Clinical trial NCT03689972: 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: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis, Relapsing-Remitting
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2018-10-01
Enrollment: 585
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Week 72
timeFrame: Week 72
measure: Part 2: Percentage of Participants Indicating a Preference for Natalizumab SC Administration at the End of Crossover Period of Part 2
timeFrame: Week 150
Secondary outcomes:
measure: Part 1: Time to First Relapse as Adjudicated by an Independent Neurology Evaluation Committee (INEC)
timeFrame: Up to Week 72
measure: Part 1: Annualized Relapse Rate at Week 72
timeFrame: Week 72
measure: Part 1: Time to Expanded Disability Status Scale (EDSS) Worsening
timeFrame: Up to Week 72
measure: Part 1: Mean Number of New T1 Hypointense Lesions at Weeks 24, 48, and 72
timeFrame: Weeks 24, 48, and 72
measure: Part 1: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions at Weeks 24 and 48
timeFrame: Weeks 24 and 48
measure: Part 1: Mean Number of New Gadolinium (Gd) Enhancing Lesions at Weeks 24, 48, and 72
timeFrame: Weeks 24, 48, and 72
measure: Part 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to Week 84
measure: Part 2: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Scores During the Crossover Period
timeFrame: Part 2 Baseline (Week 108) up to Week 156
measure: Part 2: Mean Time for Drug Preparation and Drug Administration During the Crossover Period
timeFrame: Week 108 up to Week 156
measure: Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Part 2: Baseline (Week 108) up to Week 180
measure: Part 2: Percentage of Participants With Anti-Natalizumab Antibodies During the Crossover Period
timeFrame: Part 2 Baseline (Week 108) up to Week 156
measure: Part 2: Mean Number of New or Newly Enlarging T2 Hyperintense Lesions During the Crossover Period
timeFrame: Part 2 Baseline (Week 108) up to Week 156
measure: Part 2: Time to First Relapse During the Crossover Period
timeFrame: Part 2 Baseline (Week 108) up to Week 156
measure: Part 2: Annualized Relapse Rate During the Crossover Period
timeFrame: Part 2 Baseline (Week 108) up to Week 156
measure: Part 2: Change From Baseline in EDSS Score During the Crossover Period
timeFrame: Part 2 Baseline (Week 108) up to Week 156
measure: Part 2: Mean Number of New Gd Enhancing Lesions During the Crossover Period
timeFrame: Week 108 up to Week 156
measure: Part 2: Mean Number of New T1 Hypointense Lesions During the Crossover Period
timeFrame: Week 108 up to Week 156
measure: Part 2: Mean Percentage Change From Baseline in Brain Volume During the Crossover Period
timeFrame: Part 2 Baseline (Week 108) up to Week 156
measure: Part 2: Change From Baseline in Cortical and Thalamic Brain Region Volume During the Crossover Period
timeFrame: Part 2 Baseline (Week 108) up to Week 156
measure: Part 2: Trough Serum Concentration of Natalizumab (Ctrough) During the Crossover Period
timeFrame: Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156
measure: Part 2: Mean Trough α4 Integrin Saturation During the Crossover Period
timeFrame: Pre-dose at Weeks 108, 114, 120, 126, 132, 138, 144, 150, and 156
Other outcomes:
Locations:
city: Cullman
country: United States
facility: North Central Neurology Associates, P.C.
state: Alabama
city: Homewood
country: United States
facility: Alabama Neurology Associates
state: Alabama
city: Irvine
country: United States
facility: UCI MIND
state: California
city: La Jolla
country: United States
facility: UC San Diego Movement Disorder Center
state: California
city: Laguna Hills
country: United States
facility: MS Center of California
state: California
city: Palo Alto
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital Anschutz Outpatient Pavillion
state: Colorado
city: Fort Collins
country: United States
facility: Advanced Neurosciences Research
state: Colorado
city: Fairfield
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Hospital-Medstar
state: District of Columbia
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Sunrise
country: United States
facility: Infinity Clinical Research, LLC
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Shepherd Center, Inc.
state: Georgia
city: Atlanta
country: United States
facility: Atlanta Neuroscience Institute
state: Georgia
city: Evanston
country: United States
facility: NorthShore University HealthSystem
state: Illinois
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Overland Park
country: United States
facility: College Park Family Care Center
state: Kansas
city: Burlington
country: United States
facility: Lahey Clinic Inc. - PARENT ACCOUNT
state: Massachusetts
city: Foxboro
country: United States
facility: Neurology Center of New England P.C.
state: Massachusetts
city: Jamaica Plain
country: United States
facility: Beth Israel Deaconess Medical Center, Inc.
state: Massachusetts
city: Wellesley
country: United States
facility: Dragonfly Research, LLC
state: Massachusetts
city: Weymouth
country: United States
facility: South Shore Neurology Associates
state: Massachusetts
city: Farmington Hills
country: United States
facility: Michigan Institute for Neurological Disorders
state: Michigan
city: Grand Rapids
country: United States
facility: Michigan State University
state: Michigan
city: Owosso
country: United States
facility: Memorial Healthcare
state: Michigan
city: Golden Valley
country: United States
facility: Minneapolis Clinic of Neurology
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University, School of Medicine
state: Missouri
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
city: Newark
country: United States
facility: RWJ Barnabas Health
state: New Jersey
city: Teaneck
country: United States
facility: Holy Name Medical Center
state: New Jersey
city: New York
country: United States
facility: NYU Langone Clinical Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Hervert Irving Comprehensive Cancer Center
state: New York
city: Plainview
country: United States
facility: Island Neurological Associates, P.C.
state: New York
city: Raleigh
country: United States
facility: Raleigh Neurology Associates
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: OhioHealth Riverside Methodist Hospital
state: Ohio
city: Dayton
country: United States
facility: Dayton Center for Neurological Disorders
state: Ohio
city: Portland
country: United States
facility: Providence Neurological Specialties
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee-Womens Hospital of UPMC
state: Pennsylvania
city: Knoxville
country: United States
facility: Sibyl Wray, MD Neurology, PC
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants
state: Texas
city: Salt Lake City
country: United States
facility: Rocky Mountain MS Research Group LLC
state: Utah
city: Charlottesville
country: United States
facility: University Of Virginia
state: Virginia
city: Vienna
country: United States
facility: Multiple Sclerosis Center of Greater Washington
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Wheaton Franciscan Healthcare
state: Wisconsin
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Brain and Mind Centre
state: New South Wales
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires de Bruxelles Hopital Erasme
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Edegem
country: Belgium
facility: UZA
city: La Louvière
country: Belgium
facility: CHU de Tivoli
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Gatineau
country: Canada
facility: Clinique Neuro-Outaouais
state: Quebec
city: Greenfield Park
country: Canada
facility: Recherche SEPMUS
state: Quebec
city: Montreal
country: Canada
facility: CHUM Centre de Recherche
state: Quebec
city: Montreal
country: Canada
facility: Montreal Neurological Institute Clinical Research Unit
state: Quebec
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin - Hôpital Pellegrin
city: Caen
country: France
facility: CHU CAEN - Hôpital de la Côte de Nacre
city: Lille
country: France
facility: Hopital Roger Salengro - CHU Lille
city: Nice
country: France
facility: CHU Nice - Hôpital Pasteur
city: Saint Herblain
country: France
facility: CHU Nantes - Hopital Nord Laënnec
city: Strasbourg
country: France
facility: CHU Strasbourg - Nouvel Hôpital Civil
city: Bamberg
country: Germany
facility: Neurologie im Alphamed
city: Berlin
country: Germany
facility: Charité - Campus Charité Mitte
city: Bochum
country: Germany
facility: Katholisches Klinikum Bochum gGmbH
city: Erbach
country: Germany
facility: Neuro Centrum Science GmbH
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Marburg
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH Standort Marburg
city: Muenster
country: Germany
facility: Universitaetsklinikum Muenster
city: Munich
country: Germany
facility: Klinikum rechts der Isar der TU Muenchen
city: Stuttgart
country: Germany
facility: Synconcept GmbH - Neuro MVZ
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico "Gaspare Rodolico - San Marco" (Presidio G. Rodolico)
city: Cefalù
country: Italy
facility: Fondazione Istituto G.Giglio di Cefalù
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria- Università degli Studi della Campania "Luigi Vanvitelli"
city: Pozzilli
country: Italy
facility: I.R.C.C.S. Neuromed-Istituto Neurologico Mediterraneo
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis, Molengracht
city: Nieuwegein
country: Netherlands
facility: St. Antonius Ziekenhuis
city: Sittard
country: Netherlands
facility: Zuyderland Medisch Centrum - Sittard-Geleen
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
state: Catalonia
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
state: Murcia
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: London
country: United Kingdom
facility: King's College Hospital
state: Greater London
city: London
country: United Kingdom
facility: The National Hospital for Neurology & Neurosurgery
state: Greater London
city: Liverpool
country: United Kingdom
facility: Walton Centre for Neurology & Neurosurgery.
state: Merseyside
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital Campus
state: Strathclyde
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle University- Clinical Ageing Research Unit
state: Tyne & Wear
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital, Queen's Medical Centre
city: Salford
country: United Kingdom
facility: Salford Care Organisation
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Swansea
country: United Kingdom
facility: Morriston Hospital
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Foley JF, Defer G, Ryerson LZ, Cohen JA, Arnold DL, Butzkueven H, Cutter G, Giovannoni G, Killestein J, Wiendl H, Smirnakis K, Xiao S, Kong G, Kuhelj R, Campbell N; NOVA study investigators. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 Jul;21(7):608-619. doi: 10.1016/S1474-4422(22)00143-0. Epub 2022 Apr 25.