A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis

• Register: EUCTR
• Last refreshed on: 15 April 2024
• Main ID: EUCTR2020-000894-26-HU
• Date of registration: 06/08/2020
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis
• Scientific title: A PHASE IIIB MULTICENTER, RANDOMIZED, DOUBLE-BLIND, CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY AND PHARMACOKINETICS OF A HIGHER DOSE OF OCRELIZUMAB IN ADULTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS
• Date of first enrolment: 22/09/2020
• Target sample size: 699
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-000894-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Ocrelizumab approved dose compared to higher dose Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Belgium, Brazil, Bulgaria, Canada, Czechia, Denmark, France, Germany, Greece, Hungary, Italy, Mexico, New Zealand, Peru, Poland, Portugal, Russian Federation, Spain, Switzerland, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
? Ages 18-55 years at time of screening
? Ability to comply with the study protocol
? Diagnosis of PPMS in accordance with the revised McDonald Criteria 2017
? Expanded disability status scale (EDSS) score at screening and baseline >=3- 6.5, inclusive
? Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds
? Average 9HPT score over four trials (two trials with each hand) at screening and over four trials at baseline (two trials with each hand) respectively, up to 250 (inclusive) seconds
? Score of >=2.0 on the Functional Systems (FS) scale for the pyramidal system that was due to lower extremity findings at screening and baseline
? Documented MRI of brain with abnormalities consistent with MS
? Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization
? Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments
? Disease duration from the onset of MS symptoms: 1] If EDSS score at screening is <=5.0, disease duration from the onset of MS symptoms must be less than 10 years , 2] If EDSS score at screening is >5.0, disease duration from the onset of MS symptoms must be less than 15 years Documented evidence of the presence of at least one cerebrospinal fluid-specific oligoclonal bands
? For females of childbearing potential, agreement to remain abstinent or use adequate contraceptive method
? For female patients without reproductive potential: Females may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 699
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
? History of relapsing remitting or secondary progressive MS at screening
? Any known or suspected active infection at screening or baseline, or any major episode of infection requiring hospitalization or treatment with IV anti microbials within 8 weeks prior to and during screening or treatment with oral anti microbials within 2 weeks prior to and during screening
? History of confirmed or suspected progressive multifocal leukoencephalopathy (PML)
? History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
? Immunocompromised state
? Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization
? Inability to complete an MRI or contraindication to gadolinium administration
? Contraindications to mandatory pre medications for IRRs
? Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study
? Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
? Significant, uncontrolled disease, that may preclude patient from participating in the study
? History of or currently active primary or secondary (non-drug related) immunodeficiency
? Pregnant or breastfeeding or intending to become pregnant during the study
? Lack of peripheral venous access
? History of alcohol or other drug abuse within 12 months prior to screening
? Treatment with any investigational agent within 24 weeks prior to screening or five half-lives of the investigational drug (whichever is longer) or treatment with any experimental procedure for MS Previous use of anti-CD20s (including ocrelizumab), unless the last infusion was more than 2 years before screening, or if B-cell count is normal, and if the stop of the treatment was not motivated by safety reasons or lack of efficacy
? Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab and daclizumab
? Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline
? Previous treatment with natalizumab within 4.5 months of baseline
? Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline
? Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label. If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication. The PD effects of the previous medication must also be considered when determining the required time for washout.
? Any previous treatment with bone marrow transplantation and 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 screening tests for active, latent, or inadequately treated hepatitis B
? Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab
? Any additional exclusionary criterion as per ocrelizumab (Ocrevus) local label, if more stringent than the above



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Primary Progressive Multiple Sclerosis (MS)
MedDRA version: 21.1 Level: PT Classification code 10063401 Term: Primary progressive multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.1 Level: LLT Classification code 10039720 Term: Sclerosis multiple System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Trade Name: Ocrevus
Product Name: Ocrelizumab
Product Code: RO4964913/F07-01
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Ocrelizumab
CAS Number: 637334-45-3
Current Sponsor code: RO4964913
Other descriptive name: OCRELIZUMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 30-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Main Objective: • To demonstrate the superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab as assessed by risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks

Secondary Objective: ? To demonstrate superiority of a higher dose of ocrelizumab over the approved dose of ocrelizumab on the basis of time to onset of 24 week cCDP (cCDP24), CDP12, CDP24, time to >= 20% increase in 12 and 24 week confirmed timed 25-foot walk test (T25FWT) and 9-hole peg test (9-HPT), change from baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) at week 120, annual rate of percent change from baseline in total brain volume, Time to 12 week confirmed 4 point worsening in Symbol Digit Modalities test (SDMT)
? To evaluate the safety profile of a higher dose of ocrelizumab compared with the approved dose of ocrelizumab as well as the overall safety profile and safety profile by treatment arm over time
? To assess the exposure to ocrelizumab in serum in all patients in both study arms
? To characterize the ocrelizumab PD profile
? To evaluate the immune response to ocrelizumab
? To identify biomarkers that are predictive of response to a higher dose of ocrelizumab

Timepoint(s) of evaluation of this end point: 1. From Baseline up to 4.3 years (Double blind treatment [DBT])

Primary end point(s): 1. Reduction in cCDP sustained for at least 12 weeks, measured by time to onset of cCDP sustained for at least 12 weeks. Time to onset of cCDP is defined as the first occurrence of a predefined confirmed progression even measured by EDSS, T25FWT or 9-HPT

Secondary Outcome(s)

Secondary end point(s): 1. Time to onset of 24 week cCDP (cCDP24)
2. Time to onset of 12-week CDP (CDP12)
3. Time to onset of 24-week CDP (CDP24)
4. Time to >= 20% increase in 12 week confirmed T25FWT
5. Time to >= 20% increase in 24 week confirmed T25FWT
6. Time to >= 20% increase in 12 week confirmed 9-HPT
7. Time to >= 20% increase in 24 week confirmed 9-HPT
8. Change from baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) physical scale at Week 120
9. Annual rate of percent change from baseline in total brain volume
10. Time to 12 week confirmed 4 point worsening in Symbol Digit Modality test (SDMT)
11. Serum concentration of ocrelizumab at specified timepoints
12. Change in B cell levels in blood
13. Proportion of participants achieving 5 or less B-cells per microliter of blood
14. Proportion of participants achieving 5 or less B-cells per microliter of blood in participants with the high versus low affinity Fc gamma Receptor 3A (FcgR3A) genotype per arm
15. Change from Baseline in the anti-drug antibodies (ADAs) levels
16. Levels of Neurofilament Light Chain (NfL) in blood
17. Levels of Interleukin-6 (IL-6) in blood18. Levels of blood B-cells
19 Levels of Lymphocytes in blood
20. Proportion of participants with different DNA genotypes

Timepoint(s) of evaluation of this end point: 1-7. Baseline up to approximately 4.3 years
8 Baseline to Week 120
9-10 Baseline to approximately 4.3 years
11. Weeks 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
12-13. Baseline up to approximately 4.3 years
14 Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96, 120
15 Week 0, 24, 48, 72, 96, 120
16-19 Baseline up to approximately 4.3 years
20 Week 0, 2, 12, 24, 48, 72, 96, 120

Secondary ID(s)

BN42083

2020-000894-26-PT

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date: 15/09/2020
Contact: