Evaluation of Ozanimod on Meningeal Inflammation and Glial Activation in Relapsing Multiple Sclerosis: A Phase 4 Study

Trial ID: 2024-518859-27-00
Sponsor: Azienda Ospedaliera Universitaria Integrata Verona

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Diseases & Conditions

Multiple sclerosis Relapsing-remitting multiple sclerosis Progressive relapsing multiple sclerosis

Objectives

The primary objective of this study is to elucidate the effect of **ozanimod** on compartmentalized inflammation by examining its impact on meningeal inflammation in the cerebrospinal fluid (CSF) in patients with Relapsing Multiple Sclerosis, including both relapsing-remitting and relapsing-progressive forms. This is clinically relevant as meningeal inflammation is a critical factor in the progression of Multiple Sclerosis, and understanding the therapeutic potential of ozanimod could lead to improved management of the disease.

Secondary objectives include:

To determine whether and how ozanimod treatment can reduce or halt meningeal inflammation as indicated by additional CSF and serum biomarkers and combined MRI parameters.
To assess whether and how ozanimod treatment can reduce or halt microglial activation.
To evaluate the effect of ozanimod treatment on neuronal damage.
To identify specific molecular, peripheral, and intrathecal changes related to ozanimod treatment.
To identify potential biomarkers of treatment response concerning clinical and neuropsychological evolution over time.
To report known and unknown adverse reactions to ozanimod.
To characterize the variation of lymphoid and myeloid cells within the CSF in response to ozanimod treatment using high-resolution single-cell gene expression analysis.

Participants

The clinical trial involves participants diagnosed with **Relapsing Multiple Sclerosis**, specifically relapsing-remitting and relapsing-progressive forms. The study population includes both male and female subjects, aged between 18 and 65 years, who are generally in good health as indicated by an Expanded Disability Status Scale (EDSS) score between 0 and 5 at the time of ozanimod initiation. The trial population was selected based on specific criteria, including a recent diagnosis of relapsing-remitting MS according to the 2017 revision of the McDonald criteria and recent initiation of ozanimod treatment. Participants must have met at least one disease activity criterion, such as experiencing a relapse or having a gadolinium-enhancing lesion within the past 12 months. Lifestyle considerations include the requirement for a negative pregnancy test and the use of highly effective contraception methods. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the effect of **ozanimod** on meningeal inflammation and glial activation in patients with **Relapsing Multiple Sclerosis**. This is a one-year, phase IV, randomized, double-blind, controlled study. The trial will involve participants aged 18-65 years who have been diagnosed with relapsing-remitting multiple sclerosis according to the 2017 revision of the McDonald criteria. Participants must have started treatment with ozanimod within 30-90 days prior to enrollment, following a specific dose escalation regimen. The study will assess both primary and secondary endpoints, including the concentration of specific proteins and markers in cerebrospinal fluid (CSF) and serum, as well as changes in lesion volume and cortical thickness.

The trial will commence with a screening visit to confirm eligibility based on the inclusion criteria, such as a recent MRI scan and a negative pregnancy test. Following the screening, participants will undergo a baseline visit where pre-treatment measurements will be taken. Subsequent follow-up visits will occur at regular intervals to monitor the effects of ozanimod, with the final visit marking the end of the study at 12 months. The expected duration of participant involvement is approximately one year, with conditions for early termination including adverse events or withdrawal of consent.

Throughout the trial, participants will be required to adhere to the study protocol, including the use of highly effective contraception methods if applicable. The primary endpoint will focus on the CSF concentration of CXCL13 protein, while secondary endpoints will evaluate additional markers of inflammation and neuronal damage. The study aims to provide insights into the impact of ozanimod on compartmentalized inflammation in multiple sclerosis, contributing to the understanding of its therapeutic potential.

Treatment

The clinical trial involves the administration of **Zeposia** 0.92 mg hard capsules, which contain the active substance **ozanimod**. This pharmaceutical form is a hard capsule designed for **oral use**. The maximum daily dose of ozanimod is 920 micrograms, and the treatment period extends up to 12 months. The capsules are manufactured by Bristol-Myers Squibb Pharma EEIG and are classified under the ATC code L04AE02. The active substance, ozanimod, is of chemical origin and is also known by the synonym RPC1063. The trial aims to evaluate the effect of ozanimod on meningeal inflammation and glial activation in patients with Multiple Sclerosis.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as per the study protocol. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the impact of ozanimod on compartmentalized inflammation by studying its effect on meningeal inflammation in cerebrospinal fluid (CSF).

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint involves measuring the concentration of **CXCL13 protein** in cerebrospinal fluid (CSF) and serum, both before the initiation of ozanimod treatment (Prebaseline) and at the 12-month mark (T12). Secondary endpoints include the concentration of specific markers of activated meningeal inflammation, such as **CXCL12**, **TNF-a**, and **IFN-γ**, as well as markers of activated microglia/macrophages like **Chitinase 3-like1**, **Osteopontin**, **sCD163**, and **CX3CL1**. Additionally, markers of neuronal/axonal damage, including **neurofilament light chains** and **parvalbumin**, will be evaluated. These measurements will also be taken at Prebaseline and T12.

Further secondary endpoints include the assessment of the number and volume of cortical lesions, the number and susceptibility of paramagnetic rim lesions, and the variation in the volume of white matter lesions. These will be measured at Prebaseline, baseline (T0), and after one year of treatment (T12). The study will also evaluate changes in global and regional cortical thickness over the same time periods. A significant linear relationship between the variation of the aforementioned cytokines and changes in the Expanded Disability Status Scale (EDSS) or the number of relapses by the end of the follow-up (T12) will be analyzed. These efficacy parameters will be collected and analyzed using validated laboratory tests and imaging techniques at specified timepoints throughout the study duration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age 18-65 years
Relapsing-remitting MS (RRMS) diagnosed according to 2017 revision of McDonald criteria
Treatment with ozanimod started within 30-90 days before the enrollment according to the AIFA indications for prescribing ozanimod (dose escalation regimen of ozanimod from Day 1 to Day 7: Days 1 – 4 0.23 mg once daily; Days 5 – 7 0.46 mg once daily; Days 8 and thereafter 0.92 mg once daily)
Met 1 of the following disease activity criteria: 1) at least one relapse within 12 months before the therapy initiation or 2) at least one gadolinium-enhancing lesion or at least new T2/FLAIR lesion within 12 months before the therapy initiation
Available EDSS score between 0 and 5 at the time of ozanimod initiation
At least 2mL of CSF and 10 mL of blood acquired any time before the beginning of ozanimod treatment and stored at -80°C
Availability of an MRI scan performed at least 90 days before the beginning of ozanimod including 3DT1,3D FLAIR/T2-weighted sequences and 3D Gradient Echo Planar Imaging Susceptibility weighted (Magnitude and Phase)
Positive varicella zoster virus immunoglobulin G antibody status or varicella zoster virus vaccination at least 28 days before ozanimod initiation
Pregnancy test negative and a highly effective methods of contraception

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Exclusion Criteria

Individuals with inactive primary or secondary progressive multiple sclerosis
Disease duration more than 15 years with an EDSS of 2.0 or less;
History of relapse or systemic corticosteroid use from 30 days before therapy initiation
Hypersensitivity to ozanimod or to any of the listed excipients
Primary or secondary immunodeficiency syndrome or lymphocyte count not within normal limits due to any cause, ongoing immunosuppressive therapy (including chronic use of steroid)
Resting heart rate less than 55 beats per min (bpm) at screening; patients who in the last 6 months experienced myocardial infarction (MI), unstable angina, stroke, transient ischaemic attack (TIA), decompensated heart failure requiring hospitalization or New York Heart Association (NYHA) Class III/IV heart failure, patients with history or presence of second-degree atrioventricular (AV) block Type II or third- degree AV block or sick sinus syndrome unless the patient has a functioning pacemaker
Primary or secondary immunodeficiency syndrome, lymphocyte count not within normal limits due to any cause
Ongoing immunosuppressive therapy (including chronic use of steroid)
Platelet count < 100.000/mcL; Hemoglobin < 8.5 g/dL; Leukocytes < 3500/mcL; Neutrophils <1500/mcL
Active acute infections or chronic infections including HBV, HCV, HIV, ● Active or chronic TBC assessed performing an intradermal reaction test or chest x-ray ● Active malignancies or history of malignancies
Severe hepatic impairment (Child-Pugh class C)
Pregnancy or breastfeeding. ● Fertile women who do not use effective methods of contraception.
Received a live vaccine within 4 weeks prior to ozanimod administration or intends to receive a live vaccination during the trial
Macular oedema excluded by an ophthalmologic evaluation for patients with diabetes mellitus, uveitis or positive history of retinopathy, before starting treatment with ozanimod