Multiple Sclerosis
Conditions
Keywords
PPMS, Primary progressive MS, Primary progressive multiple sclerosis, Rituxan, MS
Brief summary
This is a Phase II/III, randomized, double-blind, parallel group, placebo controlled, multicenter study to evaluate the safety and efficacy of rituximab in adults with PPMS. The study will enroll approximately 435 subjects at up to 60 sites in the United States and Canada.
Interventions
DRUGplacebo
Intravenous repeating dose
DRUGrituximab
Intravenous repeating dose
Sponsors
Genentech, Inc.
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
* Definitive diagnosis of PPMS * Disease duration of ≥ 1 year * EDSS at baseline between 2.0 and 6.5 points, inclusive * Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system or gait that is due to lower extremity findings * Presence of at least one of the following in a CSF specimen obtained during the screening period and analyzed by the central laboratory or results from a CSF sample obtained during the previous 24 months: * For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during study treatment and for 1 year following the last dose of study drug
Exclusion criteria
* Pregnancy or lactation * Incompatibility with MRI * Lack of peripheral venous access * History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies * Known active bacterial, viral, fungal, mycobacterial, or other infection (including atypical mycobacterial disease, but excluding fungal infections of nail beds or recurrent herpes zoster or simplex infections) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 30 days prior to screening or oral antibiotics within 14 days prior to screening * History or presence of recurrent or chronic infection (e.g., hepatitis B or C, HIV, syphilis) * History of cancer, including solid tumors and hematologic malignancies (except resected and fully resolved cutaneous basal cell and squamous cell carcinomas) * History of alcohol or drug abuse within 6 months prior to screening * History of or currently active primary or secondary immunodeficiency * Significant cardiac or pulmonary disease (including obstructive pulmonary disease) * Presence of other significant, uncontrolled cardiovascular, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease that might interfere with a subject's ability to participate and to complete approximately 2.5 years of study participation * History or presence of MS relapse or exacerbation * History or presence of vascular disease potentially affecting the brain or spinal cord (e.g., stroke, transient ischemic attack, carotid stenosis, aortic aneurysm, intracranial aneurysm, hemorrhage, arteriovenous malformation) * History or presence of myelopathy due to spinal cord compression by disk or vertebral disease * History of severe, clinically significant central nervous system trauma (e.g., cerebral contusion, spinal cord compression) * History of intracranial or intraspinal tumor (e.g., meningioma, glioma) * History or presence of potential metabolic cause of myelopathy or encephalopathy (e.g., vitamin B12 deficiency, thyroid abnormalities) * History or presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 \[HTLV-1\], or herpes zoster myelopathy) * History of genetically inherited progressive CNS degenerative disorder (e.g., X-linked adrenoleukodystrophy, hereditary spastic paraparesis) * Neuromyelitis optica * History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sj�gren syndrome, Beh�et disease) * History or presence of sarcoidosis * Previous treatment with rituximab (MabThera(R)/Rituxan(R)) * Previous treatment with lymphocyte-depleting therapies (e.g., cyclophosphamide, Campath(R), anti-CD4, cladribine, total body irradiation, bone marrow transplantation), except mitoxantrone, which should not be used 12 months prior to randomization * Treatment with an investigational agent within 90 days or 5 half-lives of the investigational drug (whichever is longer) prior to randomization * Receipt of a live vaccine within 30 days prior to randomization * Systemic corticosteroid therapy within 30 days prior to randomization * Treatment with IFN-β, glatiramer acetate, IVIg, or plasmapheresis within 60 days prior to randomization * Treatment with non-lymphocyte-depleting immunosuppressive therapies (e.g., azathioprine, mycophenolate mofetil \[MMF\], cyclosporine) within 90 days prior to randomization * Statins or hormone replacement therapy started within 30 days prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Confirmed Disease Progression (CDP) | 96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression) | Disease progression was assessed using the Expanded Disability Status Scale (EDSS), a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of greater than or equal to (≥) 1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score greater than (\>) 5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. Those who did not meet criteria for CDP, completed treatment with only initial progression, or received an exclusionary therapy were censored at last EDSS assessment. Time to CDP was the time from randomization to initial disease progression, estimated using Kaplan-Meier (KM) analysis. |
| Percentage of Participants With CDP | 96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression) | Disease progression was assessed using the EDSS, a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of ≥1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score \>5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. The percentage of participants with CDP was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 96 in Total Volume of Transverse Relaxation Time (T2) Brain Lesions on Magnetic Resonance Imaging (MRI) Scan | At Baseline and Week 96 | Scheduled T2-weighted MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total volume of T2 (ie, hyperintense) brain lesions at each visit was documented. Missing Week 96 values were imputed using a last observation carried forward (LOCF) approach, while participants with missing Baseline values were excluded. The change in T2 lesion volume was calculated as \[volume at Week 96 minus volume at Baseline\] and expressed in cubic millimeters (mm\^3). |
| Change From Baseline to Week 96 in Brain Volume on MRI Scan | At Baseline and Week 96 | Scheduled MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total brain volume was documented at Baseline and at visits occurring during Weeks 48 and 96. Missing Week 96 values were imputed using a LOCF approach, while participants with missing Baseline values were excluded. The change in brain volume was calculated as \[volume at Week 96 minus volume at Baseline\] and expressed in cubic centimeters (cm\^3). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received the placebo equivalent to rituximab via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of placebo separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks. | 147 |
| Rituximab Participants received rituximab 1 gram via IV infusion, for a treatment period of 96 weeks. Each treatment course involved 2 separate infusions of rituximab separated by 14 days without study drug. The first course was administered on Days 1 and 15, and subsequent courses were initiated every 24 weeks. | 292 |
| Total | 439 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 8 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Did Not Continue to Safety Follow-Up | 5 | 5 |
| Overall Study | Disease Progression | 5 | 4 |
| Overall Study | Initiation of Excluded Therapy | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Participant Decision | 14 | 37 |
| Overall Study | Participant Noncompliance | 0 | 1 |
| Overall Study | Physician Decision | 4 | 8 |
| Overall Study | Pregnancy | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Rituximab | Total |
|---|---|---|---|
| Age, Continuous | 49.6 years STANDARD_DEVIATION 8.69 | 50.1 years STANDARD_DEVIATION 9.02 | 49.9 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 81 Participants | 140 Participants | 221 Participants |
| Sex: Female, Male Male | 66 Participants | 152 Participants | 218 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 147 / 147 | 289 / 292 |
| serious Total, serious adverse events | 20 / 147 | 47 / 292 |
Outcome results
Primary
Percentage of Participants With CDP
Disease progression was assessed using the EDSS, a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of ≥1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score \>5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. The percentage of participants with CDP was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
Time frame: 96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With CDP | 36.1 percentage of participants |
| Rituximab | Percentage of Participants With CDP | 28.4 percentage of participants |
Primary
Time to Confirmed Disease Progression (CDP)
Disease progression was assessed using the Expanded Disability Status Scale (EDSS), a disability scale that ranges from 0 to 10, where higher scores represent increased disability. Progression was defined as either an increase of greater than or equal to (≥) 1 point from a Baseline EDSS score within 2.0 to 5.5 points, or an increase of ≥0.5 points from a Baseline EDSS score greater than (\>) 5.5 points, for which the change was not attributable to another etiology. Repeat assessment to determine CDP must have occurred at a regularly scheduled visit at least 12 weeks after initial progression; those who discontinued treatment early without confirmatory EDSS assessment were considered as having CDP. Those who did not meet criteria for CDP, completed treatment with only initial progression, or received an exclusionary therapy were censored at last EDSS assessment. Time to CDP was the time from randomization to initial disease progression, estimated using Kaplan-Meier (KM) analysis.
Time frame: 96 weeks (from Screening to Week 96, and at least 12 weeks after initial progression)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Confirmed Disease Progression (CDP) | NA weeks |
| Rituximab | Time to Confirmed Disease Progression (CDP) | NA weeks |
p-value: 0.144295% CI: [0.546, 1.093]Log Rank
Secondary
Change From Baseline to Week 96 in Brain Volume on MRI Scan
Scheduled MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total brain volume was documented at Baseline and at visits occurring during Weeks 48 and 96. Missing Week 96 values were imputed using a LOCF approach, while participants with missing Baseline values were excluded. The change in brain volume was calculated as \[volume at Week 96 minus volume at Baseline\] and expressed in cubic centimeters (cm\^3).
Time frame: At Baseline and Week 96
Population: ITT Population. Participants with missing Baseline values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 96 in Brain Volume on MRI Scan | -14.00 cm^3 |
| Rituximab | Change From Baseline to Week 96 in Brain Volume on MRI Scan | -13.10 cm^3 |
Comparison: Treatment difference in LS means and the associated 95% confidence intervals were estimated from the ANOVA model, which included the following factors: Baseline EDSS (≤ 4.0 versus \>4.0 points), prior treatment with interferon-beta or glatiramer acetate, and treatment group.p-value: 0.623795% CI: [-9.49, 7.34]Friedman ranked ANOVA test
Secondary
Change From Baseline to Week 96 in Total Volume of Transverse Relaxation Time (T2) Brain Lesions on Magnetic Resonance Imaging (MRI) Scan
Scheduled T2-weighted MRI scans of the brain and cervical spinal cord were performed with and without gadolinium contrast at Screening and Week 6, and without gadolinium at Weeks 48, 96, and 122 and/or upon early termination. The total volume of T2 (ie, hyperintense) brain lesions at each visit was documented. Missing Week 96 values were imputed using a last observation carried forward (LOCF) approach, while participants with missing Baseline values were excluded. The change in T2 lesion volume was calculated as \[volume at Week 96 minus volume at Baseline\] and expressed in cubic millimeters (mm\^3).
Time frame: At Baseline and Week 96
Population: ITT Population. Participants with missing Baseline values were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 96 in Total Volume of Transverse Relaxation Time (T2) Brain Lesions on Magnetic Resonance Imaging (MRI) Scan | 809.50 mm^3 |
| Rituximab | Change From Baseline to Week 96 in Total Volume of Transverse Relaxation Time (T2) Brain Lesions on Magnetic Resonance Imaging (MRI) Scan | 301.95 mm^3 |
Comparison: Treatment difference in least-squares (LS) means and the associated 95% confidence intervals were estimated from the analysis of variance (ANOVA) model, which included the following factors: Baseline EDSS (≤ 4.0 versus \>4.0 points), prior treatment with interferon-beta or glatiramer acetate, and treatment group.p-value: 0.000895% CI: [-1504.48, 68]Friedman ranked ANOVA test