REMIBRUTINIB for Relapsing multiple sclerosis

Inclusion criteria

• {"criterion_text":"- Signed informed consent obtained prior to any assessment performed (confirm at screening visit"}
• {"criterion_text":"- Male or female participants 18 to 55 years of age (inclusive) at screening"}
• {"criterion_text":"- Diagnosis of RMS according to the 2017 McDonald diagnostic criteria (this would include RRMS or active SPMS) as confirmed at screening visit"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- EDSS score of 0 to 5.5 (inclusive) at screening and randomization"}
• {"criterion_text":"- Neurologically stable within 1 month prior to screening and randomization (including no Multiple Sclerosis (MS) relapse in this period)"}

Exclusion criteria

• {"criterion_text":"- Disease duration of more than 10 years in participants with EDSS score of 2 or less at screening"}
• {"criterion_text":"- Use of exclusionary medication prior to screening/randomization"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Significant bleeding risk or coagulation disorders, at screening"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or neurological symptoms consistent with PML prior to randomization"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Participants who have had a splenectomy"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- Active, chronic disease of the immune system (including stable disease treated with immune therapy, eg. leflunomide, methotrexate) other than MS (e.g. rheumatoid arthritis, systemic lupus erythematosus, etc.) with the exception of well-controlled diabetes or thyroid disorder"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Resting QT interval corrected by Fridericia’s formula (QTcF) ≥450 msec (male) or ≥460 msec (female) at pre-treatment as per central ECG reading at screening"}

Primary endpoints

• {"endpoint_text":"- Annualized relapse rate (ARR) of confirmed relapses","definition_or_measurement_approach":"Annualized relapse rate = rate of confirmed MS relapses per participant per year (frequency of confirmed relapses annualized over follow-up)."}

Secondary endpoints

• {"endpoint_text":"- Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS)","definition_or_measurement_approach":"Time-to-event measured as time from randomization to sustained (3-month) confirmed increase in EDSS score per protocol-defined criteria."}
• {"endpoint_text":"- Time to 6-month confirmed disability progression (6mCDP) on EDSS","definition_or_measurement_approach":"Time-to-event measured as time from randomization to sustained (6-month) confirmed increase in EDSS score per protocol-defined criteria."}
• {"endpoint_text":"- Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate)","definition_or_measurement_approach":"MRI assessment: count of new or enlarging T2 lesions per participant per year (annualized rate) from centrally read MRI scans."}
• {"endpoint_text":"- Total number of Gd-enhancing T1 lesions per MRI scan","definition_or_measurement_approach":"MRI assessment: count of gadolinium-enhancing T1 lesions per scan (central MRI reading)."}
• {"endpoint_text":"- Neurofilament light chain (NfL) concentration in serum","definition_or_measurement_approach":"Biomarker measurement: serum NfL concentration measured in blood samples using validated assay per laboratory procedures."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Composite endpoint: participant is NEDA-3 if there are no confirmed relapses, no 6-month confirmed disability progression (6mCDP), and no new/enlarging T2 MRI lesions during assessment window."}
• {"endpoint_text":"- Time to first confirmed relapse","definition_or_measurement_approach":"Time-to-event: time from randomization to first protocol-defined confirmed relapse."}
• {"endpoint_text":"- Time to 6-month confirmed disability improvement (6mCDI) on EDSS (pooled data)","definition_or_measurement_approach":"Time-to-event: time to sustained (6-month) confirmed improvement on EDSS compared with baseline (using pooled study data)."}
• {"endpoint_text":"- Time to 3mCDP and 6mCDP independent of relapse activity (PIRA, pooled data)","definition_or_measurement_approach":"Time-to-event: progression independent of relapse activity (PIRA) assessed as 3mCDP/6mCDP events not temporally related to relapses (using pooled data)."}
• {"endpoint_text":"- Change from baseline in the Symbol Digit Modalities Test (SDMT) (pooled data)","definition_or_measurement_approach":"Cognitive assessment: change from baseline in SDMT score measured at scheduled visits; pooled across studies as indicated."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Time-to-event: time to sustained (6-month) confirmed ≥20% worsening on T25FW or 9HPT compared with baseline (pooled data)."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Composite time-to-event endpoint combining 6mCDP or confirmed ≥20% worsening on T25FW or 9HPT sustained for 6 months."}
• {"endpoint_text":"- Change from baseline in T2 lesion volume","definition_or_measurement_approach":"MRI assessment: change in total T2 lesion volume from baseline measured on central MRI analysis."}
• {"endpoint_text":"- Multiple Sclerosis Impact Scale (MSIS-29)","definition_or_measurement_approach":"Patient-reported outcome: MSIS-29 score (physical and psychological impact) change from baseline."}
• {"endpoint_text":"- Adverse events, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating","definition_or_measurement_approach":"Safety assessments: collection and reporting of adverse events, central lab tests, vital signs, ECG readings and C-SSRS scores per safety monitoring plan."}
• {"endpoint_text":"- Remibrutinib blood concentrations","definition_or_measurement_approach":"Pharmacokinetic endpoint: measured remibrutinib plasma/blood concentrations at scheduled PK timepoints."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Extension part endpoints include long-term safety (AEs, labs, vitals, ECG, C-SSRS) and efficacy measures (ARR, MRI lesion rates, time to 6mCDP, SDMT, NfL, PROs) assessed over extension follow-up."}

Methods

• Country-specific recruitment arrangements documents (K1) submitted for each participating country (e.g. K1_Recruitment Arrangements files for Romania, Spain, Germany, etc.).
• Use of paid or unpaid advertisements and country-language recruitment adverts (K2_Advertisements documents present for multiple countries, e.g. Spain, France, Germany).
• Third-party recruitment and patient-facing materials support by Jumo Health USA Inc. (listed as 'Recruitment and Patient facing materials').
• Pre-screening software/tool support provided by Reify Health Inc. ("Software services for pre-screening tool" listed among sponsor third parties).
• Site-based recruitment through participating neurology clinics and hospitals (multiple hospital/clinic sites listed per country).

Primary sponsor

Full Name

Novartis Pharma AG

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Study management and CRO services (listed duties include code 1)

Name

Syneos Health Inc.

Responsibilities

Study management and CRO services (listed duties include code 1)

Name

Parexel International (IRL) Limited

Responsibilities

Clinical trial services (code 12)

Name

IQVIA Limited

Responsibilities

Clinical trial services, provision of ECG machines and ECG analysis/review, and other duties (codes 1, 15, 3)

Name

Catalent Pharma Solutions, LLC (Clinical Supply Services)

Responsibilities

Supply of commercial drug products / clinical supply responsibilities

Third parties

• {"country":"Switzerland","full_name":"Neurostatus-UHB AG","duties_or_roles":"EDSS licensing and consultancy","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Code 7 (electronic/data services) - listed as sponsor duty code 7","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Study management (code 1)","organisation_type":"Pharmaceutical company / CRO"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited (duplicate entry)","duties_or_roles":"Study management (code 1)","organisation_type":"Pharmaceutical company / CRO"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"Study management (code 1)","organisation_type":"Pharmaceutical company / CRO"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"Provision of electronic tablet & handheld devices for patient data capture; other duties (codes 15 and 7)","organisation_type":"Pharmaceutical company / ePRO vendor"}
• {"country":"United States","full_name":"RWS Life Sciences Inc.","duties_or_roles":"PRO licensing and translation services","organisation_type":"Pharmaceutical company / vendor"}
• {"country":"Poland","full_name":"Komtur Polska Sp. z o.o.","duties_or_roles":"Local purchase of medicinal products (non-IMP)","organisation_type":"Pharmaceutical company / vendor"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Data capture/electronic systems (code 7)","organisation_type":"Non-Pharmaceutical company / eClinical vendor"}
• {"country":"United States","full_name":"Jumo Health USA Inc.","duties_or_roles":"Recruitment and patient-facing materials","organisation_type":"Hospital/Clinic/Other health care facility / recruitment vendor"}
• {"country":"Latvia","full_name":"Oribalt Riga SIA","duties_or_roles":"Cholestyramine provision to sites in Estonia (collection, storage & destruction of IMP, relabeling, locally purchasing supportive, IMP home delivery)","organisation_type":"Pharmaceutical company / vendor"}
• {"country":"United Kingdom","full_name":"Medical Equipment Supplies And Management Limited","duties_or_roles":"Provision of ancillary supplies","organisation_type":"Pharmaceutical company / vendor"}
• {"country":"United States","full_name":"Reify Health Inc.","duties_or_roles":"Software services for pre-screening tool","organisation_type":"Hospital/Clinic/Other health care facility / software"}
• {"country":"Germany","full_name":"DATAMAP-Gesellschaft fuer Datenmanagement Datenanalyse und Datenpraesentation mbH","duties_or_roles":"Data management / analysis (code 10)","organisation_type":"Non-Pharmaceutical company / data vendor"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Laboratory services (code 4)","organisation_type":"Pharmaceutical company / central laboratory"}
• {"country":"Croatia","full_name":"Medical Intertrade d.o.o.","duties_or_roles":"Import/entry of study drugs and medical equipment, storage & logistics, return and destruction of study drugs, relabelling material","organisation_type":"Pharmaceutical company / vendor"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Clinical trial services (codes 1, 15 [provision of ECG machines to site and ECG analysis/review], 3)","organisation_type":"Pharmaceutical company / CRO"}
• {"country":"United Kingdom","full_name":"Q Squared Solutions Limited","duties_or_roles":"Laboratory services (code 4)","organisation_type":"Non-Pharmaceutical company / lab services"}
• {"country":"Canada","full_name":"Neurorx Research Inc.","duties_or_roles":"MRI imaging central review","organisation_type":"Pharmaceutical company / imaging central review"}
• {"country":"France","full_name":"SGS France","duties_or_roles":"Laboratory services (code 4)","organisation_type":"Pharmaceutical company / lab services"}
• {"country":"Germany","full_name":"Catalent Pharma Solutions, LLC, Clinical Supply Services (CSS)","duties_or_roles":"Supply of commercial drug products","organisation_type":"Industry / clinical supply"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"Regulatory / other services (code 12)","organisation_type":"Pharmaceutical company / CRO"}