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

Relapsing-Remitting Multiple Sclerosis (RRMS) Clinical Trial

— Antelope  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04115488
• Other study ID #: PB006-03-01
• Status: Completed
• Phase: Phase 3
• Start date: October 1, 2019
• Est. completion date: February 7, 2022

Study information

• Verified date: June 2023
• Source: Polpharma Biologics S.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 265
• Est. completion date: February 7, 2022
• Est. primary completion date: August 23, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing-Remitting Multiple Sclerosis (RRMS)
• Sclerosis

Intervention

Biological:
• Intravenous (IV) infusions
Intravenous (IV) infusions of a dose of 300mg, every 4 weeks with a total of 12 doses

Locations

Country	Name	City	State
Belarus	Grodno Regional Clinical Hospital	Grodno
Belarus	Minsk City Clinical Hospital #5	Minsk
Belarus	Minsk Scientific and Practical Center of Surgery, Transplantology and Hematology	Minsk
Belarus	Republican Research and Development Center for Neurology and Neurosurgery	Minsk
Belarus	Vitebsk Regional Clinical Hospital	Vitebsk
Belarus	Vitebsk Regional Diagnostic Center	Vitebsk
Croatia	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
Georgia	LTD Aversi Clinic	Tbilisi
Georgia	LTD S.Khechinashvili University Hospital	Tbilisi
Georgia	LTD Saint Michael Archangel Multifunctional Clinical Hospital	Tbilisi
Georgia	Malkhaz Katsiashvili Multiprofile Emergency Medicine Center	Tbilisi
Georgia	P. Sarajishvili Institute of Neurology, LTD	Tbilisi
Georgia	Pineo Medical Ecosystem	Tbilisi
Moldova, Republic of	Institute for Emergency Medicine, Department of Neurology	Chisinau
Moldova, Republic of	Institute for Emergency Medicine, Department of Neurology	Chisinau
Moldova, Republic of	National Institute of Neurology and Neurosurgery, Vascular Neurology Department	Chisinau
Poland	COPERNICUS Podmiot Leczniczy Sp. z o.o N. Copernicus Hospital, Department of Neurology	Gdansk	Pomerania
Poland	Neuro-Medic	Katowice
Poland	Neurology Center Krzysztof Selmaj	Lodz
Poland	Provincial Specialist Hospital in Olsztyn, Department of Neurology	Olsztyn
Poland	MED-Polonia, Sp. z o.o. (LLC)	Poznan
Poland	NeuroProtect Medical Center	Warszawa
Serbia	Clinical Center of Serbia, Clinic of Neurology	Belgrade
Serbia	Clinical Hospital Center Zemun, Department of Neurology	Belgrade
Serbia	Clinical Center Kragujevac, Clinic of Neurology	Kragujevac
Serbia	Clinical Center of Vojvodina, Clinic of Neurology	Novi Sad
Ukraine	Cherkasy Regional Hospital of Cherkasy Oblast Council	Cherkasy
Ukraine	Dnipropetrovsk I.I. Mechnykov Regional Clinical Hospital	Dnipro
Ukraine	Ivano-Frankivsk City Clinical Hospital #1	Ivano-Frankivs'k
Ukraine	Regional Clinical Hospital	Ivano-Frankivs'k
Ukraine	City Clinical Hospital #7	Kharkiv
Ukraine	Institute of Neurology, Psychiatry and Narcology	Kharkiv
Ukraine	Kharkiv Railway Clinical Hospital	Kharkiv
Ukraine	Kyiv City Clinical Hospital	Kyiv
Ukraine	Medical Center of First Private Clinic	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

Sponsors (1)

Lead Sponsor	Collaborator
Polpharma Biologics S.A.

Countries where clinical trial is conducted

Belarus,  Croatia,  Georgia,  Moldova, Republic of,  Poland,  Serbia,  Ukraine, 

References & Publications (1)

Hemmer B, Wiendl H, Roth K, Wessels H, Hofler J, Hornuss C, Liedert B, Selmaj K. Efficacy and Safety of Proposed Biosimilar Natalizumab (PB006) in Patients With Relapsing-Remitting Multiple Sclerosis: The Antelope Phase 3 Randomized Clinical Trial. JAMA N — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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).
Secondary	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.
Secondary	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).
Secondary	Change From Baseline in Heart Rate at Week 24	Change from baseline in heart rate at week 24.	At baseline and week 24.
Secondary	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).