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: 6 October 2020
• Main ID: EUCTR2020-000894-26-GB
• Date of registration: 30/07/2020
• 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 - BN42083 Study to evaluate high dose Ocrelizumab in PPMS
• Date of first enrolment: 25/09/2020
• Target sample size: 786
• Recruitment status: Authorised-recruitment may be ongoing or finished
• 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 Other trial design description: Ocrelizumab approved dose compared to higher dose 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, Canada, Czech Republic, 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:
•Signed ICF
•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 (Thompson et al. 2018)
•EDSS score at screening and baseline, from 3 to 6.5 inclusive
•Score of >= 2.0 on the Functional Systems (FS) scale for the pyramidal system that was due to lower extremity findings
•Patients requiring symptomatic treatment for MS (e.g. fampridine, cannabis) and/or physiotherapy must be treated at a stable dose during the screening period prior to the initiation of study drug on Day 1 and must have a plan to remain at a stable dose for the duration of study treatment
•Patients must be neurologically stable for at least 30 days prior to randomization and baseline assessments
•Disease duration from the onset of MS symptoms:
Less than 15 years in patients with an EDSS score at screening >5.0
Less than 10 years in patients with an EDSS score at screening >5.0
•Documented evidence of the presence of cerebrospinal fluid-specific oligoclonal bands (established by a historical lumbar puncture or presence at screening in a newly obtained CSF specimen (source documentation of historical laboratory results and method must be verified)
•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 ocrelizumab [Ocrevus] local label) after the final dose of ocrelizumab.
•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 (i.e., hysterectomy, complete bilateral oophorectomy).

Are the trial subjects under 18? no
Number of subjects for this age range: 0
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 0

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, including, but not limited to, the following:
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 spectrum disorders
History or known presence of systemic autoimmune disorders potentially causing progressive neurologic disease
History or known presence of sarcoidosis
History of severe, clinically significant brain or spinal cord trauma
•Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
•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
•History of or currently active primary or secondary immunodeficiency
•Pregnant or breastfeeding or intending to become pregnant during the study or 6 or 12 months (as applicable from the local label for ocrelizumab) after final dose of the study drug
Females of childbearing potential must have a negative serum and urine pregnancy test
• 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 (Visit 1) or five half lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency)
• Previous use of anti-CD20s is allowed if the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy.
• Previous use of mitoxantrone, cladribine, atacicept, and alemtuzumab
• 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 p

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

Health Condition(s) or Problem(s) studied

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

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

Intervention(s)

Trade Name: Ocrevus
Product Name: Ocrevus
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)

Primary end point(s): 1. Reduction in cCDP sustained for at least 12 weeks

Timepoint(s) of evaluation of this end point: 1. Up to Week 120 (Double blind treatment [DBT]) and Week 96 (Open label extension [OLE])

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 (MSIS 29), percent change in total brain volume, Time to 12 week confirmed 4
point worsening in Symbol Digit Modality 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

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 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 (MSIS 29) physical scale at Week 120
9. Percent change in total brain volume from Week 24 to Week 120
10. Time to 12 week confirmed 4 point worsening in Symbol Digit
Modality test (SDMT)
11. Presence, frequency, timing, outcome and severity of AEs, serious
adverse events (SAE) and AEs leading to study treatment withdrawal
12. Proportion of patients with AEs and SAEs
13. Incidence and severity of adverse events, with severity determined
according to the National Cancer Institute's Common Terminology
Criteria for Adverse Events (NCI CTCAE) v5.0
14. Change from baseline in clinical laboratory test results (including
hematology, chemistry, Ig levels)
15. Change from baseline in vital signs (including systolic and diastolic
blood pressure, pulse rate) following study treatment administration
16. Serum concentration of ocrelizumab at specified timepoints
17. B cell levels in blood as the pharmacodynamic marker of ocrelizumab
(including comparing the degree of B-cell depletion between the doses)
18. Proportion of patients achieving 5 or less B-cells per microliter of
blood
19. Proportion of patients achieving 5 or less B-cells per microliter of
blood in patients with the high versus low affinity Fcgamma Receptor 3A (FcgR3A) genotype per arm
20. Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study
21. Levels of soluble biomarkers
22. Levels of blood B-cells based on a highly sensitive assay that can
accurately measure below 5 B-cells per microliter in blood
23. Levels of B or T cell subsets in blood
24. DNA genotype of patients

Timepoint(s) of evaluation of this end point: 1-7. Up to Week 120 (DBT) and Week 96 (OLE)
8. Baseline to Week 120
9. Week 24 to Week 120
10. Up to Week 120 (DBT) and Week 96 (OLE)
11-13. Up to Week 120 (DBT) and Week 96 (OLE)
14-15. Baseline to Week 120 (DBT) and Week 96 (OLE)
16-19. Week 0, 2, 12, 24, 36, 48, 60, 72, 84, 96
20. Week 0, 24, 48, 72, 96
21-24. DBT: Week 0, 2, 12, 24, 48, 72, 96; OLE: Week 0, 48, 96

Secondary ID(s)

BN42083

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date: 25/09/2020
Contact: