Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing–remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study
Restricted accessResearch articleFirst published online May, 2017
Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing–remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study
The 1-year placebo-controlled (PC) phase of the Glatiramer Acetate Low-Frequency Administration (GALA) study showed that glatiramer acetate 40 mg/mL three times weekly (GA40) significantly reduced annualized relapse rate (ARR) and magnetic resonance imaging (MRI) activity in patients with relapsing–remitting multiple sclerosis. Patients completing the PC phase were invited to an open-label (OL) extension.
Objective:
To evaluate the effects of early start (ES) and delayed start (DS) of GA40 over 3 years.
Methods:
A total of 97.2% of patients completing the PC phase received GA40 in the OL extension. ES (n = 943) patients received GA40 throughout; DS (n = 461) patients received placebo during the PC phase and GA40 during the OL phase. Relapse, MRI, disease progression, and safety were evaluated.
Results:
A total of 1041 patients completed 3 years of follow-up. During the OL phase, ES and DS patients showed comparable ARRs (0.20–0.22) and similar numbers of gadolinium-enhancing T1 (p = 0.49) and new or enlarging T2 lesions (p = 0.51) at Year 3. ES patients showed significantly smaller changes in gray matter volume than DS patients from Months 12 to 36 (mean difference, 0.371%; p = 0.015), with similar trend in whole-brain volume (p = 0.080). Adverse events were mild, consistent with the well-established glatiramer acetate (GA) safety profile.
Conclusion:
GA40 conferred treatment benefit over 3 years: sustained low ARR and lesion activity and favorable safety.
CaporroMDisantoGGobbiC. Two decades of subcutaneous glatiramer acetate injection: Current role of the standard dose, and new high-dose low-frequency glatiramer acetate in relapsing-remitting multiple sclerosis treatment. Patient Prefer Adherence2014; 8: 1123–1134.
2.
BosterABartoszekMPO’ConnellC. Efficacy, safety, and cost-effectiveness of glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis. Ther Adv Neurol Disord2011; 4: 319–332.
3.
Copaxone (Prescribing information). Teva Neuroscience, Inc., Overland Park, KS, January2014.
4.
Data on file. Copaxone exposure. Teva Pharmaceutical Industries Ltd, Netanya, 30June2014.
5.
DevonshireVLapierreYMacdonellR. The Global Adherence Project (GAP): A multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis. Eur J Neurol2011; 18: 69–77.
6.
VerdundiCantognoERussellSSnowT. Understanding and meeting injection device needs in multiple sclerosis: A survey of patient attitudes and practices. Patient Prefer Adherence2011; 5: 173–180.
7.
TreadawayKCutterGSalterA. Factors that influence adherence with disease-modifying therapy in MS. J Neurol2009; 256: 568–576.
8.
Al-SabbaghABennetRKozmaC. Medication gaps in disease modifying therapy for multiple sclerosis are associated with an increased risk of relapse: Findings from a national managed care database. J Neurol2008; 255: S79.
9.
TanHCaiQAgarwalS. Impact of adherence to disease-modifying therapies on clinical and economic outcomes among patients with multiple sclerosis. Adv Ther2011; 28: 51–61.
10.
RemingtonGRodriguezYLoganD. Facilitating medication adherence in patients with multiple sclerosis. Int J MS Care2013; 15: 36–45.
11.
KhanORieckmannPBoykoA. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol2013; 73: 705–713.
12.
ComiGCohenJAArnoldDL. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol2011; 69: 75–82.
13.
ZivadinovRHavrdovaEBergslandN. Thalamic atrophy is associated with development of clinically definite multiple sclerosis. Radiology2013; 268: 831–841.
14.
JenkinsonMBannisterPBradyM. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage2002; 17: 825–841.
15.
ZivadinovRHeininen-BrownMSchirdaCV. Abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: A case-control study. Neuroimage2012; 59: 331–339.
16.
SmithSMZhangYJenkinsonM. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage2002; 17: 479–489.
17.
SmithSMDe StefanoNJenkinsonM. Normalized accurate measurement of longitudinal brain change. J Comput Assist Tomogr2001; 25: 466–475.
18.
DwyerMGBergslandNZivadinovR. Improved longitudinal gray and white matter atrophy assessment via application of a 4-dimensional hidden Markov random field model. Neuroimage2014; 90: 207–217.
19.
PatenaudeBSmithSMKennedyDN. A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage2011; 56: 907–922.
20.
UherTHorakovaDBergslandN. MRI correlates of disability progression in patients with CIS over 48 months. Neuroimage Clin2014; 6: 312–319.
21.
JohnsonKPBrooksBRCohenJA. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology1995; 45: 1268–1276.
22.
ComiGFilippiMWolinskyJS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging—Measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol2001; 49: 290–297.
23.
HealyBCEnglerDGlanzB. Assessment of definitions of sustained disease progression in relapsing-remitting multiple sclerosis. Mult Scler Int2013; 2013: 189624.
24.
ZivadinovRRederATFilippiM. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology2008; 71: 136–144.
25.
De StefanoNAirasLGrigoriadisN. Clinical relevance of brain volume measures in multiple sclerosis. CNS Drugs2014; 28: 147–156.
26.
VollmerTSignorovitchJHuynhL. The natural history of brain volume loss among patients with multiple sclerosis: A systematic literature review and meta-analysis. J Neurol Sci2015; 357: 8–18.
27.
TsivgoulisGKatsanosAHGrigoriadisN. The effect of disease modifying therapies on brain atrophy in patients with relapsing-remitting multiple sclerosis: A systematic review and meta-analysis. PLoS ONE2015; 10: e0116511.
28.
TsivgoulisGKatsanosAHGrigoriadisN. The effect of disease-modifying therapies on brain atrophy in patients with clinically isolated syndrome: A systematic review and meta-analysis. Ther Adv Neurol Disord2015; 8: 193–202.
29.
BrangerPParientiJJSormaniMP. The effect of disease-modifying drugs on brain atrophy in relapsing-remitting multiple sclerosis: A meta-analysis. PLoS ONE2016; 11: e0149685.
30.
SormaniMPRovarisMValsasinaP. Measurement error of two different techniques for brain atrophy assessment in multiple sclerosis. Neurology2004; 62: 1432–1434.
31.
Vidal-JordanaASastre-GarrigaJPerez-MirallesF. Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes. Mult Scler2013; 19: 1175–1181.
32.
WolinskyJSBorresenTEDietrichDW. GLACIER: An open-label, randomized, multicenter study to assess the safety and tolerability of glatiramer acetate 40 mg three-times weekly versus 20 mg daily in patients with relapsing-remitting multiple sclerosis. Mult Scler Relat Disord2015; 4: 370–376.
