A Study to Evaluate Efficacy, Safety, and Tolerability of EID of Natalizumab (BG00002) in Participants With RRMS Switching From Treatment With Natalizumab SID in Relation to Continued SID Treatment- Followed by Extension Study Comprising SC and IV Natalizumab Administration

Study Overview
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Brief Summary
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Part 1: The primary objective is to evaluate the efficacy of natalizumab extended interval dosing (EID) in participants who have previously been treated with natalizumab standard interval dosing (SID) for at least 12 months, in relation to continued SID 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 EID in participants who have previously been treated with natalizumab SID for at least 12 months, in relation to continued SID 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
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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.

Official Title
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A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b Study of the Efficacy, Safety, and Tolerability of 6-Week Extended Interval Dosing (EID) of Natalizumab (BG00002) in Subjects With Relapsing-Remitting Multiple Sclerosis Switching From Treatment With 4-Week Natalizumab Standard Interval Dosing (SID) in Relation to Continued SID Treatment - Followed by an Open-Label Crossover Extension Study Comprising Subcutaneous and Intravenous Natalizumab Administration

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Natalizumab


Participation Criteria
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Eligibility Criteria
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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 SID or EID. 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 EID was reverted to natalizumab SID 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 exclusion criteria for new participants who did not participate in Part 1 of the study are the same as those for participants who did participate in Part 1. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Standard Interval Dosing (SID) IV<br>Participants will receive natalizumab 300 milligram (mg) intravenous (IV) infusion every 4 weeks (-2/+5 days) up to Week 72. | Drug: Natalizumab<br>* Natalizumab 300 mg SC injection or IV infusion.<br>* Other names: BG00002;|
| Experimental: Part 1: Extended Interval Dosing (EID) IV<br>Participants will receive natalizumab 300 mg IV infusion every 6 weeks (-2/+5 days) up to Week 72. | Drug: Natalizumab<br>* Natalizumab 300 mg SC injection or IV infusion.<br>* Other names: BG00002;|
| Experimental: Part 2: EID SC, then EID IV<br>Participants will receive natalizumab 300 mg SC injection every 6 weeks from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion every 6 weeks from Week 132 through Week 150. | Drug: Natalizumab<br>* Natalizumab 300 mg SC injection or IV infusion.<br>* Other names: BG00002;|
| Experimental: Part 2: EID IV, then EID SC<br>Participants will receive natalizumab 300 mg IV infusion every 6 weeks from Week 108 through Week 126 followed by natalizumab 300 mg SC injection every 6 weeks from Week 132 through Week 150. | Drug: Natalizumab<br>* Natalizumab 300 mg SC injection or IV infusion.<br>* Other names: BG00002;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72 | Number of new or newly enlarging T2 hyperintense lesions will be analysed by magnetic resonance imaging (MRI) scans of brain. New MRI scans will be compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions. | Week 72 | 
| Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Part 2 |  | Week 156 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC) | A multiple sclerosis (MS) relapse will be 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 will be included in the analysis. | Up to Week 72 | 
| Part 1: Number of New Gadolinium (Gd) Enhancing and New T1 Hypointense Lesions at Weeks 24, 48 and 72 | Number of new Gd enhancing and new T1 hypointense lesions on brain will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse number of new Gd enhancing and new T1 hypointense lesions. | Weeks 24, 48 and 72 | 
| Part 1: Annualized Relapse Rate at Week 72 | An MS relapse will be 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 will be included in the analysis. | Week 72 | 
| Part 1: Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48 | Number of new or newly enlarging T2 hyperintense lesions will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions. | Weeks 24 and 48 | 
| Part 1: Percentage of Participants With Adverse Events (AEs) 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 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. | Up to Week 96 | 
| Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening as Confirmed After at Least 24 Weeks | 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. | Week 24, 48, 72 and 84 | 
| Part 2: Total Score on Treatment Satisfaction Questionnaire for Medication (TSQM) | The TSQM assessed participants' global satisfaction with treatment and captured information on treatment side effects, effectiveness, and convenience using transformed scores between 0 and 100 for effectiveness. Higher scores indicates greater satisfaction. | Up to Week 156 | 
| Part 2: Mean Time for Drug Preparation and Administration |  | Up to Week 156 | 
| Part 2: Number of Participants with Treatment Emergent AEs (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 in participants who had received at least 1 dose of study drug, regardless of relationship to study drug. | From Week 132 to Week 156 | 
| Part 2: Percentage of Participants With Anti-Natalizumab Antibodies |  | From Week 132 to Week 156 | 
| Part 2: Number of New or Newly Enlarging T2 Hyperintense Lesions | Number of new or newly enlarging T2 hyperintense lesions will be analysed by magnetic resonance imaging (MRI) scans of brain. New MRI scans will be compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions. | From Week 132 to Week 156 | 
| Part 2: Time to First Relapse | A MS relapse will be 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. | From Week 132 to Week 156 | 
| Part 2: Annualized Relapse Rate | Annualized relapse rate included relapses reported prior to the end of each period. | From Week 132 to Week 156 | 
| Part 2: Change in Expanded Disability Status Scale (EDSS) Score | The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. | From Week 132 to Week 156 | 
| Part 2: Number of New Gadolinium (Gd) Enhancing Lesions | Number of new Gd enhancing lesions on brain will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse number of new Gd enhancing lesions. | From Week 132 to Week 156 | 
| Part 2: Number of New T1 Hypointense Lesions | Number of new T1 hypointense lesions on brain will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse number new T1 hypointense lesions. | From Week 132 to Week 156 | 
| Part 2: Percentage of Brain Volume Change |  | From Week 132 to Week 156 | 
| Part 2: Change in Cortical and Thalamic Brain Region Volume |  | From Week 132 to Week 156 | 
| Part 2: Trough Serum Concentration of Natalizumab (Ctrough) |  | From Week 132 to Week 156 | 
| Part 2: Trough α4 Integrin Saturation |  | From Week 132 to Week 156 |