Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri®

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri® in Patients With Relapsing-Remitting Multiple Sclerosis (RRMS)

Conditions
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Relapsing-Remitting Multiple Sclerosis (RRMS)

Intervention / Treatment
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* Biological: Intravenous (IV) infusions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients (age ≥18 to 60 years), with relapsing-remitting multiple sclerosis (RRMS) defined by the 2010 revised McDonald criteria At least 1 documented relapse within the previous year and either ≥1 GdE T1-weighted brain lesions or ≥9 T2-weighted brain lesions at Screening Kurtzke Expanded Disability Status Scale (EDSS) score from 0 to 5 (inclusive) at Screening Exclusion Criteria: Manifestation of multiple sclerosis (MS) other than relapsing-remitting multiple sclerosis (RRMS) Relapse within the 30 days prior Screening and until administration of the first dose of study drug Prior treatment with natalizumab, alemtuzumab, ocrelizumab, daclizumab, rituximab, cladribine, or other B- and T-cell targeting therapies Prior total lymphoid irradiation or bone marrow or organ transplantation Patients with John Cunningham Virus (JCV) index >1.5 at Screening Past or current Progressive Multi-focal leukoencephalopathy (PML) diagnosis Severe renal function impairment as defined by serum creatinine values >120 micromol per litre

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PB006<br>Patients with relapsing-remitting multiple sclerosis (RRMS) received intravenous (IV) infusions every 4 weeks of PB006 at a dose of 300 milligram (mg) starting at Visit 1 (Week 0) through Visit 12 (Week 44), for a total of 12 infusions. | Biological: Intravenous (IV) infusions<br>* Intravenous (IV) infusions of a dose of 300mg, every 4 weeks with a total of 12 doses<br>|
| Active Comparator: Tysabri<br>Patients with relapsing-remitting multiple sclerosis (RRMS) received intravenous (IV) infusions every 4 weeks of Tysabri at a dose of 300 milligram (mg) starting at Visit 1 (Week 0) through Visit 12 (Week 44), for a total of 12 infusions. At Week 24, patients in the Tysabri group were re-randomized through a re-randomization step. Patients re-randomized and switched from Tysabri to PB006 at Week 24 still received a total of 12 infusions (6 infusions of Tysabri and 6 infusions of PB006). | Biological: Intravenous (IV) infusions<br>* Intravenous (IV) infusions of a dose of 300mg, every 4 weeks with a total of 12 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Scans performed at week 0 (baseline), week 8, 16, 20 and 24. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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]. | 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]. | Scans performed at week 0 (baseline), week 8, 16, 20 and 24. | 
| Cumulative Number of New GdE T1-weighted Lesions Over 48 Weeks | 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]. | 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]. | 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]. | 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. | 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. | 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]. | 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]. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | At baseline and week 24. | 
| Change From Baseline in Heart Rate at Week 48 | Change from baseline in heart rate at week 48. | At baseline and end of study (week 48). |