A Study to Investigate the Radiological Onset of Action After Treatment Initiation With Subcutaneous (SC) Natalizumab in Participants With Relapsing-Remitting Multiple Sclerosis (RRMS)

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate the radiological efficacy of SC natalizumab over time through Week 24 in natalizumab-naïve participants, as measured by brain magnetic resonance imaging (MRI). The secondary objectives of this study are to evaluate additional lesion-related radiological efficacy measures over time, relapse-based clinical efficacy measures, disability improvement and worsening (EDSS), pharmacokinetic and pharmacodynamic parameters, the immunogenicity of repeated doses, and safety in treatment-naïve participants of SC natalizumab.

Official Title
-----------------
A Prospective, Multicenter, Interventional, Open-Label, Single-arm Phase IV Study Over 24 Weeks to Investigate the Radiological Onset of Action After Treatment Initiation With Subcutaneous Natalizumab in Patients With Relapsing-Remitting Multiple Sclerosis (TYS-ON)

Conditions
-----------------
Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
-----------------
* Drug: Natalizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Diagnosis of RRMS according to the McDonald criteria Treatment-naïve in respect to natalizumab as disease modifying monotherapy for RRMS No or not more than one prior MS disease-modifying therapy Highly active RRMS, as defined by at least one relapse in the previous year and at least one T1 gadolinium-enhancing lesion or ≥3 new or enlarging T2 lesions EDSS score ≤ 5.5 at Screening Estimated glomerular filtration rate (eGFR) >30 millilitre per min (mL/min), as estimated using the Cockcroft-Gault formula. Key Exclusion Criteria: Primary- and secondary-progressive MS Participants 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 that would preclude participation in a clinical study History of severe allergic or anaphylactic reactions or known hypersensitivity to any antibody drug therapy. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Natalizumab<br>Participants will receive natalizumab 300 milligrams (mg) (2*150 mg), SC injection, once every 4 weeks (Q4W) up to Week 24. | Drug: Natalizumab<br>* Administered as specified in the treatment arm<br>* Other names: BG00002;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Number of Active Lesions (CUALs) Through Week 24 | Cumulative number of active lesions will be calculated as the sum of the number of gadolinium (Gd)-enhancing lesions and new or enlarging T2 hyperintense lesions that are non-enhancing on post-gadolinium T1-weighted (T1w) scans. It is also referred to as combined unique active lesions (CUALs). | Up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Number of CUALs Through Weeks 4, 8, and 12 | CUALs will be calculated as the sum of the number of Gd-enhancing lesions and new or enlarging T2 hyperintense lesions that are non-enhancing on post-gadolinium T1w scans. | Weeks 4, 8, and 12 | 
| Absolute Number of CUALs at Weeks 4, 8, 12, and 24 | CUALs will be calculated as the sum of the number of Gd-enhancing lesions and new or enlarging T2 hyperintense lesions that are non-enhancing on post-gadolinium T1w scans. | Weeks 4, 8, 12, and 24 | 
| Mean Change From Baseline of CUALs at Weeks 4, 8, 12, and 24 | CUALs will be calculated as the sum of the number of Gd-enhancing lesions and new or enlarging T2 hyperintense lesions that are non-enhancing on post-gadolinium T1w scans. | Baseline, Weeks 4, 8, 12, and 24 | 
| Cumulative Number of New Gd-Enhancing Lesions Through Weeks 4, 8, 12, and 24 | Cumulative number will be calculated as the sum of the number of Gd-enhancing lesions through Weeks 4, 8, 12, and 24. | Weeks 4, 8, 12, and 24 | 
| Absolute Number of New Gd-Enhancing Lesions at Weeks 4, 8, 12, and 24 |  | Weeks 4, 8, 12, and 24 | 
| Absolute Number of Persisting Gd-Enhancing Lesions at Weeks 4, 8, 12, and 24 |  | Weeks 4, 8, 12, and 24 | 
| Absolute Number of Any (New or Persisting) Gd-Enhancing Lesions at Weeks 4, 8, 12, and 24 |  | Weeks 4, 8, 12, and 24 | 
| Change From Baseline of Any (New or Persisting) Gd-Enhancing Lesions at Weeks 4, 8, 12, and 24 |  | Baseline, Weeks 4, 8, 12, and 24 | 
| Cumulative Number of New or Enlarging T2 Lesions at Weeks 4, 8, 12, and 24 | Cumulative number will be calculated as the sum of the number of new or enlarging T2 hyperintense lesions through Weeks 4, 8, 12, and 24. | Weeks 4, 8, 12, and 24 | 
| Absolute Number of New or Enlarging T2 Lesions at Weeks 4, 8, 12, and 24 |  | Weeks 4, 8, 12, and 24 | 
| Change From Baseline of New or Enlarging T2 Lesions at Weeks 4, 8, 12, and 24 |  | Baseline, Weeks 4, 8, 12, and 24 | 
| Annualized Relapse Rate | Multiple sclerosis (MS) relapse is defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. ARR is defined as the total number of relapses divided by the total participant-time at risk of relapse. | Week 24 | 
| Time to First Relapse | MS relapse is defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. Time to first MS relapse will be calculated as the date from first study drug administration through the date of the first relapse, if applicable. | Up to Week 24 | 
| Number of Participants With Expanded Disability Status Scale (EDSS) Improvement and Stable Disease and Worsening at Weeks 12, and 24 | The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Stable disease is defined as +/- 0.5 change of EDSS. Worsening is > 0.5 increase of EDSS. | Baseline, Weeks 12, and 24 | 
| Trough Serum Natalizumab Concentration (Ctrough) |  | Pre dose on Baseline, Weeks 4, 8, 12, and 24 | 
| Trough alpha 4 (α4) Integrin Saturation |  | Pre dose on Baseline, Weeks 4, 8, 12, and 24 | 
| Change From Baseline in Lymphocyte Subsets Count | Lymphocyte subsets include T cells, B cells and natural killer cells (cluster of differentiate 4 [CD4], CD8, CD19, and CD56). | Baseline up to Week 24 | 
| Change From Baseline in Anti-Natalizumab Antibodies |  | Pre dose on Baseline, Weeks 12, and 24 | 
| Persistence of Anti-Natalizumab Antibodies | Re-test will be done for antibodies after 6 weeks of first positive result. | Re-test after 6 weeks of first positive result (up to Week 24) | 
| Number 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. SAE is any untoward medical occurrence that at any dose results in death, in the view of the investigator, places the participant at immediate risk of death (a life-threatening event), requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or is a medically important event. | Up to Week 24 |