Ocrelizumab Discontinuation in Relapsing Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
This study is a prospective, multi-center, randomized, double blinded, placebo-controlled study of OCR treatment-discontinuation in patients with early RMS. All eligible participants will be initiated on OCR using the standard approved administration schedule of two 300 mg infusions separated by 14 days (i.e., Days 0 and 14) for a total of 600 mg, followed by 600 mg infusions at Month 6 and Month 12. At Month 12, participants will be randomized (1:1:1) to one of three Arms with randomized treatment beginning at Month 18: Arm 1: placebo infusions every 6 months; Arm 2: OCR infusions at Months 18 and 24 and then after Month 24 switch to placebo infusions every 6 months; Arm 3: OCR infusions every 6 months. The treatment period will be for a total of 48 months.

Detailed Description
-----------------
This study is a prospective, multi-center, randomized, double blinded, placebo-controlled study of OCR treatment-discontinuation in patients with early RMS. All eligible participants will be initiated on OCR using the standard approved administration schedule of two 300 mg infusions separated by 14 days (i.e., Days 0 and 14) for a total of 600 mg, followed by 600 mg infusions at Month 6 and Month 12. At Month 12, participants will be randomized (1:1:1) to one of three Arms with randomized treatment beginning at Month 18: Arm 1: placebo infusions every 6 months; Arm 2: OCR infusions at Months 18 and 24 and then after Month 24 switch to placebo infusions every 6 months; Arm 3: OCR infusions every 6 months. The treatment period will be for a total of 48 months. The study will consist of the following periods, with participants undergoing study assessments, including physical exams, neurological exams, EDSS, LCLA, SDMT, MFIS, MSQOL-54, PHQ9, EQ-5D-5L, and frequent co-registered research-quality MRI to sensitively assess for new inflammatory disease activity (new or enlarging T2 lesions), under schedules described in detail below. Biological sampling includes blood samples for functional immune profiling and stool samples for microbiome studies. Biomarker-based assessments are to include but not be limited to NfL and B cell levels. Screening Period: After obtaining informed consent, all screening assessments, and procedures to establish eligibility will be performed. These may be completed during one or more study visits within the 30-day screening window. Biological sampling will include 2 samples obtained prior to initiation of OCR treatment. Open-label Treatment Period: Participants that meet all eligibility criteria for enrollment will be initiated on OCR using the standard approved administration and will be followed for 12 months under the standard of care clinical efficacy and safety monitoring described below. Biological sampling occurs at 6 months and then at 12 months, with 2 samples to be taken prior to randomization (14 days +/- 7 days of randomization and on the day of randomization). Participants who discontinue study therapy during the open-label treatment period are asked to return for the scheduled study visits at Month 6 and Month 12 only, if these have not already occurred. Blinded Treatment Period: At Month 12, participants will be randomized (1:1:1) to either: (Arm 1) placebo infusions every 6 months; (Arm 2) continue OCR for another 12 months and then switch to placebo infusions; or (Arm 3) continue with OCR infusions every 6 months. The blinded treatment period will extend to Month 48 or until new disease activity is observed. All participants in the blinded treatment period will be closely monitored clinically and with frequent research 3Tesla (3T) MRIs using a standard protocol that assesses for the development of any new inflammatory disease activity observed following randomization. The development of such new inflammatory disease activity will represent the primary study endpoint. It will be defined as any one or more of the following: (1) one or more new clinical relapse(s) (see relapse definition) or (2) MRI evidence on frequent (every 3 months) serial scans of new disease activity. The central imaging analysis will identify incident new or enlarging MRI T2 lesions as compared to prevalent brain lesions documented in each participant from time of randomization (Month 12) and thereafter. Frequent biological sampling will include blood samples collected every 3 months and stool samples collected every 6 months through the 48-month end of study. Unblinded Follow-up period: For participants who discontinue study therapy before Month 48, including those meeting the primary endpoint by manifesting new disease activity following randomization as defined above, blinded treatment allocation will be revealed and discussed, as described in section 3.5.1. Participants may receive OCR or other treatment and are to continue with study assessments per the schedule of events. Functional immune response profiles of reconstituting B cells as well as non-B cells (T cells and myeloid cells) will be compared between participants who do, versus those do not, benefit from durable remission of relapsing biology, to identify cellular immune response profiles that may underlie the state of durable tolerance versus lack of durable tolerance. Safety Follow-up: Participants who are treated with OCR through Month 48 will have a phone visit 6 months after their last dose. If there are safety concerns, the participant can be brought in for an unscheduled visit.

Official Title
-----------------
Randomized, Blinded Discontinuation Trial of Ocrelizumab in Early Relapsing Multiple Sclerosis (AMS05)

Conditions
-----------------
Multiple Sclerosis

Intervention / Treatment
-----------------
* Drug: Ocrelizumab
* Drug: Placebo for Ocrelizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have at least one clinical episode that satisfies McDonald 2017 criteria for early Multiple sclerosis (MS) for up to 2 years post-event with a dissemination in time that can be met clinically, by Magnetic Resonance Imaging (MRI), or based on oligoclonal band (OCB) positivity Have a length of disease duration, from first symptom, of ≤ 2 years For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use effective methods of contraception during the treatment period and for at least 6 months after the last dose of study drug: A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus) Examples of contraceptive methods include bilateral tubal ligation, male sterilization, established hormonal contraceptives that inhibit ovulation, hormone- releasing intrauterine devices, and copper intrauterine devices The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception Barrier methods must always be supplemented with the use of a spermicide Immunization with an Food and Drug Administration (FDA) authorized or licensed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 vaccines) Exclusion Criteria: Inability or unwillingness of a participant to give written informed consent or comply with study protocol History of Primary Progressive Multiple Sclerosis (PPMS), Progressive Relapsing Multiple Sclerosis (PRMS), or Secondary Progressive Multiple Sclerosis (SPMS) Any metallic material or electronic device in the body, or condition that precludes the participant from undergoing Magnetic resonance imaging (MRI) Known presence or history of other neurological disorders, including but not limited to the following: Ischemic cerebrovascular disorders, including but not limited to transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebral embolism, or cerebral hemorrhage Central Nervous System (CNS) or spinal cord tumor, metabolic or infectious cause of myelopathy, genetically inherited progressive CNS disorder, CNS sarcoidosis, or systemic autoimmune disorders potentially causing progressive neurologic disease or affecting ability to perform the study assessments Pregnancy or lactation a. Female participants of childbearing potential must have a negative urine pregnancy test at screening Any concomitant disease that may require chronic systemic treatment with corticosteroids or immunosuppressants during the course of the study Lack of peripheral venous access History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies Significant, inadequately controlled (e.g. diagnostic evaluations indicated or change in medications warranted) disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine, and gastrointestinal or any other significant disease that in the opinion of the investigator may preclude participant from participating in the study Functional status of NY Heart Association (NYHA) Class III or higher for heart failure at the screening visit Known active bacterial, viral, fungal, mycobacterial infection or other infection (including tuberculosis [TB] or atypical mycobacterial disease but excluding limited superficial fungal or viral infections of the skin or nails) or any severe episode of infection requiring hospitalization or treatment with Intravenous (IV) antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to baseline visit Active or chronic infection with Human Immunodeficiency Virus (HIV), syphilis or TB (see laboratory tests below) Evidence of past or current hepatitis B or hepatitis C infection, including treated hepatitis B or hepatitis C. Hepatitis B surface antibody following hepatitis B immunization is not considered to be evidence of past infection Known active malignancy or active monitoring for recurrence of malignancy, including solid tumors and hematological malignancies, except basal cell, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix for the uterus that have been excised with clear margins Substance use disorder, including the recurrent use of alcohol and /or drugs within the past year associated with clinically significant impairment associated with failure to meet major responsibilities at work, school, or home Receipt of a live vaccine within 6 weeks prior to baseline; in rare cases when participant requires vaccination with a live vaccine, the screening period may need to be extended but cannot exceed 8 weeks Contraindications to or severe intolerance of oral or IV corticosteroids, including Intravenous (IV) methylprednisolone administered according to the country label, including: Psychosis not controlled by a treatment Hypersensitivity to any of the constituents or excipients of the preceding steroids Treatment with any Multiple sclerosis (MS) disease-modifying treatments (DMTs) including but not limited to: glatiramer acetate preparations, beta-interferon preparations, fingolimod and related agents, fumarates, cladribine, natalizumab, anti-CD20 molecules, alemtuzumab, and chemotherapeutic agents Current or prior treatment with any investigational agent or treatment with any experimental procedure for MS (e.g. treatment for chronic cerebrospinal venous insufficiency) Systemic corticosteroid therapy within 4 weeks prior to screening Laboratory test results as follows: a. Positive infection screening tests for: i. Hepatitis C (HCV) antibody, if positive screen for HCV RNA Polymerase Chain Reaction (PCR) ii. Rapid plasma reagin (RPR) iii. HIV iv. At or within twelve months of screening: Positive QuantiFERON(R)-TB Gold test or positive purified protein derivative tuberculin skin test (PPD) (>5mm induration, regardless of Bacille Calmette Guerin [BCG] vaccine administration) unless completion of treatment has been documented for active TB An indeterminate QuantiFERON(R)-TB Gold test unless followed by a subsequent negative PPD or negative QuantiFERON(R)-TB Gold test as well as a consultation with and clearance by local infectious disease (ID) department b. Levels of serum IgG<565 mg/dL c. Levels of serum IgM<40 mg/dL d. End stage renal disease estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2 using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation e. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)>= 2.0 x the upper limit of normal (ULN) f. Platelet count < 100,000 plt/mcL (< 100 x 10^9/L) g. Hemoglobin < 10 g/dL h. Total neutrophil count < 1.5 x 10^3/mL Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ocrelizumab+Placebo Arm<br>All eligible participants will be initiated on Ocrelizumab (OCR) using the standard approved administration schedule of two 300 mg infusions separated by 14 days (i.e., Days 0 and 14) for a total of 600 mg, followed by 600 mg infusions at Month 6 and Month 12. In this arm participants will then receive OCR infusions at Months 18 and 24 and then after Month 24 switch to placebo infusions every 6 months through Month 48. | Drug: Ocrelizumab<br>* Two 300 mg intravenous (IV) OCR infusions separated by 14 days (i.e., Days 0 and 14) for a total of 600 mg, followed by 600 mg OCR infusions every 6 months from Month 6 through Month 48.<br>* Other names: Ocrevus;Drug: Placebo for Ocrelizumab<br>* Placebo infusions every 6 months from Month 18 through Month 48.<br>|
| Experimental: Ocrelizumab Arm<br>All eligible participants will be initiated on OCR using the standard approved administration schedule of two 300 mg infusions separated by 14 days (i.e., Days 0 and 14) for a total of 600 mg, followed by 600 mg infusions at Month 6 and Month 12. In this arm participants will continue to receive OCR infusions every 6 months through Month 48. | Drug: Ocrelizumab<br>* Two 300 mg intravenous (IV) OCR infusions separated by 14 days (i.e., Days 0 and 14) for a total of 600 mg, followed by 600 mg OCR infusions every 6 months from Month 6 through Month 48.<br>* Other names: Ocrevus;|
| Placebo Comparator: Placebo Arm<br>All eligible participants will be initiated on OCR using the standard approved administration schedule of two 300 mg infusions separated by 14 days (i.e., Days 0 and 14) for a total of 600 mg, followed by 600 mg infusions at Month 6 and Month 12. In this arm, starting at Month 18, participants will receive placebo infusions every 6 months through Month 48. | Drug: Placebo for Ocrelizumab<br>* Placebo infusions every 6 months from Month 18 through Month 48.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absence of clinical relapse | Durable remission of relapsing disease activity. This is defined as the absence of new relapsing disease activity from randomization through Month 48. This includes absence of clinical relapse as well as absence of evidence of MS disease activity by MRI defined by new or enlarging T2 lesions. | From Month 12 to Month 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in Expanded Disability Status Scale (EDSS) score | The Expanded Disability Status Scale (EDSS) score has a minimal value of zero, and maximal value is 10, with higher scores meaning worse outcome. | Months 0, 6, 12, 18, 24, 30, 36, 42, 48 | 
| Proportion of participants with a serious adverse event (SAE) |  | Month 0 to Month 48 | 
| Proportion of participants who experience at least one Grade 3 or higher adverse event | Using National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Adverse events will be graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE manual: Grade 1 = mild adverse event Grade 2 = moderate adverse event Grade 3 = severe and undesirable adverse event Grade 4 = life-threatening or disabling adverse event Grade 5 = death | Month 0 to Month 48 | 
| Proportion of participants with infections, Grade 3 or higher |  | Month 0 to Month 48 | 
| Proportion of participants with malignancies |  | Month 0 to Month 48 | 
| Proportion of participants experiencing infusion related reactions | Defined as any at least possibly related adverse reaction within 24 hours of infusion which are Grade 3 or higher events | Month 0 to Month 48 | 
| Proportion of granulocyte-macrophage colony-stimulating factor (GM-CSF) expressing B-Cells to Interleukin 10 (IL-10) expressing B cells at Month 48 in participants who do versus do not exhibit durable disease remission |  | Month 0, Day 30, Months 6, 12, 18, 24, 30, 36, 42, 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ocrelizumab, Multiple sclerosis, Relapse