| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary progressive multiple sclerosis (PPMS) |
| Sclerosi Multipla primariamente progressiva |
|
| E.1.1.1 | Medical condition in easily understood language |
| PPMS is a form of multiple sclerosis that is characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions |
| La PPMS è una forma di sclerosi multipla caratterizzata da un peggioramento della funzionalità neurologica (accumulo di disabilità) dall'insorgenza dei sintomi senza recidive o remissioni precoci. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| 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 ocrelizumab treatment compared with placebo-in patients on progression of upper limb disability, measured based on the time to 20% worsening from baseline in the 9-Hole Peg Test (9-HPT) confirmed for at least 12 weeks in all randomized patients and in patients with magnetic resonance imaging (MRI) activity |
| valutare l’efficacia di ocrelizumab (Ocrevus®) rispetto al placebo in pazienti affetti da sclerosi multipla primariamente progressiva (SMPP), sulla progressione della disabilità degli arti superiori, definita come il peggioramento del 20% rispetto al tempo del test dei 9 pioli (9-Hole Peg Test, [9-HPT]) registrato al basale e confermato per almeno 12 settimane in tutti i pazienti randomizzati e nei pazienti con attività della risonanza magnetica (RM) |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of ocrelizumab compared with placebo:
• for all randomized patients by the time to 24 week confirmed 20% increase from baseline in 9-HPT, time to 12-week and 24-week confirmed disability progression (CDP) as measured by changes in expanded disability status scale (EDSS)
• for all patients by the % change in total volume of T2 lesions and total brain volume as measured by magnetic resonance imaging
• to evaluate the safety of ocrelizumab compared with placebo and over time for all patients who received ocrelizumab and until they receive any other immunomodulatory or immunosuppressive treatments by the proportion of patients with adverse events,laboratory abnormalities
•To assess the immunogenicity, by the presence of anti-drug antibody to ocrelizumab during the study relative to baseline and the relationship to pharmacokinetics (PK),pharmacodynamics,efficacy and safety
•To characterize the PK profile of the ocrelizumab and its PD, measured by blood Bcell levels |
To evaluate the efficacy of ocrelizumab compared with placebo:
• for all randomized patients by the time to 24 week confirmed 20% increase from baseline in 9-HPT, time to 12-week and 24-week confirmed disability progression (CDP) as measured by changes in expanded disability status scale (EDSS)
• for all patients by the % change in total volume of T2 lesions and total brain volume as measured by magnetic resonance imaging
• to evaluate the safety of ocrelizumab compared with placebo and over time for all patients who received ocrelizumab and until they receive any other immunomodulatory or immunosuppressive treatments by the proportion of patients with adverse events,laboratory abnormalities
•To assess the immunogenicity, by the presence of anti-drug antibody to ocrelizumab during the study relative to baseline and the relationship to pharmacokinetics (PK),pharmacodynamics,efficacy and safety
•To characterize the PK profile of the ocrelizumab and its PD, measured by blood Bcell levels |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Diagnosis of PPMS in accordance with the McDonald criteria (Thompson et al. 2017)
- Age 18-65 years at time of signing Informed Consent Form
- EDSS score at screening and baseline >= 3.0 to 8.0, inclusive
- Disease duration from the onset of multiple sclerosis (MS) symptoms relative to randomization date:
o Less than 20 years in patients with an EDSS score at screening 7.0-8.0
o Less than 15 years in patients with an EDSS at screening 5.0-6.5
o Less than 10 years in patients with an EDSS at screening <= 5.0
- Documented history or presence at screening of at least one of the following
laboratory findings in a cerebrospinal fluid specimen
o Elevated IgG index
o One or more IgG oligoclonal bands detected by isoelectric focusing
- Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands)
- Neurological stability for >= 30 days prior to baseline
- Ability to complete the 9-HPT within 240 seconds with each hand at screening and
baseline
- Patients previously treated with immunosuppressant, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 or 12 months (as applicable by the Ocrevus local label) after the final dose of ocrelizumab
Eligibility Criteria for OLE Phase:
- Completed the double-blind treatment phase of the trial or have received post-doubleprogression ocrelizumab (PDP OCR) in the follow-up 1 phase, and who, in the opinion of the investigator, may benefit from treatment with ocrelizumab
- Meet the re-treatment criteria for ocrelizumab |
• Diagnosi di SMPP secondo i criteri di McDonald
• Età 18-65 anni alla data della firma del Modulo di consenso informato
• Punteggio EDSS allo screening e al basale da >=3,0 a 8,0, inclusi
• Durata della malattia dall’esordio dei sintomi di SM relativamente alla data di randomizzazione:
Meno di 20 anni nei pazienrti con punteggio EDSS allo screening 7.0-8.0
Meno di 15 anni nei pazienti con punteggio EDSS allo screening 5.0-6.5
Meno di 10 anni nei pazienti con punteggio EDSS allo screening <=5,0
• Anamnesi documentata o presenza allo screening di almeno uno dei seguenti risultati
di laboratorio in un campione di liquido cerebrospinale (è necessario verificare la
documentazione originale dei risultati di laboratorio e del metodo utilizzato)
Elevato indice IgG
Una o più bande IgG oligoclonali rilevate mediante focalizzazione isoelettrica
• Test 9-HPT allo screening e al basale completato in >25 secondi (media delle due mani)
• Stabilità neurologica per >= 30 giorni precedenti il basale
• Capacità di completare il test 9-HPT entro 240 secondi con ciascuna mano allo
screening e al basale
• I pazienti precedentemente trattati con immunosoppressori, immunomodulatori o altre terapie immunomodulatorie devono sottoporsi a un periodo di washout adeguato secondo l’ etichetta locale del farmaco immunosoppressore/immunomodulatore utilizzato
I pazienti sottoposti a screening per questo studio non devono interrompere eventuali terapie al solo scopo di soddisfare i requisiti di eleggibilità previsti dalla sperimentazione. I pazienti che interrompono la loro attuale terapia per motivi non medici devono essere specificamente informati, prima di decidere di accedere allo studio, delle opzioni di trattamento a loro disposizione e del fatto che, partecipando a questo studio,
potrebbero essere randomizzati al placebo per un periodo di 120 settimane o più.
• Per le donne in età fertile: consenso a rimanere astinenti (astenersi dai rapporti eterosessuali) o a utilizzare metodi contraccettivi adeguati durante il periodo di trattamento e per 6 o 12 mesi (come applicabile in base all’RCP locale di Ocrevus) dopo l’ultima dose di ocrelizumab.
Criteri di eleggibilità per la fase di estensione in aperto
• Completamento della fase di trattamento in doppio cieco della sperimentazione o hanno ricevuto un trattamento PDP OCR nella fase FU1 e, a giudizio dello sperimentatore, potrebbero trarre beneficio dal trattamento con ocrelizumab
• Soddisfano i criteri di ritrattamento per ocrelizumab |
|
| E.4 | Principal exclusion criteria |
- History of relapsing-remitting or secondary progressive MS at screening
- Confirmed serious opportunistic infection
- Patients who have or have had confirmed or a high degree of suspicion of progressive
multifocal leukoencephalopathy
- Known active malignancy or are being actively monitored for recurrence of malignancy
- Immunocompromised state defined as one or more of the following: CD4 count < 250/µL,
absolute neutrophil count <1.5 x 103/µL, Serum IgG < 4.6 g/L
- Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
- Inability to complete an MRI or contraindication to gadolinium (Gd) administration
- Patients requiring symptomatic treatment of multiple sclerosis (MS) and/or
physiotherapy who are not on a stable regimen. Patients must not initiate symptomatic
treatment of MS or physiotherapy within 4 weeks of randomization
- Contraindications to mandatory premedication for infusion-related reactions
- Known presence of other neurologic disorders, including, but not limited to: history of ischemic cerebrovascular disorders or ischemia of the spinal cord, history or known presence of CNS or spinal cord tumor, history or known presence of potential metabolic causes of myelopathy, history or known presence of infectious causes of myelopathy,
history of genetically inherited progressive CNS degenerative disorder, neuromyelitis optica, history or known presence of non-MS systemic autoimmune disorders potentially causing progressive neurologic disease, history or known presence of sarcoidosis,history of severe, clinically significant brain or spinal cord trauma
- Pregnant or breastfeeding, or intending to become pregnant during the study and 6 or 12 months after last infusion of the study drug
- Lack of peripheral venous access
- Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study
- Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressant during the course of the study
- History of alcohol or other drug abuse
- History of primary or secondary (non-drug-related) immunodeficiency
- Treatment with any investigational agent within 24 weeks prior to screening or 5 halflives of the investigational drug, or treatment with any experimental procedure for MS
- Previous treatment with B-cell targeting therapies, bone marrow transplantation or hematopoietic stem cell transplantation
- Any previous history of transplantation or anti-rejection therapy
- Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
- Systemic corticosteroid therapy within 4 weeks prior to screening
- Positive serum ß-hCG measured at screening or positive urine ß -hCG at baseline
- Positive screening tests for hepatitis B
- Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above |
• Anamnesi di SM recidivante-remittente o secondariamente progressiva allo screening
• Grave infezione opportunistica confermata
• Pazienti con leucoencefalopatia multifocale progressiva (LMP) confermata, in corso o anamnestica, oppure elevato indice di sospetto di LMP
• Pazienti con tumore maligno noto in fase attiva o sottoposti a monitoraggio attivo per l’eventuale sviluppo di recidiva di un tumore maligno
• Stato di immunocompromissione, definito come uno o più dei seguenti:CD4 count < 250/µL, absolute neutrophil count <1.5 x 103/µL, Serum IgG < 4.6 g/L
• Vaccinazione con vaccino vivo-attenuato entro 6 settimane prima della randomizzazione
• Impossibilità di eseguire una RM (controindicazioni alla RM, tra cui, a titolo esemplificativo, pacemaker, impianti cocleari, clip vascolari intracraniche, intervento chirurgico entro 6 settimane dall’ingresso nello studio, stent coronarico impiantato entro 8 settimane prima della data della RM in programma, ecc.) o controindicazione alla
somministrazione di Gd
• Pazienti con necessità di trattamento sintomatico della SM (per es., fampridina) e/o fisioterapia che non seguono un regime stabile. I pazienti non devono avviare un trattamento sintomatico della SM o un trattamento fisioterapico entro 4 settimane dalla randomizzazione
• Controindicazioni alle premedicazioni obbligatorie per la prevenzione delle reazioni correlate all’infusione
• Presenza nota di altri disturbi neurologici, tra cui, in modo non limitativo, i seguenti:
Fare riferimento al Protocollo
• Paziente in stato di gravidanza o allattamento, o che intende avviare una gravidanza durante lo studio e nei 6 o 12 mesi successivi all’ultima infusione del farmaco dello studio
• Assenza di accesso venoso periferico
• Malattia significativa non controllata, per es. cardiovascolare (inclusa l’aritmia
cardiaca), polmonare (inclusa la pneumopatia ostruttiva), renale, epatica, endocrina o
gastrointestinale, oppure qualsiasi altra malattia significativa che possa precludere la
partecipazione del paziente allo studio
• Qualsiasi malattia concomitante che possa richiedere un trattamento cronico con
corticosteroidi sistemici o immunosoppressori nel corso dello studio
• Anamnesi di abuso di alcol o altre sostanze
• Anamnesi di immunodeficienza primaria o secondaria (non farmaco-correlata)
• Trattamento con qualsiasi agente sperimentale entro 24 settimane prima dello screening (Visita 1) o 5 emivite del farmaco sperimentale (a seconda di quale sia il periodo più lungo), oppure trattamento con qualsiasi procedura sperimentale per la SM (per es., trattamento per insufficienza venosa cerebrospinale cronica)
• Precedente trattamento con terapie mirate alle cellule B (per es., rituximab, ocrelizumab, atacicept, belimumab, ofatumumab)
• Qualsiasi trattamento precedente con trapianto di midollo osseo e trapianto di cellule staminali ematopoietiche
• Qualsiasi anamnesi pregressa di trapianto o terapia anti-rigetto
• Trattamento con Ig per via EV o plasmaferesi entro 12 settimane prima della randomizzazione
• Terapia corticosteroidea sistemica entro 4 settimane prima dello screening
Per il resto dei criteri di esclusione, fare riferimento al Protocollo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Upper limb disability progression, measured based on time to 20% worsening from
baseline in 9-HPT confirmed for at least 12 weeks and in all patients and patients
with MRI activity |
1.Upper limb disability progression, measured based on time to 20% worsening from
baseline in 9-HPT confirmed for at least 12 weeks and in all patients and patients
with MRI activity |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Double-Blind Treatment: Week 0, 12, 24, 36, 48, 60, 72, 84, n, n+12, treatment
discontinuation (TD), Follow-Up 1: Visits every 12 weeks |
1. Double-Blind Treatment: Week 0, 12, 24, 36, 48, 60, 72, 84, n, n+12, treatment
discontinuation (TD), Follow-Up 1: Visits every 12 weeks |
|
| E.5.2 | Secondary end point(s) |
1. Upper limb disability progression, measured based on time to 20% increase from
baseline in 9-HPT confirmed at least 24 weeks
2. Time to 12-week CDP in EDSS, as a pre-defined increase in EDSS score confirmed for at least 12 weeks
3. Time to 24-week CDP in EDSS, as a pre-defined increase in EDSS score confirmed for at least 24 weeks
4. Differences in the percent change in total volume of T2 lesions on MRI from
baseline up to Week 120 will be analyzed using analysis of covariance and mixed effect
model repeat measurement (MMRM) analyses
5. Differences in the mean percentage change in total brain volume on MRI scans from
Week 24 to Week 120 will be analyzed using an MMRM analysis
6. Incidence and nature of adverse events, serious adverse events, adverse events
leading to study treatment withdrawal
7. Change from baseline in laboratory test results for hematology and chemistry
association of decrease in certain laboratory parameters, and serious infections
8. Presence of ADA of ocrelizumab
9. Total plasma clearances (CL) of ocrelizumab
10. Volumes of distribution(Vd) of ocrelizumab
11. Area under the concentration-time curve (AUC) of ocrelizumab |
1. Upper limb disability progression, measured based on time to 20% increase from
baseline in 9-HPT confirmed at least 24 weeks
2. Time to 12-week CDP in EDSS, as a pre-defined increase in EDSS score confirmed for at least 12 weeks
3. Time to 24-week CDP in EDSS, as a pre-defined increase in EDSS score confirmed for at least 24 weeks
4. Differences in the percent change in total volume of T2 lesions on MRI from
baseline up to Week 120 will be analyzed using analysis of covariance and mixed effect
model repeat measurement (MMRM) analyses
5. Differences in the mean percentage change in total brain volume on MRI scans from
Week 24 to Week 120 will be analyzed using an MMRM analysis
6. Incidence and nature of adverse events, serious adverse events, adverse events
leading to study treatment withdrawal
7. Change from baseline in laboratory test results for hematology and chemistry
association of decrease in certain laboratory parameters, and serious infections
8. Presence of ADA of ocrelizumab
9. Total plasma clearances (CL) of ocrelizumab
10. Volumes of distribution(Vd) of ocrelizumab
11. Area under the concentration-time curve (AUC) of ocrelizumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Double-Blind Treatment: Week 0, 12, 24, 36, 48, 60, 72, 84, n, n+12, TD
2. From baseline to end of study (up to 5.5 years)
3. From baseline to end of study (up to 5.5 years)
4. From baseline up to Week 120
5. From Week 24 to Week 120
6. Up to 5.5 years
7. From baseline to 5.5 years
8. Double-Blind Treatment: Week 0, 24, 48, 72 and n, treatment discontinuation (TD); Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, n and TD; OLE: Week 0, 48, 96, TD; Follow-Up 2: Visits every 24 weeks
9-11. Double-Blind Treatment: Week 0, 2, 12, 24, 48, 60, 72, Week n, TD; Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, 2, 12 and n, TD; OLE: Week 0, 48, 96, TD; Follow-Up 2: Visits every 24 weeks |
1. Double-Blind Treatment: Week 0, 12, 24, 36, 48, 60, 72, 84, n, n+12, TD
2. From baseline to end of study (up to 5.5 years)
3. From baseline to end of study (up to 5.5 years)
4. From baseline up to Week 120
5. From Week 24 to Week 120
6. Up to 5.5 years
7. From baseline to 5.5 years
8. Double-Blind Treatment: Week 0, 24, 48, 72 and n, treatment discontinuation (TD); Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, n and TD; OLE: Week 0, 48, 96 TD; Follow-Up 2: Visits every 24 weeks
9-11. Double-Blind Treatment: Week 0, 2, 12, 24, 48, 60, 72, Week n, TD; Follow-Up 1: Visits every 12 weeks, PDP OCR: Week 0, 2, 12 and n, TD; OLE: Week 0, 48, 96, TD; Follow-Up 2: Visits every 24 weeks |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity, Health Status Utility and Biomarker Objectives |
| Immunogenicity, Health Status Utility and Biomarker Objectives |
|
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 103 |
| 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 |
| Australia |
| Belarus |
| Brazil |
| Canada |
| Colombia |
| Egypt |
| Georgia |
| Mexico |
| New Zealand |
| Peru |
| Russian Federation |
| Serbia |
| Ukraine |
| United States |
| Austria |
| Belgium |
| Bulgaria |
| Croatia |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
| United Kingdom |
|
| 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 the study will occur when all patients who are not being treated with an alternative B-cell depleting therapy have repleted his or her B-cells (i.e., B-cell level of the patient has returned to the baseline value or the lower limit of normal, whichever is lower). |
| La fine dello studio avverrà quando tutti i pazienti che non sono in trattamento con una terapia di deplezione dei linfociti B alternativa avranno presentato ripristino dei linfociti B (ossia, il livello dei linfociti B del paziente è tornato al valore basale o al di sotto del limite della norma, a seconda di quale sia inferiore). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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