Clinical trial NCT01416181: A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis
Official title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis, With Optional Open-Label Extension
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Secondary Progressive Multiple Sclerosis
Keywords: Natalizumab
secondary
multiple sclerosis
MS
SPMS
Tysabri
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2011-08-12
Enrollment: 889
Sex: ALL
Minimum age (years): 18
Maximum age (years): 58
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 3b, multicenter, international study conducted in 2 parts. Upon completion of the placebo-controlled period (Part 1), participants will have the option of enrolling in a 2-year open-label extension (Part 2).

Part 1: The primary objective of the study is to investigate whether treatment with natalizumab slows the accumulation of disability not related to relapses in participants with secondary progressive multiple sclerosis (SPMS).

The secondary objectives of Part 1 of this study are to determine the proportion of participants with consistent improvement in Timed 25-Foot Walk (T25FW), the change in participant-reported ambulatory status as measured by the 12-item MS Walking Scale (MSWS-12), the change in manual ability based on the ABILHAND Questionnaire, the impact of natalizumab on participant-reported quality of life using the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical), the change in whole brain volume between the end of study and Week 24 using magnetic resonance imaging (MRI) and the proportion of participants experiencing progression of disability as measured by individual physical Expanded Disability Status Scale (EDSS) system scores.

Part 2: The primary objective of Part 2 of the study is to evaluate the safety profile of natalizumab in participants with SPMS.

The secondary objectives of Part 2 of the study are to investigate long-term disability (based on clinical or participant-reported assessments) in participants with SPMS receiving natalizumab treatment for approximately 4 years and to assess change in brain volume and T2 lesion volume.


Eligibility criteria: Key Inclusion Criteria (Part 1):

* Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local subject privacy regulations.
* SPMS defined as relapsing-remitting disease followed by progression of disability independent of or not explained by multiple sclerosis (MS) relapses for at least 2 years.
* EDSS score of 3.0 to 6.5, inclusive.
* Multiple Sclerosis Severity Score of 4 or higher.
* Documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide.

Key Exclusion Criteria (Part 1):

* Relapsing remitting multiple sclerosis (RRMS) or primary progressive MS as defined by the revised McDonald Committee criteria.
* Clinical relapse (within 3 months) prior to randomization.
* T25FW test of \>30 seconds during the screening period.
* Any value below the lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils.
* Considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines, or due to prior immunosuppressive or immunomodulating treatment.
* Subjects for whom MRI is contraindicated (i.e., have pacemakers or other contraindicated implanted metal devices, are allergic to gadolinium, or have claustrophobia that cannot be medically managed).
* History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease that would preclude participation in a clinical study.
* History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
* Known history of or positive test result for human immunodeficiency virus.
* Positive test result for hepatitis C virus (test for hepatitis C virus antibody or hepatitis B virus (test for hepatitis B surface antigen and/or hepatitis B core antibody).
* History of transplantation or any anti-rejection therapy.
* Presence of any infectious disease (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening.
* History of progressive multifocal leukoencephalopathy or other opportunistic infections.

Treatment History (Part 1)

* Any prior treatment with cell-depleting therapies, including total lymphoid irradiation, cladribine, rituximab, alemtuzumab, or bone marrow ablation.
* Any prior treatment with natalizumab.
* Treatment with mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, T cell or T cell receptor vaccination, fingolimod, daclizumab, or cytapheresis within 6 months prior to randomization.
* Treatment with intravenous or oral corticosteroids, intravenous immunoglobulin, or plasmapheresis for treatment of MS within the 3 months prior to randomization.
* Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks prior to randomization.
* Treatment with 4-aminopyridine within 30 days prior to randomization, unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study.

Key Inclusion Criteria (Part 2):

* Subjects must have participated in and completed Part 1 per protocol, and have documented assessment attempts for EDSS, T25FW, and 9HPT prior to first open-label dosing.

Key Exclusion Criteria (Part 2):

* Subjects with any significant change in clinical status, including laboratory tests that, in the opinion of the Investigator, would make them unsuitable to participate in this extension study. The Investigator must re-review the subject's medical fitness for participation and consider any diseases that would preclude treatment.
* Subjects who discontinued study treatment in Part 1 OR had fewer than 20 infusions in Part 1 OR missed 2 or more consecutive infusions in Part 1.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Part 1: Percentage of Participants With Confirmed Progression of Disability in One or More of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT)
timeFrame: Up to 96 weeks (2 years)
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 218 weeks
Secondary outcomes:
measure: Part 1: Percentage of Participants With a T25FW Response
timeFrame: Up to 96 weeks
measure: Part 1: Change From Baseline in the 12-Item MS Walking Scale (MSWS-12)
timeFrame: Baseline and Week 96
measure: Part 1: Change From Baseline in Manual Ability Score Based on the ABILHAND Questionnaire
timeFrame: Baseline and Week 96
measure: Part 1: Change From Baseline in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) Score
timeFrame: Baseline and Week 96
measure: Part 1: Percentage Change From Week 24 in Whole Brain Volume at Week 96
timeFrame: Week 24 and Week 96
measure: Part 1: Percentage of Participants Defined as Confirmed Progressors on EDSS Functional System Scores
timeFrame: Up to 96 weeks
measure: Part 2: Percentage of Participants With Disability Worsening at 156 Weeks
timeFrame: Week 156
measure: Part 2: Absolute Change From Baseline (Part 1) in T25FW
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Percentage Change From Baseline (Part 1) in T25FW
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Dominant Hand)
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Dominant Hand)
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Absolute Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Percentage Change From Baseline (Part 1) in 9HPT (Non-Dominant Hand)
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Absolute Change From Baseline (Part 1) in EDSS
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Percentage Change From Baseline (Part 1) in EDSS
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Absolute Change From Baseline (Part 1) in the 6-Minute Walk Test (6MWT)
timeFrame: Baseline (Part 1) and Weeks 156 and 204
measure: Part 2: Percentage Change From Baseline (Part 1) in the 6MWT
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Absolute Change From Baseline (Part 1) in the MSIS-29 Physical Score
timeFrame: Baseline (Part 1) and Weeks 156 and 204
measure: Part 2: Percentage Change From Baseline (Part 1) in the MSIS-29 Physical Score
timeFrame: Baseline (Part 1) and Weeks 156, 204
measure: Part 2: Absolute Change From Baseline (Part 1) in the Symbol Digit Modalities Test (SDMT)
timeFrame: Baseline (Part 1) and every 4 weeks from Week 108 to Week 204
measure: Part 2: Percentage Change From Baseline (Part 1) in the SDMT
timeFrame: Baseline (Part 1) and every 4 weeks from Week 108 to Week 204
measure: Part 2: Absolute Change From Baseline (Part 2) in the Work Productivity and Activity Impairment - Multiple Sclerosis (WPAI-MS) Questionnaire
timeFrame: Part 2 Baseline (Week 108) and Weeks 156 and 204
measure: Part 2: Percentage Change From Baseline (Part 2) in the WPAI-MS Questionnaire
timeFrame: Part 2 Baseline (Week 108) and Weeks 156 and 204
measure: Part 2: Percentage Change From Week 24 (Part 1) in Whole Brain Volume
timeFrame: Week 24 (Part 1) and Weeks 156 and 204
measure: Part 2: Percentage Change From Baseline (Part 1) in Whole Gray Matter Brain Volume
timeFrame: Baseline (Part 1) and Weeks 156 and 204
measure: Part 2: Summary of New/Enlarging T2 Lesion Counts
timeFrame: Baseline (Part 1) up to Week 204
measure: Part 2: Percentage Change From Baseline (Part 1) in Number of New/Enlarging T2 Lesions
timeFrame: Baseline (Part 1) and Weeks 156 and 204
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Research Site
state: Arizona
city: Tucson
country: United States
facility: Research Site
state: Arizona
city: Fullerton
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Lake Barrington
country: United States
facility: Research Site
state: Illinois
city: Peoria
country: United States
facility: Research Site
state: Illinois
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Kansas City
country: United States
facility: Research Site
state: Kansas
city: Lexington
country: United States
facility: Research Site
state: Kentucky
city: Lexington
country: United States
facility: Research Site
state: Kentucky
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Burlington
country: United States
facility: Research Site
state: Massachusetts
city: Omaha
country: United States
facility: Research Site
state: Nebraska
city: Lebanon
country: United States
facility: Research Site
state: New Hampshire
city: Teaneck
country: United States
facility: Research Site
state: New Jersey
city: Latham
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Advance
country: United States
facility: Research Site
state: North Carolina
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Raleigh
country: United States
facility: Research Site
state: North Carolina
city: Akron
country: United States
facility: Research Site
state: Ohio
city: Uniontown
country: United States
facility: Research Site
state: Ohio
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Clackamas
country: United States
facility: Research Site
state: Oregon
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Charlottesville
country: United States
facility: Research Site
state: Virginia
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Green Bay
country: United States
facility: Research Site
state: Wisconsin
city: Milwaukee
country: United States
facility: Research Site
state: Wisconsin
city: La Louviere
country: Belgium
facility: Research Site
city: Melsbroek
country: Belgium
facility: Research Site
city: Overpelt
country: Belgium
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Halifax
country: Canada
facility: Research Site
state: Nova Scotia
city: Kingston
country: Canada
facility: Research Site
state: Ontario
city: London
country: Canada
facility: Research Site
state: Ontario
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Gatineau
country: Canada
facility: Research Site
state: Quebec
city: Greenfield Park
country: Canada
facility: Research Site
state: Quebec
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Hradec Kralove
country: Czechia
facility: Research Site
state: Bohemia
city: Brno
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Praha
country: Czechia
facility: Research Site
city: Arthus C
country: Denmark
facility: Research Site
city: Esbjerg
country: Denmark
facility: Research Site
city: Glostrup
country: Denmark
facility: Research Site
city: København Ø
country: Denmark
facility: Research Site
city: Odense
country: Denmark
facility: Research Site
city: Jyväskylä
country: Finland
facility: Research Site
city: Tampere
country: Finland
facility: Research Site
city: Turku
country: Finland
facility: Research Site
city: Nice
country: France
facility: Research Site
state: Alpes Maritimes
city: Marseille cedex 5
country: France
facility: Research Site
state: Bouches-du-Rhône
city: Nantes
country: France
facility: Research Site
state: Loire Atlantique
city: Nancy
country: France
facility: Research Site
state: Meurthe et Moselle
city: Lille Cedex
country: France
facility: Research Site
state: Nord
city: Bron cedex
country: France
facility: Research Site
state: Rhone
city: Salouel
country: France
facility: Research Site
state: Somme
city: Bordeaux
country: France
facility: Research Site
city: Bad Wilbad
country: Germany
facility: Research Site
state: Baden Wuerttemberg
city: Tuebingen
country: Germany
facility: Research Site
state: Baden Wuerttemberg
city: Bad Mergentheim
country: Germany
facility: Research Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: Research Site
state: Bayern
city: Muenchen
country: Germany
facility: Research Site
state: Bayern
city: Hennigsdorf
country: Germany
facility: Research Site
state: Brandenburg
city: Teupitz
country: Germany
facility: Research Site
state: Brandenburg
city: Kassel
country: Germany
facility: Research Site
state: Hessen
city: Duesseldorf
country: Germany
facility: Research Site
state: Nordrhein Westfalen
city: Muenster
country: Germany
facility: Research Site
state: Nordrhein Westfalen
city: Dresden
country: Germany
facility: Research Site
state: Sachsen
city: Dublin
country: Ireland
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Ramat Gan
country: Israel
facility: Research Site
city: Baggiovara
country: Italy
facility: Research Site
state: Modena
city: Cefalu
country: Italy
facility: Research Site
state: Palermo
city: Gallarate
country: Italy
facility: Research Site
state: Varese
city: Bari
country: Italy
facility: Research Site
city: Florence
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Naples
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Palermo
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Rome
country: Italy
facility: Research Site
city: Rome
country: Italy
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Breda
country: Netherlands
facility: Research Site
city: Hertogenbosch
country: Netherlands
facility: Research Site
city: Hoorn
country: Netherlands
facility: Research Site
city: Nieuwegein
country: Netherlands
facility: Research Site
city: Sittard-Geleen
country: Netherlands
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Lodz
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Olsztyn
country: Poland
facility: Research Site
city: Plewiska
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Warszawa-Miedzylesie
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Belgorod
country: Russian Federation
facility: Research Site
city: Kazan
country: Russian Federation
facility: Research Site
city: Kazan
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: Tyumen
country: Russian Federation
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: El Palmar
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Majadahonda
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Santa Cruz de Tenerife
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Göteborg
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Umeå
country: Sweden
facility: Research Site
city: Örebro
country: Sweden
facility: Research Site
city: Irvine
country: United Kingdom
facility: Research Site
state: Ayrshire
city: Edgbaston
country: United Kingdom
facility: Research Site
state: Birmingham
city: Exeter
country: United Kingdom
facility: Research Site
state: Devon
city: Plymouth
country: United Kingdom
facility: Research Site
state: Devon
city: London
country: United Kingdom
facility: Research Site
state: Greater London
city: London
country: United Kingdom
facility: Research Site
state: Greater London
city: Hammersmith
country: United Kingdom
facility: Research Site
state: London
city: Edinburgh
country: United Kingdom
facility: Research Site
state: Lothian Region
city: Salford
country: United Kingdom
facility: Research Site
state: Manchester
city: Liverpool
country: United Kingdom
facility: Research Site
state: Merseyside
city: Norwich
country: United Kingdom
facility: Research Site
state: Norfolk
city: Nottingham
country: United Kingdom
facility: Research Site
state: Nottinghamshire
city: Morriston
country: United Kingdom
facility: Research Site
state: Swansea
city: Newcastle
country: United Kingdom
facility: Research Site
state: Tyne
city: Brighton
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Beynon V, George IC, Elliott C, Arnold DL, Ke J, Chen H, Zhu L, Ke C, Giovannoni G, Scaramozza M, Campbell N, Bradley DP, Franchimont N, Gafson A, Belachew S. Chronic lesion activity and disability progression in secondary progressive multiple sclerosis. BMJ Neurol Open. 2022 Jun 7;4(1):e000240. doi: 10.1136/bmjno-2021-000240. eCollection 2022.
citation: Koch MW, Mostert J, Zhang Y, Wolinsky JS, Lublin FD, Strijbis E, Cutter G. Association of Age With Contrast-Enhancing Lesions Across the Multiple Sclerosis Disease Spectrum. Neurology. 2021 Sep 28;97(13):e1334-e1342. doi: 10.1212/WNL.0000000000012603. Epub 2021 Aug 10.
citation: Kapoor R, Ho PR, Campbell N, Chang I, Deykin A, Forrestal F, Lucas N, Yu B, Arnold DL, Freedman MS, Goldman MD, Hartung HP, Havrdova EK, Jeffery D, Miller A, Sellebjerg F, Cadavid D, Mikol D, Steiner D; ASCEND investigators. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 2018 May;17(5):405-415. doi: 10.1016/S1474-4422(18)30069-3. Epub 2018 Mar 12.