A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis

• Register: EUCTR
• Last refreshed on: 10 August 2021
• Main ID: EUCTR2018-001511-73-IE
• Date of registration: 08/05/2019
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis
• Scientific title: A PHASE IIIb MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF OCRELIZUMAB IN ADULTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS
• Date of first enrolment: 16/03/2020
• Target sample size: 1000
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001511-73
• 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: yes; Other: no; 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

Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Colombia, Croatia, Egypt, France, Georgia, Germany, Hungary, Ireland, Italy, Mexico, Netherlands, New Zealand, Poland, Portugal, Romania, Russian Federation, Serbia, Spain, 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:
- 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 5.5 - 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 or use adequate contraceptive methods during the treatment period and for 6 or 12 months after the final dose of ocrelizumab (adherence to local requirements, if more stringent, is required)

Eligibility Criteria for OLE Phase:
- Completed the double-blind treatment phase of the trial or have received post-double-progression 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
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 1000
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
- 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 of metabolic myelopathy or known presence of untreated causes of myelopathy, history or known presence of infectious metabolic 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 half-lives 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


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 (PPMS)
MedDRA version: 21.1 Level: PT Classification code 10063401 Term: Primary progressive multiple sclerosis 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 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

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

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

Secondary Objective: •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)
•To evaluate the efficacy of ocrelizumab compared with placebo 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 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 B-cell levels

Secondary Outcome(s)

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

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

Secondary ID(s)

WA40404

2018-001511-73-GB

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date: 16/03/2020
Contact: