Effect of siponimod on relevant imaging and immunological hallmarks of progressive multiple sclerosis

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

28 Feb 2022 → ongoing

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Farma Spa

External identifiers

EU CT number

2024-518374-13-00

EudraCT number

2020-005947-22

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To evaluate the effect of siponimod on paramagnetic rim lesions (as visualized by MRI) in secondary progressive MS patients

Secondary objectives 2

1. To evaluate the effect of siponimod in modifying the CSF and serum levels of biomarkers of microglial/macrophage activity and the axonal/neuronal damage
2. To evaluate the effect of siponimod on the clinical and cognitive worsening in progressive MS patients and its long-term safety

Conditions and MedDRA coding

Active progressive multiple sclerosis course after an initial relapse clinical course

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Age 18-65 years
2. Active progressive MS course after an initial relapse clinical course defined as an EDSS progression of at least 1 point with a history of relapse and/or evidence of radiological activity defined as new/enlarging T2-FLAIR hyperintense or Gd-enhancing or paramagnetic rim positive lesion on MRI acquired, in the 2 years before the enrolment
3. Availability of a 3T MRI performed within the last 2 years. This MRI must include these sequences: - 3D T1 weighted Fast Field Echo (FFE) - 3D Fluid Attenuated Inversion Recovery (FLAIR) - 3D Echo Planar Imaging Susceptibility weighted (Magnitude and Phase)
4. Availability of a detailed clinical data on medical history with neurological evaluation performed at least twice in the past two years (or once in the past year)
5. EDSS between 3.0 and 6.0
6. Less than 5 years since entering the progressive phase of the disease
7. Female subjects must not be pregnant or breast feeding at T0 nor during the study phase

Exclusion criteria 18

1. Patients homozygous for the CYP2C9 *3 *3 allele
2. Immunodeficiency syndrome
3. History of progressive multifocal leukoencephalopathy or cryptococcal meningitis
4. Hematologic alterations (lymphocyte count not within normal limits)
5. Rheumatic disease under specific treatment (including chronic use of steroid)
6. Severe active infections (regard to positive result to HBV, HCV, HIV, Quantiferon)
7. Active malignities
8. Myocardial infarction, unstable angina, stroke (any time), TIA (in the last 6 months) • NYHA Class III or IV heart failure
9. Complete left bundle branch block
10. First- or second-degree [Mobitz type I] AV block, • Second grade AV block (Mobitz type II); • Third grade AV block (unless patient has a functioning pacemaker) • Sinus bradycardia (HR < 55 bpm) or symptomatic bradycardia (i.e. history of recurrent syncope) • QTc =500 msec
11. Severe liver dysfunction (i.e. transaminase and/or bilirubin levels > 3x ULN)
12. Negativity for varicella zoster IgG antibodies (in case of vaccination by live vaccine the beginning of therapy must be postponed of at least 30 days)
13. History of hypersensitivity to any metabolites or drugs of the same class as siponimod
14. Hypersensitivity to the active substance or to peanuts, soy or to any of the excipients
15. Pregnancy or breast feeding. • Fertile women who do not use effective methods of contraception.
16. Previous and ongoing therapies: ¿ Natalizumab (last dose less than 6 months prior to enrollment); ¿ Rituximab, Ocrelizumab (last dose less than 6-months prior to enrollment); ¿ Cyclophosphamide (last dose less than 3-months prior to enrollment)
17. Previous and ongoing therapies: Fingolimod, Mitoxantrone therapy or evidence of cardiotoxicity or a cumulative dose greater than 60 mg/m2 (last dose less than 2-year prior enrollment) ¿ Alemtuzumab, cladribine, autologous stem cell transplantation and other immunosuppressive treatments with expected effect of over 6 months (any time) ¿ Intravenous corticosteroid cycle to treat MS clinical relapse (1-month before enrollment)
18. Previous and ongoing therapies: Antiarrhythmics Class Ia (e.g. quinidine, procainamide), Class III (amiodarone, sotalolo) drugs and those that may decrease heart rate (e.g. beta-blockers, calcium channel blockers, ivabradine and digoxin)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The study endpoint is the change (assumed to be a reduction) of the susceptibility of the rim lesions after treatment with siponimod in comparison to the “natural” change of this parameter during a recent period-time preceding treatment (no later than two years before) with siponimod, so that for each patient an internal comparison will be available.

Secondary endpoints 6

1. To evaluate the effect of siponimod in reducing the number of SEL comparing to the period prior the treatment (retrospective phase) with the study phase (T3 vs T12 and T3 vs T24).
2. To describe the individual changes in CSF levels of specific makers of activated microglia/macrophages (sCD14, sCD163, TNF, sTNFR1, sTNFR2, Chitinase 3-1like) and of neuronal/axonal damage (neurofilament-light chains, parvalbumin) from baseline to T24
3. To evaluate the changes of sCD14, sCD163, TNF, sTNFR1, sTNFR2, Chitinase 3-1like, neurofilament-light chains, and parvalbumin in serum of patients at baseline and at T6, T12, T18, T24
4. To evaluate the EDSS change between the retrospective phase and the study phase (T0 vs T12 and T12 vs T24
5. To evaluate changes in cognitive functioning during the two-year study phase (T0-T24)
6. Treatment emergent adverse effect (TEAE) and serious adverse event (SAE) at each follow-up visit

Investigational products

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

Test 6

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 · 2 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 11 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