Efficacy and Safety of Xacrel® (Ocrelizumab) in Participants With Relapsing Remitting Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of Ocrelizumab produced by CinnaGen compared with Ocrevus® (Roche, Switzerland) in subjects with relapsing remitting multiple sclerosis (RRMS). All the participants will receive one of the following regimens: Ocrelizumab (CinnaGen) or Ocrevus® (Roche, Switzerland) ,600 mg (given as dual infusions of ocrelizumab 300 mg on Days 1 and 15 of the first 24-week treatment cycle and as single infusions of 600 mg on Day 1 for each 24-week treatment cycle, thereafter) every 24 weeks. The primary objective of this study is to verify the equivalency of Ocrelizumab (CinnaGen) versus Ocrevus® (Roche, Switzerland) in reducing the annualized relapse rate (ARR) in participants with relapsing remitting multiple sclerosis (RRMS) at 2 years.

Official Title
-----------------
A Phase III, Randomized, Two-armed, Double-blind, Parallel, Active-controlled Clinical Trial to Evaluate Equivalency of the Efficacy and Safety of Ocrelizumab (CinnaGen, Iran) in Comparison to Reference Product, Ocrevus® (Roche, Switzerland) in Patients With Relapsing Multiple Sclerosis

Conditions
-----------------
Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
-----------------
* Biological: Ocrelizumab (CinnaGen, Iran)
* Biological: Ocrelizumab (Roche, Switzerland)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ability to provide written, informed consent and to be compliant with the schedule of protocol assessments. Ages 18-55 years at screening, inclusive. Diagnosis of MS, in accordance with the revised McDonald criteria (2010). At least two relapses having occurred within the past 2 years or one relapse within the past 12 months prior to screening. Neurological stability for ≥ 30 days prior to both screening and baseline. EDSS, at screening, from 0 to 5.5 inclusive. Patients of reproductive potential must use reliable means of contraception. Exclusion Criteria: Diagnosis of primary progressive MS. Disease duration of more than 10 years in patients with an EDSS ≤ 2.0 at screening. Inability to complete an MRI (contraindications for MRI include but are not restricted to claustrophobia, weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, etc). Known presence of other neurological disorders which may mimic MS including but not limited to: neuromeylitis optica, Lyme disease, untreated vitamin B12 deficiency, neurosarcoidosis and cerebrovascular disorders. Pregnancy or lactation. 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 such as Congestive heart failure (NYHA III or IV functional severity). Known active bacterial, viral, fungal, mycobacterial infection or other infection, excluding fungal infection of nail beds. Infection requiring hospitalization or treatment with I.V. antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to baseline visit. History or known presence of recurrent or chronic infection (e.g., hepatitis B or C, HIV). History of progressive multifocal leukoencephalopathy (PML) History of malignancy, including solid tumors and hematological malignancies, except basal cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix of the uterus that have been previously completely excised with documented, clear margins. History of alcohol or drug abuse within 24 weeks prior to baseline. History or laboratory evidence of coagulation disorders. Receipt of a live vaccine (BCG, MMR, VZV, polio, yellow fever and some influenza vaccine) within 6 weeks prior to baseline. In rare cases when patient requires vaccination with a live vaccine, the screening period may be extended but cannot exceed 8 weeks. Treatment with any investigational agent within 24 weeks of screening (Visit 1) or five half-lives of the investigational drug (whichever is longer). Contraindications to or intolerance of oral or i.v. corticosteroids, including methylprednisolone administered i.v. Treatment with dalfampridine unless on stable dose for ≥ 30 days prior to screening. Patients should remain on stable doses throughout the 48 weeks' treatment period. Previous treatment with B-cell targeted therapies (i.e. rituximab, ocrelizumab, atacicept, belimumab or ofatumumab). Systemic corticosteroid therapy within 4 weeks prior to screening. Any previous treatment with anti-CD4, cladribine, mitoxantrone, daclizumab, teriflunomide, laquinimod, total body irradiation or bone marrow transplantation. Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil (MMF), cyclosporine, methotrexate or natalizumab within 24 months prior to screening. Patients previously treated with natalizumab will be eligible for this study only if duration of treatment with natalizumab was < 1 year. Treatment with fingolimod or dimethyl fumarate (DMF) within 4 weeks prior to screening. Only patients with T lymphocyte count ≥ LLN will be eligible for this study. Treatment with I.V. immunoglobulin within 12 weeks prior to baseline. Positive serum β hCG measured at screening. Positive screening tests for hepatitis B CD4 count < 300/μL. AST/SGOT or ALT/SGPT ≥ 2.0 Upper Limit of Normal (ULN). Platelet count <100,000/μL (<100 x 109/L). Levels of serum IgG 18% below the LLN. Levels of serum IgM 8% below the LLN. Total neutrophil count <1.5 x 10^3/μL.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ocrelizumab (CinnaGen, Iran)<br>Ocrelizumab (CinnaGen, Iran) 600 mg (given as dual infusions of ocrelizumab 300 mg on Days 1 and 15 of the first 24-week treatment cycle and as single infusions of 600 mg on Day 1 for each 24-week treatment cycle, thereafter) every 24 weeks. | Biological: Ocrelizumab (CinnaGen, Iran)<br>* Ocrelizumab (CinnaGen, Iran) will be administered via intravenous (IV) infusion.<br>* Other names: Xacrel®;|
| Active Comparator: Ocrelizumab (Roche, Switzerland)<br>Ocrelizumab (Roche, Switzerland) 600 mg (given as dual infusions of ocrelizumab 300 mg on Days 1 and 15 of the first 24-week treatment cycle and as single infusions of 600 mg on Day 1 for each 24-week treatment cycle, thereafter) every 24 weeks. | Biological: Ocrelizumab (Roche, Switzerland)<br>* Ocrelizumab (Roche, Switzerland) will be administered via intravenous (IV) infusion.<br>* Other names: Ocrevus®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Relapse Rate at 48 weeks | Total number of confirmed relapses divided by the total number of days on study A relapse is defined as the appearance of a new or worsening of a previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding relapse. The abnormality must be present for at least 24 hours and occur in the absence of fever or infection | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to onset of sustained disability progression for at least 12 weeks | Disability progression is defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) At least a 1.5-point increase in patients with a baseline score of 0 B) At least a 1.0-point increase on the EDSS in patients with a baseline score of 0<EDSS≤5.5 C) At least a 0.5-point increase on the EDSS in patients with a baseline score of >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis) | Baseline up to Week 96 | 
| Time to onset of sustained disability progression for at least 24 weeks | Disability progression is defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) At least a 1.5-point increase in patients with a baseline score of 0 B) At least a 1.0-point increase on the EDSS in patients with a baseline score of 0<EDSS≤5.5 C) At least a 0.5-point increase on the EDSS in patients with a baseline score of >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis) | Baseline up to Week 96 | 
| Proportion of relapse-free patients by 96 weeks | A relapse is defined as the appearance of a new or worsening of a previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding relapse. The abnormality must be present for at least 24 hours and occur in the absence of fever or infection | Week 96 | 
| Total number of new Gadolinium (Gd)-enhancing lesions as detected by brain MRI | Sum of the individual number of (Gd)-enhancing lesions at Weeks 24, 48, and 96 | Baseline up to Week 96 | 
| Total number of new, and/or enlarging T2 hyperintense lesions as detected by brain MRI | Sum of the individual number of new, and/or enlarging T2 hyperintense lesions at Weeks 24, 48, and 96 | Baseline up to Week 96 | 
| Change in total T2 lesion volume as detected by brain MRI from baseline to week 96 |  | Baseline up to Week 96 | 
| Number of Participants With Adverse Events (AEs) | Intensity, seriousness and causality assessment of observed AEs, and abnormal laboratory findings every 12 weeks. | Baseline up to Week 96 | 
| Number of Participants With Infusion Related Reactions (IRRs) | Assessment of IRRs every 24 weeks | Baseline up to Week 96 | 
| Immunogenicity Assessment | Number of participants positive for anti-drug antibodies at weeks 24, 48 and 96 | Baseline up to Week 96 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RRMS, Annualized Relapse Rate, Monoclonal, Humanized, Ocrelizumab