Efficacy and safety of remibrutinib compared to teriflunomide in participants with relapsing multiple sclerosis, followed by long term treatment with remibrutinib

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

22 Jun 2022 → ongoing

Decision date (initial)

2024-06-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-509345-12-00

EudraCT number

2020-005899-36

WHO UTN

U1111-1321-6733

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacogenetic, Efficacy, Pharmacokinetic, Therapy, Others

To demonstrate that remibrutinib is superior to teriflunomide in reducing the frequency of confirmed relapses

Secondary objectives 9

1. To assess whether remibrutinib is superior to teriflunomide in delaying disability progression based on the pooled data from both identical pivotal studies
2. To assess whether remibrutinib is superior to teriflunomide in reducing new inflammatory activity on Magnetic Resonance Imaging (MRI), based on MRI cohort data
3. To assess whether remibrutinib is superior to teriflunomide in reducing neuronal damage, as measured by NfL
4. To assess whether remibrutinib is superior to teriflunomide in disease-activity-free status based on pooled data from both identical pivotal studies (MRI Cohort)
5. To assess the effects of remibrutinib relative to teriflunomide on additional clinical and MRI endpoints [pooled data from both identical pivotal studies will be used as indicated in the endpoint column]
6. To assess the effect of remibrutinib relative to teriflunomide on the physical and psychological impact of MS
7. To assess the safety and tolerability of remibrutinib compared to teriflunomide
8. To assess the pharmacokinetics (PK) of remibrutinib
9. Extension Part: To assess long-term safety, tolerability and efficacy parameters in participants treated with remibrutinib

Conditions and MedDRA coding

Multiple Sclerosis

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Signed informed consent obtained prior to any assessment performed (confirm at screening visit)
2. Male or female participants 18 to 55 years of age (inclusive) at screening
3. Diagnosis of RMS according to the 2017 McDonald diagnostic criteria (this would include RRMS or active SPMS) as confirmed at screening visit
4. At least: 1 documented relapse within the previous year, OR 2 documented relapses within the previous 2 years, prior to screening, OR 1 active Gadolinium (Gd)-enhancing lesion in the 12 months prior to screening
5. EDSS score of 0 to 5.5 (inclusive) at screening and randomization
6. Neurologically stable within 1 month prior to screening and randomization (including no Multiple Sclerosis (MS) relapse in this period)

Exclusion criteria 13

1. Disease duration of more than 10 years in participants with EDSS score of 2 or less at screening
2. History of clinically significant Central Nervous System (CNS) disease (e.g. stroke, traumatic brain or spinal injury, history or presence of myelopathy) or neurological disorders which may mimic MS at screening
3. Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or neurological symptoms consistent with PML prior to randomization
4. Score “yes” on item 4 or item 5 of the suicidal ideation section of the Columbia Suicide Severity Rating Scale (C-SSRS), if this ideation occurred in the past 6 months, or “yes” on any item of the suicidal behavior section, except for the “Non-Suicidal Self-Injurious Behavior” (item also included in the suicidal behavior section), if this behavior occurred in the past 2 years, prior to randomization
5. Participants who have had a splenectomy
6. Active clinically significant systemic bacterial, viral, parasitic or fungal infections in the judgement of the investigator prior to randomization (e.g. infections requiring hospitalization or i.v. antibiotics)
7. Active, chronic disease of the immune system (including stable disease treated with immune therapy (e.g. Leflunomide, Methotrexate)) other than MS (e.g. rheumatoid arthritis, systemic lupus erythematosus, etc.) with the exception of well-controlled diabetes or thyroid disorder
8. Participants with a known immunodeficiency syndrome (acquired immunodeficiency syndrome (AIDS), hereditary immune deficiency, drug induced immune deficiency), or tested positive for Human immunodeficiency virus (HIV) antibody, at screening
9. Resting QT interval corrected by Fridericia’s formula (QTcF) ≥450 msec (male) or ≥460 msec (female) at pretreatment as per central ECG reading at screening visit
10. Use of exclusionary medication prior to screening/randomization
11. Requirement for anticoagulant medication (e.g. warfarin or Novel Anti-Coagulants (NOAC)) or use of dual anti-platelet therapy (e.g. acetylsalicylic acid + clopidogrel). The use of acetylsalicylic acid up to 100 mg/day or clopidogrel up to 75 mg/day is permitted
12. Significant bleeding risk or coagulation disorders, at screening
13. Have received any live or live-attenuated vaccines (including but not limited to varicella-zoster virus or measles, oral polio, nasal influenza) within 6 weeks prior to randomization or requirement to receive these vaccinations at any time during study treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Annualized relapse rate (ARR) of confirmed relapses

Secondary endpoints 17

1. Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS)
2. Time to 6-month confirmed disability progression (6mCDP) on EDSS
3. Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate)
4. Total number of Gd-enhancing T1 lesions per MRI scan
5. Neurofilament light chain (NfL) concentration in serum
6. Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3), as assessed by absence of confirmed MS relapses, 6mCDP and new/enlarging T2 lesions on MRI
7. Time to first confirmed relapse
8. Time to 6-month confirmed disability improvement (6mCDI) on EDSS (pooled data)
9. Time to 3mCDP and 6mCDP independent of relapse activity (PIRA, pooled data)
10. Change from baseline in the Symbol Digit Modalities Test (SDMT) (pooled data)
11. Time to 6-month confirmed worsening by at least 20% in the: ● Timed 25-foot walk test (T25FW) (pooled data) ● Timed 9-hole peg test (9HPT) (pooled data)
12. Time to composite 6-month confirmed disability progression, as evaluated by 6mCDP or 6-month confirmed worsening by at least 20% in T25FW or 9HPT (pooled data)
13. Change from baseline in T2 lesion volume
14. Multiple Sclerosis Impact Scale (MSIS-29)
15. Adverse events, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating
16. Remibrutinib blood concentrations
17. Extension Part: ● Adverse events, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating ● ARR, number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate), time to 6mCDP (EDSS), change in SDMT, NfL, Patient Reported Outcomes scores

Investigational products

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

Test 1

Comparator 1

Placebo 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 20

Locations

13 EU/EEA countries · 69 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 229 files

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

Application history

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