A Randomized, Double-Blind, Double-Dummy, Parallel-Group Study To Evaluate The Efficacy And Safety Of Ocrelizumab In Comparison To Interferon Beta-1a (Rebif(RegisteredTM)) In Patients With Relapsing Multiple Sclerosis
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 multiple sclerosis in comparison to high dose high frequency IFN (Rebif(RegisteredTM)). The Open-Label Extension Phase serves to evaluate long-term safety, tolerability, and efficacy of ocrelizumab treatment in patients with relapsing forms of MS. This study is part of a broader, confirmatory clinical development program investigating the safety and efficacy of ocrelizumab in patients with both primary progressive and relapsing multiple sclerosis. An Open-Label Extension Phase of the Phase II study WA21493/ACT4422G is ongoing for eligible RRMS patients and three ongoing Phase III pivotal trials are planned, (including the one presented in this protocol), two in RMS and one in PPMS.
The primary objective of this study is to assess whether the efficacy of ocrelizumab 600 mg (given as dual infusions of 300 mg on Days 1 and 15 of the first 24-week treatment cycle and as a single infusion of 600 mg on Day 1 of each 24-week treatment cycle thereafter) intravenously every 24 weeks is superior to Rebif(RegisteredTM) as measured by the
annualized protocol-defined* relapse rate by two years (96 weeks) in patients with relapsing multiple sclerosis.
The secondary objectives of this study are to evaluate whether the efficacy of ocrelizumab is superior to Rebif(RegisteredTM), as reflected by the following measures:
* The time to onset of sustained disability progression for at least 12 weeks. The initial
event of neurological worsening must occur during the 96-week, double-blind,
double-dummy, treatment period. for at least 12 weeks during the 96-week
comparative treatment period. (See Section 18.104.22.168 for the definition of sustained
* The time to onset of sustained disability progression for at least 24 weeks for at least
24 weeks during the 96-week comparative treatment period. The initial event of
neurological worsening must occur during the 96-week, double-blind, double-dummy,
To evaluate the safety and tolerability of ocrelizumab 600 mg (given as dual infusions of 300 mg on Days 1 and 15 of the first 24-week treatment cycle and as a single infusion of 600 mg on Day 1 of each 24-week treatment cycle thereafter) intravenously every 24 weeks in patients with relapsing MS (including exploratory, long-term safety
and tolerability in those patients entering the OLE Phase).
* Proportion of disease activity free patients, defined as absence of both relapses and sustained accumulation of disability, and absence of MRI activity by Week 96.
* 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.
To explore the pharmacokinetics, immunogenicity and pharmacodynamics of ocrelizumab in patients with relapsing MS.
1. Ability to provide written, informed consent and to be compliant with the schedule of protocol assessments.
2. Ages 18-55 years at screening, inclusive.
3. Diagnosis of MS, in accordance with the revised McDonald criteria (2010).
4. 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).
5. Neurological stability for >= 30 days prior to both screening and baseline.
6. EDSS, at screening, from 0 to 5.5 inclusive.
7. Documented MRI of brain with abnormalities consistent with MS prior to screening.
8. Patients of reproductive potential must use reliable means of contraception as described below as a minimum (adherence to local requirements, if more stringent, is required*):
* 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. Acceptable methods of contraception include one primary (e.g. systemic hormonal contraception or tubal ligation of the female partner, vasectomy of the male partner) AND one secondary barrier method (e.g. latex condoms, spermicide) OR a double barrier method (e.g. latex condom, intrauterine device, vaginal ring or pessary plus spermicide [e.g. foam, vaginal suppository, gel, cream]).
9. For patients of non reproductive potential (adherence to local requirements, if more stringent, is required*):
* Women may be enrolled if postmenopausal (i.e. spontaneous amenorrhea for the past year confirmed by an FSH level greater than 40 mIU/mL) unless the patient is receiving a hormonal therapy for their
menopause or surgically sterile (i.e. hysterectomy, complete bilateral oophorectomy);
* Men may be enrolled if they are surgically sterile (castration).
* Based on local Ethics Committees or National Competent Authority feedback additional requirements to assure contraception or to confirm menopause may be required (e.g. serum estradiol compatible with post-menopause status, longer duration of amenorrhea, higher level of FSH).
10. Allow patients who are unable to receive gadolinium contrast for magnetic resonance imagining (MRI) (e.g., due to known hypersensitivity or renal dysfunction) to participate in the study, but not receive gadolinium during an MRI scan
11. Allow patients who are unable to complete exploratory assessmentsthemselves (e.g., the electronic patient reported outcome measures) due to physical/disease limitations to still be able to be enrolled in the study
12. Allow patients to continue with their therapies with [BETA]-interferons, glatirameracetate, or other permitted immunomodulatory therapies for MS until the study entry (randomization)
13.Allow patients previously treated with BG12 to enter the study following an adequate period of washout of 24 weeks
14. Patients with contraindication to methylprednisolone will be able to enter the study and will receive an equivalent dose of an alternative corticosteroid as premedication prior to ocrelizumab infusion.
15. Patients who complete the 96-week treatment period may become eligible for the
OLE Phase of the study. 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
* Prior to re-treatment with ocrelizumab, patients will be evaluated for the following
conditions and laboratory abnormalities. If any of these are present prior to
re-dosing, further administration of ocrelizumab should be suspended until resolved or
* * Life threatening (CTCAE Grade 4) infusion-related event that occurred
during a previous ocrelizumab infusion
* * Any significant or uncontrolled medical condition or treatment-emergent,
clinically significant laboratory abnormality
* * Active infection
* * Absolute neutrophil count < 1.5 x 103/[MICRO-SYMBOL]L
* * CD4 cell count < 250/[MICRO-SYMBOL]L
* * Hypogammaglobulinemia IgG < 3.3 g/L
* * Ongoing pregnancy (for female patients)
* * Please note: any critical blinded laboratory values for IgG, absolute neutrophil count and CD4 will be provided to the Treating Investigator and the Medical Monitor. Investigators
notified of their patient[Single Quote]s critical laboratory test result will be instructed to suspend
further treatment with study drug until the patient can be further evaluated. A repeat
laboratory test may be necessary to confirm the results. Patients with values below these
critical values should not be retreated until the re-treatment criteria are met and these
laboratory values have normalized.