This study will evaluate the efficacy and safety of ocrelizumab in patients with early stage relapsing remitting multiple sclerosis (RRMS).The objective of the Immune Substudy is to explore immunological changes associated with ocrelizumab treatment…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary goal of this study is to determine the efficacy of ocrelizumab by
evaluating clinical measures related to disease progression over 4 years in
patients in the early stage of their RRMS disease.
Secondary outcome
1. Time to onset of confirmed disability progression (CDP) sustained for at
least 24 weeks and 48 weeks
2. Proportion of patients who have confirmed disability improvement (CDI), CDP
for at least 24 weeks and 48 weeks at Years 1, 2 and 4
3. Proportion of patients who have improved, stable or worsened disability
compared with baseline measured by EDSS annually
4. Mean change from baseline in EDSS score over the course of the study
5. Time to first protocol-defined event of disease activity
6. Time to first relapse
7. Annualized relapse rate
8. Proportion of patient relapse free by Weeks 48, 96, 144 and 192
9. Proportion of patients with no evidence of protocol-defined disease activity
(NEDA) over Week 96, Week 144 and Week 192
10. Proportion of patients with no evidence of progression sustained for at
least 24 weeks on all the following three components (CDP; 20%
increase in timed 25 Foot Walk Test [T25FWT]; 20% increase in timed 9 hole peg
test [9HPT]) between baseline and Week 96/192
11. Proportion of patients with no active disease between Baseline and Week
96/192
12. Change from baseline of multiple sclerosis functional composite (MSFC) and
its composites (T25FW, 9HP, and Paced Auditory Serial
Addition Test [PASAT]) over time
13. Change from baseline in cognitive performance as measured by Brief
International Cognitive Assessment for Multiple Sclerosis (BICAMS)
performed annually
14. Total number of T1 Gd-enhancing lesions; and new and/or enlarging T2 lesion
as detected by brain MRI over time
15. Change in total T1 hypointense lesion volume over time
16. Total number of fluid-attenuated inversion-recovery (FLAIR) late enhancing
lesions as detected by brain MRI over time
17. Change in brain volume (including white and grey matter fractions) as
detected by brain MRI over time
18. Time to treatment discontinuation/switch
19. Employment status score (Work Productivity and Activity Impairment
Questionnaire [WPAI])
20. SymptoMScreen score
21. Quality of life score (Multiple Sclerosis Impact Scale [MSIS]-29)
22. Rate and nature of adverse events
23. Changes in vital signs, physical and neurological examinations, clinical
laboratory results, locally reviewed MRI for safety (non-MS CNS pathology) and
concomitant medications (including pre-medications and medications used during
and following ocrelizumab administration)
Background summary
This study was designed to evaluate the efficacy and safety of ocrelizumab in
patients with early stage relapsing remitting multiple sclerosis (RRMS). We say
"relapsing remitting" because this type of MS involves attacks (relapses) of
symptoms and then again a recovery phase (remitting). Suppression of disease
activity and disability progression as early as possible seems to be an
important goal of therapy in MS. Ocrelizumab is a recombinant humanized
antibody which binds to B-cells, which are believed to play a role in MS.
One optional substudy will be offered to patients at site Zuyderland Medisch
Centrum: the Immune Substudy.
The inclusion period will be reopened to include 400 patients worldwide in the
Shorter Infusion Substudy, which will evaluate the safety of a shorter infusion
of ocrelizumab in patients with early stage relapsing remitting multiple
sclerosis (RRMS).
Study objective
This study will evaluate the efficacy and safety of ocrelizumab in patients
with early stage relapsing remitting multiple sclerosis (RRMS).
The objective of the Immune Substudy is to explore immunological changes
associated with ocrelizumab treatment in a treatment naïve, early stage RRMS
population.
The objective of the Shorter Infusion Substudy is to evaluate the safety of a
shorter infusion of ocrelizumab in patients with early stage relapsing
remitting multiple sclerosis (RRMS).
Study design
This study is a prospective, multicenter, open-label, single-arm efficacy and
safety study in patients with early stage RRMS. The first dose of ocrelizumab
will be administered as an initial dose of two 300-mg infusions (600 mg total)
separated by 14 days (i.e., Days 1 and 15) followed by one 600-mg infusion
every 24 weeks for the study duration. Patients will be assessed for efficacy
and safety every 24 weeks. The study will consist of the following periods: *
- Screening period: Up to 4 weeks *
- Treatment period: Open-label treatment period of 192 weeks
- A follow-up period of at least 48 weeks
Follow-up Period: Patients who discontinue treatment early will be followed up
for at least 48 weeks after the last infusion of study drug. Patients whose
B-cells have not been repleted after 48 weeks of Follow-up Period will continue
with visits every 24 weeks, and telephone contacts every 8 weeks, until B-cell
repletion (Prolonged B-cell monitoring). If the patients are receiving other
B-cell targeted therapies, then the Follow-up Period will be stopped at 48
weeks regardless of their B-cell count. A structured telephone interview will
be conducted by site personnel every 8 weeks between the study visits during
the treatment period and follow-up to identify and collect information on any
changes in the patient*s health status that warrant an unscheduled visit.
The optional substudy will run in parallel to the main study in some selected
sites (in The Netherlands, only the Immune substudy at the Zuyderland Medisch
Centrum). The patients who participate in the substudies will have to perform
some additional tests during the standard visits of the main study. The
optional substudy described in appendix 10 of the previous protocol version has
been removed. No sites participated in this substudy in The Netherlands.
The Shorter Infusion substudy is a prospective, multicentre, randomized,
double-blind, controlled, parallel arm substudy evaluating the safety of a
shorter duration infusion of ocrelizumab in a subgroup of patients with early
stage RMS enrolled in the main MA30143 study. We expect approximately 700
patients to be enrolled in this substudy: approximately 300 patients currently
participating in the main study, and at least 400 newly enrolled patients.
Intervention
Patients that will be eligible for participation in this study will be treated
with with ocrelizumab, according to the study specific form set out in
Appendices 1 (schedule of assessments: screening through the end of treatment
period) and 2 (follow-up schedule of assessments) of the study protocol. After
the first dose, which is divided into two gifts with an interval of 14 days,
study medication will be administered 8 times within 192 weeks.
Study burden and risks
HYPERSENSITIVITY REACTIONS
No hypersensitivity reactions to ocrelizumab were reported in the controlled
clinical trials. Hypersensitivity may be difficult to distinguish from IRRs in
terms of symptoms. A hypersensitivity reaction may present during any infusion,
although typically would not present during the first infusion. For subsequent
infusions, more severe symptoms than previously experienced, or new severe
symptoms, should prompt consideration of a potential hypersensitivity reaction.
If a hypersensitivity reaction is suspected during infusion, the infusion must
be stopped immediately and permanently. Patients with known IgE-mediated
hypersensitivity to ocrelizumab must not be treated.
Progressive Multifocal Leukoencephalopathy
A very rare and severe viral infection called 'progressive multifocal
leukoencephalopathy (PML), which causes brain damage and can be fatal or cause
severe disability, has been reported in patients treated with other MS
medicines, medicines similar to ocrelizumab, and with ocrelizumab outside of
clinical trials, only where the risk for PML was pre-existing, because of prior
treatment with natalizumab or fingolimod. Most cases of PML, outside MS,
occurred in people with severe immune deficiency, such as transplant patients
on immunosuppressive medications or patients receiving certain kinds of
chemotherapy (drugs to treat cancer). At each clinic visit, the study doctor
will complete a thorough neurological examination to check for symptoms related
to PML. If the study doctor thinks that there may be a case of PML during the
study, additional tests may be carried out, including an extra brain MRI, blood
and urine samples taken and possibly a lumbar puncture to check for the
presence of John Cunningham virus (JCV). Samples for JCV antibody will only be
tested for patients who are thought to have developed PML. These samples will
be stored for up to 1 year after the last patient has made his / her last visit.
MALIGNANCIES INCLUDING BREAST CANCER
Malignancies are considered a potential risk with ocrelizumab due to the
potentially decreased immune surveillance associated with B-cell depletion in
the context of treatments which are used long-term to treat chronic diseases.
During the controlled treatment period, the incidence rate of malignancies in
the ocrelizumab treatment groups across the MS program was higher than IFN or
placebo groups with overlapping CIs. The incidence rates were within the
expected ranges for the MS population from epidemiology sources. The only
cluster identified was for breast cancer. No firm conclusion can be made to
date concerning the risk due to the low number and the limited follow-up; hence
the risk remains potential to date.
NEUTROPENIA
In the controlled treatment period, decreased neutrophils were observed in 12
and 15% of MS patients treated with ocrelizumab, in PPMS and RMS respectively.
Most were mild to moderate in severity, approximately 1% of the patients had
Grade 3 or 4 neutropenia; and no temporal association with infections was
identified.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
- Able to comply with the study protocol, in the investigator's judgment
- Age 18 * 55 years, inclusive
- Have a definite diagnosis of RRMS, as per the revised McDonald 2010 criteria
(Polman et al. 2011)
- Have a length of disease duration, from first documented clinical attack
consistent with multiple sclerosis (MS) disease of <= 3 years
- Within the last 12 months: one or more clinically reported relapse(s) or one
or more signs of MRI activity
- Expanded Disability Status Scale (EDSS) of 0.0 to 3.5 inclusive, at screening
- For women of childbearing potential: agreement to use an acceptable birth
control method during the treatment period and for at least 6 months or longer
after the last dose of ocrelizimab, as applicable in the ocrelizumab package
leaflet
Exclusion criteria
- Secondary progressive multiple sclerosis or history of primary progressive or
progressive relapsing MS
- Inability to complete a Magnetic resonance imaging (MRI)
- Known presence of other neurological disorders, including but not limited to,
the following:
• History of ischemic cerebrovascular disorders or ischemia of the spinal cord
• History or known presence of central nervous system (CNS) or spinal cord tumor
• History or known presence of potential metabolic causes of myelopathy
• History or known presence of infectious causes of myelopathy
• History of genetically inherited progressive CNS degenerative disorder
• Neuromyelitis optica
• History or known presence of systemic autoimmune disorders potentially
causing progressive neurologic disease
• History of severe, clinically significant brain or spinal cord trauma
Exclusions Related to General Health:
- Pregnancy or lactation
- Patients intending to become pregnant during the study or within 6 months
after the last dose of the study drug
- Any concomitant disease that may require chronic treatment with systemic
corticosteroids or immunosuppressants during the course of the study
- History or currently active primary or secondary immunodeficiency
- Lack of peripheral venous access
- History of severe allergic or anaphylactic reactions to humanized or murine
monoclonal antibodies
- Significant or uncontrolled somatic disease or any other significant disease
that may preclude patient from participating in the study
- Congestive heart failure (NYHA III or IV functional severity)
- Known active bacterial, viral, fungal, mycobacterial infection or other
infection, or any major episode of infection requiring hospitalization or
treatment with intravenous antibiotics within 4 weeks prior to screening or
oral antibiotics 2 weeks prior to screening
- History of major opportunistic infections
- History or known presence of recurrent or chronic infection
- History of malignancy, including solid tumors and hematological malignancies
- History of alcohol or drug abuse within 24 weeks prior to baseline
- History or laboratory evidence of coagulation disorders
Exclusions Related to Medications:
- Received any prior approved Disease modifying treatment (DMT) with a label
for MS, for example, interferons, glatiramer acetate, natalizumab, alemtuzumab,
daclizumab, fingolimod, teiflunomide and dimethylfumarate
- Received a live vaccine or attanuated live vaccine within 6 weeks prior to
the baseline visit
- Treatment with any investigational agent within 24 weeks of screening or five
half-lives of the investigational drug or treatment with any experimental
procedures for MS
- Contraindications to or intolerance of oral or intravenous (IV)
corticosteroids, including methylprednisolone administered IV, according to the
country label
- Previous treatment with B-cell targeted therapies
- Systemic corticosteroid therapy within 4 weeks prior to screening.
- Any previous treatment with
immunosuppressants/immunomodulators/antineoplastic therapies
- Treatment with IV Immunoglobulin within 12 weeks prior to baseline
- Treatment with investigational DMT
- History of recurrent aspiration pneumonia requiring antibiotic therapy
- Treatment with fampridine/dalfamipridine unless on stable dose for >= 30 days
prior to screening. Wherever possible, patients should remain on stable doses
throughout the 96-week treatment period
Exclusions Related to Laboratory Findings:
- Positive serum β human chorionic gonadotropin (hCG) measured at screening
- Positive screening tests for hepatitis B
- Lymphocyte count below lower limit of normal
- CD4 count<250/µL
- Aspartate aminotransferase/ serum glutamic oxaloacetic transaminase or
alanine aminotransferase/serum glutamic pyruvic transaminase >= 3.0 × Upper
limit of normal
- Serum creatinine >1.4 mg/dL for women or > 1.6 mg/dL for men
- Hemoglobin < 8.5 g/dL, Platelet count <100,000/µL, Absolute neutrophil count
<1.0 × 10 3/µL
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 | EUCTR2016-002937-31-NL |
| ClinicalTrials.gov | NCT03085810 |
| CCMO | NL59829.056.17 |