Effect of ozanimod on meningeal inflammation and glial activation in Multiple Sclerosis: one year phase 4 experimental study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Azienda Ospedaliera Universitaria Integrata Verona

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

6 Jul 2023 → ongoing

Decision date (initial)

2024-11-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bristol-Myers Squibb Services Unlimited Company

External identifiers

EU CT number

2024-518859-27-00

EudraCT number

2023-000018-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

The aim of the project is to clarify the effect of ozanimod on compartmentalized inflammation by studying its effect on meningeal inflammation in CSF

Secondary objectives 7

1. To clarify whether and how ozanimod treatment is able to reduce/halt meningeal inflammation as reflected by additional CSF and serum biomarkers and combined MRI parameters
2. To clarify whether and how ozanimod treatment is able to reduce/halt microglial activation
3. To clarify the effect of ozanimod treatment on neuronal damage
4. To identify specific molecular, peripheral and intrathecal changes related to the ozanimod treatment
5. To identify potential biomarkers of treatment response in terms of clinical and neuropsychological evolution over time
6. To report the known and unknown adverse reactions to ozanimod
7. To characterize the variation of lymphoid and myeloid cells within the CSF in reaction to ozanimod treatment using high-resolution single-cell gene expression analysis

Conditions and MedDRA coding

Relapsing Multiple Sclerosis (relapsing-remitting, relapsing-progressive)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age 18-65 years
2. Relapsing-remitting MS (RRMS) diagnosed according to 2017 revision of McDonald criteria
3. 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)
4. 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
5. Available EDSS score between 0 and 5 at the time of ozanimod initiation
6. At least 2mL of CSF and 10 mL of blood acquired any time before the beginning of ozanimod treatment and stored at -80°C
7. 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)
8. Positive varicella zoster virus immunoglobulin G antibody status or varicella zoster virus vaccination at least 28 days before ozanimod initiation
9. Pregnancy test negative and a highly effective methods of contraception

Exclusion criteria 14

1. Individuals with inactive primary or secondary progressive multiple sclerosis
2. Disease duration more than 15 years with an EDSS of 2.0 or less;
3. History of relapse or systemic corticosteroid use from 30 days before therapy initiation
4. Hypersensitivity to ozanimod or to any of the listed excipients
5. Primary or secondary immunodeficiency syndrome or lymphocyte count not within normal limits due to any cause, ongoing immunosuppressive therapy (including chronic use of steroid)
6. 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
7. Primary or secondary immunodeficiency syndrome, lymphocyte count not within normal limits due to any cause
8. Ongoing immunosuppressive therapy (including chronic use of steroid)
9. Platelet count < 100.000/mcL; Hemoglobin < 8.5 g/dL; Leukocytes < 3500/mcL; Neutrophils <1500/mcL
10. 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
11. Severe hepatic impairment (Child-Pugh class C)
12. Pregnancy or breastfeeding. ● Fertile women who do not use effective methods of contraception.
13. Received a live vaccine within 4 weeks prior to ozanimod administration or intends to receive a live vaccination during the trial
14. Macular oedema excluded by an ophthalmologic evaluation for patients with diabetes mellitus, uveitis or positive history of retinopathy, before starting treatment with ozanimod

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. CSF (and serum) concentration of CXCL13 protein (ng/ml/mgPro) measured before starting ozanimod treatment (Prebaseline) and at T12.

Secondary endpoints 8

1. CSF (and serum) concentration of specific markers of activated meningeal inflammation (CXCL12, TNF-a, IFN-¿) (ng/ml/mgPro) measured before starting ozanimod treatment (Prebaseline) and at T12.
2. CSF (and serum) concentration of specific makers of activated microglia/macrophages (Chitinase 3-like1, Osteopontin, sCD163, CX3CL1) (ng/ml/mgPro) measured before starting ozanimod treatment (Prebaseline) and at T12.
3. CSF (and serum) concentration of specific markers of neuronal/axonal damage (neurofilamentlight chains, parvalbumin) (ng/ml/mgPro) measured before starting ozanimod treatment (Prebaseline) and at T12
4. Number and volume of cortical lesions measured before starting ozanimod treatment (Prebaseline) and at T12
5. Number and susceptibility of of paramagnetic rim lesions measured before starting ozanimod treatment (Prebaseline), at baseline (T0) and after 1 year of ozanimod treatment (T12)
6. Variation of the volume of white matter lesions before starting ozanimod treatment (¿ prebaseline-T0) and after 1 year of ozanimod treatment (¿ T0-T12)
7. Variation global and regional cortical thickness change before starting ozanimod treatment (¿prebaseline-T0) and after 1 year of ozanimod treatment (¿ T0-T12)
8. Significant linear relationship between the variation of the above-mentioned cytokines (¿ T0-T12) and the EDSS change (¿ T0-T12) or the relapse number by the end of the follow-up (T12)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Azienda Ospedaliera Universitaria Integrata Verona

Sponsor organisation

Azienda Ospedaliera Universitaria Integrata Verona

Address

Piazzale Ludovico Antonio Scuro 10

City

Verona

Postcode

37134

Country

Italy

Scientific contact point

Organisation

Azienda Ospedaliera Universitaria Integrata Verona

Contact name

Massimiliano Calabrese

Public contact point

Organisation

Azienda Ospedaliera Universitaria Integrata Verona

Contact name

Massimiliano Calabrese

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications