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A Study to Evaluate Efficacy, Safety, and Tolerability of EID of Natalizumab (BG00002) in Participants With RRMS Switching From Treatment With Natalizumab SID in Relation to Continued SID Treatment- Followed by Extension Study Comprising SC and IV Natalizumab Administration

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ClinicalTrials.gov Identifier: NCT03689972
Recruitment Status : Active, not recruiting
First Posted : October 1, 2018
Last Update Posted : September 18, 2020
Sponsor:
Information provided by (Responsible Party):
Biogen

Tracking Information
First Submitted Date  ICMJE September 27, 2018
First Posted Date  ICMJE October 1, 2018
Last Update Posted Date September 18, 2020
Actual Study Start Date  ICMJE December 26, 2018
Estimated Primary Completion Date August 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 5, 2020)
  • Part 1: Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72 [ Time Frame: Week 72 ]
    Number of new or newly enlarging T2 hyperintense lesions will be analysed by magnetic resonance imaging (MRI) scans of brain. New MRI scans will be compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions.
  • Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Part 2 [ Time Frame: Week 156 ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 27, 2018)
Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 48 [ Time Frame: Week 48 ]
Number of new or newly enlarging T2 hyperintense lesions will be analysed by magnetic resonance imaging (MRI) scans of brain. New MRI scans will be compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 5, 2020)
  • Part1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC) [ Time Frame: Up to Week 72 ]
    A multiple sclerosis (MS) relapse will be defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination. Only relapses confirmed by an INEC will be included in the analysis.
  • Part 1: Number of New Gadolinium (Gd) Enhancing and New T1 Hypointense Lesions at Weeks 24, 48 and 72 [ Time Frame: Weeks 24, 48 and 72 ]
    Number of new Gd enhancing and new T1 hypointense lesions on brain will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse number of new Gd enhancing and new T1 hypointense lesions.
  • Part 1: Annualized Relapse Rate at Week 72 [ Time Frame: Week 72 ]
    An MS relapse will be defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination. Only relapses confirmed by an INEC will be included in the analysis.
  • Part 1: Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ]
    Number of new or newly enlarging T2 hyperintense lesions will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions.
  • Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 96 ]
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization or prolongation of existing hospitalization, results in a significant disability/incapacity or congenital anomaly, is a medically important event.
  • Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening as Confirmed After at Least 24 Weeks [ Time Frame: Week 24, 48, 72 and 84 ]
    Confirmed EDSS worsening is defined as an increase of at least 1.0 point from a baseline EDSS score ≥ 1.0 or an increase of at least 1.5 points from a baseline EDSS score of 0 that is confirmed after at least 24 weeks.
  • Part 2: Total Score on Treatment Satisfaction Questionnaire for Medication (TSQM) [ Time Frame: Up to Week 156 ]
    The TSQM assessed participants' global satisfaction with treatment and captured information on treatment side effects, effectiveness, and convenience using transformed scores between 0 and 100 for effectiveness. Higher scores indicates greater satisfaction.
  • Part 2: Mean Time for Drug Preparation and Administration [ Time Frame: Up to Week 156 ]
  • Part 2: Number of Participants with Treatment Emergent AEs (TEAEs) [ Time Frame: From Week 132 to Week 156 ]
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any event in participants who had received at least 1 dose of study drug, regardless of relationship to study drug.
  • Part 2: Percentage of Participants With Anti-Natalizumab Antibodies [ Time Frame: From Week 132 to Week 156 ]
  • Part 2: Number of New or Newly Enlarging T2 Hyperintense Lesions [ Time Frame: From Week 132 to Week 156 ]
    Number of new or newly enlarging T2 hyperintense lesions will be analysed by magnetic resonance imaging (MRI) scans of brain. New MRI scans will be compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions.
  • Part 2: Time to First Relapse [ Time Frame: From Week 132 to Week 156 ]
    A MS relapse will be defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours.
  • Part 2: Annualized Relapse Rate [ Time Frame: From Week 132 to Week 156 ]
    Annualized relapse rate included relapses reported prior to the end of each period.
  • Part 2: Change in Expanded Disability Status Scale (EDSS) Score [ Time Frame: From Week 132 to Week 156 ]
    The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability.
  • Part 2: Number of New Gadolinium (Gd) Enhancing Lesions [ Time Frame: From Week 132 to Week 156 ]
    Number of new Gd enhancing lesions on brain will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse number of new Gd enhancing lesions.
  • Part 2: Number of New T1 Hypointense Lesions [ Time Frame: From Week 132 to Week 156 ]
    Number of new T1 hypointense lesions on brain will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse number new T1 hypointense lesions.
  • Part 2: Percentage of Brain Volume Change [ Time Frame: From Week 132 to Week 156 ]
  • Part 2: Change in Cortical and Thalamic Brain Region Volume [ Time Frame: From Week 132 to Week 156 ]
  • Part 2: Trough Serum Concentration of Natalizumab (Ctrough) [ Time Frame: From Week 132 to Week 156 ]
  • Part 2: Trough α4 Integrin Saturation [ Time Frame: From Week 132 to Week 156 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2018)
  • Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC) [ Time Frame: Up to Week 72 ]
    A multiple sclerosis (MS) relapse will be defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination. Only relapses confirmed by an INEC will be included in the analysis.
  • Number of new Gadolinium (Gd) Enhancing and new T1 Hypointense Lesions at Weeks 24, 48 and 72 [ Time Frame: Weeks 24, 48 and 72 ]
    Number of new Gd enhancing and new T1 hypointense lesions on brain will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse number of new Gd enhancing and new T1 hypointense lesions.
  • Annualized Relapse Rate at Weeks 48 and 72 [ Time Frame: Weeks 48 and 72 ]
    An MS relapse will be defined as the onset of new or recurrent neurological symptoms, not associated with fever, infection, severe stress, or drug toxicity, lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination. Only relapses confirmed by an INEC will be included in the analysis.
  • Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 72 [ Time Frame: Weeks 24 and 72 ]
    Number of new or newly enlarging T2 hyperintense lesions will be analysed by MRI scans of brain. New MRI scans will be compared with the prior MRI scans to analyse the number of new or newly enlarging T2 hyperintense lesions.
  • Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 96 ]
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization or prolongation of existing hospitalization, results in a significant disability/incapacity or congenital anomaly, is a medically important event.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate Efficacy, Safety, and Tolerability of EID of Natalizumab (BG00002) in Participants With RRMS Switching From Treatment With Natalizumab SID in Relation to Continued SID Treatment- Followed by Extension Study Comprising SC and IV Natalizumab Administration
Official Title  ICMJE A Randomized, Controlled, Open-Label, Rater-Blinded, Phase 3b Study of the Efficacy, Safety, and Tolerability of 6-Week Extended Interval Dosing (EID) of Natalizumab (BG00002) in Subjects With Relapsing-Remitting Multiple Sclerosis Switching From Treatment With 4-Week Natalizumab Standard Interval Dosing (SID) in Relation to Continued SID Treatment - Followed by an Open-Label Crossover Extension Study Comprising Subcutaneous and Intravenous Natalizumab Administration
Brief Summary

Part 1: The primary objective is to evaluate the efficacy of natalizumab extended interval dosing (EID) in participants who have previously been treated with natalizumab standard interval dosing (SID) for at least 12 months, in relation to continued SID treatment. The secondary objectives is to evaluate relapse-based clinical efficacy measures, disability worsening, additional Magnetic resonance imaging (MRI)-lesion efficacy measures and safety of EID in participants who have previously been treated with natalizumab SID for at least 12 months, in relation to continued SID treatment.

Part 2: The primary objective is to evaluate participant preference for subcutaneous (SC) versus intravenous (IV) route of natalizumab administration. The secondary objectives is to evaluate treatment satisfaction, drug preparation and administration time, safety and immunogenicity, efficacy and characterize pharmacokinetic (PK) and pharmacodynamic (PD) drug preparation and administration time of SC versus IV routes of natalizumab administration.

Detailed Description

This study will be conducted in 2 parts. At the end of part 1, participants who provide consent and are eligible, and newly enrolled participants, will enter part 2, an Open Label Extension comprising a crossover analysis.

Those participants who completed part 1 and cannot participate, or elect not to participate, in Part 2 (Open label extension) will enter a 12-week follow-up.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis, Relapsing-Remitting
Intervention  ICMJE Drug: Natalizumab
Natalizumab 300 mg SC injection or IV infusion.
Other Name: BG00002
Study Arms  ICMJE
  • Experimental: Part 1: Standard Interval Dosing (SID) IV
    Participants will receive natalizumab 300 milligram (mg) intravenous (IV) infusion every 4 weeks (-2/+5 days) up to Week 72.
    Intervention: Drug: Natalizumab
  • Experimental: Part 1: Extended Interval Dosing (EID) IV
    Participants will receive natalizumab 300 mg IV infusion every 6 weeks (-2/+5 days) up to Week 72.
    Intervention: Drug: Natalizumab
  • Experimental: Part 2: EID SC, then EID IV
    Participants will receive natalizumab 300 mg SC injection every 6 weeks from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion every 6 weeks from Week 132 through Week 150.
    Intervention: Drug: Natalizumab
  • Experimental: Part 2: EID IV, then EID SC
    Participants will receive natalizumab 300 mg IV infusion every 6 weeks from Week 108 through Week 126 followed by natalizumab 300 mg SC injection every 6 weeks from Week 132 through Week 150.
    Intervention: Drug: Natalizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 21, 2019)
500
Original Estimated Enrollment  ICMJE
 (submitted: September 27, 2018)
480
Estimated Study Completion Date  ICMJE February 15, 2023
Estimated Primary Completion Date August 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

For Part 1:

  • Ability of the participant to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulations.
  • Diagnosis of relapsing remitting multiple sclerosis (RRMS) according to the McDonald criteria [Thompson 2018].
  • Treatment with natalizumab as disease-modifying monotherapy for RRMS that is consistent with the approved dosing for a minimum of 12 months prior to randomization. The participant must have received at least 11 doses of natalizumab in the 12 months prior to randomization with no missed doses in the 3 months prior to randomization.
  • Expanded Disability Status Scale (EDSS) score <=5.5 at screening.
  • No relapses in the last 12 months prior to randomization, as determined by the enrolling Investigator.

For Part 2:

  • Ability of the participants to understand the purpose and risks of the study and provide signed and dated informed consent for Part 2 and authorization to use confidential health information in accordance with national and local participant privacy regulations.
  • Completed Part 1 Week 72 visit while remaining on their randomized treatment assignment of SID or EID.

Key Exclusion Criteria:

For Part 1:

  • Primary and secondary progressive multiple sclerosis (MS).
  • MRI positive for Gd-enhancing lesions at screening.
  • Participants for whom MRI is contraindicated (e.g., have a contraindicated pacemaker or other contraindicated implanted metal device, have suffered, or are at risk for, side effects from Gd, or have claustrophobia that cannot be medically managed).
  • History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic (including diabetes), urologic, pulmonary, neurologic (except for RRMS), dermatologic, psychiatric, renal, or other major disease that would preclude participation in a clinical study, in the opinion of the Investigator.
  • Presence of anti-natalizumab antibodies at screening.

For Part 2:

  • Participants treated with natalizumab EID was reverted to natalizumab SID by choice or as rescue treatment in Part 1.
  • Participant received treatment with any MS disease-modifying therapy other than natalizumab in Part 1 or in the period between Part 1 and Part 2.
  • History of human immunodeficiency virus or history of other immunodeficient conditions.
  • Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 30 days (or 5 half-lives of the agent, whichever is longer) prior to the Baseline Visit or at any time during this study.
  • Inability to comply with study requirements.
  • Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the participant unsuitable for enrollment.

The inclusion and exclusion criteria for new participants who did not participate in Part 1 of the study are the same as those for participants who did participate in Part 1.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   France,   Germany,   Israel,   Italy,   Netherlands,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03689972
Other Study ID Numbers  ICMJE 101MS329
2018-002145-11 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Please refer data queries to DataSharing@biogen.com.
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP