Multiple Sclerosis, Relapsing-Remitting
Conditions
Brief summary
Part 1: The primary objective is to evaluate the efficacy of natalizumab extended interval dosing (EID) (every 6 weeks \[Q6W\]) in participants who have previously been treated with natalizumab standard interval dosing (SID) (every 4 weeks \[Q4W\]) for at least 12 months, in relation to continued Q4W treatment. The secondary objectives is to evaluate relapse-based clinical efficacy measures, disability worsening, additional Magnetic resonance imaging (MRI)-lesion efficacy measures and safety of Q6W in participants who have previously been treated with natalizumab Q4W for at least 12 months, in relation to continued Q4W treatment. Part 2: The primary objective is to evaluate participant preference for subcutaneous (SC) versus intravenous (IV) route of natalizumab administration. The secondary objectives is to evaluate treatment satisfaction, drug preparation and administration time, safety and immunogenicity, efficacy and characterize pharmacokinetic (PK) and pharmacodynamic (PD) drug preparation and administration time of SC versus IV routes of natalizumab administration.
Detailed description
This study will be conducted in 2 parts. At the end of part 1, participants who provide consent and are eligible, and newly enrolled participants, will enter part 2, an Open Label Extension comprising a crossover analysis. Those participants who completed part 1 and cannot participate, or elect not to participate, in Part 2 (Open label extension) will enter a 12-week follow-up.
Interventions
DRUGNatalizumab
Natalizumab 300 mg IV infusion.
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: For Part 1: * Ability of the participant to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulations. * Diagnosis of relapsing remitting multiple sclerosis (RRMS) according to the McDonald criteria \[Thompson 2018\]. * Treatment with natalizumab as disease-modifying monotherapy for RRMS that is consistent with the approved dosing for a minimum of 12 months prior to randomization. The participant must have received at least 11 doses of natalizumab in the 12 months prior to randomization with no missed doses in the 3 months prior to randomization. * Expanded Disability Status Scale (EDSS) score \<=5.5 at screening. * No relapses in the last 12 months prior to randomization, as determined by the enrolling Investigator. For Part 2: * Ability of the participants to understand the purpose and risks of the study and provide signed and dated informed consent for Part 2 and authorization to use confidential health information in accordance with national and local participant privacy regulations. * Completed Part 1 Week 72 visit while remaining on their randomized treatment assignment of Q4W or Q6W. Key
Exclusion criteria
For Part 1: * Primary and secondary progressive multiple sclerosis (MS). * MRI positive for Gd-enhancing lesions at screening. * Participants for whom MRI is contraindicated (e.g., have a contraindicated pacemaker or other contraindicated implanted metal device, have suffered, or are at risk for, side effects from Gd, or have claustrophobia that cannot be medically managed). * History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic (including diabetes), urologic, pulmonary, neurologic (except for RRMS), dermatologic, psychiatric, renal, or other major disease that would preclude participation in a clinical study, in the opinion of the Investigator. * Presence of anti-natalizumab antibodies at screening. For Part 2: * Participants treated with natalizumab Q6W was reverted to natalizumab Q4W by choice or as rescue treatment in Part 1. * Participant received treatment with any MS disease-modifying therapy other than natalizumab in Part 1 or in the period between Part 1 and Part 2. * History of human immunodeficiency virus or history of other immunodeficient conditions. * Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 30 days (or 5 half-lives of the agent, whichever is longer) prior to the Baseline Visit or at any time during this study. * Inability to comply with study requirements. * Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the participant unsuitable for enrollment. The inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72 | Week 72 | T2 hyperintense lesions were analyzed by magnetic resonance imaging (MRI) scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions at Week 72 relative to baseline. |
| Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Period of Part 2 | Week 150 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Annualized Relapse Rate at Week 72 | Week 72 | Annualized relapse rate is calculated as the total number of INEC-confirmed relapses that occurred during the treatment period divided by the total number of participant-years followed in the period. |
| Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening | Up to Week 72 | Confirmed EDSS worsening is defined as an increase of at least 1.0 point from a baseline EDSS score ≥ 1.0 or an increase of at least 1.5 points from a baseline EDSS score of 0 that is confirmed after at least 24 weeks. Time to EDSS worsening is estimated by Kaplan-Meier method. |
| Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72 | Weeks 24, 48, and 72 | T1 hypointense lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new T1 hypointense lesions at Weeks 24, 48, and 72 relative to baseline. |
| Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48 | Weeks 24 and 48 | T2 hyperintense lesions were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions at Weeks 24 and 48 relative to baseline. |
| Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72 | Weeks 24, 48, and 72 | Gd enhancing lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new Gd enhancing lesions at Weeks 24, 48, and 72 relative to baseline. |
| Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Baseline up to Week 84 | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. 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 (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any event occurring on or after first dose after randomization up to 12 weeks (or 24 weeks for PML \[progressive multifocal leukoencephalopathy\] events) following the last dose on the study.An SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization or prolongation of existing hospitalization, results in a significant disability/incapacity or congenital anomaly, is a medically important event. |
| Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period | Part 2 Baseline (Week 108) up to Week 156 | The TSQM has 14 questions that assesses participants' global satisfaction level with their treatment in 4 domains: side effects (There are 5 questions in the side effects domain, however one of them is a Yes/No question and there are 4 sub-components, hence a maximum score of 20), effectiveness (3 questions), global satisfaction (3 questions), and convenience (3 questions). All questions are scored from 1 (least satisfied) to 5 or 7 (most satisfied). The total score is summed for each domain to obtain: side effects (1-20), effectiveness (1-21), global satisfaction (1-17), and convenience (1-21), using transformed scores between 0 and 100 for effectiveness. Lower total scores in each domain indicate dissatisfaction with the study medication and higher total scores indicate satisfaction. |
| Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period | Week 108 up to Week 156 | — |
| Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | Part 2: Baseline (Week 108) up to Week 180 | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. 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 (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any event occurring on or after first dose after randomization up to and including 12 weeks (or 24 weeks for PML events) following the last dose on the study. |
| Part 2: Mean Trough α4 Integrin Saturation During the Crossover Period | Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156 | — |
| Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period | Part 2 Baseline (Week 108) up to Week 156 | — |
| Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period | Part 2 Baseline (Week 108) up to Week 156 | T2 hyperintense lesions were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions during the crossover period of Part 2 relative to baseline. |
| Part 2: Time to First Relapse During the Crossover Period | Part 2 Baseline (Week 108) up to Week 156 | Relapse is defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours. The time to first relapse is defined as the time from the first randomized dose in Part 2 up to the first relapse. Time to First Relapse is estimated by Kaplan-Meier method. |
| Part 2: Annualized Relapse Rate During the Crossover Period | Part 2 Baseline (Week 108) up to Week 156 | Annualized relapse rate is calculated as the total number of relapses that occurred during the treatment period divided by the total number of participant-years followed in the period. |
| Part 2: Change From Baseline in EDSS Score During the Crossover Period | Part 2 Baseline (Week 108) up to Week 156 | The EDSS is a scale based on standardized neurological examination which comprised of optic, brain stem, pyramidal, cerebellar, sensory and cerebral functions, as well as walking ability. It measures the MS disability status on a scale ranging from 0 (normal) to 10 (death due to MS), with higher scores indicating more disability. |
| Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period | Week 108 up to Week 156 | Gd enhancing lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new Gd enhancing lesions during the crossover period of Part 2 relative to baseline. |
| Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period | Week 108 up to Week 156 | T1 hypointense lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new T1 hypointense lesions during the crossover period of Part 2 relative to baseline. |
| Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period | Part 2 Baseline (Week 108) up to Week 156 | — |
| Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period | Part 2 Baseline (Week 108) up to Week 156 | — |
| Part 2: Trough Serum Concentration of Natalizumab (Ctrough) During the Crossover Period | Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156 | — |
| Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC) | Up to Week 72 | Relapse is defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination. Only relapses confirmed by an INEC were included in the analysis. Time to First Relapse was estimated by Kaplan-Meier method. |
Countries
Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at the investigative sites in Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, the United Kingdom, and the United States from 27 November 2018 to 20 June 2021.
Pre-assignment details
585 participants were enrolled in the study, out of which 499 participants were randomized in Part 1. A total of 396 participants completed Part 1 of the study, out of which 67 participants entered Part 2 of the study. A total of 153 participants (including 86 new participants) entered Part 2 crossover period and 123 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: IV Q4W Participants received natalizumab 300 mg IV infusion Q4W up to Week 72. | 248 |
| Part 1: IV Q6W Participants received natalizumab 300 mg IV infusion Q6W up to Week 72. | 251 |
| Part 2: Crossover Period Participants who were newly enrolled in Part 2 received natalizumab 300 mg IV infusion Q6W from Week 108 through Week 126 followed by natalizumab 300 mg SC injection Q6W from Week 132 through Week 150, or natalizumab 300 mg SC injection Q6W from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion Q6W from Week 132 through Week 150, along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant's choice at Week 156. | 86 |
| Total | 585 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Part 1 (Day 1 up to Week 72) | Adverse Event | 1 | 3 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Consent Withdrawn | 14 | 9 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Developed Persistent Anti-Natalizumab Antibodies | 1 | 3 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Investigator Decision | 9 | 6 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Lost to Follow-up | 0 | 2 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Pregnancy | 5 | 1 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Protocol-Defined Rescue Criteria | 0 | 6 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Randomized but not Dosed | 1 | 1 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Reason not Specified | 20 | 16 | 0 | 0 | 0 |
| Part 1 (Day 1 up to Week 72) | Unwilling to Comply With Protocol | 3 | 2 | 0 | 0 | 0 |
| Part2CrossoverPeriod(Week108uptoWeek156) | Adverse Event | 0 | 0 | 0 | 1 | 1 |
| Part2CrossoverPeriod(Week108uptoWeek156) | Consent Withdrawn | 0 | 0 | 0 | 7 | 1 |
| Part2CrossoverPeriod(Week108uptoWeek156) | Investigator Decision | 0 | 0 | 0 | 2 | 2 |
| Part2CrossoverPeriod(Week108uptoWeek156) | Pregnancy | 0 | 0 | 0 | 0 | 1 |
| Part2CrossoverPeriod(Week108uptoWeek156) | Randomized but not Dosed | 0 | 0 | 0 | 0 | 12 |
| Part2CrossoverPeriod(Week108uptoWeek156) | Reason not Specified | 0 | 0 | 0 | 2 | 1 |
| Part 2:Run-in Period (Week73uptoWeek107) | Consent Withdrawn | 0 | 0 | 2 | 0 | 0 |
| Part 2:Run-in Period (Week73uptoWeek107) | Pregnancy | 0 | 0 | 1 | 0 | 0 |
| Part 2:Run-in Period (Week73uptoWeek107) | Reason not Specified | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Part 1: IV Q4W | Part 1: IV Q6W | Part 2: Crossover Period |
|---|---|---|---|---|
| Age, Continuous | 40.3 Years STANDARD_DEVIATION 9.9 | 40.5 Years STANDARD_DEVIATION 10.03 | 41.0 Years STANDARD_DEVIATION 9.66 | 37.6 Years STANDARD_DEVIATION 9.85 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 10 Participants | 9 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 514 Participants | 223 Participants | 224 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 51 Participants | 15 Participants | 18 Participants | 18 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 5 Participants | 1 Participants | 4 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 37 Participants | 23 Participants | 14 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not Reported | 40 Participants | 11 Participants | 15 Participants | 14 Participants |
| Race/Ethnicity, Customized Race Other | 8 Participants | 1 Participants | 6 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 493 Participants | 211 Participants | 211 Participants | 71 Participants |
| Sex: Female, Male Female | 417 Participants | 181 Participants | 178 Participants | 58 Participants |
| Sex: Female, Male Male | 168 Participants | 67 Participants | 73 Participants | 28 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 247 | 0 / 250 | 0 / 158 | 0 / 136 | 0 / 132 |
| other Total, other adverse events | 104 / 247 | 105 / 250 | 42 / 158 | 48 / 136 | 56 / 132 |
| serious Total, serious adverse events | 17 / 247 | 17 / 250 | 3 / 158 | 2 / 136 | 4 / 132 |
Outcome results
Primary
Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72
T2 hyperintense lesions were analyzed by magnetic resonance imaging (MRI) scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions at Week 72 relative to baseline.
Time frame: Week 72
Population: Modified intent to treat (mITT) population included all randomized participants who received at least one dose of study treatment and had at least one postbaseline result in Part 1. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 1: IV Q4W | Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72 | 0.05 number of T2 lesions |
| Part 1: IV Q6W | Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72 | 0.20 number of T2 lesions |
p-value: =0.075595% CI: [0.86, 20.85]Negative Binomial Regression
Primary
Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Period of Part 2
Time frame: Week 150
Population: mITT population included all randomized participants who received at least one dose of SC natalizumab after randomization in Part 2 and who completed at least the first question in the Patient Preference Questionnaire (PPQ) on one occasion. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis. (Confidence interval=CI)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: IV Q4W | Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Period of Part 2 | 83.9 percentage of participants |
| Part 1: IV Q6W | Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Period of Part 2 | 91.8 percentage of participants |
95% CI: [80.68, 93.01]Exact Binomial method
Secondary
Part 1: Annualized Relapse Rate at Week 72
Annualized relapse rate is calculated as the total number of INEC-confirmed relapses that occurred during the treatment period divided by the total number of participant-years followed in the period.
Time frame: Week 72
Population: mITT population included all randomized participants who received at least one dose of study treatment and had at least one postbaseline result in Part 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: IV Q4W | Part 1: Annualized Relapse Rate at Week 72 | 0.00010 relapses per participant-year |
| Part 1: IV Q6W | Part 1: Annualized Relapse Rate at Week 72 | 0.0001 relapses per participant-year |
p-value: =0.631295% CI: [0.42016, 4.17725]Poisson Regression
Secondary
Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72
Gd enhancing lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new Gd enhancing lesions at Weeks 24, 48, and 72 relative to baseline.
Time frame: Weeks 24, 48, and 72
Population: mITT population included all randomized participants who received at least one dose of study treatment and had at least one postbaseline result in Part 1. 'Overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis. Here, 'number analyzed' signifies the number of participants with data available for analysis at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: IV Q4W | Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72 | Week 24 | 0.0 number of Gd lesions | Standard Deviation 0.07 |
| Part 1: IV Q4W | Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72 | Week 48 | 0.0 number of Gd lesions | Standard Deviation 0.07 |
| Part 1: IV Q4W | Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72 | Week 72 | 0.0 number of Gd lesions | Standard Deviation 0.07 |
| Part 1: IV Q6W | Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72 | Week 24 | 0.0 number of Gd lesions | Standard Deviation 0 |
| Part 1: IV Q6W | Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72 | Week 48 | 0.0 number of Gd lesions | Standard Deviation 0 |
| Part 1: IV Q6W | Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72 | Week 72 | 0.1 number of Gd lesions | Standard Deviation 0.83 |
Secondary
Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48
T2 hyperintense lesions were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions at Weeks 24 and 48 relative to baseline.
Time frame: Weeks 24 and 48
Population: mITT population included all randomized participants who received at least one dose of study treatment and had at least one postbaseline result in Part 1. 'Overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis. Here, 'number analyzed' signifies the number of participants with data available for analysis at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: IV Q4W | Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48 | Week 24 | 0.0 number of T2 lesions | Standard Deviation 0.16 |
| Part 1: IV Q4W | Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48 | Week 48 | 0.0 number of T2 lesions | Standard Deviation 0.21 |
| Part 1: IV Q6W | Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48 | Week 24 | 0.0 number of T2 lesions | Standard Deviation 0.35 |
| Part 1: IV Q6W | Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48 | Week 48 | 0.1 number of T2 lesions | Standard Deviation 1.03 |
Secondary
Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72
T1 hypointense lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new T1 hypointense lesions at Weeks 24, 48, and 72 relative to baseline.
Time frame: Weeks 24, 48, and 72
Population: mITT population included all randomized participants who received at least one dose of study treatment and had at least one postbaseline result in Part 1. 'Overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis. Here, 'number analyzed' signifies the number of participants with data available for analysis at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: IV Q4W | Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72 | Week 24 | 0.0 number of T1 lesions | Standard Deviation 0.13 |
| Part 1: IV Q4W | Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72 | Week 48 | 0.0 number of T1 lesions | Standard Deviation 0.16 |
| Part 1: IV Q4W | Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72 | Week 72 | 0.0 number of T1 lesions | Standard Deviation 0.16 |
| Part 1: IV Q6W | Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72 | Week 24 | 0.0 number of T1 lesions | Standard Deviation 0.06 |
| Part 1: IV Q6W | Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72 | Week 48 | 0.0 number of T1 lesions | Standard Deviation 0.07 |
| Part 1: IV Q6W | Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72 | Week 72 | 0.0 number of T1 lesions | Standard Deviation 0.32 |
Secondary
Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. 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 (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any event occurring on or after first dose after randomization up to 12 weeks (or 24 weeks for PML \[progressive multifocal leukoencephalopathy\] events) following the last dose on the study.An SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization or prolongation of existing hospitalization, results in a significant disability/incapacity or congenital anomaly, is a medically important event.
Time frame: Baseline up to Week 84
Population: Safety population included all randomized participants who received at least one dose of study treatment in Part 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: IV Q4W | Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 76.9 percentage of participants |
| Part 1: IV Q4W | Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 6.9 percentage of participants |
| Part 1: IV Q6W | Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 77.6 percentage of participants |
| Part 1: IV Q6W | Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 6.8 percentage of participants |
Secondary
Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening
Confirmed EDSS worsening is defined as an increase of at least 1.0 point from a baseline EDSS score ≥ 1.0 or an increase of at least 1.5 points from a baseline EDSS score of 0 that is confirmed after at least 24 weeks. Time to EDSS worsening is estimated by Kaplan-Meier method.
Time frame: Up to Week 72
Population: mITT population included all randomized participants who received at least one dose of study treatment and had at least one postbaseline result in Part 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: IV Q4W | Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening | NA weeks |
| Part 1: IV Q6W | Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening | NA weeks |
Secondary
Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC)
Relapse is defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination. Only relapses confirmed by an INEC were included in the analysis. Time to First Relapse was estimated by Kaplan-Meier method.
Time frame: Up to Week 72
Population: mITT population included all randomized participants who received at least one dose of study treatment and had at least one postbaseline result in Part 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: IV Q4W | Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC) | NA weeks |
| Part 1: IV Q6W | Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC) | NA weeks |
Secondary
Part 2: Annualized Relapse Rate During the Crossover Period
Annualized relapse rate is calculated as the total number of relapses that occurred during the treatment period divided by the total number of participant-years followed in the period.
Time frame: Part 2 Baseline (Week 108) up to Week 156
Population: Data was not analyzed for this outcome measure as only one relapse was observed in the Part 2 crossover period.
Secondary
Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period
Time frame: Part 2 Baseline (Week 108) up to Week 156
Population: Full analysis set included all randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. 'Overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis. Here number analyzed signifies the number of participants with data available for analysis at specified categories.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: IV Q4W | Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period | Cortical Brain Region | -1478.82 cubic centimeters (cm^3) | Standard Error 363.714 |
| Part 1: IV Q4W | Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period | Thalamic Brain Region | -25.98 cubic centimeters (cm^3) | Standard Error 14.582 |
| Part 1: IV Q6W | Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period | Cortical Brain Region | -881.34 cubic centimeters (cm^3) | Standard Error 367.155 |
| Part 1: IV Q6W | Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period | Thalamic Brain Region | -17.96 cubic centimeters (cm^3) | Standard Error 14.796 |
Secondary
Part 2: Change From Baseline in EDSS Score During the Crossover Period
The EDSS is a scale based on standardized neurological examination which comprised of optic, brain stem, pyramidal, cerebellar, sensory and cerebral functions, as well as walking ability. It measures the MS disability status on a scale ranging from 0 (normal) to 10 (death due to MS), with higher scores indicating more disability.
Time frame: Part 2 Baseline (Week 108) up to Week 156
Population: Full analysis set included all randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: IV Q4W | Part 2: Change From Baseline in EDSS Score During the Crossover Period | 0.02 Score on a scale | Standard Error 0.055 |
| Part 1: IV Q6W | Part 2: Change From Baseline in EDSS Score During the Crossover Period | 0.10 Score on a scale | Standard Error 0.056 |
p-value: =0.35795% CI: [-0.09, 0.25]Linear Mixed Effects Model
Secondary
Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period
The TSQM has 14 questions that assesses participants' global satisfaction level with their treatment in 4 domains: side effects (There are 5 questions in the side effects domain, however one of them is a Yes/No question and there are 4 sub-components, hence a maximum score of 20), effectiveness (3 questions), global satisfaction (3 questions), and convenience (3 questions). All questions are scored from 1 (least satisfied) to 5 or 7 (most satisfied). The total score is summed for each domain to obtain: side effects (1-20), effectiveness (1-21), global satisfaction (1-17), and convenience (1-21), using transformed scores between 0 and 100 for effectiveness. Lower total scores in each domain indicate dissatisfaction with the study medication and higher total scores indicate satisfaction.
Time frame: Part 2 Baseline (Week 108) up to Week 156
Population: Full analysis set included all randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: IV Q4W | Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period | 0.17 Score on a scale | Standard Error 0.899 |
| Part 1: IV Q6W | Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period | 0.64 Score on a scale | Standard Error 0.902 |
p-value: =0.76495% CI: [-2.61, 3.54]Linear Mixed Effects Model
Secondary
Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period
Gd enhancing lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new Gd enhancing lesions during the crossover period of Part 2 relative to baseline.
Time frame: Week 108 up to Week 156
Population: Full analysis set included all randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: IV Q4W | Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period | 0.0 number of Gd lesions | Standard Deviation 0 |
| Part 1: IV Q6W | Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period | 0.0 number of Gd lesions | Standard Deviation 0 |
Secondary
Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period
T2 hyperintense lesions were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions during the crossover period of Part 2 relative to baseline.
Time frame: Part 2 Baseline (Week 108) up to Week 156
Population: Full analysis set included all randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: IV Q4W | Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period | 0.0 number of T2 lesions | Standard Deviation 0.09 |
| Part 1: IV Q6W | Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period | 0.0 number of T2 lesions | Standard Deviation 0.22 |
Secondary
Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period
T1 hypointense lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new T1 hypointense lesions during the crossover period of Part 2 relative to baseline.
Time frame: Week 108 up to Week 156
Population: Full analysis set included all randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: IV Q4W | Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period | 0.0 number of T1 lesions | Standard Deviation 0.09 |
| Part 1: IV Q6W | Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period | 0.0 number of T1 lesions | Standard Deviation 0 |
Secondary
Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period
Time frame: Part 2 Baseline (Week 108) up to Week 156
Population: Full analysis set included all randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: IV Q4W | Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period | -0.11 percent change | Standard Error 0.042 |
| Part 1: IV Q6W | Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period | -0.10 percent change | Standard Error 0.042 |
Secondary
Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period
Time frame: Week 108 up to Week 156
Population: Full analysis set included all randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline assessment in Part 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: IV Q4W | Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period | Drug Preparation Time | 4.9 minutes | Standard Deviation 3.86 |
| Part 1: IV Q4W | Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period | Drug Administration Time | 62.6 minutes | Standard Deviation 10.45 |
| Part 1: IV Q6W | Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period | Drug Preparation Time | 0 minutes | Standard Deviation 0 |
| Part 1: IV Q6W | Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period | Drug Administration Time | 4.3 minutes | Standard Deviation 5.11 |
Secondary
Part 2: Mean Trough α4 Integrin Saturation During the Crossover Period
Time frame: Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156
Population: Pharmacodynamic (PD) population included all participants who received at least one dose of SC or IV natalizumab after randomization in Part 2 and had at least one post-baseline assessment of the PD parameter. Here 'overall number of participants analyzed' indicates the number of participants without any relapse at the beginning of the crossover period of Part 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: IV Q4W | Part 2: Mean Trough α4 Integrin Saturation During the Crossover Period | 71.2 percentage | Standard Deviation 15.31 |
| Part 1: IV Q6W | Part 2: Mean Trough α4 Integrin Saturation During the Crossover Period | 67.2 percentage | Standard Deviation 17.8 |
Secondary
Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period
Time frame: Part 2 Baseline (Week 108) up to Week 156
Population: Immunogenicity population included all participants who received at least one dose of SC or IV natalizumab and had at least one assessment for anti-drug antibody during crossover period of Part 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: IV Q4W | Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period | 0 percentage of participants |
| Part 1: IV Q6W | Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period | 0 percentage of participants |
Secondary
Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. 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 (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any event occurring on or after first dose after randomization up to and including 12 weeks (or 24 weeks for PML events) following the last dose on the study.
Time frame: Part 2: Baseline (Week 108) up to Week 180
Population: Safety population included all randomized participants who received at least one dose of study treatment during the crossover period of Part 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: IV Q4W | Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 57.4 percentage of participants |
| Part 1: IV Q6W | Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 62.9 percentage of participants |
Secondary
Part 2: Time to First Relapse During the Crossover Period
Relapse is defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours. The time to first relapse is defined as the time from the first randomized dose in Part 2 up to the first relapse. Time to First Relapse is estimated by Kaplan-Meier method.
Time frame: Part 2 Baseline (Week 108) up to Week 156
Population: FAS: all randomized participants receiving ≥1 dose of study treatment during at least one study period and had ≥1 baseline assessment in Part 2. Overall number analyzed: participants without any relapse at beginning of crossover period of Part 2. As pre-specified in the Statistical Analysis Plan(SAP), time to event analyses was planned 'per treatment sequence' rather than 'per intervention' in Part 2 as protocol-specified analysis does not account for correlation of within participant effect.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: IV Q4W | Part 2: Time to First Relapse During the Crossover Period | NA weeks |
| Part 1: IV Q6W | Part 2: Time to First Relapse During the Crossover Period | NA weeks |
Secondary
Part 2: Trough Serum Concentration of Natalizumab (Ctrough) During the Crossover Period
Time frame: Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156
Population: Pharmacokinetic (PK) population included all participants who received at least one dose of SC or IV natalizumab and had at least one assessment for the concentration of natalizumab in serum during the crossover period of Part 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: IV Q4W | Part 2: Trough Serum Concentration of Natalizumab (Ctrough) During the Crossover Period | 11.9 micrograms per milliliter (µg/mL) | Standard Deviation 11.5 |
| Part 1: IV Q6W | Part 2: Trough Serum Concentration of Natalizumab (Ctrough) During the Crossover Period | 10.3 micrograms per milliliter (µg/mL) | Standard Deviation 10.94 |