Prospective Evaluation of Sequencing From antiCD-20 Therapies to Ozanimod (COAST: CD20 and Ozanimod Sequencing Trial)
Phase: PHASE4
Conditions: Relapsing Multiple Sclerosis
Sponsor: University of Colorado, Denver

1 
 
Prospective Evaluation of Sequencing from antiCD-20 Therapies to Ozanimod 
Enrique Alvarez, MD/PhD 
23-1686 
Version 02Jul2024 
 
 
 
 
 
 
Background 
Multiple sclerosis (MS) is a complex autoimmune disorder of the central nervous system. This condition 
affects nearly 1 million patients in the United States(1). A unique aspect of this condition is that relapses occur 
more frequently at the beginning of the illness as demonstrated by natural history studies(2, 3). This suggests 
that starting with a high efficacy approach followed by de-escalation in treatment may be ideal especially if high 
efficacy treatments have long term safety concerns and/or if the efficacy with time becomes more comparable 
between treatments. Both conditions are met in the care of MS patients. Increasingly patients are starting with 
higher efficacy treatments with a substantial number of patients being treated with anti-CD20 treatments. 
However, anti-CD20 treatments with time are associated with increased risk of infection particularly as IgG 
levels begin to decrease.  In work done in collaboration between the University of Colorado and New York 
University looking at 1000 patients on rituximab we noted an over 3-fold increase in infections if IgG was <500 
mg/dL (Table) (7).  Additionally, the difference in efficacy between therapies becomes less pronounced with 
time. The difference in efficacy between natalizumab and rituximab (together forming the infusible high efficacy 
group) decreases over time as compared to dimethyl fumarate and fingolimod (oral mid-tier efficacy group; 
Figure) (8).
 
Table. Infections resulting in Hospitalization, Extended Dosing Antibiotics or IV Antibiotics in patients with IgG 
<500. There was over a 3-fold increased risk even after adjusting for other factors. 

2 
 
 
Figure 1. Relative efficacy of disease modifying therapies in the treatment of MS. Rituximab and natalizumab 
(Infusibles, blue) are more efficacious than the oral treatments composed of dimethyl fumarate and fingolimod 
(red). As patients with MS age, the likelihood of disease activity decreases and the difference between orals and 
infusibles becomes negligible. Dashed lines represent the 95% confidence intervals (8).  
 
Because of the decreasing efficacy of higher efficacy treatments and the increased risk with age and 
time on treatment, a strategy to switch to safer and more convenient therapies becomes a rational treatment 
option. This approach, known as de-escalation, may help mitigate risk but still maintain good efficacy in patients 
with MS. One such study to demonstrate the impact of de-escalation therapy was STRATEGY (Multicenter, 
Retrospective, Observational Study Evaluating Real-world Clinical Outcomes in Relapsing-remitting Multiple 
Sclerosis Patients Who Transition from Tysabri® [Natalizumab] to Tecfidera® [Dimethyl Fumarate])(4). This 
retrospective study evaluated the effectiveness of dimethyl fumarate (DMF) in patients de-escalating from 
natalizumab across 45 US Centers. Eligible patients were ≥18 years of age at study enrollment; had a diagnosis of 
relapsing remitting MS; had received ≥12 months of natalizumab prior to de-escalating to DMF and followed for 
12 months post de-escalation. Of the 506 eligible patients, the mean age was 47 years at initiation of de-
escalation with DMF therapy and 12.7 years since MS diagnosis. Mean duration on natalizumab was 3.4 years. 
The overall probability of a relapse one year after de-escalation from natalizumab to DMF was 19.6% (93/506 
with 15% experiencing one relapse, 3% experiencing 2 relapses, and 0.6% experiencing 3 relapses). With regards 
to safety outcomes, 8% of patients reported ≥1 adverse event following de-escalation leading to DMF 
discontinuation, the most common being gastrointestinal disorders. About 1 % (7/506) of patients were 
hospitalized due to more severe relapses in the year after DMF initiation. While this study showed evidence of 
some of the benefits of de-escalation, there were some limitations associated with it. Primarily, all adult 
patients, regardless of their age and disease stability status were included in the study. This resulted in some 
continued disease activity in the form of relapses post de-escalation. This was a retrospective study resulting in 
the ability to capture limited outcomes as acknowledged by the authors.  
 
Teriflunomide, another oral DMT, was used as a de-escalating agent for patients with relapsing forms of 
MS who were previously taking natalizumab. Edwards and colleagues examined the safety and efficacy in 
patients de-escalating from natalizumab to teriflunomide with relapsing forms of MS(5). The authors examined 
51 patients with a mean age of 47 years, who had completed 3.4 years on natalizumab and were relapse free in 
the 12 months of natalizumab prior to de-escalation to teriflunomide. De-escalation to teriflunomide, occurred 

3 
 
at 14mg daily and within 4 weeks after their last dose of natalizumab. Relapse assessment, EDSS and MRI scans 
were conducted at baseline and monthly for 6 months until month 12. MRI results showed 15 patients with new 
MRI activity during the first 12 months (29.4%), of which 14 had contrast enhancing lesions. Three patients 
(5.8%) required a change of DMT due to MRI progression. Three patients (5.8%) dropped out of the study due to 
adverse events or lack of efficacy. 
 
The limited experience with de-escalation therapy has shown the following: 1) all patients regardless of 
age have been included in these evaluations; 2) disease stability has been limited to patients who have been 
merely relapse free in the year prior to de-escalation; and 3) the only high efficacy DMT examined prior to de-
escalation has been natalizumab. These results demonstrate that between 70-80% of patients show no disease 
activity in the first 12 months following de-escalation. The studies above also have focused on natalizumab, a 
therapy that can demonstrate a prompt resumption of inflammatory activity which is a known side effect of 
natalizumab interruption. These gaps demonstrate a critical need to further explore the concept of de-escalation 
on efficacy and safety outcomes in patients who have been stable for longer periods of time and de-escalating 
from other high efficacy treatments such as anti-CD20 treatments, which has not been associated with rebound 
disease activity. The investigation of anti-CD20 agents is of particular importance as the efficacy of the 
medication after discontinuation is related to a relatively slow re-population of CD20 cells. This would allow a 
greater window for the next therapy to become active as seen in the HERMES study allowing for de-escalation to 
fully take effect (6). 
 
A transition to ozanimod may provide some advantages over other treatments such as a transition after 
B-cell depletion. Ozanimod is a once daily oral medication providing great convenience with great tolerability. 
This provides an advantage over fumarates, which are twice daily treatments that have a high rate of GI 
intolerability (9). Additionally, ozanimod may have advantages over fingolimod, which was the first S1P partial 
agonist approved in the treatment of MS patients, in that it may be safer. There are no reported cases of fungal 
meningitis such as cryptococcus and patients appear to have better responses to vaccination (10). The efficacy 
of ozanimod was evaluated in two phase III trials that suggested efficacy similar to dimethyl fumarate and 
fingolimod (11, 12).  Additionally, ozanimod is not associated with developing hypogammaglobulinemia which as 
described above can occur with B-cell depletion and is associated with infections.  
 
Objective 
We propose a multi-center pilot study, which aims to evaluate safety and efficacy of ozanimod as de-escalation 
therapy in clinically stable MS patients previously treated with anti-CD20 therapy. This will be evaluated using 
the endpoints listed below.  
 
Primary Endpoints: 
1) Number of new T2 lesions on MRI scans over at least 36 months of follow up. 
2) Serious infections are defined as infections requiring hospitalization, intravenous antibiotic use, or prolonged 
antibiotic use for treatment of an infection for at least 30 days. 
 
Secondary Endpoints (from baseline to 36 months):  
1) Evidence of relapse activity –protocol defined relapses are described below. Additionally, suspected relapses 
will be evaluated.  
2) IgG and IgM levels 
3) All infections including opportunistic infections 
The following will be described only on the open label arm: 
4) 6 months Confirmed Disability progression (CDP6): measured by the EDSS assessed at baseline and every 6 
months. CDP6 is defined as an increase in Expanded Disability Status Scale (EDSS) score of ≥1.5 if baseline EDSS 

4 
 
was 0; or ≥1.0 points if baseline EDSS was ≥0.5-≤5.5; or by ≥0.5 points if baseline EDSS ≥6, sustained over two 
consecutive visits, in the absence of a relapse. 
5) No Evidence of Disease Activity (NEDA-3), percent of patients not meeting any of the following criteria:  
a. Evidence of Relapse activity - collected every 3 months via phone calls/clinic visits.  
b. MRI disease activity - presence of new T2 lesions from MRI scans conducted at any timepoint. 
c. 6 months Confirmed Disability progression (CDP6): measured by the EDSS assessed at baseline and 
every 6 months. CDP6 is defined as an increase in Expanded Disability Status Scale (EDSS) score of ≥1.5 if 
baseline EDSS was 0; or ≥1.0 points if baseline EDSS was ≥0.5-≤5.5; or by ≥0.5 points if baseline EDSS ≥6, 
sustained over two consecutive visits.  
6) Neurofilament light (NFL) and Glial Fibrillary Acid Protein (GFAP) levels  
7) Brain parenchymal and thalamic volume loss  
8) Adverse events  
 
Exploratory Measures (from baseline to 36 months):  
1) a 4 points or 10% change in cognition (measured by the Symbol Digital Modalities Test)  
2) a 20% change in hand function (measured by the 9-hole peg test)  
3) a 20% change in walking speed (measured by the 25-foot walk speed)  
4) Multiple Sclerosis Functional Composite (MSFC) defined as a change in any of the above three criteria 
5) a minimum of 5% in change scores in PRO outcomes to include treatment satisfaction (TSQM), MS fatigue 
scale (Modified Fatigue Impact Scale [MFIS]), or quality of life (MSIS-29) 
6) we will also describe changes in employment and full employment proportions 
 
Study Population 
Prospective: Twenty-four patients >18 years of age with a minimum of 2 years of MS disease stability (no relapse 
or new magnetic resonance imaging lesions) and at least two years of experience on an anti-CD20 agent prior to 
initiating de-escalation with ozanimod (Zeposia®) will be followed for 36 months post de-escalation. 
 
Retrospective secondary Use Cohort: At least 500 patients at Cleveland Clinic or at the University of Colorado on 
anti-CD20 treatment for at least 2 years since March of 2020 (date of ozanimod approval), who also meet the 
above inclusion and exclusion criteria, with follow up of an additional 36 months on B-cell depleting treatments. 
 
Inclusion criteria: 
• Participants have been diagnosed with relapsing forms of MS and have had multiple sclerosis related 
symptoms at least 3 years prior to baseline visit 
• Male or female participants > 18 years of age at the time of initiation of de-escalation 
• Participants do not have evidence of new inflammatory disease activity (no new T2/contrast enhancing 
lesions, absence of relapses) for a minimum of two years prior to de-escalation 
• Participant is taking an anti-CD20 therapy as a DMT continuously for a minimum of two years (e.g., has 
received at least 3 courses of rituximab, ocrelizumab, ublituximab; 24 months of treatment with ofatumumab; 
or a combination of treatments whereby the patient has been deemed to be B-cell depleted for 2 years) prior to 
initiation of de-escalation  
• Participants received their last anti-CD20 infusion within 6-12 months or received their last ofatumumab 
injection within 30 –180 days from Day 1 
• Participants must provide written informed consent and be able to comply with the visit schedule and study 
related assessments 
• Participants must be able to undergo a brain MRI without anesthesia 
• Woman of Childbearing Potential must agree to practice a highly effective method of contraception 
throughout the study until completion and willing to follow pregnancy precautions as outlined in Appendix A. 

5 
 
 
Exclusion criteria:  
•Any progression of neurological disability in the year prior to the screening visit that would be consistent with 
progressive MS 
• Participant has an EDSS >6.5 
• Participant has a history of other chronic neurological illnesses that might mimic MS with chronic or 
intermittent symptoms (i.e. ALS, myasthenia gravis, chronic neuropathy, etc.)  
• Participant is considering pregnancy in the short term, is pregnant, lactating or has a positive serum beta 
human chorionic gonadotropin (B-hCG) measured during screening.  
• Participant has any other significant medical or psychiatric illness, if uncontrolled, that could jeopardize a 
subject’s health or put them at significant safety risk during the course of the study in the opinion of treating 
investigator. Examples: uncontrolled hypertension, uncontrolled diabetes, uncontrolled asthma, uncontrolled 
depression 
• Participant has a history of cancer within the last 5 years, including solid tumors and hematological 
malignancies (except basal cell and in situ squamous cell carcinomas of the skin or cervical dysplasia/cancer that 
has been excised and resolved)  
• Participant has a history in the last 6 months of myocardial infarction, unstable angina, stroke, transient 
ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure 
• Participant has Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, 
or sino-atrial block, unless the patient has a functioning pacemaker  
• Participant has severe untreated sleep apnea 
• Participant has a history of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin 
A1c (HbA1c) > 9%, or is a diabetic subject with significant comorbid conditions such as retinopathy or 
nephropathy, or a history of uveitis 
• Participant has a history or known presence of recurrent or chronic infection (e.g., hepatitis B virus (HBV), 
hepatitis C virus (HCV), human immunodeficiency virus (HIV); recurrent urinary tract infections are allowed. 
• Any known or suspected active infection (excluding onychomycosis) at screening, including but not limited to a 
confirmed or suspected progressive multifocal leukoencephalopathy (PML). Known currently active tuberculosis 
(TB). History of incompletely treated Mycobacterium tuberculosis (TB) infection, as indicated by: Subject’s 
medical records documenting incomplete treatment for Mycobacterium TB; Subject’s self-reported history of 
incomplete treatment for Mycobacterium TB; Subjects with a history of TB who have undergone treatment 
accepted by the local health authorities (within 1 year from screening) may be eligible for study entry. 
 
Exclusions related to Medications: 
• Concomitant use of a monoamine oxidase inhibitor 
• Use of systemic corticosteroids in the last 2 years. (Note: Use of inhaled or topical steroids; use of oral steroids 
for no greater than 14 days given for a non-MS condition are allowed) 
• Prior use of alemtuzumab, mitoxantrone, cyclophosphamide, methotrexate, cyclosporine, or any experimental 
MS treatment within the last 5 years 
• Prior allergy to ozanimod 
 
Exclusions related to Laboratory results: 
• Participant has IgG levels <400 mg/dL 
• Participant has neutrophils < 1500/μL (1.5 GI/L) 
• Participant has an absolute white blood cell (WBC) count < 3500/μL (3.5 GI/L) 
• Participant has an absolute lymphocyte count (ALC) < 800 cells/μL (0.80 GI/L).  
• Participant has liver function impairment or persisting elevations of aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) results > 3 x the upper limit of normal (ULN) 

6 
 
 
VZV testing and vaccination will not be required as part of this protocol. This will be conducted by principal 
investigator (PI) discretion and could be done as standard of care. 
 
Study Design 
Multicenter, Open Label, Prospective Study examining the safety and efficacy of de-escalation therapy to 
ozanimod (Zeposia®) over 36 months from anti-CD20 therapy for stable patients with relapsing forms of MS.  A 
comparison to patients continuing anti-CD20 treatment will be done with propensity scoring to a cohort of at 
least 500 patients followed at Cleveland Clinic and the University of Colorado who also meet the above inclusion 
and exclusion criteria at the time when they could be followed for 36 months. This study will be listed in 
clinicaltrials.gov once approved. 
 
Data Capture 
An electronic data capture system will be generated to provide a standardized tool with clear instructions on 
how to obtain and submit data. Data will be shared in a secure de-identified manner and stored in a HIPAA 
compliant manner.  
 
Sites:  
- 
Mellen Center for Multiple Sclerosis Treatment and Research at Cleveland Clinic (PI Devon Conway, MD, 
MSc) 
- 
Cleveland Clinic Lou Ruvo Center for Brain Health (PI Carrie M. Hersh, DO, MSc) 
- 
The Rocky Mountain MS Center at the University of Colorado (PI Enrique Alvarez, MD/PhD, Coordinating 
site) 
 
Institutional Review Board Approval 
The Rocky Mountain MS Center at the University of Colorado will be the data coordinating/statistical analysis 
site and the other sites will have their own IRB approval and oversight. Each site will pursue its own IRB 
approval. A Spanish language consent and advertising will be developed and approved by the IRB. It is expected 
that recruitment will be primarily with patients who have a treatment relationship at the approved sites, but 
local advertising will be pursued if recruitment becomes delayed. 
 
Monitoring Plan 
The project management team at the Rocky Mountain MS Center at the University of Colorado will monitor 
compliance and the data for this study at all sites. This team will be independent of the team completing the 
study. They will ensure that training and delegation logs are completed as a site becomes active. After the first 
patient is enrolled in the study and at least twice per year, they will review data at all of the sites, remotely, to 
ensure completeness and accuracy of the entered data. They will also visit each site in person up to 2 times 
throughout the duration of the study.  
 
Dosing Regimen  
Ozanimod will be started 6-12 months after the last anti-CD20 infusion or 30-180 days from their last 
ofatumumab injection. Ozanimod will be provided by the study.  
 
Ozanimod titration will begin with 0.23mg orally once a day on days 1-4 and followed by 0.46mg (taken as 2 pills 
of 0.23mg orally once a day) on days 5-7. Subjects will be provided with 2 bottles with 7 pills of the 0.23mg dose 
to initiate treatment.  
 

7 
 
Ozanimod maintenance will start on day 8 with 0.92mg daily provided to subjects in bottles of 30 pills of 0.92mg 
each with enough bottles to last until the next appt allowing for enough excess to cover the window around 
each visit.  
 
Subjects should be instructed that if they forget to take a dose, they can take the dose within 4 hours of the 
normal dosing time; otherwise, they should take their next dose at the regular time on the following day.  If the 
subject vomits the capsule, he/she should be instructed not to take another capsule on the same day, but to 
take the next dose at the regular time on the following day. If a dose is missed during the first 2 weeks of 
treatment, or for more than 7 consecutive days during Days 15-28 or for more than 14 consecutive doses, 
reinitiate treatment using the 7-day titration regimen. 
 
Biorepository  
Leftover samples from this study will be stored in the Rocky Mountain MS Center Biorepository (University of 
Colorado COMIRB 12-0968), if the subject consents to this. All samples collected in this study at external sites to 
the University of Colorado will be de-identified at the time of transfer to protect the confidentiality of the 
participants. 
 
Statistical analysis: 
The emergence of new T2 lesions and serious infections (primary outcomes) will be described using product-
limit estimates (Kaplan-Meier plots).   Proportions of patients with disease activity will be reported, along with 
95% confidence intervals.  With 24 patients, if there is no evidence of disease activity in any patients in 36 
months, we are 97.5% confident that the true rate is below 14.2%.  Similarly with 1, 2, and 3 patients with 
observable disease activity in 24 months, we are 95% confident the true rates are between 0.1-21.1%, 1.0-27.0% 
and 2.7-32.4% respectively. Product-limit estimates (Kaplan-Meier plots) will also be used to analyze relapses 
and IgG and IgM levels. 
 
A comparison will be made between new T2 lesions and serious infections in the open label de-escalation arm to 
the CD20 maintained retrospective cohort over 36 months using propensity score (PS)-adjusted analysis. 
Baseline covariates healthcare providers find important in DMT decision-making will be incorporated into the PS 
model: demographics (e.g. age, sex, race, ethnicity), baseline clinical characteristics (e.g. disease course, disease 
duration, prior DMTs, relapse status, PDDS), baseline radiographic characteristics (e.g. prior T2/GdE lesions), and 
PROs (Neuro-QoL). The investigators will plan to use baseline information in selecting cases to meet the 
positivity assumption (e.g., age ≥40 years old and started B-cell depletion recently enough for study entry). The 
appropriateness of using a PS-adjusted analysis will be determined by creating a PS density plot to ensure there 
is sufficient overlap between the two cohorts. The PS technique used [e.g., 1:1 greedy matching, Inverse 
probability of treatment weighting (IPTW)] will be determined based on the best overall covariate balance using 
the following definition: excellent covariate balance defined as an absolute standardized difference <10% on the 
means of the covariate across the two treatment strategies. A more robust PS-adjusted analysis will be 
conducted using the linear PS, for which excellent balance will be determined as a linear PS < 50%. Standardized 
difference plots will be used to determine the PS technique yielding the best overall covariate balance. Once this 
is determined, these adjusted data will be used in making conclusions on the above comparative endpoints. 
Rosenbaum bounds will be used to measure the amount of hidden bias in the model that will help determine 
the robustness of statistically significant results. Because of the low number of expected events, exact methods 
for proportion tests may be required, such as Clopper-Pearson exact confidence intervals and Fisher’s exact 
association test. Interim analysis will be done at 12 and 24 months. 
 

8 
 
 
Figure 2. Propensity Score (PS) methodology. 
MRI protocol:  
A short MRI protocol will be employed to evaluate for new T2 lesions, which is one of the primary end points for 
this study. High resolution T2 FLAIR sequences will allow for evaluation of new lesions and characterize their 
localization, size, and shape to evaluate if they are consistent with MS. To aid in this decision making, central 
vein sign will be evaluated with T2* sequences. To measure acuity of lesions, diffusion imaging will be obtained. 
A high resolution T1 sequence will allow for determination of volumetrics. The following MRI sequences will be 
obtained: 
  
1. MPRAGE (Magnetization-Prepared Rapid Acquisition Gradient Echo) - Whole brain T1-weighted images 
acquired using 3D fast spoiled-gradient recalled acquisitions (T1-3D-FSPGR) with in plane resolution of 
1x1 mm with 1 mm slice thickness (isotropic voxel dimensions). 
2. Central vein sequence - Whole brain 3D EPI T2*-weighted gradient recalled images with 0.7 mm 
isotropic voxels. 
3. 3D T2 FLAIR (Fluid Attenuated Inversion Recovery) and 3D T2 images - Whole brain 3D T2-weighted 
images with bright and dark fluid contrast acquired via fast spin echo 3D T2 SPACE technique with 1 mm 
slice thickness and isotropic voxel dimensions.  
4. Diffusion weighed images (DWI) with apparent diffusion coefficient (ADC) maps – 2D whole brain DWI 
images with 0.6 mm x 0.6 mm x 3.0 mm voxels and b=1000 weighing. 
 
Risks/Safety: 
New T2 MRI lesions: 
MRI images will be read by a centralized neuroradiologist who is blinded to patient identifiers. A new lesion will 
be defined as any new T2 weighed lesion at least 3 mm in size felt to be due to MS. For subcortical lesions, this 
will include a sensitivity analysis including only those lesions with a central vein.  
 
Relapse:  
If a participant has either new symptoms to suggest a relapse and/or a new/enlarging brain MRI lesion they will 
be evaluated for a relapse and be considered for remaining on ozanimod or through standard of care switched 
to restarting a B-Cell depleting DMT or an alternative DMT. Relapse treatment will be at the discretion of the 
treating provider. All subjects including those who discontinue drug, for any reason, will continue to be 
followed at all study time points and will have all study procedures if they decide to continue in the study to 
help evaluate efficacy and safety. 
 

9 
 
A relapse will be defined as the appearance of new neurological symptoms or worsening of pre-existing 
neurological symptoms and accompanied by objective change in the neurological examination corresponding to 
that symptom by the examining clinician which could include the treating clinician. Once the subject feels that 
they have experienced a relapse, the subject will contact the PI and/or study coordinator as soon as possible. 
Events may also be identified during study visits or follow-up telephone calls. It is important that the subject be 
seen as soon as a potential relapse is identified. Subjects should be seen as soon as possible and ideally 7 days 
of onset of symptoms.  
 
Each Relapse event will be categorized on CRFs as one of the below: 
• 
Protocol defined relapse: defined as an increase of ≥ 0.5 EDSS, or 2 points increase on 1 of the functional 
system scores (FSS), or 1-point increase on ≥ 2 of the FSS. The increase in FSS scores must be related to 
the neurological symptoms which were reported as new or worsening and the change must affect the 
selected FSS (i.e., pyramidal, cerebellar, brainstem, sensory, or visual, excluding cerebral, bladder or 
bowel). 
• 
Suspected relapse: Relapse that fails to meet the above changes in EDSS but is considered by the 
examining clinician to be a relapse. Symptoms must have lasted at least 24 hours in the absence of fever 
and preceded by stability or improvement for at least 30 days. 
• 
Pseudo-relapse, i.e. a worsening of pre-existing neurological symptoms in the context of any significant 
stressor, including, but not limited to, infection, physical, psychological, or mental stress, as determined 
by the treating physician; or other symptoms felt not to be related to MS. 
 
Adverse events: An adverse event (AE) is the appearance or worsening of any undesirable sign, symptom, or 
condition occurring after starting the study even if the event is not considered to be related to study conditions 
or assignment. Study conditions or assignment includes assignment to continue or discontinue prior DMT. 
Medical conditions and diseases present before starting the study are only considered AEs if they worsen after 
starting the study and if they are self-reported by the patient. Abnormal laboratory values or test results 
constitute AEs only if they induce clinical signs or symptoms, are considered clinically significant, or require 
therapy. 
 
The occurrence of AEs should be sought by nondirective questioning of the patient at each visit during the study, 
including monthly phone calls. Only those AEs self-reported by the patient are documented. All AEs must be 
recorded with the following information: 
 
1. the severity grade (mild, moderate, or severe) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final examination) 
4. whether it constitutes a serious AE (SAE) 
 
Serious adverse events such as hospital admissions for > 24 hours, new significant medical diagnoses such as 
cancer (other than basal cell carcinoma), and MS relapse requiring corticosteroid use will be ascertained at each 
visit. SAEs should be reported to the sponsor via email. 
 
Data Safety Monitoring Board (DSMB) 
A Data Safety Monitoring Board (DSMB) will be formed to help monitor the study for feasibility to continue the 
study and adverse events (AEs). This board will consist of two board-certified neurologists not otherwise 
associated with the study and a biostatistician. They will meet yearly after the first patient is enrolled until the 
last patient completes the study.  
 

10 
 
It is possible that, despite a prolonged period with no new inflammatory disease activity, those who de-escalate 
their DMTs will have an increase in inflammatory disease activity.  The DSMB will be required to consider 
discontinuing the study if either of the following occurred at either interim analysis time point: 
-  Efficacy: one half of the subjects enrolled in the study experience a new MRI lesion concerning for MS. These 
patients would be expected to have a low rate of accumulation of new T2 lesions but patients with MS can 
develop new lesions. As a reference, according to DAYBREAK CSR (Table 14.2.2.3): over 3 years in the extension 
study of the phase 3 study RADIANCE, 56% of the subjects continuously treated with ozanimod developed 
new/enlarging T2 lesions relative to the baseline of the open-label extension study. (13).  
-  Safety: Evaluate serious AEs that to the discretion of the DSMB should lead to the discontinuation of the study 
due to the placement of subjects at significant risk to continue in the study.  
 
Additionally, any of the sites or the sponsor can decide to stop the study at any time due to concerns for safety. 
There will be a regular meeting with the site PIs and BMS that will occur at least quarterly and more frequently 
as needed to review recruitment and safety events.   
 
Study Timeline  
Recruitment will be over 9 months (approximately 1 patient per site per month). Patients, including dropouts, 
will be followed for 36 months. Interim analyses will be done every 6 months with reports/updates made at 
ACTRIMS/AAN and ECTRIMS.  
 
 
 

11 
 
Visit schedule:  
 
Visit 
Screening 
 (<30 days 
before 
baseline) 
Baseline 
(can be 
with 
screening)  
Month 
3  
(+/- 30 
days) 
Month 
6  
(+/- 30 
days) 
Month 
12  
(+/- 30 
days) 
Month 
18  
(+/- 30 
days) 
Month 
24  
(+/- 30 
days) 
Month 
30  
(+/- 30 
days) 
Month 
36 
(+/- 30 
days) 
Consent 
X 
 
 
 
 
 
 
 
 
CBC with diff, 
CMP  
X 
 
X 
X 
X 
X 
X 
X 
X 
IgG and IgM 
X 
 
 
 
X 
 
X 
 
X 
Biomarker 
evaluation^ 
X 
 
X 
X 
X 
X 
X 
X 
X 
B-cell levels* 
X 
 
 
X 
X 
X 
X 
X 
X 
Inclusion/ 
exclusion 
review  
X 
 
 
 
 
 
 
 
Demographic 
X 
 
 
 
 
 
 
 
Pregnancy 
evaluation% 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
OCT$ 
X 
X 
 
 
 
 
 
 
EDSS 
X 
 
X 
X 
X 
X 
X 
X 
MRI  
X 
 
X 
 
X 
 
 
X 
MSFC@ 
X 
 
X 
X 
X 
X 
X 
X 
PROs# 
X 
 
X 
X 
X 
X 
X 
X 
Drug 
Dispensing 
 
X 
 
X 
X 
X 
X 
X 
 
 
Relapse, pregnancy, and AE/tolerability assessments will be done in above visits and the 
following phone calls (+/- 5 business days): Month 1, 9, 15, 21, 27, 33 
^ NFL, GFAP, biobank samples [Patients will have the option to consent to storing blood (serum and peripheral 
blood mononuclear cells (PBMCs) in the University of Colorado Biorepository]. 
* PBMCs sent to the University of Colorado for evaluation of B-cell levels. 
% Pregnancy can be assessed via history and does not require a serum/pregnancy test. This can be done via 
standard of care if there is concern for current pregnancy. If a pregnancy is identified, the patient will be 
followed for 90 days after treatment discontinuation to collect the following information: the outcome of your 
pregnancy including spontaneous or voluntary termination; details of the birth (full-term, premature, or involves 
complications); the presence or absence of any birth defects, abnormalities, or complications; and the health 
status of your child. 
$ OCT – Not required on all subjects but will be performed on subjects at high risk for macular edema (e.g., Type 
2 Diabetes) and to be performed as standard of care and will be done via standard of care. A history of uveitis is 
exclusionary. 
@ MSFC to include SDMT (oral and written), 9-hole peg test, and 25-foot timed walk  
# PRO outcomes to include treatment satisfaction, employability status, fatigue, PDDS, MFIS, and quality of life 
(MSIS-29).  

12 
 
Unscheduled visits for further discussion of relapses, pregnancy, AEs, and/or drug tolerability will be done as 
determined by the site PI or sub-investigator. If there is a concern for a relapse, a history and physical exam by 
the PI or sub-PI to help assess if there was a relapse, a pseudorelapse, or something else.  These visits will 
include as much as possible NFL, GFAP, B-cell levels, biobank samples, EDSS, MSFC, and PROs. For pregnancy 
assessments, a discussion will include stopping treatment if the subject is pregnant and collection of outcomes 
as described in appendix A should be conducted.  
 
Funding/Budget 
The planned budget is $2 million and sponsored by BMS. The University of Colorado will serve as the primary 
site and will subcontract with the remaining sites. See separate documentation for full budgetary details.  
 
 
 

13 
 
References 
1. 
Wallin MT, Culpepper WJ, Campbell JD, Nelson LM, Langer-Gould A, Marrie RA, et al. The prevalence of 
MS in the United States: A population-based estimate using health claims data. Neurology. 2019;92(10):e1029-
e40. 
2. 
Inusah S, Sormani MP, Cofield SS, Aban IB, Musani SK, Srinivasasainagendra V, et al. Assessing changes in 
relapse rates in multiple sclerosis. Mult Scler. 2010;16(12):1414-21. 
3. 
Kalincik T, Vivek V, Jokubaitis V, Lechner-Scott J, Trojano M, Izquierdo G, et al. Sex as a determinant of 
relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136(Pt 12):3609-17. 
4. 
Cohan SL, Moses H, Calkwood J, Tornatore C, LaGanke C, Smoot KE, et al. Clinical outcomes in patients 
with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl fumarate: 
A multicenter retrospective observational study (STRATEGY). Mult Scler Relat Disord. 2018;22:27-34. 
5. 
Cohan SL, Edwards K, Lucas L, Gervasi-Follmar T, O'Connor J, Siuta J, et al. Reducing return of disease 
activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month 
interim results of teriflunomide therapy. Mult Scler J Exp Transl Clin. 2019;5(1):2055217318824618. 
6. 
Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in 
relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-88. 
7.           Vollmer BL, Wallach AI, Corboy JR, Dubovskaya K, Alvarez E, Kister I. Serious safety events in rituximab-
treated multiple sclerosis and related disorders. Ann Clin Transl Neurol. 2020 Sep;7(9):1477-1487. 
8.           Vollmer BL, Wolf AB, Sillau S, Corboy JR, Alvarez E. Evolution of Disease Modifying Therapy Benefits and 
Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis. Front 
Neurol. 2022 Jan 25;12:799138. 
9.  
Vollmer B, Ontaneda D, Harris H, Nair K, Bermel RA, Corboy JR, Fox RJ, Vollmer T, Cohen JA, Alvarez E, 
Hersh CM. Comparative discontinuation, effectiveness, and switching practices of dimethyl fumarate and 
fingolimod at 36-month follow-up. J Neurol Sci. 2019 Dec 15;407:116498.  
10.  
Cree BAC, Maddux R, Bar-Or A, Hartung HP, Kaur A, Brown E, Li Y, Hu Y, Sheffield JK, Silva D, Harris S. 
SARS-CoV-2 vaccination and infection in ozanimod-treated participants with relapsing multiple sclerosis. Ann 
Clin Transl Neurol. 2023 Oct;10(10):1725-1737. 
11.  
Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala 
Havrdová E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Ding N, Cohen JA; SUNBEAM Study Investigators. 
Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a 
multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1009-1020. 
12.  
Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala 
Havrdová E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Huang V, Kappos L; RADIANCE Trial Investigators. 
Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a 
multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1021-1033. 
13.  
Cree BA, Selmaj KW, Steinman L, Comi G, Bar-Or A, Arnold DL, Hartung HP, Montalbán X, Havrdová 
EK, Sheffield JK, Minton N, Cheng C, Silva D, Kappos L, Cohen JA. Long term safety and efficacy of ozanimod in 
relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial. Clinical Trial 
Mult Scler. 2022 Oct;28(12):1944-1962. 
 

14 
 
Appendix A - Risks Associated with Pregnancy 
 
The risks to an unborn child or nursing child from ozanimod are not known at this time. Ozanimod should not be 
taken by pregnant or nursing women. 
 
Studies in animals have shown that ozanimod can harm a fetus, and it is possible the study treatment may harm 
a nursing child or may cause a miscarriage. 
 
If you are a woman 
 
If you are pregnant, planning to become pregnant, or you are nursing a baby, you should not take part in this 
study. The study doctor will discuss effective birth control methods with you if you are able to become pregnant. 
This is to make sure that you do not become pregnant while in the study. Your chosen form of birth control must 
be effective by the time you receive your first dose of study drug. For example, birth control pills should be 
started at least 28 days before your first dose of study drug. 
 
If you can become pregnant, 
- 
pregnancy will be assessed at your study visits, and you must avoid any sexual activity that may lead to 
pregnancy or 
- 
you must use one of the approved options for birth control while taking the study drug and for at least 
90 days after your last dose of study drug. 
 
Approved options are any one of the following highly effective birth control methods: 
- 
Hormonal contraception (for example, birth control pills, intravaginal ring, transdermal patch, injection, 
implant); 
- 
intrauterine device (IUD); 
- 
tubal ligation (tying your tubes); 
- 
a partner with a vasectomy; or 
- 
abstinence. 
 
Certain other drugs may reduce the effectiveness of hormonal birth control treatments during and up to 30 days 
after discontinuation of these concurrent therapies. Please talk to your doctor for further information about 
birth control treatments. 
 
You must inform the study doctor, if at any time during the study: 
- 
your birth control method changes, or 
- 
you experience a problem with your current birth control method. 
 
If your ability to become pregnant changes (for example, you have an IUD removed, accidently miss taking any 
of your birth control pills, or enter menopause), you must inform and discuss with the study doctor or nurse 
about other birth control methods. 
 
If you suspect that you have become pregnant during the study or within 90 of the last dose of study drug, you 
must tell the study doctor right away.  Your study doctor must then require you to stop taking the study drug. 
Your study doctor will want to check on you during the pregnancy and ask you questions about the pregnancy.