E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Progressive Multiple Sclerosis (PPMS) |
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E.1.1.1 | Medical condition in easily understood language |
Primary Progressive Multiple Sclerosis (PPMS) |
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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 |
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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 investigate the efficacy of ocrelizumab compared with placebo in patients with primary progressive multiple sclerosis, as measured by the time to onset of confirmed disability progression over the treatment period, defined as an increase in EDSS that is sustained for at least 12 weeks, based on regularly scheduled visits. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of ocrelizumab compared with placebo, as reflected by the following: • The time to onset of confirmed disability progression over the treatment period, defined as an increase in EDSS that is sustained for at least 24 weeks • The change in 25-foot timed walk from baseline to Week 120 • The change in total volume of T2 lesions on MRI scans of the brain from baseline to week 120 • The percentage change in total brain volume as detected by brain MRI from Week 24 to Week 120 • The change in SF-36 Health Survey version 2 (SF-36v2) Physical Component Summary (PCS) score from baseline to Week 120 • To evaluate the safety and tolerability of ocrelizumab 300 mg × 2 (over 24-week treatment cycles) compared with placebo in patients with PPMS |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optical Coherence Tomography Exploratory Substudy
This substudy is run under the main study protocol and will be used to evaluate the neuroprotective effect of ocrelizumab as measured by retinal nerve fiber layer (RNFL) thickness and macular volume in both eyes.
Optional Exploratory Substudies
Consenting patients who enrolled in the main study WA25046 and who are eligible will be offered the opportunity to participate in optional substudies, which are run under separate protocols.
Other exploratory substudies are run under separate study protocols: • B cell and T cell repertoires in ocrelizumab-treated MS patients (BE29353) • Brain myelin mapping to quantify demyelination and repair in MS in a Phase III trial of ocrelizumab (BE29340) • Assessment of ocrelizumab treatment effects on disability of MS patients enrolled in the Phase III Orchestra program using multimodal evoked potentials (mEP) and high-resolution electroencephalogram (EEG; BE29354) • Substudy of brain and spinal cord MRI in patients with MS participating in the OPERA clinical trial (BE29352).
Substudies will be run only at the specific assigned sites that are referred to in the substudy protocols. |
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E.3 | Principal inclusion criteria |
• Adult patients, 18-55 years of age • Primary Progressive Multiple Sclerosis (according to revised McDonald criteria) • Expanded Disability Status Scale (EDSS) 3.0 to 6.5 points • Disease duration from onset of MS symptoms < 15 years if EDSS > 5.0, < 10 years if EDSS ≤ 5.0 • Sexually active male and female patients of reproductive potential must use two methods of contraception throughout the study treatment phase and for 48 weeks for females and 24 weeks for males after the last dose
Patients who meet the following entry criteria may participate in the OLE phase: • Completed the Blinded Treatment Period of the trial and who, in the opinion of the Investigator, may benefit from treatment with ocrelizumab; • Able and willing to provide written informed consent to participate in the OLE phase and to comply with the study protocol; • Willing to continue to use at least two contraceptive methods • Meet the re-treatment criteria with ocrelizumab |
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E.4 | Principal exclusion criteria |
• History of relapsing remitting multiple sclerosis, secondary progressive, or progressive relapsing multiple sclerosis at screening • Contraindications for Magnetic Resonance Imaging (MRI) • Known presence of other neurologic disorders • Known active infection or history of or presence of recurrent or chronic infection • History of cancer, including solid tumors and hematological malignancies (except for basal cell, in situ squamous cell carcinomas of the skin and in situ carcinoma of the cervix that have been excised and resolved) • Previous treatment with B-cell targeted therapies (e.g. rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab) • Any previous treatment with lymphocyte trafficking blockers, with alemtuzumab, anti-CD4, cladribine, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study; |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Efficacy: Time to onset of confirmed disability progression, defined as an increase in Expanded Disability Status Scale (EDSS) score that is sustained for at least 12 weeks |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Time to confirmed disability progression, defined as an increase in EDSS score that is sustained for at least 24 weeks 2. Change in timed 25-foot walk 3. Change in total volume of T2 lesions on magnetic resonance imaging (MRI) scans of the brain 4. Safety and tolerability: Incidence of adverse events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 11 years 2. From baseline to Week 120 3. From baseline to Week 180 4. Up to 11 years |
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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 | Yes |
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 98 |
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 | No |
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 |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
Czechia |
Denmark |
Finland |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Lithuania |
Mexico |
Netherlands |
New Zealand |
Norway |
Peru |
Poland |
Portugal |
Russian Federation |
Slovakia |
Spain |
Switzerland |
Ukraine |
United Kingdom |
United States |
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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
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LPLV of the OLE phase or the LPLV in the Safety Follow-Up or B-cell monitoring of Safety Follow-Up Period, whichever is later. The OLE phase will continue as per local regulation or until such a time as the Sponsor decides to terminate the ocrelizumab program for MS. The B-cell monitoring of the Safety Follow-Up Period of each patient will last until the B cell count has returned to the baseline value or to the LLN range (whichever is lower). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 10 |
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 |