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

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03689972
• Other study ID #: 101MS329
• Secondary ID: 2018-002145-11
• Status: Completed
• Phase: Phase 3
• Start date: November 27, 2018
• Est. completion date: July 24, 2023

Study information

• Verified date: May 2024
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 585
• Est. completion date: July 24, 2023
• Est. primary completion date: January 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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 Q4W or Q6W.

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 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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Drug:
• Natalizumab
Natalizumab 300 mg IV infusion.
• Natalizumab
Natalizumab 300 mg SC injection or IV infusion.

Locations

Country	Name	City	State
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Brain and Mind Centre	Sydney	New South Wales
Belgium	Cliniques Universitaires de Bruxelles Hopital Erasme	Bruxelles
Belgium	Cliniques Universitaires Saint-Luc	Bruxelles
Belgium	UZA	Edegem
Belgium	CHU de Tivoli	La Louvière
Canada	Clinique Neuro-Outaouais	Gatineau	Quebec
Canada	Recherche SEPMUS	Greenfield Park	Quebec
Canada	CHUM Centre de Recherche	Montreal	Quebec
Canada	Montreal Neurological Institute Clinical Research Unit	Montreal	Quebec
Canada	St. Michael's Hospital	Toronto	Ontario
France	Groupe Hospitalier Pellegrin - Hôpital Pellegrin	Bordeaux
France	CHU CAEN - Hôpital de la Côte de Nacre	Caen
France	Hopital Roger Salengro - CHU Lille	Lille
France	CHU Nice - Hôpital Pasteur	Nice
France	CHU Nantes - Hopital Nord Laënnec	Saint Herblain
France	CHU Strasbourg - Nouvel Hôpital Civil	Strasbourg
Germany	Neurologie im Alphamed	Bamberg
Germany	Charité - Campus Charité Mitte	Berlin
Germany	Katholisches Klinikum Bochum gGmbH	Bochum
Germany	Neuro Centrum Science GmbH	Erbach
Germany	Universitaetsklinikum Essen	Essen
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Universitaetsklinikum Giessen und Marburg GmbH Standort Marburg	Marburg
Germany	Universitaetsklinikum Muenster	Muenster
Germany	Klinikum rechts der Isar der TU Muenchen	Munich
Germany	Synconcept GmbH - Neuro MVZ	Stuttgart
Israel	Chaim Sheba Medical Center	Ramat Gan
Italy	Azienda Ospedaliero Universitaria Policlinico "Gaspare Rodolico - San Marco" (Presidio G. Rodolico)	Catania
Italy	Fondazione Istituto G.Giglio di Cefalù	Cefalù
Italy	Fondazione IRCCS Istituto Neurologico Carlo Besta	Milano
Italy	Azienda Ospedaliera Universitaria- Università degli Studi della Campania "Luigi Vanvitelli"	Napoli
Italy	I.R.C.C.S. Neuromed-Istituto Neurologico Mediterraneo	Pozzilli
Netherlands	Amphia Ziekenhuis, Molengracht	Breda
Netherlands	St. Antonius Ziekenhuis	Nieuwegein
Netherlands	Zuyderland Medisch Centrum - Sittard-Geleen	Sittard
Spain	Hospital Universitario Virgen de la Arrixaca	El Palmar	Murcia
Spain	Hospital Universitari Arnau de Vilanova	Lleida	Catalonia
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Regional Universitario de Malaga	Malaga
Spain	Hospital Universitario Virgen Macarena	Sevilla
United Kingdom	Queen Elizabeth University Hospital Campus	Glasgow	Strathclyde
United Kingdom	Walton Centre for Neurology & Neurosurgery.	Liverpool	Merseyside
United Kingdom	Charing Cross Hospital	London
United Kingdom	King's College Hospital	London	Greater London
United Kingdom	The National Hospital for Neurology & Neurosurgery	London	Greater London
United Kingdom	Newcastle University- Clinical Ageing Research Unit	Newcastle upon Tyne	Tyne & Wear
United Kingdom	Nottingham University Hospital, Queen's Medical Centre	Nottingham
United Kingdom	Salford Care Organisation	Salford
United Kingdom	Royal Hallamshire Hospital	Sheffield
United Kingdom	Morriston Hospital	Swansea
United States	Atlanta Neuroscience Institute	Atlanta	Georgia
United States	Shepherd Center, Inc.	Atlanta	Georgia
United States	University of Colorado Hospital Anschutz Outpatient Pavillion	Aurora	Colorado
United States	Lahey Clinic Inc. - PARENT ACCOUNT	Burlington	Massachusetts
United States	University Of Virginia	Charlottesville	Virginia
United States	University of Cincinnati	Cincinnati	Ohio
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	OhioHealth Riverside Methodist Hospital	Columbus	Ohio
United States	North Central Neurology Associates, P.C.	Cullman	Alabama
United States	Dayton Center for Neurological Disorders	Dayton	Ohio
United States	NorthShore University HealthSystem	Evanston	Illinois
United States	Northwestern University	Evanston	Illinois
United States	Yale University	Fairfield	Connecticut
United States	Michigan Institute for Neurological Disorders	Farmington Hills	Michigan
United States	Advanced Neurosciences Research	Fort Collins	Colorado
United States	Neurology Center of New England P.C.	Foxboro	Massachusetts
United States	Minneapolis Clinic of Neurology	Golden Valley	Minnesota
United States	Michigan State University	Grand Rapids	Michigan
United States	Alabama Neurology Associates	Homewood	Alabama
United States	UCI MIND	Irvine	California
United States	Beth Israel Deaconess Medical Center, Inc.	Jamaica Plain	Massachusetts
United States	Sibyl Wray, MD Neurology, PC	Knoxville	Tennessee
United States	UC San Diego Movement Disorder Center	La Jolla	California
United States	MS Center of California	Laguna Hills	California
United States	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada
United States	University of Miami Miller School of Medicine	Miami	Florida
United States	Wheaton Franciscan Healthcare	Milwaukee	Wisconsin
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia University Hervert Irving Comprehensive Cancer Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	NYU Langone Clinical Cancer Center	New York	New York
United States	RWJ Barnabas Health	Newark	New Jersey
United States	College Park Family Care Center	Overland Park	Kansas
United States	Memorial Healthcare	Owosso	Michigan
United States	Stanford Hospital and Clinics	Palo Alto	California
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Magee-Womens Hospital of UPMC	Pittsburgh	Pennsylvania
United States	Island Neurological Associates, P.C.	Plainview	New York
United States	Providence Neurological Specialties	Portland	Oregon
United States	Raleigh Neurology Associates	Raleigh	North Carolina
United States	Central Texas Neurology Consultants	Round Rock	Texas
United States	Washington University, School of Medicine	Saint Louis	Missouri
United States	Rocky Mountain MS Research Group LLC	Salt Lake City	Utah
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Infinity Clinical Research, LLC	Sunrise	Florida
United States	University of South Florida	Tampa	Florida
United States	Holy Name Medical Center	Teaneck	New Jersey
United States	Multiple Sclerosis Center of Greater Washington	Vienna	Virginia
United States	Georgetown University Hospital-Medstar	Washington	District of Columbia
United States	Dragonfly Research, LLC	Wellesley	Massachusetts
United States	South Shore Neurology Associates	Weymouth	Massachusetts
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Biogen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Israel,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at 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.	Week 72
Primary	Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Period of Part 2		Week 150
Secondary	Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC)	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.	Up to Week 72
Secondary	Part 1: Annualized Relapse Rate at 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.	Week 72
Secondary	Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening	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.	Up to Week 72
Secondary	Part 1: Mean Number of New T1 Hypointense Lesions at 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.	Weeks 24, 48, and 72
Secondary	Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at 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.	Weeks 24 and 48
Secondary	Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at 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.	Weeks 24, 48, and 72
Secondary	Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	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.	Baseline up to Week 84
Secondary	Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period	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 Baseline (Week 108) up to Week 156
Secondary	Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period		Week 108 up to Week 156
Secondary	Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)	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: Baseline (Week 108) up to Week 180
Secondary	Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period		Part 2 Baseline (Week 108) up to Week 156
Secondary	Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period	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 Baseline (Week 108) up to Week 156
Secondary	Part 2: Time to First Relapse During the Crossover Period	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 Baseline (Week 108) up to Week 156
Secondary	Part 2: Annualized Relapse Rate During the Crossover Period	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 Baseline (Week 108) up to Week 156
Secondary	Part 2: Change From Baseline in EDSS Score During the Crossover Period	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 2 Baseline (Week 108) up to Week 156
Secondary	Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period	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.	Week 108 up to Week 156
Secondary	Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period	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.	Week 108 up to Week 156
Secondary	Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period		Part 2 Baseline (Week 108) up to Week 156
Secondary	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
Secondary	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
Secondary	Part 2: Mean Trough a4 Integrin Saturation During the Crossover Period		Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156