Glatiramer acetate in primary progressive multiple sclerosis

Results of a multinational, multicenter, double-blind, placebo-controlled trial

Jerry S. Wolinsky, Ponnada A. Narayana, Paul O'Connor, Patricia K. Coyle, Corey Ford, Kenneth Johnson, Aaron Miller, Lillian Pardo, Shaul Kadosh, David Ladkani, Lorne Kastrukoff, Pierre Duquette, Mark Freedman, Marc Debouverie, Catherine Lubetski, Gilles Edan, Etienne Roullet, Christian Confavreux, Alan Thompson, Lance Blumhardt & 60 others Stanley Hawkins, Thomas Scott, Daniel Wynn, Joanna Cooper, Stephen Thurston, Stanton Elias, Clyde Markowitz, David Mattson, John Noseworthy, Elizabeth Shuster, Jonathan Carter, Fred Lublin, William Stuart, Michael Kaufman, Gary Birnbaum, Kottil Rammohan, Ruth Whitham, Cornelia Mihai, Steven Greenberg, Craig Smith, Mark Agius, Stan Van Den Noort, Lawrence Myers, James Nelson, Douglas Goodin, Barry Arnason, Khurram Bashir, Sharon Lynch, Patricia Coyle, Stephen Kamin, William Sheremata, Galen Mitchell, Andrew Goodman, Norman Kachuck, Peter Dunne, J. William Lindsey, Elliot Frohman, James Bowen, Benjamin Brooks, John Rose, Harold Moses, Douglas Jeffrey, Ann Cross, Robert Lisak, Tim Vollmer, Jack Antel, Gary Cutter, Luanne Metz, Henry McFarland, Steven Reingold, Fred D. Lublin, Irina Vainrub, Lucie Lambert, Fengwei Zhong, Jeff Rasmituth, Saria Momin, Rivka Kreitman, Galia Shifroni, Irit Pinchasi, Yafit Stark

Research output: Contribution to journalArticle

Abstract

Objective: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. Methods: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1- (entry expanded disability status scale, 3.0-5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. Results: There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p = 0.0193). Interpretation: The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

Original languageEnglish (US)
Pages (from-to)14-24
Number of pages11
JournalAnnals of Neurology
Volume61
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

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Chronic Progressive Multiple Sclerosis
Placebos
Intention to Treat Analysis
Clinical Trials Data Monitoring Committees
Confidence Intervals
Survival Analysis
Glatiramer Acetate
Therapeutics
Magnetic Resonance Imaging

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Glatiramer acetate in primary progressive multiple sclerosis : Results of a multinational, multicenter, double-blind, placebo-controlled trial. / Wolinsky, Jerry S.; Narayana, Ponnada A.; O'Connor, Paul; Coyle, Patricia K.; Ford, Corey; Johnson, Kenneth; Miller, Aaron; Pardo, Lillian; Kadosh, Shaul; Ladkani, David; Kastrukoff, Lorne; Duquette, Pierre; Freedman, Mark; Debouverie, Marc; Lubetski, Catherine; Edan, Gilles; Roullet, Etienne; Confavreux, Christian; Thompson, Alan; Blumhardt, Lance; Hawkins, Stanley; Scott, Thomas; Wynn, Daniel; Cooper, Joanna; Thurston, Stephen; Elias, Stanton; Markowitz, Clyde; Mattson, David; Noseworthy, John; Shuster, Elizabeth; Carter, Jonathan; Lublin, Fred; Stuart, William; Kaufman, Michael; Birnbaum, Gary; Rammohan, Kottil; Whitham, Ruth; Mihai, Cornelia; Greenberg, Steven; Smith, Craig; Agius, Mark; Van Den Noort, Stan; Myers, Lawrence; Nelson, James; Goodin, Douglas; Arnason, Barry; Bashir, Khurram; Lynch, Sharon; Coyle, Patricia; Kamin, Stephen; Sheremata, William; Mitchell, Galen; Goodman, Andrew; Kachuck, Norman; Dunne, Peter; Lindsey, J. William; Frohman, Elliot; Bowen, James; Brooks, Benjamin; Rose, John; Moses, Harold; Jeffrey, Douglas; Cross, Ann; Lisak, Robert; Vollmer, Tim; Antel, Jack; Cutter, Gary; Metz, Luanne; McFarland, Henry; Reingold, Steven; Lublin, Fred D.; Vainrub, Irina; Lambert, Lucie; Zhong, Fengwei; Rasmituth, Jeff; Momin, Saria; Kreitman, Rivka; Shifroni, Galia; Pinchasi, Irit; Stark, Yafit.

In: Annals of Neurology, Vol. 61, No. 1, 01.2007, p. 14-24.

Research output: Contribution to journalArticle

Wolinsky, JS, Narayana, PA, O'Connor, P, Coyle, PK, Ford, C, Johnson, K, Miller, A, Pardo, L, Kadosh, S, Ladkani, D, Kastrukoff, L, Duquette, P, Freedman, M, Debouverie, M, Lubetski, C, Edan, G, Roullet, E, Confavreux, C, Thompson, A, Blumhardt, L, Hawkins, S, Scott, T, Wynn, D, Cooper, J, Thurston, S, Elias, S, Markowitz, C, Mattson, D, Noseworthy, J, Shuster, E, Carter, J, Lublin, F, Stuart, W, Kaufman, M, Birnbaum, G, Rammohan, K, Whitham, R, Mihai, C, Greenberg, S, Smith, C, Agius, M, Van Den Noort, S, Myers, L, Nelson, J, Goodin, D, Arnason, B, Bashir, K, Lynch, S, Coyle, P, Kamin, S, Sheremata, W, Mitchell, G, Goodman, A, Kachuck, N, Dunne, P, Lindsey, JW, Frohman, E, Bowen, J, Brooks, B, Rose, J, Moses, H, Jeffrey, D, Cross, A, Lisak, R, Vollmer, T, Antel, J, Cutter, G, Metz, L, McFarland, H, Reingold, S, Lublin, FD, Vainrub, I, Lambert, L, Zhong, F, Rasmituth, J, Momin, S, Kreitman, R, Shifroni, G, Pinchasi, I & Stark, Y 2007, 'Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial', Annals of Neurology, vol. 61, no. 1, pp. 14-24. https://doi.org/10.1002/ana.21079
Wolinsky, Jerry S. ; Narayana, Ponnada A. ; O'Connor, Paul ; Coyle, Patricia K. ; Ford, Corey ; Johnson, Kenneth ; Miller, Aaron ; Pardo, Lillian ; Kadosh, Shaul ; Ladkani, David ; Kastrukoff, Lorne ; Duquette, Pierre ; Freedman, Mark ; Debouverie, Marc ; Lubetski, Catherine ; Edan, Gilles ; Roullet, Etienne ; Confavreux, Christian ; Thompson, Alan ; Blumhardt, Lance ; Hawkins, Stanley ; Scott, Thomas ; Wynn, Daniel ; Cooper, Joanna ; Thurston, Stephen ; Elias, Stanton ; Markowitz, Clyde ; Mattson, David ; Noseworthy, John ; Shuster, Elizabeth ; Carter, Jonathan ; Lublin, Fred ; Stuart, William ; Kaufman, Michael ; Birnbaum, Gary ; Rammohan, Kottil ; Whitham, Ruth ; Mihai, Cornelia ; Greenberg, Steven ; Smith, Craig ; Agius, Mark ; Van Den Noort, Stan ; Myers, Lawrence ; Nelson, James ; Goodin, Douglas ; Arnason, Barry ; Bashir, Khurram ; Lynch, Sharon ; Coyle, Patricia ; Kamin, Stephen ; Sheremata, William ; Mitchell, Galen ; Goodman, Andrew ; Kachuck, Norman ; Dunne, Peter ; Lindsey, J. William ; Frohman, Elliot ; Bowen, James ; Brooks, Benjamin ; Rose, John ; Moses, Harold ; Jeffrey, Douglas ; Cross, Ann ; Lisak, Robert ; Vollmer, Tim ; Antel, Jack ; Cutter, Gary ; Metz, Luanne ; McFarland, Henry ; Reingold, Steven ; Lublin, Fred D. ; Vainrub, Irina ; Lambert, Lucie ; Zhong, Fengwei ; Rasmituth, Jeff ; Momin, Saria ; Kreitman, Rivka ; Shifroni, Galia ; Pinchasi, Irit ; Stark, Yafit. / Glatiramer acetate in primary progressive multiple sclerosis : Results of a multinational, multicenter, double-blind, placebo-controlled trial. In: Annals of Neurology. 2007 ; Vol. 61, No. 1. pp. 14-24.
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abstract = "Objective: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. Methods: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1- (entry expanded disability status scale, 3.0-5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. Results: There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95{\%} confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95{\%} confidence interval, 0.53-0.95]; p = 0.0193). Interpretation: The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.",
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TY - JOUR

T1 - Glatiramer acetate in primary progressive multiple sclerosis

T2 - Results of a multinational, multicenter, double-blind, placebo-controlled trial

AU - Wolinsky, Jerry S.

AU - Narayana, Ponnada A.

AU - O'Connor, Paul

AU - Coyle, Patricia K.

AU - Ford, Corey

AU - Johnson, Kenneth

AU - Miller, Aaron

AU - Pardo, Lillian

AU - Kadosh, Shaul

AU - Ladkani, David

AU - Kastrukoff, Lorne

AU - Duquette, Pierre

AU - Freedman, Mark

AU - Debouverie, Marc

AU - Lubetski, Catherine

AU - Edan, Gilles

AU - Roullet, Etienne

AU - Confavreux, Christian

AU - Thompson, Alan

AU - Blumhardt, Lance

AU - Hawkins, Stanley

AU - Scott, Thomas

AU - Wynn, Daniel

AU - Cooper, Joanna

AU - Thurston, Stephen

AU - Elias, Stanton

AU - Markowitz, Clyde

AU - Mattson, David

AU - Noseworthy, John

AU - Shuster, Elizabeth

AU - Carter, Jonathan

AU - Lublin, Fred

AU - Stuart, William

AU - Kaufman, Michael

AU - Birnbaum, Gary

AU - Rammohan, Kottil

AU - Whitham, Ruth

AU - Mihai, Cornelia

AU - Greenberg, Steven

AU - Smith, Craig

AU - Agius, Mark

AU - Van Den Noort, Stan

AU - Myers, Lawrence

AU - Nelson, James

AU - Goodin, Douglas

AU - Arnason, Barry

AU - Bashir, Khurram

AU - Lynch, Sharon

AU - Coyle, Patricia

AU - Kamin, Stephen

AU - Sheremata, William

AU - Mitchell, Galen

AU - Goodman, Andrew

AU - Kachuck, Norman

AU - Dunne, Peter

AU - Lindsey, J. William

AU - Frohman, Elliot

AU - Bowen, James

AU - Brooks, Benjamin

AU - Rose, John

AU - Moses, Harold

AU - Jeffrey, Douglas

AU - Cross, Ann

AU - Lisak, Robert

AU - Vollmer, Tim

AU - Antel, Jack

AU - Cutter, Gary

AU - Metz, Luanne

AU - McFarland, Henry

AU - Reingold, Steven

AU - Lublin, Fred D.

AU - Vainrub, Irina

AU - Lambert, Lucie

AU - Zhong, Fengwei

AU - Rasmituth, Jeff

AU - Momin, Saria

AU - Kreitman, Rivka

AU - Shifroni, Galia

AU - Pinchasi, Irit

AU - Stark, Yafit

PY - 2007/1

Y1 - 2007/1

N2 - Objective: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. Methods: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1- (entry expanded disability status scale, 3.0-5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. Results: There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p = 0.0193). Interpretation: The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

AB - Objective: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. Methods: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1- (entry expanded disability status scale, 3.0-5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. Results: There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p = 0.0193). Interpretation: The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

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