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
- Registration Number
- NCT03689972
- Lead Sponsor
- Biogen
- Brief Summary
Part 1: The primary objective is to evaluate the efficacy of natalizumab extended interval dosing (EID) (every 6 weeks \[Q6W\]) in participants who have previously been treated with natalizumab standard interval dosing (SID) (every 4 weeks \[Q4W\]) for at least 12 months, in relation to continued Q4W 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 Q6W in participants who have previously been treated with natalizumab Q4W for at least 12 months, in relation to continued Q4W 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 585
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 Q4W or Q6W.
Key
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 Q6W was reverted to natalizumab Q4W 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1: IV Q4W Natalizumab Participants received natalizumab 300 mg intravenous (IV) infusion once Q4W up to Week 72. Part 1: IV Q6W Natalizumab Participants received natalizumab 300 mg IV infusion once Q6W up to Week 72. Part 2: Run-in Period: IV Q6W Natalizumab Participants who completed Part 1 or were newly enrolled in Part 2 received natalizumab 300 mg IV infusion Q6W from Week 72 through Week 102. Part 2: Crossover Period: IV Q6W, then SC Q6W Natalizumab Participants who completed run-in period of Part 2 were randomized to receive natalizumab 300 mg IV infusion Q6W from Week 108 through Week 126 followed by natalizumab 300 mg subcutaneous (SC) injection Q6W from Week 132 through Week 150 along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant's choice at Week 156. Part 2: Crossover Period: SC Q6W, then IV Q6W Natalizumab Participants who completed run-in period of Part 2 were randomized to receive natalizumab 300 mg SC injection Q6W from Week 108 through Week 126 followed by natalizumab 300 mg IV infusion Q6W from Week 132 through Week 150 along with a single dose of natalizumab 300 mg SC injection or IV infusion as per participant's choice at Week 156.
- Primary Outcome Measures
Name Time Method Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72 Week 72 T2 hyperintense lesions were analyzed by magnetic resonance imaging (MRI) scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions at Week 72 relative to baseline.
Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Period of Part 2 Week 150
- Secondary Outcome Measures
Name Time Method Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period Part 2 Baseline (Week 108) up to Week 156 Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Baseline up to Week 84 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 occurring on or after first dose after randomization up to 12 weeks (or 24 weeks for PML \[progressive multifocal leukoencephalopathy\] events) following the last dose on the study.An 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 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Part 2: Baseline (Week 108) up to Week 180 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 occurring on or after first dose after randomization up to and including 12 weeks (or 24 weeks for PML events) following the last dose on the study.
Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period Part 2 Baseline (Week 108) up to Week 156 T2 hyperintense lesions were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions during the crossover period of Part 2 relative to baseline.
Part 2: Time to First Relapse During the Crossover Period Part 2 Baseline (Week 108) up to Week 156 Relapse is 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. The time to first relapse is defined as the time from the first randomized dose in Part 2 up to the first relapse. Time to First Relapse is estimated by Kaplan-Meier method.
Part 2: Annualized Relapse Rate During the Crossover Period Part 2 Baseline (Week 108) up to Week 156 Annualized relapse rate is calculated as the total number of relapses that occurred during the treatment period divided by the total number of participant-years followed in the period.
Part 2: Change From Baseline in EDSS Score During the Crossover Period Part 2 Baseline (Week 108) up to Week 156 The EDSS is a scale based on standardized neurological examination which comprised of optic, brain stem, pyramidal, cerebellar, sensory and cerebral functions, as well as walking ability. It measures the MS disability status on a scale ranging from 0 (normal) to 10 (death due to MS), with higher scores indicating more disability.
Part 1: Annualized Relapse Rate at Week 72 Week 72 Annualized relapse rate is calculated as the total number of INEC-confirmed relapses that occurred during the treatment period divided by the total number of participant-years followed in the period.
Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening Up to Week 72 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. Time to EDSS worsening is estimated by Kaplan-Meier method.
Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48 Weeks 24 and 48 T2 hyperintense lesions were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new or newly enlarging T2 hyperintense lesions at Weeks 24 and 48 relative to baseline.
Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period Part 2 Baseline (Week 108) up to Week 156 The TSQM has 14 questions that assesses participants' global satisfaction level with their treatment in 4 domains: side effects (There are 5 questions in the side effects domain, however one of them is a Yes/No question and there are 4 sub-components, hence a maximum score of 20), effectiveness (3 questions), global satisfaction (3 questions), and convenience (3 questions). All questions are scored from 1 (least satisfied) to 5 or 7 (most satisfied). The total score is summed for each domain to obtain: side effects (1-20), effectiveness (1-21), global satisfaction (1-17), and convenience (1-21), using transformed scores between 0 and 100 for effectiveness. Lower total scores in each domain indicate dissatisfaction with the study medication and higher total scores indicate satisfaction.
Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period Week 108 up to Week 156 Gd enhancing lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new Gd enhancing lesions during the crossover period of Part 2 relative to baseline.
Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC) Up to Week 72 Relapse is 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 were included in the analysis. Time to First Relapse was estimated by Kaplan-Meier method.
Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72 Weeks 24, 48, and 72 Gd enhancing lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new Gd enhancing lesions at Weeks 24, 48, and 72 relative to baseline.
Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period Part 2 Baseline (Week 108) up to Week 156 Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72 Weeks 24, 48, and 72 T1 hypointense lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new T1 hypointense lesions at Weeks 24, 48, and 72 relative to baseline.
Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period Week 108 up to Week 156 Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period Part 2 Baseline (Week 108) up to Week 156 Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period Week 108 up to Week 156 T1 hypointense lesions on brain were analyzed by MRI scans of brain. New MRI scans were compared with the prior MRI scans to analyze the number of new T1 hypointense lesions during the crossover period of Part 2 relative to baseline.
Part 2: Trough Serum Concentration of Natalizumab (Ctrough) During the Crossover Period Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156 Part 2: Mean Trough α4 Integrin Saturation During the Crossover Period Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156
Trial Locations
- Locations (107)
CHU de Tivoli
🇧🇪La Louvière, Belgium
MS Center of California
🇺🇸Laguna Hills, California, United States
UCI MIND
🇺🇸Irvine, California, United States
Central Texas Neurology Consultants
🇺🇸Round Rock, Texas, United States
Northwestern University
🇺🇸Evanston, Illinois, United States
UZA
🇧🇪Edegem, Belgium
North Central Neurology Associates, P.C.
🇺🇸Cullman, Alabama, United States
Charité - Campus Charité Mitte
🇩🇪Berlin, Germany
Amphia Ziekenhuis, Molengracht
🇳🇱Breda, Netherlands
Azienda Ospedaliera Universitaria- Università degli Studi della Campania "Luigi Vanvitelli"
🇮🇹Napoli, Italy
St. Antonius Ziekenhuis
🇳🇱Nieuwegein, Netherlands
Hospital Regional Universitario de Malaga
🇪🇸Malaga, Spain
Fondazione IRCCS Istituto Neurologico Carlo Besta
🇮🇹Milano, Italy
I.R.C.C.S. Neuromed-Istituto Neurologico Mediterraneo
🇮🇹Pozzilli, Italy
Nottingham University Hospital, Queen's Medical Centre
🇬🇧Nottingham, United Kingdom
St. Michael's Hospital
🇨🇦Toronto, Ontario, Canada
CHU CAEN - Hôpital de la Côte de Nacre
🇫🇷Caen, France
The National Hospital for Neurology & Neurosurgery
🇬🇧London, Greater London, United Kingdom
Morriston Hospital
🇬🇧Swansea, United Kingdom
Salford Care Organisation
🇬🇧Salford, United Kingdom
Zuyderland Medisch Centrum - Sittard-Geleen
🇳🇱Sittard, Netherlands
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain
Shepherd Center, Inc.
🇺🇸Atlanta, Georgia, United States
Atlanta Neuroscience Institute
🇺🇸Atlanta, Georgia, United States
OhioHealth Riverside Methodist Hospital
🇺🇸Columbus, Ohio, United States
The Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Magee-Womens Hospital of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Virginia Mason Medical Center
🇺🇸Seattle, Washington, United States
Cleveland Clinic Lou Ruvo Center for Brain Health
🇺🇸Las Vegas, Nevada, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Rocky Mountain MS Research Group LLC
🇺🇸Salt Lake City, Utah, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
CHUM Centre de Recherche
🇨🇦Montreal, Quebec, Canada
Royal Hallamshire Hospital
🇬🇧Sheffield, United Kingdom
Walton Centre for Neurology & Neurosurgery.
🇬🇧Liverpool, Merseyside, United Kingdom
Queen Elizabeth University Hospital Campus
🇬🇧Glasgow, Strathclyde, United Kingdom
UC San Diego Movement Disorder Center
🇺🇸La Jolla, California, United States
Georgetown University Hospital-Medstar
🇺🇸Washington, District of Columbia, United States
University of Miami Miller School of Medicine
🇺🇸Miami, Florida, United States
Yale University
🇺🇸Fairfield, Connecticut, United States
NorthShore University HealthSystem
🇺🇸Evanston, Illinois, United States
Infinity Clinical Research, LLC
🇺🇸Sunrise, Florida, United States
Lahey Clinic Inc. - PARENT ACCOUNT
🇺🇸Burlington, Massachusetts, United States
Beth Israel Deaconess Medical Center, Inc.
🇺🇸Jamaica Plain, Massachusetts, United States
Neurology Center of New England P.C.
🇺🇸Foxboro, Massachusetts, United States
Washington University, School of Medicine
🇺🇸Saint Louis, Missouri, United States
Michigan Institute for Neurological Disorders
🇺🇸Farmington Hills, Michigan, United States
Minneapolis Clinic of Neurology
🇺🇸Golden Valley, Minnesota, United States
RWJ Barnabas Health
🇺🇸Newark, New Jersey, United States
Memorial Healthcare
🇺🇸Owosso, Michigan, United States
NYU Langone Clinical Cancer Center
🇺🇸New York, New York, United States
Mount Sinai Medical Center
🇺🇸New York, New York, United States
Columbia University Hervert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Raleigh Neurology Associates
🇺🇸Raleigh, North Carolina, United States
Sibyl Wray, MD Neurology, PC
🇺🇸Knoxville, Tennessee, United States
University Of Virginia
🇺🇸Charlottesville, Virginia, United States
Lyell McEwin Hospital
🇦🇺Elizabeth Vale, South Australia, Australia
Cliniques Universitaires Saint-Luc
🇧🇪Bruxelles, Belgium
Cliniques Universitaires de Bruxelles Hopital Erasme
🇧🇪Bruxelles, Belgium
Recherche SEPMUS
🇨🇦Greenfield Park, Quebec, Canada
Groupe Hospitalier Pellegrin - Hôpital Pellegrin
🇫🇷Bordeaux, France
CHU Nantes - Hopital Nord Laënnec
🇫🇷Saint Herblain, France
CHU Nice - Hôpital Pasteur
🇫🇷Nice, France
Hopital Roger Salengro - CHU Lille
🇫🇷Lille, France
Montreal Neurological Institute Clinical Research Unit
🇨🇦Montreal, Quebec, Canada
Alabama Neurology Associates
🇺🇸Homewood, Alabama, United States
Katholisches Klinikum Bochum gGmbH
🇩🇪Bochum, Germany
Stanford Hospital and Clinics
🇺🇸Palo Alto, California, United States
Holy Name Medical Center
🇺🇸Teaneck, New Jersey, United States
CHU Strasbourg - Nouvel Hôpital Civil
🇫🇷Strasbourg, France
Universitaetsklinikum Giessen und Marburg GmbH Standort Marburg
🇩🇪Marburg, Germany
Neuro Centrum Science GmbH
🇩🇪Erbach, Germany
Island Neurological Associates, P.C.
🇺🇸Plainview, New York, United States
College Park Family Care Center
🇺🇸Overland Park, Kansas, United States
Klinikum rechts der Isar der TU Muenchen
🇩🇪Munich, Germany
Dragonfly Research, LLC
🇺🇸Wellesley, Massachusetts, United States
Michigan State University
🇺🇸Grand Rapids, Michigan, United States
Universitaetsklinikum Muenster
🇩🇪Muenster, Germany
South Shore Neurology Associates
🇺🇸Weymouth, Massachusetts, United States
Synconcept GmbH - Neuro MVZ
🇩🇪Stuttgart, Germany
Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
Neurologie im Alphamed
🇩🇪Bamberg, Germany
Chaim Sheba Medical Center
🇮🇱Ramat Gan, Israel
Fondazione Istituto G.Giglio di Cefalù
🇮🇹Cefalù, Italy
Dayton Center for Neurological Disorders
🇺🇸Dayton, Ohio, United States
Clinique Neuro-Outaouais
🇨🇦Gatineau, Quebec, Canada
Azienda Ospedaliero Universitaria Policlinico "Gaspare Rodolico - San Marco" (Presidio G. Rodolico)
🇮🇹Catania, Italy
Multiple Sclerosis Center of Greater Washington
🇺🇸Vienna, Virginia, United States
Royal North Shore Hospital
🇦🇺St Leonards, New South Wales, Australia
Brain and Mind Centre
🇦🇺Sydney, New South Wales, Australia
Universitaetsklinikum Essen
🇩🇪Essen, Germany
Universitaetsklinikum Freiburg
🇩🇪Freiburg, Germany
Box Hill Hospital
🇦🇺Box Hill, Victoria, Australia
The Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Hospital Universitario Virgen de la Arrixaca
🇪🇸El Palmar, Murcia, Spain
Hospital Universitari Arnau de Vilanova
🇪🇸Lleida, Catalonia, Spain
King's College Hospital
🇬🇧London, Greater London, United Kingdom
Newcastle University- Clinical Ageing Research Unit
🇬🇧Newcastle upon Tyne, Tyne & Wear, United Kingdom
University of Colorado Hospital Anschutz Outpatient Pavillion
🇺🇸Aurora, Colorado, United States
University of South Florida
🇺🇸Tampa, Florida, United States
Providence Neurological Specialties
🇺🇸Portland, Oregon, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Wheaton Franciscan Healthcare
🇺🇸Milwaukee, Wisconsin, United States
Advanced Neurosciences Research
🇺🇸Fort Collins, Colorado, United States
Charing Cross Hospital
🇬🇧London, United Kingdom