Multiple Sclerosis, Primary Progressive
Conditions
Brief summary
This study will evaluate the efficacy and safety of ocrelizumab (Ocrevus®) compared with placebo in participants with primary progressive multiple sclerosis (PPMS), including participants later in their disease course. This study will consist of the following phases: screening, double-blind treatment, an optional post-double-progression ocrelizumab (PDP OCR) treatment, follow-up 1 (FU1), an optional open-label extension (OLE), and follow-up 2 (FU2).
Detailed description
The screening phase will last up to 24 weeks. In the double-blind treatment phase, participants will undergo at least 144 weeks of study treatment. Study drug (ocrelizumab or placebo) will be administered every 24 weeks. All participants who discontinue prematurely from the double-blind treatment phase will enter the FU1 phase, including participants receiving other immunomodulatory or immunosuppressive treatment(s) for MS, commercial ocrelizumab, or no treatment. The FU1 phase will run in parallel with the double-blind treatment phase for 144 weeks or until the primary analysis is performed, whichever occurs first. An optional OLE phase is planned for eligible participants who either have either completed 144 weeks of the double-blind treatment phase or are ongoing in the double-blind treatment phase at the time of the primary analysis and, in the opinion of the investigator, could benefit from ocrelizumab treatment. The following participants will move into the FU2 phase: participants who are ongoing in the FU1 at 144 weeks from randomization or at the time of the primary analysis; participants who have either completed 144 weeks of the double-blind treatment phase or are ongoing in the double-blind treatment phase at the time of the primary analysis and will not enter the OLE phase; participants who have completed or withdrawn from the OLE phase or from PDP OCR treatment phase.
Interventions
DRUGOcrelizumab
The first dose of ocrelizumab will be administered as two 300 milligrams (mg), IV infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 600 mg infusion every 24 weeks. A minimum interval of 20 or 22 weeks, depending on if the previous dose was administered in one or two infusion, should be maintained between each infusion.
DRUGPlacebo
The first dose of placebo will be administered as two IV infusions given 14 days apart. For the subsequent doses, placebo will be administered as a single infusion every 24 weeks, with a minimum interval of 20 or 22 weeks, depending on if the previous dose was administered in one or two infusions, maintained between each infusion.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* EDSS score at screening and baseline \>= 3.0 to 8.0, inclusive * Disease duration from the onset of MS symptoms relative to randomization date: Less than 20 years in participants with an EDSS score at screening 7.0 - 8.0 Less than 15 years in participants with an EDSS at screening 5.5 - 6.5 Less than 10 years in participants 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: Elevated immunoglobulin G (IgG) index or 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 * Neurological stability for \>/= 30 days prior to baseline * Participants 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 * 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 after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required. * For female participants without reproductive potential: Women may be enrolled if surgically sterile (i.e hysterectomy, complete bilateral oophorectomy) or post-menopausal unless the participant is receiving a hormonal therapy for her menopause or if surgically sterile
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 * Participants 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 * Receipt of a live-attenuated vaccine within 6 weeks prior to randomization * Inability to complete an MRI or contraindication to Gd administration. * Participants requiring symptomatic treatment of MS and/or physiotherapy who are not on a stable regimen. Participants must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization. * Contraindications to mandatory premedications for infusion-related reactions, including: uncontrolled psychosis for corticosteroids and closed-angle glaucoma for antihistamines * Known presence of other neurologic disorders * Pregnant or breastfeeding, or intending to become pregnant during the study and for 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 participant 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 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 * Previous treatment with B-cell targeting therapies * 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 serum human chorionic gonadotropin (hCG) measured at screening or positive urine β-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 * Lack of MRI activity at screening/baseline if more than 650 participants 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, to ensure that at least 350 participants with MRI activity will be randomized Eligibility Criteria for OLE Phase: * Completed the 144 weeks of double-blind treatment phase of the trial or are ongoing in the double blind treatment phase at the time of the primary analysis, and who, in the opinion of the investigator, may benefit from treatment with Ocrelizumab. Participants who withdrew from study treatment and received another DMT or commercial ocrelizumab will not be allowed to enter in the OLE phase. * 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 after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required. * For female participants without reproductive potential: Women may be enrolled if surgically sterile (i.e. hysterectomy, complete bilateral oophorectomy) or post-menopausal unless the participant is receiving a hormonal therapy for her menopause or if surgically sterile
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of cCDP12 in Magnetic Resonance Imaging (MRI) Activity Analysis Set | Up to approximately 243 weeks | Time to onset of cCDP12 was defined as the time from randomization to the first occurrence of at least one of the following progression events: 1) 20% worsening from baseline in 9-HPT confirmed for at least 12 weeks; 2) increase of ≥ 1.0 point from baseline in EDSS score in participants with a baseline EDSS score ≤5.5 or an increase of ≥ 0.5 point in participants with a baseline EDSS score of \>5.5 that is confirmed for at least 12 weeks. EDSS disability scale is based on a standard neurological examination, incorporating functional systems \& ambulation, that ranges in 0.5-point steps from 0 \[normal\] to 10.0 \[death\]. 9-HPT is a quantitative measure of arm \& hand function, where participants placed \& removed pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the total time (in seconds) required was recorded. The longer it took to complete the test, the higher the scores, indicating deterioration. |
| Time to Onset of 12-week Composite Confirmed Disability Progression (cCDP12) in FAS | Up to approximately 243 weeks | Time to onset of cCDP12=time from randomization to the first occurrence of at least one of the following progression events: 1) 20% worsening from baseline in 9-hole Peg Test (9-HPT) confirmed for at least 12 weeks; 2) increase of ≥ 1.0 point from baseline in Expanded Disability Status Scale (EDSS) score in participants with a baseline EDSS score ≤5.5 or an increase of ≥ 0.5 point in participants with a baseline EDSS score of \>5.5 that is confirmed for at least 12 weeks. EDSS disability scale is based on a standard neurological examination, incorporating functional systems \& ambulation, that ranges in 0.5-point steps from 0 \[normal\] to 10.0 \[death\]. 9-HPT is a quantitative measure of arm \& hand function, where participants placed \& removed pegs 1 by 1 into 9 holes arranged in a board \& complete 2 successful trials for each hand \& the total time (in seconds) required was recorded. The longer it took to complete the test, the higher the scores, indicating deterioration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With ADAs to Ocrelizumab | Baseline up to approximately 10.5 years | Prevalence of ADAs at baseline is defined as the number of participants that is ADA positive at baseline. For determining post-baseline incidence, participants are considered to be ADA-positive if they are ADA-negative or have missing data at baseline but develop an ADA response following study drug exposure, or if they are ADA-positive at baseline and the titer of 1 or more post-baseline samples is at least 0.60 titer unit (t.u.) greater than the baseline titer result. |
| Time to 12-week CDP in 9-HPT | Up to approximately 243 weeks | 12-week CDP in 9-HPT was defined as a 20% worsening from baseline in 9-HPT confirmed for at least 12 weeks. 9-HPT is a quantitative measure of upper extremity (arm and hand) function. The test device consists of a container containing nine pegs and a wood or plastic block containing nine empty holes. Participants were required to pick up each of the 9 pegs one at a time and place them in the 9 holes. Once all the pegs were in the holes, the participants then removed them as quickly as possible. Both dominant and non-dominant hands were tested twice, and the total time (in seconds) to complete the task was recorded. The longer it took to complete the test, the higher the scores, indicating deterioration. |
| Time to 12-week CDP in EDSS | Up to approximately 243 weeks | 12-week CDP in EDSS=an increase of ≥1.0 point from baseline EDSS score in participants with a baseline EDSS score of ≤5.5 or an increase of ≥0.5 points in participants with a baseline EDSS score of \<5.5 that is confirmed for at least 12 weeks after initial documentation of the progression. EDSS was used to measure changes in the disability level of participants with MS over time. EDSS is based on a standard neurological examination, incorporating functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel \& bladder, \& cerebral \[or mental\]) that are rated \& then scored as a functional system scores (FSS), \& ambulation, which is scored as ambulation score. Each FSS is an ordinal clinical rating scale where score ranges from 0-5/6, \& ambulation score that is rated from 0 to 16. These ratings along with observations \& assistive devices were then used to determine the total EDSS score. The total EDSS score ranges from 0 (normal) to 10.0 (death) in 0.5-point steps. |
| Time to 24-week CDP in 9-HPT | Up to approximately 243 weeks | 24-week CDP in 9-HPT was defined as a 20% worsening from baseline in 9-HPT confirmed for at least 24 weeks. 9-HPT is a quantitative measure of upper extremity (arm and hand) function. The test device consists of a container containing nine pegs and a wood or plastic block containing nine empty holes. Participants were required to pick up each of the 9 pegs one at a time and place them in the 9 holes. Once all the pegs were in the holes, the participants then removed them as quickly as possible. Both dominant and non-dominant hands were tested twice, and the amount of time (in seconds) to complete the task was recorded. The longer it took to complete the test, the higher the scores, indicating deterioration. |
| Time to 24-week CDP in EDSS | Up to approximately 243 weeks | 24-week CDP in EDSS=an increase of ≥1.0 point from baseline EDSS score in participants with a baseline EDSS score of ≤5.5 or an increase of ≥0.5 points in participants with a baseline EDSS score of \<5.5 that is confirmed for at least 24 weeks after initial documentation of the progression. EDSS was used to measure changes in the disability level of participants with MS over time. EDSS is based on a standard neurological examination, incorporating functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel \& bladder, \& cerebral \[or mental\]) that are rated and then scored as a FSS, and ambulation, which is scored as ambulation score. Each FSS is an ordinal clinical rating scale where score ranges from 0 to 5 or 6, and ambulation score that is rated from 0 to 16. These ratings along with observations and assistive devices were then used to determine the total EDSS score. The total EDSS score ranges from 0 (normal) to 10.0 (death) in 0.5-point steps. |
| Annual Rate of Change From Baseline in Radius of Total Volume of T2 Lesions | Up to approximately 120 weeks | Volume of T2 lesions was measured using MRI scans. Mean difference in annual rate of change from baseline in radius of total volume of T2 lesions between the ocrelizumab and placebo arms in participants with PPMS, including participants later in their disease course, where no treatment discontinuation nor initiation of alternative MS disease-modifying treatment (DMT) or commercial ocrelizumab occurred, is reported. Random Coefficient Regression (RCRM) Model was used to estimate annual rate of change. |
| Annual Rate of Percent Change From Week 24 in Total Brain Volume | From Week 24 up to approximately 120 weeks | Brain volume was measured using MRI scans. Mean difference in annual rate of percent change from Week 24 in total brain volume between the ocrelizumab and placebo arms in participants with PPMS, including participants later in their disease course, where no treatment discontinuation nor initiation of alternative MS DMT or commercial ocrelizumab occurred, is reported. RCRM Model was used to estimate annual rate of change. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From initiation of study drug up to approximately 10.5 years | AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any AE that is: Fatal; Life-threatening; Requires or prolongs inpatient hospitalization; Results in persistent or significant disability/incapacity; A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug OR a significant medical event in the investigator's judgment. |
| Serum Concentration of Ocrelizumab | Up to approximately 10.5 years | — |
| B-cell Levels in Blood | Baseline, Weeks 2, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204 and 228 | — |
| Change From Baseline in B-cell Levels | Weeks 2, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204 and 228 | — |
| Percentage of Participants With B-cell Counts ≤5 Cells/μL | Baseline, Weeks 2, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204 and 228 | Percentages have been rounded off. |
| Percentage of Participants With B-cell Counts ≤10 Cells/μL | Baseline, Weeks 2, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204 and 228 | Percentages have been rounded off. |
Countries
Australia, Belgium, Bulgaria, Canada, Colombia, Croatia, France, Georgia, Italy, Lebanon, Mexico, Morocco, New Zealand, Poland, Portugal, Romania, Russia, Serbia, Spain, Tunisia, Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 1013 participants with primary progressive multiple sclerosis (PPMS) took part in the study at 148 investigative sites across 23 countries. Participants were randomized in a 1:1 ratio to receive double-blinded treatment (DBT) with either ocrelizumab or placebo followed by an optional post-double-progression ocrelizumab (PDP OCR) treatment, follow-up 1 (FU1), an optional open-label extension (OLE), & follow-up 2 (FU2).
Pre-assignment details
1 participant randomized to the placebo group received a single dose of ocrelizumab & was included in the ocrelizumab group for the safety analysis. 1 participant in placebo group did not receive any study treatment & was not included in safety analysis. The study is still ongoing.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 47.7 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 476 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 27 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 32 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 944 Participants |
| Sex: Female, Male Female | 568 Participants |
| Sex: Female, Male Male | 215 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 506 | 14 / 506 |
| other Total, other adverse events | 257 / 506 | 201 / 506 |
| serious Total, serious adverse events | 65 / 506 | 68 / 506 |
Outcome results
None listed