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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04115488
Recruitment Status : Completed
First Posted : October 4, 2019
Results First Posted : July 3, 2023
Last Update Posted : July 3, 2023
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Relapsing-Remitting Multiple Sclerosis (RRMS) Biological: Intravenous (IV) infusions Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 265 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri® in Patients With Relapsing-Remitting Multiple Sclerosis (RRMS)
Actual Study Start Date : October 1, 2019
Actual Primary Completion Date : August 23, 2021
Actual Study Completion Date : February 7, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Natalizumab

Arm Intervention/treatment
Experimental: PB006
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
Intravenous (IV) infusions of a dose of 300mg, every 4 weeks with a total of 12 doses

Active Comparator: Tysabri
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
Intravenous (IV) infusions of a dose of 300mg, every 4 weeks with a total of 12 doses




Primary Outcome Measures :
  1. Cumulative Number of New Active Lesions Over 24 Weeks [ Time Frame: 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 :
  1. Cumulative Number of New Active Lesions Over 48 Weeks [ Time Frame: 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].

  2. Cumulative Number of New GdE T1-weighted Lesions Over 24 Weeks [ Time Frame: 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].

  3. Cumulative Number of New GdE T1-weighted Lesions Over 48 Weeks [ Time Frame: 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].

  4. Number of Patients Without New GdE T1-weighted Lesions Over 24 Weeks [ Time Frame: 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].

  5. Number of Patients Without New GdE T1-weighted Lesions Over 48 Weeks [ 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 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].

  6. Cumulative Number of New/Enlarging T2-weighted Lesions Over 24 Weeks [ Time Frame: 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.

  7. Cumulative Number of New/Enlarging T2-weighted Lesions Over 48 Weeks [ Time Frame: 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.

  8. Number of Persistent Lesions After 24 Weeks [ Time Frame: 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].

  9. Number of Persistent Lesions After 48 Weeks [ Time Frame: 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].

  10. Annualized Relapse Rate After 24 Weeks [ Time Frame: 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.

  11. Annualized Relapse Rate After 48 Weeks [ Time Frame: 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.

  12. Change From Baseline in Expanded Disability Status Scale (EDSS) After 24 Weeks [ Time Frame: 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.

  13. Change From Baseline in Expanded Disability Status Scale (EDSS) After 48 Weeks [ Time Frame: 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.

  14. Percentage of Subjects With Anti-drug (Natalizumab) Antibodies (ADA) and Persistent Antibodies After 24 Weeks [ Time Frame: 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.

  15. Percentage of Subjects With Anti-drug (Natalizumab) Antibodies (ADA) and Persistent Antibodies After 48 Weeks [ Time Frame: 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.

  16. Percentage of Subjects With Neutralizing Antibodies After 24 Weeks [ Time Frame: Up to 24 weeks. ]
    Percentage of subjects with positive (transient and persistent) neutralizing antibodies after 24 weeks.

  17. Percentage of Subjects With Neutralizing Antibodies After 48 Weeks [ Time Frame: Up to 48 weeks. ]
    Percentage of subjects with positive (transient and persistent) neutralizing antibodies after 48 weeks.

  18. 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 24 weeks.

  19. 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. ]
    Number of subjects with any Treatment-Emergent Adverse Event (TEAE) or any Treatment-Emergent Serious Adverse Event (SAE) after 48 weeks.

  20. Natalizumab Trough Concentration (Ctrough) Over Time, Week 8 [ Time Frame: 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.

  21. Natalizumab Trough Concentration (Ctrough) Over Time, Week 16 [ Time Frame: 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.

  22. Natalizumab Trough Concentration (Ctrough) Over Time, Week 24 [ Time Frame: 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.

  23. Natalizumab Trough Concentration (Ctrough) Over Time, Week 32 [ Time Frame: 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.

  24. Natalizumab Trough Concentration (Ctrough) Over Time, Week 48 [ Time Frame: 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.

  25. Number of Patients Without New/Enlarging T2-weighted Lesions Over 24 Weeks [ Time Frame: 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.

  26. Number of Patients Without New/Enlarging T2-weighted Lesions Over 48 Weeks [ Time Frame: 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.

  27. 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 24.

  28. Number of Patients With Abnormal Clinical Laboratory Tests at Week 48 [ Time Frame: At week 48. ]
    Number of patients with abnormal clinical laboratory tests at week 48.

  29. 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 24.

  30. Number of Patients With Abnormal Findings in Physical Examination at Week 48 [ Time Frame: End of study (week 48). ]
    Number of patients with abnormal findings in physical examination at week 48.

  31. Change From Baseline in Blood Pressure at Week 24 [ Time Frame: At baseline and week 24. ]
    Change from baseline in diastolic and systolic blood Pressure at week 24.

  32. Change From Baseline in Blood Pressure at Week 48 [ Time Frame: At baseline and end of study (week 48). ]
    Change from baseline in diastolic and systolic blood Pressure at week 48.

  33. Change From Baseline in Heart Rate at Week 24 [ Time Frame: At baseline and week 24. ]
    Change from baseline in heart rate at week 24.

  34. Change From Baseline in Heart Rate at Week 48 [ Time Frame: At baseline and end of study (week 48). ]
    Change from baseline in heart rate at week 48.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04115488


Locations
Show Show 48 study locations
Sponsors and Collaborators
Polpharma Biologics S.A.
Investigators
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Study Director: Karsten Roth, Dr. Polpharma Biologics S.A.
  Study Documents (Full-Text)

Documents provided by Polpharma Biologics S.A.:
Study Protocol  [PDF] July 15, 2020
Statistical Analysis Plan  [PDF] April 28, 2021

Publications of Results:
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Responsible Party: Polpharma Biologics S.A.
ClinicalTrials.gov Identifier: NCT04115488    
Other Study ID Numbers: PB006-03-01
First Posted: October 4, 2019    Key Record Dates
Results First Posted: July 3, 2023
Last Update Posted: July 3, 2023
Last Verified: June 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases