Exploring the effect of a novel therapy on chronic intrathecal inflammation in patients with active progressive multiple sclerosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Azienda Ospedaliera Universitaria Integrata Verona

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

29 May 2023 → ongoing

Decision date (initial)

2024-08-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ministry of Health

External identifiers

EU CT number

2024-512283-65-00

EudraCT number

2023-000142-42

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To evaluate the effect of siponimod in secondary progressive MS patients with reference to the effect of the drug on advanced immunological measures of chronic inflammation, in paired blood and cerebrospinal fluid (CSF) in a cohort of 40 SPMS
patients, treated with Siponimod and followed-up for at least two-years

Secondary objectives 2

1. To evaluate the effect of Siponimod on MRI biomarkers of compartmentalized inflammation linked to disease progression
2. To evaluate clinical, neuropsychological and safety data in a real-life population of SPMS treated with Siponimod

Conditions and MedDRA coding

patients with secondary progressive MS

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 lesion on MRI acquired, in the previous 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
4. Availability of 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 breastfeeding at T0 nor during the study phase. Before enrollment, female subjects of childbearing potential must be informed about risks to the fetus, must have a negative pregnancy test and must use highly effective methods of contraception to prevent pregnancy during treatment as well as for at least 10 days after stopping treatment. Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: a) combined (estrogen and progestin containing) hormonal contraception associated with inhibition of ovulation: i) oral ii) intravaginal iii) transdermal b) progestogen-only hormonal contraception associated with inhibition of ovulation: i) oral ii) injectable iii) implantable c) intrauterine device (IUD) d) intrauterine hormone-releasing system (IUS) e) bilateral tubal occlusion f) vasectomised partner g) sexual abstinence Male subjects must use a condom if their partners are fertile, and the female partner must use a highly effective contraception measure, according to the document “Recommendations related to contraception and pregnancy testing in clinical trials, Version 1.1” (CTFG 21/09/2020

Exclusion criteria 15

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 or platelets 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 ¿ Complete left bundle branch block ¿ 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
9. Severe liver dysfunction (i.e. transaminase and/or bilirubin levels > 3x ULN) or kidney dysfunction (serum creatinine not within normal limits dysfunction
10. 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)
11. History of hypersensitivity to any metabolites or drugs of the same class as siponimod. ¿ Hypersensitivity to the active substance or to peanuts, soy or to any of the excipients
12. Abnormal skin or ophthalmic examination
13. Diabetes mellitus
14. Pregnancy positive test or breastfeeding
15. Fertile women who do not use highly effective methods of contraception

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To characterize the effect of the drug on cerebrospinal fluid markers of chronic intrathecal inflammation. According to literature, to our previous studies and preliminary data, that pointed to a key role of CXCL13 in mediating B-cell accumulation and its association with disease severity and progression, the sample size has been calculated taking in account as primary endpoint to measure changes in the CSF levels of CXCL13.

Secondary endpoints 8

1. the characterization of intrathecal (and paired blood) adaptive and immune cell subsets through a high-dimensional flow cytometry performed at T0 and after two years of treatment (T24)
2. Evaluation of paired blood and CSF markers of inflammation and neurodegeneration at T0 and T24
3. Assessment of CSF oligoclonal bands status and number at T0 and after two years of treatment (T24)
4. Assessment of the main pro-inflammatory (e.g., prostaglandins and leukotriens) and pro-resolving (e.g., resolvins, protectins, maresins and lipoxins) lipids at T0 and T24
5. evaluation of cortical lesions (CLs) number and volume and their changes, evaluation of chronic active lesions number and evolution (such analysis will be performed by identifying rim-positive lesions on SWI), the rate of global and regional cortical thickness change using 3D T1 FFE sequences, longitudinal change of MTSat/MWF multiparametric combination will be computed in WM lesions and normal appearing white matter, longitudinal changes in the cross sectional area of the spinal cord.
6. To evaluate the EDSS change before, during, and after the treatment
7. To evaluate changes in cognitive functioning from T0 to T24
8. 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 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Azienda Ospedaliera Universitaria Integrata Verona

Sponsor organisation

Azienda Ospedaliera Universitaria Integrata Verona

Address

Piazzale Aristide Stefani 1

City

Verona

Postcode

37126

Country

Italy

Scientific contact point

Organisation

Azienda Ospedaliera Universitaria Integrata Verona

Contact name

Damiano Marastoni

Public contact point

Organisation

Azienda Ospedaliera Universitaria Integrata Verona

Contact name

Damiano Marastoni

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 8 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