Relapsing-Remitting Multiple Sclerosis
Conditions
Brief summary
The primary objective of this study is to explore the effects of multiple regimens of natalizumab on disease activity and safety in participants with relapsing-remitting Multiple Sclerosis (RRMS).
Detailed description
This is a a dose and frequency (but not route of administration) blinded, prospective, randomized, dose-ranging study in patients with RRMS who have received natalizumab for at least 12 months according to the local prescribing guidelines. The study will explore dosing of natalizumab by subcutaneous and intravenous routes. Participants will be randomly assigned to 1 of 6 dosing regimens, blinded to natalizumab dose, but not route, for 60 weeks of treatment.
Interventions
DRUGnatalizumab IV
natalizumab for IV Infusion
DRUGnatalizumab SC
natalizumab for Subcutaneous Injection
DRUGIV Placebo
Intravenous placebo to natalizumab
DRUGSC Placebo
Subcutaneous placebo to natalizumab
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Ability to provide written informed consent * Subjects of childbearing potential must practice effective contraception during the study * A documented diagnosis of Relapsing Remitting Multiple Sclerosis (RRMS) * Free of MS relapse for 12 months prior to randomization * Treatment with natalizumab for a minimum of 12 months immediately prior to randomization. * In the 12 months prior to commencing natalizumab, subject must have experienced a minimal level of disease activity as defined by 2 or more documented clinical relapses OR 1 relapse and documented MRI activity, defined by the presence of at least 1 Gd enhancing lesion on MRI, unrelated to the relapse. Key
Exclusion criteria
* Known history of Human Immunodeficiency Virus (HIV), hepatitis C and/or hepatitis B virus * Positive for anti-natalizumab antibodies at screening * MRI positive for Gd-enhancing lesions at study entry * Subjects for whom MRI is contraindicated * History of any clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic (including diabetes), urologic, pulmonary, neurologic (except for RRMS), dermatologic, psychiatric, renal, or other major disease * History of malignant disease, including solid tumors and hematologic malignancies (with the exception of cured basal cell and squamous cell carcinomas of the skin) * History of transplantation or any anti-rejection therapy * History of severe allergic or anaphylactic reactions or known hypersensitivity to any drug * A clinically significant infectious illness within 30 days prior to screening or progressive multifocal leukoencephalopathy (PML) or other opportunistic infections at any time * Signs or symptoms suggestive of any serious infection, based on medical history, physical examination or laboratory testing NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Number of Combined Unique Active Lesions | Up to Week 60 | Cumulative number of combined unique active lesions (sum of the number of new gadolinium (Gd)-enhancing lesions and new or newly enlarging T2 hyperintense lesions not associated with Gd-enhancement on T1 weighted scans) based on brain magnetic resonance imaging (MRI) scans Up to Week 60. |
Countries
Belgium, France, Germany, Italy, Spain
Participant flow
Pre-assignment details
Four of the 6 arms in the Randomized Treatment Period (the 'every 12 weeks' arms) were closed prematurely. Participants who completed randomized treatment, met rescue criteria, or were impacted by arm closure (and met rescue criteria) were eligible to enroll in the open-label treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Period: Natalizumab 300 mg IV Every 4 Weeks Natalizumab 300 mg IV every 4 weeks for 60 weeks. | 54 |
| Randomized Period: Natalizumab 300 mg SC Every 4 Weeks Natalizumab 300 mg SC every 4 weeks for 60 weeks. | 45 |
| Randomized Period: Natalizumab 300 mg IV Every 12 Weeks Natalizumab 300 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. | 52 |
| Randomized Period: Natalizumab 300 mg SC Every 12 Weeks Natalizumab 300 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. | 54 |
| Randomized Period: Natalizumab 150 mg IV Every 12 Weeks Natalizumab 150 mg IV every 12 weeks for 60 weeks with matching IV placebo administered during the intervening 4-week periods. | 47 |
| Randomized Period: Natalizumab 150 mg SC Every 12 Weeks Natalizumab 150 mg SC every 12 weeks for 60 weeks with matching SC placebo administered during the intervening 4-week periods. | 38 |
| Total | 290 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Open-Label Treatment Period | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Open-Label Treatment Period | Other | 1 | 1 | 1 | 1 | 1 | 1 |
| Open-Label Treatment Period | Physician Decision | 0 | 0 | 1 | 2 | 1 | 0 |
| Open-Label Treatment Period | Withdrawal by Subject | 3 | 1 | 1 | 1 | 0 | 1 |
| Randomized Treatment Period | Adverse Event | 3 | 3 | 3 | 0 | 2 | 1 |
| Randomized Treatment Period | Death | 0 | 0 | 0 | 1 | 0 | 0 |
| Randomized Treatment Period | Incorrect Study Treatment | 0 | 0 | 3 | 0 | 2 | 0 |
| Randomized Treatment Period | Other | 2 | 2 | 1 | 1 | 0 | 0 |
| Randomized Treatment Period | Physician Decision | 0 | 2 | 1 | 0 | 0 | 0 |
| Randomized Treatment Period | Rescue | 0 | 1 | 13 | 10 | 8 | 8 |
| Randomized Treatment Period | Treatment Arm Closed | 0 | 0 | 20 | 36 | 33 | 28 |
| Randomized Treatment Period | Withdrawal by Subject | 6 | 2 | 2 | 2 | 0 | 0 |
| Randomized Treatment Period | Withdrew Prior to Dosing | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Randomized Period: Natalizumab 300 mg IV Every 4 Weeks | Randomized Period: Natalizumab 300 mg SC Every 4 Weeks | Randomized Period: Natalizumab 300 mg IV Every 12 Weeks | Randomized Period: Natalizumab 300 mg SC Every 12 Weeks | Randomized Period: Natalizumab 150 mg IV Every 12 Weeks | Randomized Period: Natalizumab 150 mg SC Every 12 Weeks | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 38.4 years STANDARD_DEVIATION 7.84 | 36.3 years STANDARD_DEVIATION 8.92 | 38.7 years STANDARD_DEVIATION 8.43 | 38.7 years STANDARD_DEVIATION 7.85 | 38.7 years STANDARD_DEVIATION 8.61 | 36.0 years STANDARD_DEVIATION 9.03 | 37.9 years STANDARD_DEVIATION 8.41 |
| Age, Customized 18 to 19 years | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Age, Customized 20 to 29 years | 7 participants | 11 participants | 7 participants | 7 participants | 5 participants | 11 participants | 48 participants |
| Age, Customized 30 to 39 years | 22 participants | 15 participants | 21 participants | 24 participants | 21 participants | 14 participants | 117 participants |
| Age, Customized 40 to 49 years | 20 participants | 16 participants | 17 participants | 17 participants | 16 participants | 9 participants | 95 participants |
| Age, Customized 50 to 56 years | 5 participants | 2 participants | 7 participants | 6 participants | 5 participants | 4 participants | 29 participants |
| Sex: Female, Male Female | 39 Participants | 29 Participants | 37 Participants | 41 Participants | 34 Participants | 24 Participants | 204 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 15 Participants | 13 Participants | 13 Participants | 14 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 40 / 54 | 31 / 45 | 31 / 52 | 34 / 53 | 31 / 47 | 17 / 38 | 2 / 44 | 4 / 35 | 2 / 42 | 0 / 42 | 4 / 42 | 6 / 32 |
| serious Total, serious adverse events | 7 / 54 | 4 / 45 | 4 / 52 | 3 / 53 | 4 / 47 | 1 / 38 | 0 / 44 | 1 / 35 | 0 / 42 | 1 / 42 | 1 / 42 | 2 / 32 |
Outcome results
Primary
Cumulative Number of Combined Unique Active Lesions
Cumulative number of combined unique active lesions (sum of the number of new gadolinium (Gd)-enhancing lesions and new or newly enlarging T2 hyperintense lesions not associated with Gd-enhancement on T1 weighted scans) based on brain magnetic resonance imaging (MRI) scans Up to Week 60.
Time frame: Up to Week 60
Population: Modified intent-to-treat (mITT) population: all randomized participants who received at least 1 dose of study drug, had at least 1 efficacy assessment, and had no statistical protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Period: Natalizumab 300 mg IV Every 4 Weeks | Cumulative Number of Combined Unique Active Lesions | 0.23 lesions | Standard Deviation 1.262 |
| Randomized Period: Natalizumab 300 mg SC Every 4 Weeks | Cumulative Number of Combined Unique Active Lesions | 0.02 lesions | Standard Deviation 0.151 |
| Randomized Period: Natalizumab 300 mg IV Every 12 Weeks | Cumulative Number of Combined Unique Active Lesions | 3.84 lesions | Standard Deviation 8.054 |
| Randomized Period: Natalizumab 300 mg SC Every 12 Weeks | Cumulative Number of Combined Unique Active Lesions | 3.08 lesions | Standard Deviation 8.216 |
| Randomized Period: Natalizumab 150 mg IV Every 12 Weeks | Cumulative Number of Combined Unique Active Lesions | 6.09 lesions | Standard Deviation 15.424 |
| Randomized Period: Natalizumab 150 mg SC Every 12 Weeks | Cumulative Number of Combined Unique Active Lesions | 6.44 lesions | Standard Deviation 11.285 |