Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri®
- Conditions
- Relapsing-Remitting Multiple Sclerosis (RRMS)
- Interventions
- Biological: Intravenous (IV) infusions
- Registration Number
- NCT04115488
- Lead Sponsor
- Polpharma Biologics S.A.
- Brief Summary
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
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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 265
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description PB006 Intravenous (IV) infusions 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. Tysabri Intravenous (IV) infusions 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).
- Primary Outcome Measures
Name Time Method Cumulative Number of New Active Lesions Over 24 Weeks Scans performed at week 0 (baseline), week 8, 16, 20 and 24. 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.
- Secondary Outcome Measures
Name Time Method Cumulative Number of New Active Lesions Over 48 Weeks Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48. 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 \[mmol/kg\].
Cumulative Number of New GdE T1-weighted Lesions Over 24 Weeks Scans performed at week 0 (baseline), week 8, 16, 20 and 24. 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 \[mmol/kg\].
Cumulative Number of New GdE T1-weighted Lesions Over 48 Weeks Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48. 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 \[mmol/kg\].
Number of Patients Without New GdE T1-weighted Lesions Over 48 Weeks Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48. 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 \[mmol/kg\].
Annualized Relapse Rate After 48 Weeks Up to 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.
Percentage of Subjects With Neutralizing Antibodies After 48 Weeks Up to 48 weeks. Percentage of subjects with positive (transient and persistent) neutralizing antibodies after 48 weeks.
Number of Patients Without New GdE T1-weighted Lesions Over 24 Weeks Scans performed at week 0 (baseline), week 8, 16, 20 and 24. 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 \[mmol/kg\].
Cumulative Number of New/Enlarging T2-weighted Lesions Over 48 Weeks Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48. 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.
Number of Persistent Lesions After 48 Weeks Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48. 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 \[mmol/kg\].
Annualized Relapse Rate After 24 Weeks Up to 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.
Number of Patients Without New/Enlarging T2-weighted Lesions Over 48 Weeks Scans performed at week 0 (baseline), week 8, 16, 20, 24 and 48. 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.
Cumulative Number of New/Enlarging T2-weighted Lesions Over 24 Weeks Scans performed at week 0 (baseline), week 8, 16, 20 and 24. 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.
Percentage of Subjects With Neutralizing Antibodies After 24 Weeks Up to 24 weeks. Percentage of subjects with positive (transient and persistent) neutralizing antibodies 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 24 weeks.
Natalizumab Trough Concentration (Ctrough) Over Time, Week 16 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.
Number of Patients With Abnormal Clinical Laboratory Tests at Week 24 At week 24. Number of patients with abnormal clinical laboratory tests at week 24.
Change From Baseline in Blood Pressure at Week 48 At baseline and end of study (week 48). Change from baseline in diastolic and systolic blood Pressure at week 48.
Number of Persistent Lesions After 24 Weeks Scans performed at week 0 (baseline), week 8, 16, 20 and 24. 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 \[mmol/kg\].
Percentage of Subjects With Anti-drug (Natalizumab) Antibodies (ADA) and Persistent Antibodies After 48 Weeks Up to 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.
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. Number of subjects with any Treatment-Emergent Adverse Event (TEAE) or any Treatment-Emergent Serious Adverse Event (SAE) after 48 weeks.
Change From Baseline in Blood Pressure at Week 24 At baseline and week 24. Change from baseline in diastolic and systolic blood Pressure at week 24.
Change From Baseline in Heart Rate at Week 48 At baseline and end of study (week 48). Change from baseline in heart rate at week 48.
Change From Baseline in Expanded Disability Status Scale (EDSS) After 24 Weeks Baseline and week 24. 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.
Change From Baseline in Expanded Disability Status Scale (EDSS) After 48 Weeks FAS: Baseline (week 0) and week 48. SSW: Baseline (week 24) and week 48. 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.
Percentage of Subjects With Anti-drug (Natalizumab) Antibodies (ADA) and Persistent Antibodies After 24 Weeks Up to 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.
Natalizumab Trough Concentration (Ctrough) Over Time, Week 8 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.
Natalizumab Trough Concentration (Ctrough) Over Time, Week 24 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.
Natalizumab Trough Concentration (Ctrough) Over Time, Week 32 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.
Natalizumab Trough Concentration (Ctrough) Over Time, Week 48 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.
Number of Patients Without New/Enlarging T2-weighted Lesions Over 24 Weeks Week 0 (baseline), week 8, 16, 20 and 24. 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.
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 24.
Number of Patients With Abnormal Findings in Physical Examination at Week 48 End of study (week 48). Number of patients with abnormal findings in physical examination at week 48.
Number of Patients With Abnormal Clinical Laboratory Tests at Week 48 At week 48. Number of patients with abnormal clinical laboratory tests at week 48.
Change From Baseline in Heart Rate at Week 24 At baseline and week 24. Change from baseline in heart rate at week 24.
Trial Locations
- Locations (47)
Republican Research and Development Center for Neurology and Neurosurgery
🇧🇾Minsk, Belarus
Minsk City Clinical Hospital #5
🇧🇾Minsk, Belarus
Minsk Scientific and Practical Center of Surgery, Transplantology and Hematology
🇧🇾Minsk, Belarus
Clinical Hospital Center Osijek, Clinic of Neurology
🇭🇷Osijek, Croatia
Clinical Hospital Center Split, Clinic of Neurology
🇭🇷Split, Croatia
University Hospital Centre Zagreb, Clinic of Neurology
🇭🇷Zagreb, Croatia
P. Sarajishvili Institute of Neurology, LTD
🇬🇪Tbilisi, Georgia
LTD S.Khechinashvili University Hospital
🇬🇪Tbilisi, Georgia
Neuro-Medic
🇵🇱Katowice, Poland
Pineo Medical Ecosystem
🇬🇪Tbilisi, Georgia
LTD Aversi Clinic
🇬🇪Tbilisi, Georgia
Provincial Specialist Hospital in Olsztyn, Department of Neurology
🇵🇱Olsztyn, Poland
Institute for Emergency Medicine, Department of Neurology
🇲🇩Chisinau, Moldova, Republic of
COPERNICUS Podmiot Leczniczy Sp. z o.o N. Copernicus Hospital, Department of Neurology
🇵🇱Gdansk, Pomerania, Poland
National Institute of Neurology and Neurosurgery, Vascular Neurology Department
🇲🇩Chisinau, Moldova, Republic of
Neurology Center Krzysztof Selmaj
🇵🇱Lodz, Poland
NeuroProtect Medical Center
🇵🇱Warszawa, Poland
Clinical Center Kragujevac, Clinic of Neurology
🇷🇸Kragujevac, Serbia
Regional Clinical Hospital
🇺🇦Ivano-Frankivs'k, Ukraine
Dnipropetrovsk I.I. Mechnykov Regional Clinical Hospital
🇺🇦Dnipro, Ukraine
Ivano-Frankivsk City Clinical Hospital #1
🇺🇦Ivano-Frankivs'k, Ukraine
Medical Center of First Private Clinic
🇺🇦Kyiv, Ukraine
Kharkiv Railway Clinical Hospital
🇺🇦Kharkiv, Ukraine
Kyiv City Clinical Hospital
🇺🇦Kyiv, Ukraine
National Research Center for Radiation Medicine
🇺🇦Kyiv, Ukraine
Communal Noncommercial Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital
🇺🇦Lviv, Ukraine
Lviv City Clinical Hospital #5
🇺🇦Lviv, Ukraine
Center for Reconstructive and Restorative Medicine (University Clinic)
🇺🇦Odesa, Ukraine
Sklifosovskyi Regional Clinical Hospital
🇺🇦Poltava, Ukraine
Ternopil Regional Clinical Psychonevrological Hospital
🇺🇦Ternopil', Ukraine
Vinnytsia O.I. Yushchenko Regional Psychoneurology Hospital
🇺🇦Vinnytsia, Ukraine
Clinical Hospital No. 9 under Zaporizhia City Council
🇺🇦Zaporizhia, Ukraine
City Clinical Hospital #2
🇺🇦Zaporizhzhya, Ukraine
Zaporizhia Regional Clinical Hospital
🇺🇦Zaporizhzhya, Ukraine
O.F. Herbachevskyi Regional Clinical Hospital
🇺🇦Zhytomyr, Ukraine
Grodno Regional Clinical Hospital
🇧🇾Grodno, Belarus
Vitebsk Regional Diagnostic Center
🇧🇾Vitebsk, Belarus
Vitebsk Regional Clinical Hospital
🇧🇾Vitebsk, Belarus
LTD Saint Michael Archangel Multifunctional Clinical Hospital
🇬🇪Tbilisi, Georgia
Malkhaz Katsiashvili Multiprofile Emergency Medicine Center
🇬🇪Tbilisi, Georgia
MED-Polonia, Sp. z o.o. (LLC)
🇵🇱Poznan, Poland
Clinical Center of Serbia, Clinic of Neurology
🇷🇸Belgrade, Serbia
Clinical Center of Vojvodina, Clinic of Neurology
🇷🇸Novi Sad, Serbia
City Clinical Hospital #7
🇺🇦Kharkiv, Ukraine
Institute of Neurology, Psychiatry and Narcology
🇺🇦Kharkiv, Ukraine
Clinical Hospital Center Zemun, Department of Neurology
🇷🇸Belgrade, Serbia
Cherkasy Regional Hospital of Cherkasy Oblast Council
🇺🇦Cherkasy, Ukraine