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, 12, 18, and 24. At Month 24, participants will be randomized (2:1) to one of two Arms with randomized treatment beginning at Month 30: Arm 1: placebo infusions every 6 months; Arm 2: 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 24 months under the standard of care clinical efficacy and safety monitoring described below. Biological sampling occurs at 6, 12, 18, and 24 months as well as prior to the 12 and 24 months visits (14 days +/- 7 days of the visit). Participants who discontinue study therapy during the open-label treatment period are asked to return for an early withdrawal visit and a safety follow-up phone call approximately 6 months after their last dose.
Blinded Treatment Period:
At Month 24, participants will be randomized (2:1) to either: (Arm 1) placebo infusions every 6 months; or (Arm 2) 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 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 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 24) 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 blinded 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 choose to receive OCR or other treatment and are encouraged to continue with study assessments per the schedule of events. For participants that meet the primary endpoint, OCR will be provided by the study for those who choose to receive OCR after unblinding and 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.
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 24 months under the standard of care clinical efficacy and safety monitoring described below. Biological sampling occurs at 6, 12, 18, and 24 months as well as prior to the 12 and 24 months visits (14 days +/- 7 days of the visit). Participants who discontinue study therapy during the open-label treatment period are asked to return for an early withdrawal visit and a safety follow-up phone call approximately 6 months after their last dose.
Blinded Treatment Period:
At Month 24, participants will be randomized (2:1) to either: (Arm 1) placebo infusions every 6 months; or (Arm 2) 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 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 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 24) 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 blinded 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 choose to receive OCR or other treatment and are encouraged to continue with study assessments per the schedule of events. For participants that meet the primary endpoint, OCR will be provided by the study for those who choose to receive OCR after unblinding and 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.
Visit ClinicalTrials.gov for details.
Contact Information
Office/Contact: Katerina Palma
Email: Katerina.palma@yale.edu