Efficacy and safety of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: Further outcomes from the IMPROVE study

8BACKGROUND: The IMPROVE study demonstrated that the fetal bovine serum (FBS)- and human serum albumin (HSA)-free formulation of subcutaneous (sc) interferon (IFN) beta-1a had beneficial effects on the numbers of combined unique active magnetic resonance imaging (MRI) lesions in relapsing-remitting multiple sclerosis (RRMS). Here we report additional MRI endpoints (including post hoc analyses), and clinical efficacy, safety, and immunogenicity outcomes. METHODS: Patients with active RRMS were randomized (2:1) to IFN beta-1a, 44 mcg sc three times weekly (tiw) (n=120), or placebo (n=60), for 16 weeks (double-blind phase). All patients then received IFN beta-1a, 44 mcg sc tiw, for 24 weeks (rater-blind phase). Patients underwent MRI brain scans every 4 weeks. RESULTS: Compared with placebo, there was a 68% reduction in the mean cumulative number of new gadolinium-enhancing lesions with IFN beta-1a as early as week 4 (p<0.001), and a 53% reduction in the mean cumulative number of new T2 lesions as early as week 8 (p=0.025; post hoc analyses). During the 16-week double-blind phase, the relapse rate was 0.14 (95% confidence interval [CI] 0.09-0.23) with IFN beta-1a and 0.33 (95% CI 0.22-0.52) with placebo (p=0.010). Safety outcomes were consistent with those expected with IFN-beta treatment. CONCLUSIONS: The FBS/HSA-free formulation of sc IFN beta-1a has a beneficial impact on MRI and efficacy outcomes as early as 4 weeks after treatment initiation in patients with RRMS and has a safety profile consistent with previous trials of sc IFN beta-1a.reservedmixedDE STEFANO, Nicola; Sormani, Mp; Stubinski, B; Blevins, G; Drulovic, Js; Issard, D; Shotekov, P; Gasperini, C.DE STEFANO, Nicola; Sormani, Mp; Stubinski, B; Blevins, G; Drulovic, Js; Issard, D; Shotekov, P; Gasperini, C

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

reserved328Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS.Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3.0-6.5 were randomly assigned (2: 1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials. gov, number NCT01665144.Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years (SD 8.3), and the mean time since conversion to SPMS was 3.8 years (SD 3.5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0.79, 95% CI 0.65-0.95; relative risk reduction 21%; p=0.013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.mixedKappos L.; Bar-Or A.; Cree B.A.C.; Fox R.J.; Giovannoni G.; Gold R.; Vermersch P.; Arnold D.L.; Arnould S.; Scherz T.; Wolf C.; Wallstrom E.; Dahlke F.; Achiron A.; Achtnichts L.; Agan K.; Akman-Demir G.; Allen A.B.; Antel J.P.; Antiguedad A.R.; Apperson M.; Applebee A.M.; Ayuso G.I.; Baba M.; Bajenaru O.; Balasa R.; Balci B.P.; Barnett M.; Bass A.; Becker V.U.; Bejinariu M.; Bergh F.T.; Bergmann A.; Bernitsas E.; Berthele A.; Bhan V.; Bischof F.; Bjork R.J.; Blevins G.; Boehringer M.; Boerner T.; Bonek R.; Bowen J.D.; Bowling A.; Boyko A.N.; Boz C.; Bracknies V.; Braune S.; Brescia Morra V.; Brochet B.; Brola W.; Brownstone P.K.; Brozman M.; Brunet D.; Buraga I.; Burnett M.; Buttmann M.; Butzkueven H.; Cahill J.; Calkwood J.C.; Camu W.; Cascione M.; Castelnovo G.; Centonze D.; Cerqueira J.; Chan A.; Cimprichova A.; Cohan S.; Comi G.; Conway J.; Cooper J.A.; Corboy J.; Correale J.; Costell B.; Cottrell D.A.; Coyle P.K.; Craner M.; Cui L.; Cunha L.; Czlonkowska A.; da Silva A.M.; de Sa J.; de Seze J.; Debouverie M.; Debruyne J.; Decoo D.; Defer G.; Derfuss T.; Deri N.H.; Dihenia B.; Dioszeghy P.; Donath V.; Dubois B.; Duddy M.; Duquette P.; Edan G.; Efendi H.; Elias S.; Emrich P.J.; Estruch B.C.; Evdoshenko E.P.; Faiss J.; Fedyanin A.S.; Feneberg W.; Fermont J.; Fernandez O.F.; Ferrer F.C.; Fink K.; Ford H.; Ford C.; Francia A.; Freedman M.; Frishberg B.; Galgani S.; Garmany G.P.; Gehring K.; Gitt J.; Gobbi C.; Goldstick L.P.; Gonzalez R.A.; Grandmaison F.; Grigoriadis N.; Grigorova O.; Grimaldi L.M.E.; Gross J.; Gross-Paju K.; Gudesblatt M.; Guillaume D.; Haas J.; Hancinova V.; Hancu A.; Hardiman O.; Harmjanz A.; Heidenreich F.R.; Hengstman G.J.D.; Herbert J.; Herring M.; Hodgkinson S.; Hoffmann O.M.; Hofmann W.E.; Honeycutt W.D.; Hua L.H.; Huang D.; Huang Y.; Huang D.; Hupperts R.; Imre P.; Jacobs A.K.; Jakab G.; Jasinska E.; Kaida K.; Kalnina J.; Kaprelyan A.; Karelis G.; Karussis D.; Katz A.; Khabirov F.A.; Khatri B.; Kimura T.; Kister I.; Kizlaitiene R.; Klimova E.; Koehler J.; Komatineni A.; Kornhuber A.; Kovacs K.; Koves A.; Kozubski W.; Krastev G.; Krupp L.B.; Kurca E.; Lassek C.; Laureys G.; Lee L.; Lensch E.; Leutmezer F.; Li H.; Linker R.A.; Linnebank M.; Liskova P.; Llanera C.; Lu J.; Lutterotti A.; Lycke J.; Macdonell R.; Maciejowski M.; Maeurer M.; Magzhanov R.V.; Maida E.-M.; Malciene L.; Mao-Draayer Y.; Marfia G.A.; Markowitz C.; Mastorodimos V.; Matyas K.; Meca-Lallana J.; Merino J.A.G.; Mihetiu I.G.; Milanov I.; Miller A.E.; Millers A.; Mirabella M.; Mizuno M.; Montalban X.; Montoya L.; Mori M.; Mueller S.; Nakahara J.; Nakatsuji Y.; Newsome S.; Nicholas R.; Nielsen A.S.; Nikfekr E.; Nocentini U.; Nohara C.; Nomura K.; Odinak M.M.; Olsson T.; van Oosten B.W.; Oreja-Guevara C.; Oschmann P.; Overell J.; Pachner A.; Panczel G.; Pandolfo M.; Papeix C.; Patrucco L.; Pelletier J.; Piedrabuena R.; Pless M.; Polzer U.; Pozsegovits K.; Rastenyte D.; Rauer S.; Reifschneider G.; Rey R.; Rizvi S.A.; Robertson D.; Rodriguez J.M.; Rog D.; Roshanisefat H.; Rowe V.; Rozsa C.; Rubin S.; Rusek S.; Sacca F.; Saida T.; Salgado A.V.; Sanchez V.E.F.; Sanders K.; Satori M.; Sazonov D.V.; Scarpini E.A.; Schlegel E.; Schluep M.; Schmidt S.; Scholz E.; Schrijver H.M.; Schwab M.; Schwartz R.; Scott J.; Selmaj K.; Shafer S.; Sharrack B.; Shchukin I.A.; Shimizu Y.; Shotekov P.; Siever A.; Sigel K.-O.; Silliman S.; Simo M.; Simu M.; Sinay V.; Siquier A.E.; Siva A.; Skoda O.; Solomon A.; Stangel M.; Stefoski D.; Steingo B.; Stolyarov I.D.; Stourac P.; Strassburger-Krogias K.; Strauss E.; Stuve O.; Tarnev I.; Tavernarakis A.; Tello C.R.; Terzi M.; Ticha V.; Ticmeanu M.; Tiel-Wilck K.; Toomsoo T.; Tubridy N.; Tullman M.J.; Tumani H.; Turcani P.; Turner B.; Uccelli A.; Urtaza F.J.O.; Vachova M.; Valikovics A.; Walter S.; Van Wijmeersch B.; Vanopdenbosch L.; Weber J.R.; Weiss S.; Weissert R.; Vermersch P.; West T.; Wiendl H.; Wiertlewski S.; Wildemann B.; Willekens B.; Visser L.H.; Vorobeychik G.; Xu X.; Yamamura T.; Yang Y.N.; Yelamos S.M.; Yeung M.; Zacharias A.; Zelkowitz M.; Zettl U.; Zhang M.; Zhou H.; Zieman U.; Ziemssen T.Kappos, L.; Bar-Or, A.; Cree, B. A. C.; Fox, R. J.; Giovannoni, G.; Gold, R.; Vermersch, P.; Arnold, D. L.; Arnould, S.; Scherz, T.; Wolf, C.; Wallstrom, E.; Dahlke, F.; Achiron, A.; Achtnichts, L.; Agan, K.; Akman-Demir, G.; Allen, A. B.; Antel, J. P.; Antiguedad, A. R.; Apperson, M.; Applebee, A. M.; Ayuso, G. I.; Baba, M.; Bajenaru, O.; Balasa, R.; Balci, B. P.; Barnett, M.; Bass, A.; Becker, V. U.; Bejinariu, M.; Bergh, F. T.; Bergmann, A.; Bernitsas, E.; Berthele, A.; Bhan, V.; Bischof, F.; Bjork, R. J.; Blevins, G.; Boehringer, M.; Boerner, T.; Bonek, R.; Bowen, J. D.; Bowling, A.; Boyko, A. N.; Boz, C.; Bracknies, V.; Braune, S.; Brescia Morra, V.; Brochet, B.; Brola, W.; Brownstone, P. K.; Brozman, M.; Brunet, D.; Buraga, I.; Burnett, M.; Buttmann, M.; Butzkueven, H.; Cahill, J.; Calkwood, J. C.; Camu, W.; Cascione, M.; Castelnovo, G.; Centonze, D.; Cerqueira, J.; Chan, A.; Cimprichova, A.; Cohan, S.; Comi, G.; Conway, J.; Cooper, J. A.; Corboy, J.; Correale, J.; Costell, B.; Cottrell, D. A.; Coyle, P. K.; Craner, M.; Cui, L.; Cunha, L.; Czlonkowska, A.; da Silva, A. M.; de Sa, J.; de Seze, J.; Debouverie, M.; Debruyne, J.; Decoo, D.; Defer, G.; Derfuss, T.; Deri, N. H.; Dihenia, B.; Dioszeghy, P.; Donath, V.; Dubois, B.; Duddy, M.; Duquette, P.; Edan, G.; Efendi, H.; Elias, S.; Emrich, P. J.; Estruch, B. C.; Evdoshenko, E. P.; Faiss, J.; Fedyanin, A. S.; Feneberg, W.; Fermont, J.; Fernandez, O. F.; Ferrer, F. C.; Fink, K.; Ford, H.; Ford, C.; Francia, A.; Freedman, M.; Frishberg, B.; Galgani, S.; Garmany, G. P.; Gehring, K.; Gitt, J.; Gobbi, C.; Goldstick, L. P.; Gonzalez, R. A.; Grandmaison, F.; Grigoriadis, N.; Grigorova, O.; Grimaldi, L. M. E.; Gross, J.; Gross-Paju, K.; Gudesblatt, M.; Guillaume, D.; Haas, J.; Hancinova, V.; Hancu, A.; Hardiman, O.; Harmjanz, A.; Heidenreich, F. R.; Hengstman, G. J. D.; Herbert, J.; Herring, M.; Hodgkinson, S.; Hoffmann, O. M.; Hofmann, W. E.; Honeycutt, W. D.; Hua, L. H.; Huang, D.; Huang, Y.; Huang, D.; Hupperts, R.; Imre, P.; Jacobs, A. K.; Jakab, G.; Jasinska, E.; Kaida, K.; Kalnina, J.; Kaprelyan, A.; Karelis, G.; Karussis, D.; Katz, A.; Khabirov, F. A.; Khatri, B.; Kimura, T.; Kister, I.; Kizlaitiene, R.; Klimova, E.; Koehler, J.; Komatineni, A.; Kornhuber, A.; Kovacs, K.; Koves, A.; Kozubski, W.; Krastev, G.; Krupp, L. B.; Kurca, E.; Lassek, C.; Laureys, G.; Lee, L.; Lensch, E.; Leutmezer, F.; Li, H.; Linker, R. A.; Linnebank, M.; Liskova, P.; Llanera, C.; Lu, J.; Lutterotti, A.; Lycke, J.; Macdonell, R.; Maciejowski, M.; Maeurer, M.; Magzhanov, R. V.; Maida, E. -M.; Malciene, L.; Mao-Draayer, Y.; Marfia, G. A.; Markowitz, C.; Mastorodimos, V.; Matyas, K.; Meca-Lallana, J.; Merino, J. A. G.; Mihetiu, I. G.; Milanov, I.; Miller, A. E.; Millers, A.; Mirabella, M.; Mizuno, M.; Montalban, X.; Montoya, L.; Mori, M.; Mueller, S.; Nakahara, J.; Nakatsuji, Y.; Newsome, S.; Nicholas, R.; Nielsen, A. S.; Nikfekr, E.; Nocentini, U.; Nohara, C.; Nomura, K.; Odinak, M. M.; Olsson, T.; van Oosten, B. W.; Oreja-Guevara, C.; Oschmann, P.; Overell, J.; Pachner, A.; Panczel, G.; Pandolfo, M.; Papeix, C.; Patrucco, L.; Pelletier, J.; Piedrabuena, R.; Pless, M.; Polzer, U.; Pozsegovits, K.; Rastenyte, D.; Rauer, S.; Reifschneider, G.; Rey, R.; Rizvi, S. A.; Robertson, D.; Rodriguez, J. M.; Rog, D.; Roshanisefat, H.; Rowe, V.; Rozsa, C.; Rubin, S.; Rusek, S.; Sacca, F.; Saida, T.; Salgado, A. V.; Sanchez, V. E. F.; Sanders, K.; Satori, M.; Sazonov, D. V.; Scarpini, E. A.; Schlegel, E.; Schluep, M.; Schmidt, S.; Scholz, E.; Schrijver, H. M.; Schwab, M.; Schwartz, R.; Scott, J.; Selmaj, K.; Shafer, S.; Sharrack, B.; Shchukin, I. A.; Shimizu, Y.; Shotekov, P.; Siever, A.; Sigel, K. -O.; Silliman, S.; Simo, M.; Simu, M.; Sinay, V.; Siquier, A. E.; Siva, A.; Skoda, O.; Solomon, A.; Stangel, M.; Stefoski, D.; Steingo, B.; Stolyarov, I. D.; Stourac, P.; Strassburger-Krogias, K.; Strauss, E.; Stuve, O.; Tarnev, I.; Tavernarakis, A.; Tello, C. R.; Terzi, M.; Ticha, V.; Ticmeanu, M.; Tiel-Wilck, K.; Toomsoo, T.; Tubridy, N.; Tullman, M. J.; Tumani, H.; Turcani, P.; Turner, B.; Uccelli, A.; Urtaza, F. J. O.; Vachova, M.; Valikovics, A.; Walter, S.; Van Wijmeersch, B.; Vanopdenbosch, L.; Weber, J. R.; Weiss, S.; Weissert, R.; Vermersch, P.; West, T.; Wiendl, H.; Wiertlewski, S.; Wildemann, B.; Willekens, B.; Visser, L. H.; Vorobeychik, G.; Xu, X.; Yamamura, T.; Yang, Y. N.; Yelamos, S. M.; Yeung, M.; Zacharias, A.; Zelkowitz, M.; Zettl, U.; Zhang, M.; Zhou, H.; Zieman, U.; Ziemssen, T

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.Journal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial

Background: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke or other cardiovascular events. We compared the selective thromboxane-prostaglandin receptor antagonist terutroban with aspirin in the prevention of cerebral and cardiovascular ischaemic events in patients with a recent non-cardioembolic cerebral ischaemic event. &lt;p/&gt;Methods: This randomised, double-blind, parallel-group trial was undertaken in 802 centres in 46 countries. Patients who had an ischaemic stroke in the previous 3 months or a TIA in the previous 8 days were randomly allocated with a central interactive response system to 30 mg per day terutroban or 100 mg per day aspirin. Patients and investigators were masked to treatment allocation. The primary efficacy endpoint was a composite of fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (excluding haemorrhagic death). We planned a sequential statistical analysis of non-inferiority (margin 1·05) followed by analysis of superiority. Analysis was by intention to treat. The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee. This study is registered, number ISRCTN66157730. &lt;p/&gt;Findings: 9562 patients were assigned to terutroban (9556 analysed) and 9558 to aspirin (9544 analysed); mean follow-up was 28·3 months (SD 7·7). The primary endpoint occurred in 1091 (11%) patients receiving terutroban and 1062 (11%) receiving aspirin (hazard ratio [HR] 1·02, 95% CI 0·94–1·12). There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints. We recorded some increase in minor bleedings with terutroban compared with aspirin (1147 [12%] vs 1045 [11%]; HR 1·11, 95% CI 1·02–1·21), but no significant differences in other safety endpoints. &lt;p/&gt;Interpretation: The trial did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban. In a worldwide perspective, aspirin remains the gold standard antiplatelet drug for secondary stroke prevention in view of its efficacy, tolerance, and cost

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

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