E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Active progressive multiple sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Patients of both genders with active progressive multiple sclerosis, defined with Lublin 2013 classification |
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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 | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10052785 |
E.1.2 | Term | Multiple sclerosis acute and progressive |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028245 |
E.1.2 | Term | Multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 | 10053395 |
E.1.2 | Term | Progressive multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 | 10063400 |
E.1.2 | Term | Secondary progressive multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 | 10067063 |
E.1.2 | Term | Progressive relapsing multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10048393 |
E.1.2 | Term | Multiple sclerosis relapse |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10080700 |
E.1.2 | Term | Relapsing 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 |
The primary efficacy objective for this study is to determine the evolution of leptomeningeal lesions in patients with active progressive multiple sclerosis: •The number of LMCE foci at the Month 24 visit compared to the number of LMCE foci at the Baseline visit in the LMCE-positive group. The exploratory efficacy objective for this study is to investigate influence of leptomeningeal lesions evolution on brain atrophy estimates at 2 years with regard to LMCE-status: •Percentage of brain volume change (PBVC) after 2 years in the LMCE-positive group and the LMCE-negative group separately. The safety objective for this study is to evaluate the safety of ocrelizumab: •Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0. •Change from baseline in vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure). •Change from baseline in laboratory test results (hematology and chemistry panel).
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objective for this study is to determine the evolution of leptomeningeal lesions in patients with active progressive multiple sclerosis based on the following endpoints: •The change from the Baseline visit in LMCE foci at the Month 12 visit in the LMCE- positive group and in the LMCE-negative group. •The change from the Baseline visit in LMCE foci at the Month 24 visit in the LMCE-negative group. •Time until 3-months composite confirmed disability progression in the LMCE-positive group and the LMCE-negative group separately. •Time until 3-months confirmed disability progression in the LMCE-positive group and the LMCE-negative group separately. •Time until 3-months confirmed 20% worsening in arm function (9-HPT) in the LMCE-positive group and the LMCE-negative group separately. •Time until 3-months confirmed 20% worsening of gait function (T25FWT) in the LMCE-positive group and the LMCE-negative group separately. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Signed Informed Consent Form. •Age ≥ 18 and ≤ 65 years at time of signing Informed Consent Form. •Ability to comply with the study protocol. •Patients of both genders with active progressive multiple sclerosis, defined with Lublin 2013 classification: primary progressive multiple sclerosis with subsequent relapses or MRI activity (McDonald 2017 criteria), secondary progressive multiple sclerosis with relapses or MRI activity during 2 years prior to initiation of ocrelizumab. •It is indicated to treat patients with ocrelizumab according to local regulations. •EDSS ≤ 6.0. •Readiness for blood sampling from peripheral vein puncture. •Neurological stability (no clinically significant worsening according to neurological examination) for ≥30 days prior to both screening and baseline. •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, as defined below: Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 6 months after the final dose of ocrelizumab. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of ocrelizumab to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
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E.4 | Principal exclusion criteria |
•Inability to provide informed consent. •Inability to undergo MRI due to devices or metallic foreign bodies considered unsafe in the MRI magnet (contraindications for MRI include but are not restricted to claustrophobia, weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, etc.). •Known presence of other neurological disorders which may mimic MS including but not limited to: neuromeylitis optica, Lyme disease, untreated vitamin B12 deficiency, neurosarcoidosis and cerebrovascular disorders. •Known allergies to contrast agent. •Pregnant or breastfeeding, or intending to become pregnant during the study or within 6 months after the final dose of ocrelizumab. Women of childbearing potential must have a negative serum pregnancy test result at screening. •Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study. •History or currently active primary or secondary immunodeficiency. •Moderately to severe kidney function decreased or severe kidney failure (Glomerular filtration rate <45 mL/min/1.73 m2 as calculated through use of the Chronic Kidney Disease Epidemiology Collaboration equation). •History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. •Significant or uncontrolled somatic disease or any other significant disease that may preclude patient from participating in the study. •Congestive heart failure (NYHA III or IV functional severity). •Known active bacterial, viral, fungal, mycobacterial infection or other infection, excluding fungal infection of nail beds. •Infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to the Baseline visit or oral antibiotics within 2 weeks prior to the Baseline visit. •History or known presence of recurrent or chronic infection (e.g., hepatitis B or C, HIV, syphilis, tuberculosis). •History of progressive multifocal leukoencephalopathy (PML). •History of malignancy, including solid tumors and hematological malignancies, except basal cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix of the uterus that have been previously completely excised with documented, clear margins. •History of illicit drug or alcohol abuse within 24 weeks prior to screening, in the investigator’s judgment. •History or laboratory evidence of coagulation disorders. •Receipt of a live vaccine within 6 weeks prior to baseline. •Treatment with any investigational agent within screening period or five half-lives of the investigational drug (whichever is longer). •Contraindications to or intolerance of oral or intravenous corticosteroids, including methylprednisolone administered intravenously, according to the country label, including: psychosis not yet controlled by a treatment and hypersensitivity to any of the constituents. •Previous therapy with B-cell depleting agents (i.e. rituximab, ocrelizumab, atacicept, belimumab or ofatumumab). •Systemic corticosteroid therapy within 4 weeks prior to screening. •Any previous treatment with alemtuzumab, anti-CD4 antibodies, cladribine, mitoxantrone, daclizumab, dimethyl fumarate, teriflunomide, laquinimod, total body irradiation or bone marrow transplantation. •Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil (MMF), cyclosporine, methotrexate or natalizumab within 24 months prior to screening. •Treatment with fingolimod or other S1P receptor modulator within 24 weeks prior to screening. •Treatment with intravenous immunoglobulin within 12 weeks prior to baseline. •Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, or positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral deoxyribonucleic acid [DNA] polymerase chain reaction [PCR]) or hepatitis C (HepCAb). •Positive syphilis (RPR) test. •Positive HIV infection serological test. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy objective for this study is to determine the evolution of leptomeningeal lesions in patients with active progressive multiple sclerosis (MS) based on the following endpoint: •The number of LMCE foci at the Month 24 visit compared to the number of LMCE foci at the Baseline visit in the LMCE-positive group.
The first exploratory efficacy objective for this study is to investigate influence of leptomeningeal lesions evolution on brain atrophy estimates at 2 years with regard to LMCE-status based on the following endpoint: •Percentage of brain volume change (PBVC) after 2 years in the LMCE-positive group and the LMCE-negative group separately.
The safety objective for this study is to evaluate the safety of ocrelizumab on the basis of the following endpoints: • Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0. • Change from baseline in vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure). • Change from baseline in laboratory test results (hematology and chemistry panel).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline, 24 month, 2 years
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E.5.2 | Secondary end point(s) |
•The change from the Baseline visit in LMCE foci at the Month 12 visit in the LMCE- positive group. •The change from the Baseline visit in LMCE foci at the Month 12 visit in the LMCE-negative group. •The change from the Baseline visit in LMCE foci at the Month 24 visit in the LMCE-negative group. •Time until 3-months composite confirmed disability progression in the LMCE-positive group and the LMCE-negative group separately. •Time until 3-months confirmed disability progression in the LMCE-positive group and the LMCE-negative group separately. •Time until 3-months confirmed 20% worsening in arm function (9-HPT) in the LMCE-positive group and the LMCE-negative group separately. •Time until 3-months confirmed 20% worsening of gait function (T25FWT) in the LMCE-positive group and the LMCE-negative group separately. •B-cell repertoire at baseline in the LMCE-positive group and the LMCE-negative group separately. •The change in the B-cell repertoire at Month 24 compared to baseline in the LMCE-positive group and the LMCE-negative group separately. •The change in the B-cell repertoire at Month 24 compared to baseline in the subgroup of LMCE-positive patients with decreased amount of LMCE foci at Month 24 and subgroup of LMCE-positive patients with stable or increased amount of LMCE foci at Month 24 separately.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, 3 months, 12 month, 24 month, 2 year |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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 |
Greece |
Russian Federation |
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E.8.7 | Trial has a data monitoring committee | No |
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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The end of study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis or long-term follow-up is received from the last patient, whichever occurs later. LPLV is expected to occur after 24 months after the last patient is enrolled. |
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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 | 4 |
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 | 4 |
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 |