Primary progressive multiple sclerosis Primary progressive multiple sclerosis
Conditions
Interventions
Eligible patients will be randomized (1:1) in a blinded fashion to either placebo or ocrelizumab.
The expected sample size will be approximately 1000 patients, with at least 350 patients in the MRI ac
Eligible patients will be randomized (1:1) in a blinded fashion to either placebo or ocrelizumab.
Treatment
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Inclusion criteria
Inclusion criteria: Patients must meet the following criteria for study entry: 1-Ability to provide written informed consent and be compliant with the study protocol 2-Diagnosis of PPMS in accordance with the McDonald criteria (Thompson et al.2017). 3-Age 18-65 years at time of signing Informed Consent Form 4-Expanded Disability Status Scale (EDSS) score at screening and baseline = 3.0 to 8.0, inclusive 5-Disease duration from the onset of MS symptoms relative to randomization date: Less than 20 years in patients with an EDSS score at screening 7-8.0 Less than 15 years in patients with an EDSS at screening 5.5-6.5 Less than 10 years in patients with an EDSS at screening =5.0 6-Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen (source documentation of laboratory results and method must be verified) - Elevated IgG index - One or more IgG oligoclonal bands detected by isoelectric focusing 7-Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands) 8-Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline 9-Neurological stability for = 30 days prior to baseline. 10-Patients previously treated with immunosuppressants, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used. Patients screened for this study should not be withdrawn from therapies for the sole purpose of meeting eligibility for the trial. Patients who discontinue their current therapy for non-medical reasons should specifically be informed before deciding to enter the study of their treatment options and, that by participating in this study, they may be randomized to placebo for a period of 120 weeks or greater. 11-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 Ocrevus local label) after the final dose of ocrelizumab. A woman is considered to be of childbearing potential if she is post menarcheal, has not reached a postmenopausal state ( =12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. The following are considered adequate contraceptive methods: bilateral tubal ligation; male sterilization; hormonal contraceptives; copper intrauterine devices; male or female condom with or without spermicide; and cap, diaphragm, or sponge with spermicide. 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 acceptable methods of contraception. For female patients without reproductive potential: Women may be enrolled if surgically sterile (i.e., hysterectomy, complete bilateral oophorectomy) or post-menopausal (i.e., spontaneous amenorrhea for the past year confirmed by a follicle-stimulating hormone [FSH] level > 40 mIU/mL) unless the patient is receiving a hormonal therapy for her menopause.
Exclusion criteria
Exclusion criteria: Patients who meet any of the following criteria will be excluded from study entry: 1- History of relapsing-remitting or secondary progressive MS at screening 2- Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease 3- Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML) 4- Known active malignancy or are being actively monitored for recurrence of malignancy 5- Immunocompromised state, defined as one or more of the following: -CD4 count < 250/microlitre -Absolute neutrophil count <1.5 x 10^3/microlitre -Serum IgG < 4.6 g/L 6- Receipt of a live-attenuated vaccine within 6 weeks prior to randomization 7- Inability to complete an MRI (contraindications for MRI, including but not restricted to pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, etc.) or contraindication to Gd administration. 8- Patients requiring symptomatic treatment of MS (e.g., fampridine) 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. 9- Contraindications to mandatory premedications (i.e., corticosteroids and antihistamines) for infusion-related reactions, including: -Uncontrolled psychosis for corticosteroids -Closed-angle glaucoma for antihistamines 10- Known presence of other neurologic disorders, including but not limited to, the following: History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or ischemia of the spinal cord History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma) History of metabolic myelopathy or known presence of untreated causes of metabolic myelopathy (e.g., untreated vitamin B12 deficiency) disease, HTLV 1, herpes zoster) History of genetically inherited progressive CNS degenerative disorder (e.g., mitochondrial myopathy, encephalopathy, lactic acidosis, stroke [MELAS]syndrome, and hereditary paraparesis) Neuromyelitis optica History or known presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sjögren syndrome, Behçet disease) History or known presence of sarcoidosis History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression) 11- Pregnant or breastfeeding, or intending to become pregnant during the study and for 6 or 12 months (as applicable by the Ocrevus local label) after last infusion of the study drug 12- Lack of peripheral venous access 13- Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study 14- Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study 15- History of alcohol or other drug abuse 16- History of primary or secondary (non-drug-related) immunodeficiency 17- Treatment with any investigational agent within 24 weeks pr
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Name: The primary efficacy objective for this study is to evaluate the efficacy of ocrelizumab-treated patients compared with placebo-treated patients on upper extremity disability progression;Timepoints: 12 weeks from baseline;Measure: upper limb disability progression defined as time to 20% worsening from baseline in 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 (MRI activity is defined as presence of T1 gadolinium (Gd)+ lesion[s] and/or new and/or enlarging T2 lesion[s] as detected by MRI scans during the screening phase). | — |
Secondary
| Measure | Time frame |
|---|---|
| Name: The secondary efficacy objective for this study is to evaluate the efficacy of ocrelizumab compared with placebo for all randomized patients ;Timepoints: 1;Measure: Upper limb disability progression defined as time to 20% increase from baseline in 9-HPT confirmed for at least 24 weeks;Name: The secondary efficacy objective for this study is to evaluate the efficacy of ocrelizumab compared with placebo for all randomized patients;Timepoints: 2;Measure: Time to 12-week Confirmed Disability Progression (CDP) in EDSS, defined as an increase in EDSS score that is confirmed for at least 12 weeks (an increase of =1.0 point from baseline EDSS score in patients with a baseline EDSS score = 5.5 or an increase of = 0.5 point in patients with a baseline EDSS score of > 5.5);Name: The secondary efficacy objective for this study is to evaluate the efficacy of ocrelizumab compared with placebo for all randomized patients ;Timepoints: 3;Measure: Time to 24-week CDP in EDSS, defined as an increase in EDSS score that is confirmed for at least 24 weeks (an increase of = 1.0 point from baseline EDSS in patients with a baseline EDSS score = 5.5 or an increase of =0.5 point in patients with a baseline EDSS score of > 5.5);Name: The secondary efficacy objective for this study is to evaluate the efficacy of ocrelizumab compared with placebo for all randomized patients ;Timepoints: 4;Measure: Percent change in total volume of T2 lesions from baseline up to Week 120;Name: The secondary efficacy objective for this study is to evaluate the efficacy of ocrelizumab compared with placebo for all randomized patients ;Timepoints: 5;Measure: Percent change in total brain volume from Week 24 to Week 120 | — |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Colombia, Croatia, France, Georgia, Hungary, Ireland, Italy, Mexico, New Zealand, Poland, Portugal, Republic of Serbia, Romania, Russian Federation, Spain, Ukraine, United Kingdom, United States of America
Contacts
Public ContactAziz Zoghbi
Director of Country Oversight and Manageme nt MENA, Gulf and Africa
Outcome results
None listed