from baseline to
Week 96.
* The proportion of patients who have no evidence of disease activity (NEDA) by
Week 96.
Exploratory Objectives:
* To evaluate the long-term safety, tolerability, and efficacy of ocrelizumab
in patients with the relapsing form of MS who are enrolled in the OLE Phase.
See further protocol section 2.3.
Background summary
Multiple sclerosis (MS) is an inflammatory and degenerative demyelinating
disease of the human central nervous system (CNS). Multiple sclerosis affects
around 2.5 million people worldwide: it is one of the most common neurological
disorders and cause of disability of young adults. The condition manifests as
neurological deficits referable to damage to the spinal cord, brainstem, optic
nerves, cerebellum, and cerebrum. Resulting symptoms may include weakness,
pain, visual loss, bowel/bladder dysfunction, and cognitive dysfunction.
Diagnosis of MS typically occurs through the application of highly structured
diagnostic criteria that rely on clinical observation, neurological
examination, brain and spinal cord Magnetic Resonance Imaging (MRI) scans,
evoked potentials, and examination of cerebrospinal fluid (CSF). The term
relapsing MS (RMS) applies to those patients either with a relapsing remitting
MS (RRMS) form or a secondary progressive MS (SPMS) form that are suffering
relapses. Patients with RMS, in spite of suffering from different MS forms,
constitute a common target for current treatments. Currently available
first-line therapies for the treatment of either relapsing MS or
relapsing-remitting MS include interferon (IFN)- *-1a (Rebif® and Avonex®),
IFN-*-1b (Betaferon® / Extavia®) and glatiramer acetate (Copaxone®).
Natalizumab (Tysabri®) use due to a risk of Progressive Multifocal
Leukoencephalopathy (PML) is limited to RRMS nonresponsive to immunomodulatory
treatment or to highly active RRMS. Mitoxantrone (Novantrone®) is also approved
for treatment of relapsing MS, but is generally reserved for secondary
progressive and severe relapsing*remitting forms of disease. Other drugs have
been used with varying degrees of success, including corticosteroids,
methotrexate, cyclophosphamide, azathioprine, and intravenous immunoglobulin.
The currently approved first-line treatments are modestly effective in reducing
the frequency of relapses and in prevention of disability in patients with RMS.
The magnitude of these disease modifying effects are an approximately 30%
relative improvement versus placebo. Licensed disease modifying agents reduce
the frequency of new episodes but do not reverse fixed deficits and have
questionable effects on the long-term accumulation of disability and disease
progression. Despite significant advances in MS therapy many patients continue
to experience disease activity; therefore there remains a need to develop more
effective and better tolerated therapies for the treatment of RMS.
This study serves as a pivotal Phase III clinical trial, and is composed of the
following periods: a double-blind, double-dummy treatment period, a Safety
Follow-Up Period, and an Open-Label Extension Phase. The double-blind,
double-dummy treatment period is designed to demonstrate the efficacy and
safety of ocrelizumab in relapsing MS in comparison to high-dose,
high-frequency (HDHF) IFN (Rebif®). The Open-Label Extension Phase serves to
evaluate long-term safety, tolerability, and efficacy of ocrelizumab treatment
in patients with relapsing forms of MS.
Rationale open label:
Results of long-term, follow-up exploratory studies suggest that exposure to
DMT for more than 2 years improves outcomes by delaying the time to disability
progression. Furthermore, there is accumulating evidence that, in MS,
inflammatory damage is a continuous process leading to demyelination and axonal
transection, and is the substrate of permanent disability in MS. Based on the
long-term efficacy and safety data of the Phase II study WA21493/ACT4422G, it
is justified to offer ocrelizumab to patients who would otherwise receive
treatment that, in the majority of cases, is modestly effective in reducing the
frequency of relapses and in preventing sustained disability.
Thus, patients who complete the 96-week, double-blind, double-dummy treatment
period will be offered participation in an OLE Phase of the study. Providing
patients with the opportunity to prolong treatment with ocrelizumab beyond 2
years will provide more information on the long-term safety of ocrelizumab in
RMS, (e.g., the risk of infections/serious infections/opportunistic infections
or potential loss of previously acquired immunity [e.g., hypogammaglobulinemia,
specific serological titers]), as well as further collection of tolerability
and efficacy information from patients with long-term exposure. Furthermore,
the OLE Phase will increase the overall number of patients exposed and
patient-year exposure, thus increasing the likelihood of detecting rare events
prior to launch, and understanding the safety/efficacy profile. Analyzing the
long-term safety, tolerability, and efficacy of ocrelizumab is of critical
importance to eventually help clinicians make informed decisions on therapy for
patients.
Study objective
The primary objective of this study is to assess whether the efficacy of
ocrelizumab given as two dose regimens of 600 mg (given as 300 mg infusions on
days 1 and 15 and 600 mg infusion in the following cycles) or 400 mg (given as
200 mg infusions on days 1 and 15 and 400 mg infusion in the following cycles)
intravenously every 24 weeks is superior to Rebif® as measured by the
annualized protocol-defined relapse rate at two years (96 weeks) in patients
with relapsing MS.
Study design
Multicentre, randomized, double-blind, double-dummy, parallel-group study and
Open-label extension.
Intervention
Patients will be randomized 1:1 to receive the following treatments: Group A: a
dual i.v. infusion of 300 mg ocrelizumab (on days 1 and 15) in the first 24week
cycle followed by a single infusions of 600 mg every 24 weeks (in subsequent
cycles). Group B: Initiating treatment: * during weeks one and two, Rebif® 8.8
µg (one pre-filled syringe (0.2 ml ) containing 8.8 µg (2.4 MIU) of interferon
beta-1a) will be injected subcutaneously three times per week * during weeks
three and four, Rebif® 22 µg (one pre-filled syringe (0.5 ml ) containing 22 µg
(6 MIU) of interferon beta-1a)syringe will be injected three times per week.
Treatment continuation: * From the fifth week onwards, Rebif® 44 µg (one
pre-filled syringe (0.5 ml ) containing 44 µg (12 MIU) of interferon beta-1a)
will be given three times per week by subcutaneous injection * A lower dose of
22 µg, also given three times per week by subcutaneous injection, is
recommended for patients who cannot tolerate the higher dose of Rebif®.
Patients randomized to active ocrelizumab group will also receive dummy placebo
of Rebif® (administered via subcutaneous injection three times per week).
Patients randomized to active Rebif® group will also receive dummy placebo of
ocrelizumab (administered as intravenous infusions at similar time points to
those of the ocrelizumab group)
Study burden and risks
Patients should be informed of the risks associated with taking ocrelizumab and
Rebif®. Below are listed specific major risks of Ocrelizumab of which the
patients should be made aware. Further information on ocrelizumab is given in
the current version of IB. Infusion-Related Reactions - All CD20 depleting
agents including ocrelizumab have been associated with acute infusion-related
reactions Infection Risks - Prolonged peripheral B-cell depletion is the
expected outcome of ocrelizumab treatment. Infection is a potentially serious
complication of B-cell depleting therapy and thus requires vigilant attention
and prompt investigation and treatment in patients that exhibit signs of
infection at any time following anti-CD20 antibody therapy. Prolonged B-cell
Depletion - In patients with Reumatoid Arthritis (RA) that were treated with
rituximab, prolonged peripheral B-cell depletion has been reported up to 4
years following a single course of therapy. Cardiovascular Disorders - Rarely,
cardiac arrhythmias, cardiac ischemia and death due to myocardial dysfunction
have been associated with rituximab administration in patients with oncologic
disorders. Immunogenicity - Positive HAHA responses were observed and were most
frequent in the lower dose groups in both RA studies; no HAHA responses were
observed in the NHL study. Immunization - The effect of ocrelizumab on the
response to immunization is not known The investigator must refer to the local
Rebif label for details on major risks of Rebif®.
Beneluxbaan 2a
Woerden 3446 GR
NL
Beneluxbaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
- adult patients, 18 - 55 years of age inclusive
- multiple sclerosis confirmed according to revised McDonald criteria (2010)
- relapsed-remitting or secondary progressive disease
- At least 2 documented clinical attacks within the last 2 years prior to screening or one clinical attack in the year prior to screening (but not within 30 days prior to screening).
- Neurological stability for * 30 days prior to both screening and baseline
- EDSS, at screening, from 0 to 5.5 inclusive
Patients who meet the following entry criteria may participate in the OLE Phase:
-Complete the 96-week, double-blind, double-dummy treatment period, and who, in the opinion of the Investigator, may benefit from treatment with ocrelizumab;
-Are able and willing to provide written informed consent for the OLE Phase (e.g., before the first infusion at Cycle 5) and to comply with the study protocol;
-Are willing to continue to use at least two contraceptive methods;
-Meet re-treatment criteria with ocrelizumab (see Section 6.1.4).
Exclusion criteria
1. Diagnosis of primary progressive MS.
2. Disease duration of more than 10 years in patients with an EDSS * 2.0 at screening.
3. Inability to complete an MRI
4. Known presence of other neurological disorders which may mimic MS.
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 | EUCTR2010-020337-99-NL |
| ClinicalTrials.gov | NCT10063399 |
| CCMO | NL37276.100.11 |