This is a multi-center, randomized, parallel arm, double-blind study with a total duration of subjects' participation of 48 weeks. Approximately 260 participants with relapsing-remitting multiple sclerosis will be randomized to receive 12 doses of either PB006 or EU-licensed Natalizumab.
This is a Phase 3 multicenter, double-blind, active-controlled, randomized, parallel-group study to assess the equivalence in efficacy and similarity in safety of biosimilar PB006 compared to Tysabri in patients with RRMS. All eligible patients will be randomly assigned to one of two treatment groups in a 1:1 ratio, to receive a total of twelve intravenous (IV) infusion of either PB006 or Tysabri at a dose of 300 mg at each intravenous (IV) infusion administered with every single one intravenous (IV) infusion administered every 4 weeks of either PB006 or Tysabri at a dose of 300 mg starting at visit 1 (week 0) through visit 12 (week 44), for a total of 12 infusions. The End-of-Study Visit (visit 13, week 48) will be performed 4 weeks after the last infusion
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
265
Intravenous (IV) infusions of a dose of 300mg, every 4 weeks with a total of 12 doses
Cumulative Number of New Active Lesions Over 24 Weeks
Cumulative number of new active lesions over 24 weeks, calculated as the sum of all new gadolinium-enhancing (GdE) T1-weighted and new/enlarging T2-weighted lesion. Assessment was performed using Magnetic Resonance Imaging (MRI). Identification of GdE T1-weighted and T2-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center.
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20 and 24.
Cumulative Number of New Active Lesions Over 48 Weeks
Cumulative number of new active lesions over 48 weeks, calculated as the sum of all new gadolinium-enhancing (GdE) T1-weighted and new/enlarging T2-weighted lesion. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of GdE T1-weighted lesions and T2-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center. A macrocyclic Gd-based contrast agent was administered as an Intravenous infusion of 0.1 Millimole per kilogram \[mmol/kg\].
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48.
Cumulative Number of New GdE T1-weighted Lesions Over 24 Weeks
Cumulative number of new GdE T1-weighted lesions over 24 weeks, calculated as the sum of all new gadolinium-enhancing (GdE) T1-weighted. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of GdE T1-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center. A macrocyclic Gd-based contrast agent (gadobutrol, gadoteric acid, or gadoteridol) was to be administered as an Intravenous infusion of 0.1 Millimole per kilogram \[mmol/kg\].
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20 and 24.
Cumulative Number of New GdE T1-weighted Lesions Over 48 Weeks
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Cumulative number of new GdE T1-weighted lesions over 48 weeks, calculated as the sum of all new gadolinium-enhancing (GdE) T1-weighted. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of GdE T1-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center. A macrocyclic Gd-based contrast agent (gadobutrol, gadoteric acid, or gadoteridol) was to be administered as an Intravenous infusion of 0.1 Millimole per kilogram \[mmol/kg\].
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48.
Number of Patients Without New GdE T1-weighted Lesions Over 24 Weeks
Number of patients without new GdE T1-weighted lesions over 24 weeks. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of GdE T1-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center. A macrocyclic Gd-based contrast agent (gadobutrol, gadoteric acid, or gadoteridol) was to be administered as an Intravenous infusion of 0.1 Millimole per kilogram \[mmol/kg\].
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20 and 24.
Number of Patients Without New GdE T1-weighted Lesions Over 48 Weeks
Number of patients without new GdE T1-weighted lesions over 48 weeks. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of GdE T1-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center. A macrocyclic Gd-based contrast agent (gadobutrol, gadoteric acid, or gadoteridol) was to be administered as an Intravenous infusion of 0.1 Millimole per kilogram \[mmol/kg\].
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48.
Cumulative Number of New/Enlarging T2-weighted Lesions Over 24 Weeks
Cumulative number of new/enlarging T2-weighted lesions over 24 weeks. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of T2-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center.
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20 and 24.
Cumulative Number of New/Enlarging T2-weighted Lesions Over 48 Weeks
Cumulative number of new/enlarging T2-weighted lesions over 48 weeks. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of T2-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center.
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48.
Number of Persistent Lesions After 24 Weeks
Number of persistent lesions after 24 weeks. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of GdE T1-weighted lesions and T2-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center. A macrocyclic Gd-based contrast agent (gadobutrol, gadoteric acid, or gadoteridol) was to be administered as an Intravenous infusion of 0.1 Millimole per kilogram \[mmol/kg\].
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20 and 24.
Number of Persistent Lesions After 48 Weeks
Number of persistent lesions after 48 weeks. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of GdE T1-weighted lesions and T2-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center. A macrocyclic Gd-based contrast agent (gadobutrol, gadoteric acid, or gadoteridol) was to be administered as an Intravenous infusion of 0.1 Millimole per kilogram \[mmol/kg\].
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48.
Annualized Relapse Rate After 24 Weeks
Annualized relapse rate after 24 weeks. Relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality had to be present for at least 24 hours and have occurred in the absence of fever or infection. Annualized relapse rate: A: Number of medically confirmed relapses overall. B: Duration of follow-up time overall, where follow-up time was defined as: (last day of follow-up - day of randomization + 1) / 365.25. The ratio of relapses per patient-year: A/B. Annualized Relapse Rate was calculated across the entire group.
Time frame: Up to 24 weeks.
Annualized Relapse Rate After 48 Weeks
Annualized relapse rate after 48 weeks. Relapse was defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The abnormality had to be present for at least 24 hours and have occurred in the absence of fever or infection. Annualized relapse rate: A: Number of medically confirmed relapses overall. B: Duration of follow-up time overall, where follow-up time was defined as: (last day of follow-up - day of randomization + 1) / 365.25. The ratio of relapses per patient-year: A/B. Annualized Relapse Rate was calculated across the entire group.
Time frame: Up to 48 weeks.
Change From Baseline in Expanded Disability Status Scale (EDSS) After 24 Weeks
Change from baseline in Expanded Disability Status Scale (EDSS) after 24 weeks. The Kurtzke EDSS, commonly used to evaluate the degree of neurologic impairment in multiple sclerosis (MS), is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. Based on a standard neurological examination, the 7 functional systems (plus "other") are rated. These ratings are then used in conjunction with observations and information concerning gait and use of assistive devices to rate the EDSS. EDSS ratings were performed by independent examining neurologists. After re-randomization, Week 24 is considered baseline.
Time frame: Baseline and week 24.
Change From Baseline in Expanded Disability Status Scale (EDSS) After 48 Weeks
Change from baseline in Expanded Disability Status Scale (EDSS) after 48 weeks. The Kurtzke EDSS, commonly used to evaluate the degree of neurologic impairment in MS, is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. Based on a standard neurological examination, the 7 functional systems (plus "other") are rated. These ratings are then used in conjunction with observations and information concerning gait and use of assistive devices to rate the EDSS. EDSS ratings were performed by independent examining neurologists.
Time frame: FAS: Baseline (week 0) and week 48. SSW: Baseline (week 24) and week 48.
Percentage of Subjects With Anti-drug (Natalizumab) Antibodies (ADA) and Persistent Antibodies After 24 Weeks
Percentage of subjects with anti-drug (natalizumab) antibodies (ADA) and persistent antibodies after 24 weeks. A positive ADA patient was defined as a patient who had at least 1 positive ADA result in any post-baseline sample. A persistently positive ADA patient was defined as a patient with confirmed positive ADAs in 2 or more consecutive positive ADA samples at post-dose visits.
Time frame: Up to 24 weeks.
Percentage of Subjects With Anti-drug (Natalizumab) Antibodies (ADA) and Persistent Antibodies After 48 Weeks
Percentage of subjects with anti-drug (natalizumab) antibodies (ADA) and persistent antibodies after 48 weeks. A positive ADA patient was defined as a patient who had at least 1 positive ADA result in any post-baseline sample. A persistently positive ADA patient was defined as a patient with confirmed positive ADAs in 2 or more consecutive positive ADA samples at post-dose visits.
Time frame: Up to 48 weeks.
Percentage of Subjects With Neutralizing Antibodies After 24 Weeks
Percentage of subjects with positive (transient and persistent) neutralizing antibodies after 24 weeks.
Time frame: Up to 24 weeks.
Percentage of Subjects With Neutralizing Antibodies After 48 Weeks
Percentage of subjects with positive (transient and persistent) neutralizing antibodies after 48 weeks.
Time frame: Up to 48 weeks.
Number of Subjects With Any Treatment-Emergent Adverse Event (TEAE) or Any Treatment-Emergent Serious Adverse Event (SAE) After 24 Weeks
Number of subjects with any Treatment-Emergent Adverse Event (TEAE) or any Treatment-Emergent Serious Adverse Event (SAE) after 24 weeks.
Time frame: Up to week 24
Number of Subjects With Any Treatment-Emergent Adverse Event (TEAE) or Any Treatment-Emergent Serious Adverse Event (SAE) After 48 Weeks
Number of subjects with any Treatment-Emergent Adverse Event (TEAE) or any Treatment-Emergent Serious Adverse Event (SAE) after 48 weeks.
Time frame: Up to 48 weeks.
Natalizumab Trough Concentration (Ctrough) Over Time, Week 8
Natalizumab trough concentration (Ctrough) over time, week 8. Serum samples were collected prior to treatment. Sample was taken prior to treatment for each patient.
Time frame: Week 8
Natalizumab Trough Concentration (Ctrough) Over Time, Week 16
Natalizumab trough concentration (Ctrough) over time, week 16. Serum samples were collected prior to treatment. Sample was taken prior to treatment for each patient.
Time frame: Week 16
Natalizumab Trough Concentration (Ctrough) Over Time, Week 24
Natalizumab trough concentration (Ctrough) over time, week 24. Serum samples were collected prior to treatment. Sample was taken prior to treatment for each patient.
Time frame: Week 24
Natalizumab Trough Concentration (Ctrough) Over Time, Week 32
Natalizumab trough concentration (Ctrough) over time, week 32. Serum samples were collected prior to treatment. Sample was taken prior to treatment for each patient.
Time frame: Week 32
Natalizumab Trough Concentration (Ctrough) Over Time, Week 48
Natalizumab trough concentration (Ctrough) over time, week 48. Serum samples were collected prior to treatment. Sample was taken prior to treatment for each patient.
Time frame: Week 48
Number of Patients Without New/Enlarging T2-weighted Lesions Over 24 Weeks
Number of patients without new/enlarging T2-weighted lesions over 24 weeks. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of T2-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center.
Time frame: Week 0 (baseline), week 8, 16, 20 and 24.
Number of Patients Without New/Enlarging T2-weighted Lesions Over 48 Weeks
Number of patients without new/enlarging T2-weighted lesions over 48 weeks. Assessment of lesions was performed using Magnetic Resonance Imaging (MRI). Identification of T2-weighted lesions was done by a trained and certified radiology reviewer according to standard procedures at the MRI central reading center.
Time frame: Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48.
Number of Patients With Abnormal Clinical Laboratory Tests at Week 24
Number of patients with abnormal clinical laboratory tests at week 24.
Time frame: At week 24.
Number of Patients With Abnormal Clinical Laboratory Tests at Week 48
Number of patients with abnormal clinical laboratory tests at week 48.
Time frame: At week 48.
Number of Patients With Abnormal Findings in Physical Examination at Week 24
Number of patients with abnormal findings in physical examination at week 24.
Time frame: Week 24.
Number of Patients With Abnormal Findings in Physical Examination at Week 48
Number of patients with abnormal findings in physical examination at week 48.
Time frame: End of study (week 48).
Change From Baseline in Blood Pressure at Week 24
Change from baseline in diastolic and systolic blood Pressure at week 24.
Time frame: At baseline and week 24.
Change From Baseline in Blood Pressure at Week 48
Change from baseline in diastolic and systolic blood Pressure at week 48.
Time frame: At baseline and end of study (week 48).
Change From Baseline in Heart Rate at Week 24
Change from baseline in heart rate at week 24.
Time frame: At baseline and week 24.
Change From Baseline in Heart Rate at Week 48
Change from baseline in heart rate at week 48.
Time frame: At baseline and end of study (week 48).