| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple sclerosis |
| Sclerosi multipla |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple Sclerosis (MS) is a condition that can affect the brain and spinal cord, causing a wide range of potential symptoms, including problems with vision, arm or leg movement, sensation or balance |
| La SM è una condizione che può colpire il cervello e il midollo spinale causando una vasta gamma di potenziali sintomi tra cui problemi di vista di movimento di braccia o gambe,sensazione o equilibrio |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063401 |
| E.1.2 | Term | Primary progressive multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the efficacy of fenebrutinib compared with ocrelizumab in patients with primary progressive multiple sclerosis (PPMS) regardless of adherence to randomized treatment based on time to onset of composite 12-week confirmed disability progression (cCDP12) |
| • valutare l’efficacia di fenebrutinib rispetto a ocrelizumab in pazienti con sclerosi multipla primariamente progressiva (SMPP) indipendentemente dall’aderenza al trattamento randomizzato sulla base del tempo alla comparsa di progressione confermata della disabilità a 12 settimane in funzione dell’indice composito (cCDP12). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of fenebrutinib compared with ocrelizumab in patients with PPMS regardless of adherence to randomized treatment based on time to onset of composite 24-week CDP (cCDP24), time to onset of 12-week CDP (CDP12) and time to onset of 24-week CDP (CDP24)
• To evaluate the efficacy of fenebrutinib had patients not switched to post-CDP24 open-label ocrelizumab (PC-OCR)
• To evaluate the safety of fenebrutinib compared with ocrelizumab
• To characterize the fenebrutinib pharmacokinetic (PK) profile
|
• valutare l’efficacia del trattamento con fenebrutinib rispetto a ocrelizumab, indipendentemente dall’aderenza al trattamento randomizzato, in pazienti con SMPP in base al tempo alla comparsa di CDP a 24 settimane in funzione dell’indice composito (cCDP24) al tempo alla comparsa di CDP a 12 settimane (CDP12), tempo alla comparsa di CDP a 24 settimane (CDP24)
• valutare l’efficacia di fenebrutinib in caso di mancato passaggio dei pazienti al trattamento con ocrelizumab in aperto post-CDP24 (PC-OCR)
• valutare la sicurezza di fenebrutinib rispetto a ocrelizumab
• caratterizzare il profilo PK di fenebrutinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age 46-65 years
• A diagnosis of PPMS in accordance to revised 2017 McDonald Criteria
• Disability progression in the 12 months prior to screening, as assessed by the Pre-Baseline Disability Progression Questionnaire
• Expanded Disability Status Scale (EDSS) score from 3.0 to 6.5 inclusive at screening
• Pyramidal functional subscore >=2 at screening
• For patients currently receiving proton pump inhibitors (PPIs) or H2-receptor antagonists (H2RAs): treatment at a stable dose during the screening period prior to the initiation of study treatment and plans to remain at a stable dose for the duration of study treatment
• For patients requiring symptomatic treatment for MS and/or physiotherapy: treatment at a stable dose/regimen during the screening period prior to the initiation of study drug and plans to remain at a stable dose/regimen for the duration of study treatment
• Neurologically stable for at least 30 days prior to randomization and baseline assessments
• Ability to complete the 9-Hole Peg Test (9-HPT) for each hand in <240 seconds
• Ability to perform Timed 25-Foot Walk Test (T25FWT) in <150 seconds
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for 6 or 12 months after the final dose of study medication
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm during the treatment period and for 28 days after the final dose of study medication to avoid exposing the embryo |
• Età compresa tra 46 e 65 anni
• Diagnosi di SMPP secondo i criteri rivisti di McDonald del 2017
• Progressione della disabilità nei 12 mesi precedenti lo screening in base al Pre Baseline Disability Progression Questionnaire
• Punteggio EDSS compreso tra 3,0 e 6,5 allo screening
• Sottopunteggio relativo al sistema funzionale piramidale ¿ 2 allo screening
• Per i pazienti attualmente trattati con inibitori della pompa protonica (PPI) o antagonisti dei recettori H2 (H2RA): trattamento a una dose stabile durante il periodo di screening prima dell’inizio del trattamento in studio e che si prevede rimarrà a una dose stabile per l’intera durata del trattamento in studio
• Per i pazienti che necessitano di trattamento sintomatico per la SM e/o fisioterapia: trattamento a una dose/un regime stabile durante il periodo di screening prima dell’inizio del trattamento con il farmaco studio e che si prevede rimarrà a una dose/un regime stabile per l’intera durata del trattamento in studio
• Pazienti neurologicamente stabili per almeno 30 giorni prima della randomizzazione e delle valutazioni basali
• Capacità di effettuare il test 9 HPT con ciascuna mano in ¿ 240 secondi
• Capacità di effettuare il test T25FWT in ¿ 150 secondi
• Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o ad adottare metodi contraccettivi durante il periodo di trattamento e per 6 o 12 mesi dopo l’ultima dose del farmaco in studio
• Per gli uomini: consenso a praticare l’astinenza dai rapporti eterosessuali o a usare il preservativo e consenso ad astenersi dalla donazione del seme durante il periodo di trattamento e per 28 giorni dopo l’ultima dose del farmaco in studio, al fine di evitare l’esposizione dell’embrione |
|
| E.4 | Principal exclusion criteria |
• Gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (T1Gd+) lesion present on the screen MRI
• Any known or suspected active infection at screen or baseline,or any major episode of infection requiring hospitaliz or tx with IV anti-microbials
• Hx of confirmed or suspected progressive multifocal leukoencephalopathy
• Pt with a previous Hx of a serious IRR(CTCAE Grade >=4) and/or any hypersensitivity reaction to ocrelizumab
• Hx of cancer,including hematologic malignancy and solid tumors,within 10 years of screen
• Immunocompromised state
• Known presence of other neuro disorders
• Evidence of clinic signif cardiov,psychiatric,pulmonary,renal, hepatic,endocrine,metabolic,gastrointestinal (GI) disease that, in the PI opinion,would preclude pt participation
• Pt meeting the New York Heart Association Class III and Class IV criteria for congestive heart failure
• Screen 12-lead ECG that demonstrates clinic relevant abnormalities
• Current tx with medications that are well known to prolong the QT interval at doses that have a clinic meaningful effect on QT, as determined by the PI
• Hx of ventricular dysrhythmias or risk factors for ventricular dysrhythmias
• Any concomitant disease that may require chronic tx with systemic corticosteroids or immunosuppressants during the study
• Hx of alcohol or other drug abuse within 12 months prior to screen
• Pregnant or breastfeeding,or intending to become pregnant during the study or 6 or 12 months after final dose of study drug
• Men intending to father a child during the study or for 28 days after final dose of study drug
• + screen tests for active,latent,or inadequately treated hepatitis B
• + screen tests for hepatitis C
• Evidence of active or latent or inadequately treated infection with tuberculosis
• Hx of hospital or transfusion for a GI bleed
• Known bleeding diathesis
• Any condition possibly affecting oral drug absorption
• Hx of or currently active primary or secondary immunodeficiency
• Contraindications to mandatory pre-medications for IPRs
• Inability to complete an MRI scan
• Lack of peripheral venous access
• Any prev tx with bone marrow transplantation and hematopoietic stem cell transplantation
• Any prev Hx of transplantation or anti-rejection therapy
• Systemic corticosteroid therapy within 4 weeks prior to screen or during the screen period
• Tx with IV Ig or plasmapheresis within 12 weeks prior to RDM
• Sensitivity or intolerance to any ingredient of fenebrutinib or ocrelizumab
• Receipt of a live or live-attenuated vaccine within 6 weeks prior to RDM
• Need for systemic anti-coagulation (oral or injectable) or anti-platelet agent
• Prev tx with fenebrutinib or another Bruton's tyrosine kinase (BTK) inhibitor for any indication
• Tx with any investigational agent within 24 weeks prior to screen (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or tx with any experimental procedure for MS
• Requirement for any prohibited concomitant medications
• Tx with strong CYP3A4 inhibitors,strong or moderate CYP3A4 inducers,within 7 days or 5 drug elimination half-lives(whichever is longer)prior to RDM
• Tx with CYP3A4 substrates with a narrow therapeutic window within 7 days or 5 drug elimination half-lives(whichever is longer)prior to RDM
• Prev use of an anti-CD20 therapy within 6 months of RDM
• Prev use of fingolimod, siponimod, or ozanimod within 8 weeks of RDM or ponesimod within 4 weeks of RDM
• Prev use of natalizumab within 6 months of RDM
• Prev tx with dimethyl fumarate, interferons or glatiramer acetate within 4 weeks of RDM
• Prev tx with mycophenolate mofetil, methotrexate or azathioprine within 12 weeks of RDM
• Prev use of teriflunomide, unless >=24 months from screen or teriflunomide plasma concentrations are <0.02 mg/L at screen
• Any prev tx with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide
• Prev tx with any other immunomodulatory or immunosuppressive medication
• Abnor lab results |
•Lesioni T1Gd+ alla MRI di screen
•Infez attiva nota o sospetta allo screen o al basale o qls episodio maggiore di infez che richieda ospedalizz o il tratt con antimicrobici EV
•Storia di leucoencefalopatia multifocale progressiva confermata o sospetta
•Storia di IRR grave[CTCAE] Grado >=4)e/o qls reazione di ipersensibilità a ocrelizumab
•Storia di tumore,compresi neoplasia maligna ematologica e tumori solidi,entro 10 anni dallo screen
•Stato immunocompromesso
•Presenza nota di disturbi neurologici
•Evidenza di malattie cardiovascolari,psichiatriche,polmonari,renali,epatiche, endocrine,metaboliche o gastrointestinali(GI)clinic significative che,secondo lo sperimentatore,precluderebbero la partecipazione del pz
•Pz con insuff cardiaca congestizia di classe III o IV secondo New York Heart Association
•ECG a 12 derivazioni allo screen dal quale emergano anomalie clinic rilevanti
•Tratt con medicinali notoriamente associati a prolungamento dell’intervallo QT a dosi che hanno un effetto clinic significativo sul QT,secondo lo sperimentatore
•Storia di disaritmie ventricolari o fattori di rischio per disaritmie ventricolari
•Qls malattia concomitante che richiede un tratt cronico con corticosteroidi sistemici o immunosoppressori
•Abuso di alcool o droghe nei 12mesi precedenti lo screen
• Gravidanza o allattamento,o intenzione di iniziare una gravidanza durante lo studio o 6 o 12mesi successivi l’ultima dose del farmaco
•Uomini che intendono procreare durante lo studio o nei 28gg succ l’ultima dose del farmaco
•Test di screen + per l'epatite B attiva,latente o nn trattata
•Test di screen + per l'epatite C
•Evidenza di infezione TBC attiva,latente o nn trattata
•Storia di ricoveri in ospedale o trasfusioni per un’emorragia GI
•Diatesi emorragica
•Qls condiz che influenza l'assorbimento orale del farmaco
•Immunodeficienza primaria o secondaria pregressa o attualmente attiva
•Controindicaz alle premedicazioni obbligatorie per reazioni correlate all’infusione
•Impossibilità di sottoporsi alla RM
•Assenza di accesso venoso periferico
•Qls prec tratt con trapianto di midollo osseo e trapianto di cellule staminali ematopoietiche
•Qls trapianto o terapia antirigetto precedente
•Terapia sistemica a base di corticosteroidi nelle 4sett precedenti o allo screen
•Tratt con Ig IV o plasmaferesi nelle 12sett prec la randomiz
•Sensibilità o intolleranza a qls ingrediente di fenebrutinib o ocrelizumab
•Somministraz di vaccino vivo/attenuato entro 6sett dalla randomiz
•Necessità di anticoagulanti sistemici(orali o iniettabili)o agenti antipiastrinici
•Tratt prec con fenebrutinib o altro inibitore della tirosin-chinasi di Bruton(BTK)per qls indicaz
•Tratt con qls agente sperimentale entro 24sett dallo screen(visita 1)o 5 emivite del farmaco(a seconda di quale sia più lungo)o tratt con qls procedura sperimentale per la SM
•Necessità di medicinali concomitanti nn ammessi
•Tratt con inibitori del CYP3A4 o potenti/moderati induttori del CYP3A4 nei 7gg o 5 emivite del farmaco(qualora queste ultime abbiano durata superiore) precedenti la randomiz
•Tratt con substrati del CYP3A4 aventi finestra terapeutica ristretta nei 7gg o 5 emivite del farmaco(qualora queste ultime abbiano durata superiore)precedenti la randomiz
•Uso pregresso di terapia anti-CD20 entro 6mesi dalla randomiz
•Uso pregresso di fingolimod,siponimod o ozanimod entro 8sett dalla randomiz o ponesimod entro 4sett dalla randomiz
•Uso pregresso di natalizumab entro 6mesi dalla randomiz
•Prec tratt con dimetilfumarato,interferoni o glatiramer acetato entro 4sett dalla randomiz
•Prec tratt con micofenolato mofetile,metotrexato o azatioprina entro 12sett dalla randomiz
•Uso precedente di teriflunomide,tranne se risalente a >=24mesi prima dello screen o in caso di concentraz plasmatiche di teriflunomide ¿ 0,02 mg/l allo screen
•Prec tratt con cladribina,mitoxantrone,daclizumab,alemtuzumab o ciclofosfamide
•Tratt prec con qls farmaco immunomodulatore o immunosoppressore
•Risultati di lab anormali |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Time to onset of composite 12-week confirmed disability progression (cCDP12) |
| 1. Tempo alla comparsa di progressione confermata della disabilità a 12 settimane in funzione dell’indice composito (cCDP12) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to 4.7 years [estimated duration of Double-Blind Treatment (DBT)] |
| 1. Fino a 4,7 anni [durata stimata del trattamento in doppio cieco (DBT)] |
|
| E.5.2 | Secondary end point(s) |
1. Time to onset of composite 24 week CDP (cCDP24)
2. Time to onset of 12-week CDP (CDP12)
3. Time to onset of 24 week CDP (CDP24)
4. Percent change in total brain volume from Week 24 as assessed by MRI scan
5. Change from baseline in patient-reported physical impacts of MS (as measured by Multiple Sclerosis Impact Scale, 29-Item [MSIS-29] physical scale
6. Time to onset of 12 week confirmed 4 point worsening in Symbol Digit Modality Test (SDMT) score
7. The nature, frequency, timing, and severity of adverse events; serious adverse events; and adverse events leading to study treatment withdrawal
8. Change from baseline in targeted vital signs
9. Change from baseline in targeted ECG parameters
10. Change from baseline in clinical laboratory results following study treatment administration
11. Proportion of patients with suicidal ideation or behavior, as assessed by Columbia Suicide Severity Rating Scale (C-SSRS)
12. Plasma concentration of fenebrutinib at specified timepoints |
1. Tempo alla comparsa della CDP composita a 24 settimane (cCDP24)
2. Tempo alla comparsa della CDP a 12 settimane (CDP12)
3. Tempo alla comparsa della CDP a 24 settimane (CDP24)
4. Variazione % del volume cerebrale tot alla Settimana 24 in base alla risonanza magnetica (RM).
5. Variazione dell’impatto fisico della sclerosi multipla (SM) riferito dai pazienti (in funzione della scala fisica della Multiple Sclerosis Impact Scale, 29 Item)
6. Tempo alla comparsa di un peggioramento confermato del punteggio ottenuto nel Symbol Digit Modality Test (SDMT) pari a 4 punti a 12 settimane
7. La natura, frequenza, tempistica e gravità degli eventi avversi; eventi avversi gravi ed eventi avversi che portano all’interruzione del trattamento in studio
8. Variazione dei parametri vitali di interesse rispetto al basale.
9. Variazione dei parametri dell’elettrocardiogramma (ECG) rispetto al basale.
10. Variazione dei risultati clinici di laboratorio rispetto al basale dopo la somministrazione del trattamento in studio.
11. Percentuale di pazienti con ideazione o comportamento suicidario in base alla Columbia Suicide Severity Rating Scale.
12. Concentrazione plasmatica di fenebrutinib a specifici timepoint |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to 4.7 years (estimated duration of DBT)
4-5. At Week 120
6-11. Up to 4.7 years (estimated duration of DBT)
12. Week 0, 2, 12, 24, 48, 72, 96, 120, at treatment discontinuation or unscheduled visit
|
1-3. Fino a 4,7 anni (durata stimata del DBT)
4-5. Alla settimana 120
6-11. Fino a 4,7 anni (durata stimata del DBT)
12. Settimana 0, 2, 12, 24, 48, 72, 96, 120, all'interruzione del trattamento o visita non programmata |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Latvia |
| Lithuania |
| Mexico |
| New Zealand |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Switzerland |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of this study is defined as the date when the last patient, last visit occurs in the OLE or the last patient last visit in the SFU, whichever occurs later. The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 369 weeks or approximately 7 years.
In addition, the Sponsor may decide to terminate the study at any time. |
| La fine dello studio coinciderà con la data in cui avrà luogo l’ultima visita dell’ultimo paziente (LPLV) nella fase OLE o la LPLV nella fase OLE SFU, a seconda della circostanza che si verifichi per ultima.Si prevede che la durata massima dello studio, dallo screening del primo paziente alla conclusione della ricerca, sarà di circa 370 settimane o 7 anni. Inoltre, lo Sponsor può decidere di interrompere lo studio in qualsiasi momento. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
