| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| MedDRA Classification |
| 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 evaluate the efficacy of
ocrelizumab-treated patients compared with placebo-treated patients on upper extremity disability progression. |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of ocrelizumab compared with placebo of upper limb disability progression defined as 20% increase from baseline in 9-HPT,
•To evaluate the efficacy of ocrelizumab compared with placebo of time to 12-week and 24-week confirmed disability progression (CDP) 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 from baseline to week 120
•To evaluate the safety of ocrelizumab compared with placebo and over time for all patients who received ocrelizumab and until they receive any other immunomodulatory or immunosuppressive treatments 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 t |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Ability to provide written informed consent and be compliant with the study protocol
- 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 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 history or presence at screening of at least one of the following Laboratory findings in a CSF specimen (source documentation of laboratory results & method must be verified)
Elevated IgG index
One or more IgG oligoclonal bands detected by isoelectric focusing
- Screening and baseline 9-HPT completed in ≥ 25 seconds (average of the two hands)
- Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline
- 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.
- 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 postmenarcheal, 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 postovulation methods) and withdrawal are not acceptable methods of contraception.
- For female patients without reproductive potential:
Women may be enrolled if 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 or if surgically sterile (i.e., hysterectomy, complete bilateral oophorectomy). |
|
| E.4 | Principal exclusion criteria |
- History of relapsing-remitting or secondary progressive MS at screening
- Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease
- Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML)
- 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/uL
Absolute neutrophil count < 1.5 x 10'3/uL
Serum IgG < 4.6 g/L
- Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
- 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
- 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.
- Contraindications to mandatory premedications (i.e., corticosteroids and antihistamines) for IRRs, including:
Uncontrolled psychosis for corticosteroids
Closed-angle glaucoma for antihistamines
- 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 or known presence of potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)
History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy)
History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke [MELAS] syndrome)
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)
- Pregnant or breastfeeding, or intending to become pregnant during the study and 6 or 12 months (as applicable by the Ocrevus local label)after the final dose of ocrelizumab.
- Lack of peripheral venous access
- 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
- Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants 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 (Visit 1) or 5 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 treatment with B-cell targeting therapies (e.g., rituximab, ocrelizumab, atacicept, belimumab, ofatumumab)
- 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
The screening period may be extended for patients who have used systemic corticosteroids for MS before screening. For a patient to be eligible, systemic
corticosteroids should also not have been administered between screening and baseline.
- Positive serum β-hCG measured at screening or positive urine β-hCG at 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 DNA polymerase chain reaction [PRC])
- Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above
- Lack of MRI activity at screening/baseline if more than 650 patients without MRI activity have already been enrolled, as defined by T1 Gd+ lesion(s) and/or new and/or enlarged T2 lesion(s) in the screening |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| 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 | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 181 |
| 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 |
|
| 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
|
| The end of the study will occur when all patients who are not being treated with an alternative B-cell depleting therapy have repleted his or her B-cells (i.e., B-cell level of the patient has returned to the baseline value or the lower limit of normal, whichever is lower). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| 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 | 20 |
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