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

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Standard

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. / Kapoor, Raju; Ho, Pei-Ran; Campbell, Nolan; Chang, Ih; Deykin, Aaron; Forrestal, Fiona; Lucas, Nisha; Yu, Bei; Arnold, Douglas L; Freedman, Mark S; Goldman, Myla D; Hartung, Hans-Peter; Havrdová, Eva Kubala; Jeffery, Douglas; Miller, Aaron; Sellebjerg, Finn; Cadavid, Diego; Mikol, Dan; Steiner, Deborah; ASCEND investigators.

I: Lancet Neurology, Bind 17, Nr. 5, 2018, s. 405-415.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Kapoor, R, Ho, P-R, Campbell, N, Chang, I, Deykin, A, Forrestal, F, Lucas, N, Yu, B, Arnold, DL, Freedman, MS, Goldman, MD, Hartung, H-P, Havrdová, EK, Jeffery, D, Miller, A, Sellebjerg, F, Cadavid, D, Mikol, D, Steiner, D & ASCEND investigators 2018, '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 Neurology, bind 17, nr. 5, s. 405-415. https://doi.org/10.1016/S1474-4422(18)30069-3

APA

Kapoor, R., Ho, P-R., Campbell, N., Chang, I., Deykin, A., Forrestal, F., Lucas, N., Yu, B., Arnold, D. L., Freedman, M. S., Goldman, M. D., Hartung, H-P., Havrdová, E. K., Jeffery, D., Miller, A., Sellebjerg, F., Cadavid, D., Mikol, D., Steiner, D., & ASCEND investigators (2018). 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 Neurology, 17(5), 405-415. https://doi.org/10.1016/S1474-4422(18)30069-3

Vancouver

Kapoor R, Ho P-R, Campbell N, Chang I, Deykin A, Forrestal F o.a. 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 Neurology. 2018;17(5):405-415. https://doi.org/10.1016/S1474-4422(18)30069-3

Author

Kapoor, Raju ; Ho, Pei-Ran ; Campbell, Nolan ; Chang, Ih ; Deykin, Aaron ; Forrestal, Fiona ; Lucas, Nisha ; Yu, Bei ; Arnold, Douglas L ; Freedman, Mark S ; Goldman, Myla D ; Hartung, Hans-Peter ; Havrdová, Eva Kubala ; Jeffery, Douglas ; Miller, Aaron ; Sellebjerg, Finn ; Cadavid, Diego ; Mikol, Dan ; Steiner, Deborah ; 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. I: Lancet Neurology. 2018 ; Bind 17, Nr. 5. s. 405-415.

Bibtex

@article{2b396f6cf0154103aad2512324ca013a,
title = "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",
abstract = "BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.",
keywords = "Adolescent, Adult, Disease Progression, Double-Blind Method, Female, Hand/physiopathology, Humans, Immunologic Factors/administration & dosage, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive/drug therapy, Natalizumab/administration & dosage, Outcome Assessment (Health Care), Research Design, Severity of Illness Index, Young Adult",
author = "Raju Kapoor and Pei-Ran Ho and Nolan Campbell and Ih Chang and Aaron Deykin and Fiona Forrestal and Nisha Lucas and Bei Yu and Arnold, {Douglas L} and Freedman, {Mark S} and Goldman, {Myla D} and Hans-Peter Hartung and Havrdov{\'a}, {Eva Kubala} and Douglas Jeffery and Aaron Miller and Finn Sellebjerg and Diego Cadavid and Dan Mikol and Deborah Steiner and {ASCEND investigators}",
note = "Copyright {\textcopyright} 2018 Elsevier Ltd. All rights reserved.",
year = "2018",
doi = "10.1016/S1474-4422(18)30069-3",
language = "English",
volume = "17",
pages = "405--415",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "TheLancet Publishing Group",
number = "5",

}

RIS

TY - JOUR

T1 - Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND)

T2 - a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

AU - Kapoor, Raju

AU - Ho, Pei-Ran

AU - Campbell, Nolan

AU - Chang, Ih

AU - Deykin, Aaron

AU - Forrestal, Fiona

AU - Lucas, Nisha

AU - Yu, Bei

AU - Arnold, Douglas L

AU - Freedman, Mark S

AU - Goldman, Myla D

AU - Hartung, Hans-Peter

AU - Havrdová, Eva Kubala

AU - Jeffery, Douglas

AU - Miller, Aaron

AU - Sellebjerg, Finn

AU - Cadavid, Diego

AU - Mikol, Dan

AU - Steiner, Deborah

AU - ASCEND investigators

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

PY - 2018

Y1 - 2018

N2 - BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

AB - BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

KW - Adolescent

KW - Adult

KW - Disease Progression

KW - Double-Blind Method

KW - Female

KW - Hand/physiopathology

KW - Humans

KW - Immunologic Factors/administration & dosage

KW - Male

KW - Middle Aged

KW - Multiple Sclerosis, Chronic Progressive/drug therapy

KW - Natalizumab/administration & dosage

KW - Outcome Assessment (Health Care)

KW - Research Design

KW - Severity of Illness Index

KW - Young Adult

U2 - 10.1016/S1474-4422(18)30069-3

DO - 10.1016/S1474-4422(18)30069-3

M3 - Journal article

C2 - 29545067

VL - 17

SP - 405

EP - 415

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 5

ER -

ID: 218516306