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Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

Brown, J William L; Coles, Alasdair; Horakova, Dana; Havrdova, Eva; Izquierdo, Guillermo; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Trojano, Maria; Lugaresi, Alessandra; Bergamaschi, Roberto; Grammond, Pierre; Alroughani, Raed; Hupperts, Raymond; McCombe, Pamela; Van Pesch, Vincent; Sola, Patrizia; Ferraro, Diana; Grand'Maison, Francois; Terzi, Murat; Lechner-Scott, Jeannette; Flechter, Schlomo; Slee, Mark; Shaygannejad, Vahid; Pucci, Eugenio; Granella, Franco; Jokubaitis, Vilija; Willis, Mark; Rice, Claire; Scolding, Neil; Wilkins, Alastair; Pearson, Owen R; Ziemssen, Tjalf; Hutchinson, Michael; Harding, Katharine; Jones, Joanne; McGuigan, Christopher; Butzkueven, Helmut; Kalincik, Tomas; Robertson, Neil
Importance:Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. Objective:To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. Design, Setting, and Participants:Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. Exposures:The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). Main Outcome and Measure:Conversion to objectively defined secondary progressive MS. Results:Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance:Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.
PMID: 30644981
ISSN: 1538-3598
CID: 4269602

Neural correlates of abnormal sensory discrimination in laryngeal dystonia

Termsarasab, Pichet; Ramdhani, Ritesh A; Battistella, Giovanni; Rubien-Thomas, Estee; Choy, Melissa; Farwell, Ian M; Velickovic, Miodrag; Blitzer, Andrew; Frucht, Steven J; Reilly, Richard B; Hutchinson, Michael; Ozelius, Laurie J; Simonyan, Kristina
Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder.
PMCID:4660380
PMID: 26693398
ISSN: 2213-1582
CID: 2041932

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Miller, David H; Fox, Robert J; Phillips, J Theodore; Hutchinson, Michael; Havrdova, Eva; Kita, Mariko; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; MacManus, David G; Yousry, Tarek A; Goodsell, Mary; Yang, Minhua; Zhang, Ray; Viglietta, Vissia; Dawson, Katherine T; Wilson, Kate; Antel, Jack; Ware, James; Polman, Chris; Kowey, Peter R; Chung, Raymond; Bakris, George; Richert, John; Seibert, Burt; Brandes, David; Brassat, David; Cohen, Bruce; Diem, Ricarda; Goldman, Myla; Herndon, Robert; Miller, Aaron; Tumani, Hayrettin; Alfaro-Vidal, Teresa; Crespo, Carolina; Foster, Jo; Hunter, Kelvin; Garcia-Gomez, Almudena; Santana, Virginia; Kneebone, Christopher; Fedulau, Aliaksandr; Likhachev, Sergey; Mikhailova, Elena; Naumova, Halina; Decoo, Danny; Gaer, Luc Vande; Sindic, Christian; Grgic, Sanja; Sinanovic, Osman; Suljic, Enra Mehmedika; Deleva, Nadezhda; Georgiev, Dimitar; Haralanov, Lyubomir; Ivanova, Sonyia; Manchev, Ivan; Minchev, Dimitar; Stamenova, Paraskeva; Tournev, Ivailo; Vacheva, Elena; Zahariev, Zahari; Bar-Or, Amit; Blevins, Gregg; Kremenchutzky, Marcelo; Veloso, Felix; Witt, Norbert; Vargas Howell, Roberto; Vindas, Alexander Parajeles; Habek, Mario; Rudež, Josip; Soldo-Butković, Silva; Vurdelja, Ranka Baraba; Doležil, David; Havrdova, Eva; Nova'k, Jiří; Vaclavik, Daniel; Antsov, Katrin; Gross-Paju, Katrin; Haldre, Sulev; Palu, Alla; Toomsoo, Toomas; Al Khedr, Abdullatif; Camu, William; Debouverie, Marc; Defer, Gilles; De Seze, Jérôme; Labauge, Pierre; Moreau, Thibault; Pelletier, Jean; Rumbach, Lucien; Daskalovska, Vera; Angnstwurm, Klemens; Benes, Heike; Berthele, Achim; Boldt, Hans-Jürgen; Christopher, Angelika; Derfuß, Tobias; Eisensehr, Ilonka; Emrich, Peter; Feneberg, Wolfgang; Hoffmann, Frank; Hohlfeld, Reinhard; Hüntemann, Reinhard; Kallmann, Boris-Alexander; Kieseier, Bernd; Landefeld, Harald; Lüer, Wilfried; Masri, Sabine; Nelles, Gereon; Oschmann, Patrick; Paschen, Christine; Reifschneider, Gerd; Sailer, Michael; Schimrigk, Sebastian; Spiegel-Meixensberger, Mechthild; Storch-Hagenlocher, Brigitte; Tackenberg, Björn; Tiel-Wilck, Klaus; Karageorgiou, Clementine; Papathanasopoulos, Panagiotis; Thomaides, Thomas; Vlaikidis, Nicholas; Arjundas, Deepak; Behari, Madhuri; Ghosh, Amitabha; Ghosh, Pahari; Ichaporia, Nasli Rustom; Khurana, Dheeraj; Kulkarni, Rahul Vitthal; Kumar, Suresh; Mehndiratta, Man Mohan; Mehta, Neeta Abhay; Misra, Usha Kant; Mukherji, Joy Dev; Nellikunja, Shankara; Salem, Abdul; Sethi, Prahlad Kumar; Shah, Shalin Dipinkumar; Singh, Gagandeep; Singh, Maneesh Kumar; Singh, Yash Pal; Srinivasa, Rangasetty; Vijayan, Krishnan; Sweeney, Bernard; Gilad, Ronit; Shahien, Radi; Paegle, Anita; Delgado, Cesar; Escamilla, Juan; Estañol, Bruno; Lopez, Minerva; Macias, Miguel Angel; Punzo, Guillermo; Quiñones, Sandra; Renteria, Mariela; Santos, Jose; Gavriliuc, Mihail; Groppa, Stanislav; Odainic, Olesea; Timmings, Paul; Czlonkowska, Anna; Dorobek, Malgorzata; Drozdowski, Wieslaw; Fryze, Waldemar; Hertmanowska, Hanka; Kaminska, Anna; Kapelusiak-Pielok, Magdalena; Kleczkowska, Magdalena; Kochanowicz, Jan; Losy, Jacek; Nowacki, Przemyslaw; Nyka, Walenty; Pierzchala, Krystyna; Podemski, Ryszard; Potemkowski, Andrzej; Selmaj, Krzysztof; Stelmasiak, Zbigniew; Szczudlik, Andrzej; Tutaj, Andrzej; Wajgt, Andrzej; Zielinski, Tomasz; Balasa, Rodica; Ionescu-Dimancea, Valentin; Mihancea, Petru; Popescu, Cristian; Protosevici, Liviu Codrut; Miletić Drakulić, Svetlana; Nadj, Congor; Raicevic, Ranko; Vojinovic, Slobodan; Kahancová, Edita; Kurca, Egon; Lisý, L'ubomir; Turčáni, Peter; Arroyo, Rafael; Fernández, Oscar; Guijarro, Cristina; Izquierdo, Guillermo; Lopez, Fernando Sanchez; Montalbán, Xavier; Oreja-Guevara, Celia; Prieto, Jose Maria; Buchakchyys'ka, Nataliya; Chmyr, Galyna; Goloborodko, Alla; Kobys, Tetyana; Kushnir, Grygory; Lebedynets, Volodymyr; Lytvynenko, Nataliya; Moskovko, Sergii; Nehrych, Tetyana; Palamar, Borys; Pasyura, Igor; Ryabichenko, Tatyana; Voloshina, Nataliya; Apperson, Michelle; Applebee, Angela; Asher, Stephen; Ayala, Ricardo; Ayres, Donald; Azizi, S Ausim; Baker, Matthew; Bauer, Brendan; Bomprezzi, Roberto; Buckler, Richard; Carlini, Walter; Chinea, Angel; Cohan, Stanley; Crowell, Giles; Edwards, Keith; Eubank, Geoffery; Felton, Warren 3rd; Fodor, Patricia; Foley, John; Ford, Corey; Fox, Edward; Fox, Robert; Forester, Mary; Freedman, Steven; Garmany, George Jr; Gazda, Suzanne; Giang, Daniel; Glaun, Braeme; Gold, Scott; Gottesman, Malcolm; Gudesblatt, Mark; Herbert, Joseph; Herskowitz, Allan; Honeycutt, William; Huddlestone, John; Hull, Richard; Hunter, Samuel; Hutton, George; Jacobs, Dina; Janicki, Mark; Khatri, Bhupendra; Kinkel, Revere Philip; Kita, Mariko; Krolczyk, Stanley; Krupp, Lauren; LaGanke, Christopher; Levin, Michael; Licht, Jonathan; Luzzio, Christopher; Lynch, Sharon; Mattson, David; Mikol, Daniel; Miller, Tamara; Minagar, Alireza; Mitchell, Galen; Moses, Harold Jr; Negroski, Donald; Newman, Stephen; Pardo, Gabriel; Patel, Malti; Perel, Allan; Phillips, Joseph Jr; Picone, Mary Ann; Rammohan, Kottil; Rao, T Hemanth; Rinker, John 2nd; Sadiq, Saud; Schaeffer, John; Sheremata, William; Shin, Robert; Shubin, Richard; Silverman, Stuart; Smith, Robert; Stein, Lee; Stein, Michael; Steiner, David; Steingo, Brian; Sullivan, Herman; Sunter, William Jr; Vaishnav, Anand; Vasquez, Alberto; Voci, James; Warach, Jonathan; Weinstock-Guttman, Bianca; Williams, Mitzi; Wray, Sibyl
OBJECTIVE:To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. METHODS:CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). RESULTS:DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. CONCLUSIONS:The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.
PMCID:4371413
PMID: 25681448
ISSN: 1526-632x
CID: 5348212

Spin-Lattice Distribution MRI Maps Nigral Pathology in Progressive Supranuclear Palsy (PSP) during Life: A Pilot Study

Hutchinson, Michael; Raff, Ulrich; Chana, Pedro; Huete, Isidro
An MRI biomarker for Parkinsonism has long been sought, but almost all attempts at conventional field strengths have proved unsatisfactory, since patients and controls are not separated. The exception is Spin-Lattice Distribution MRI (SLD-MRI), a technique which detects changes in the substantia nigra (SN) due to changes in the spin-lattice relaxation time, T1. This easily separates patients with Parkinson's disease (PD) from control subjects at 1.5 Tesla, suggesting that it may be sensitive to presymptomatic disease. SLD-MRI demonstrates a topography of signal change within the SN which is the same as the known topography of pathological change, where the lateral portions of the nucleus are more affected than the medial. In a further step towards its validation, we apply SLD-MRI to a disease control, Progressive Supranuclear Palsy (PSP), the most common of the atypical forms of Parkinsonism. In PSP the topography of pathological change in the SN is reversed. We therefore hypothesized that PSP would show a topography of SLD-MRI signal change in the SN that is the reverse of PD (i.e. the medial portion is more affected than the lateral). All 7 patients showed such a topography of MR signal, and all patients were separated from control subjects. Although this is a step toward validation of SLD-MRI with respect to sensitivity and disease specificity, nevertheless we stress that this is a pilot project only. Validation will only be possible when comparing larger cohorts of PSP, PD and control subjects.
PMCID:3904838
PMID: 24489655
ISSN: 1932-6203
CID: 800102

Reply

Hutchinson, Michael; Rowe, Elizabeth S
PMID: 24059409
ISSN: 0361-803x
CID: 542872

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis

Fox, Robert J; Miller, David H; Phillips, J Theodore; Hutchinson, Michael; Havrdova, Eva; Kita, Mariko; Yang, Minhua; Raghupathi, Kartik; Novas, Mark; Sweetser, Marianne T; Viglietta, Vissia; Dawson, Katherine T; Antel, Jack; Ware, James; Polman, Chris; Kowey, Peter R; Chung, Raymond; Bakris, George; Richert, John; Seibert, Burt; Brandes, David; Brassat, David; Cohen, Bruce; Diem, Ricarda; Goldman, Myla; Herndon, Robert; Miller, Aaron; Tumani, Hayrettin; Alfaro-Vidal, Teresa; Crespo, Carolina; Foster, Jo; Hunter, Kelvin; Garcia-Gomez, Almudena; MacManus, David; Miller, David; Santana, Virginia; Tozer, Dan; Kingshott-Wheeler, Claudia; Yousry, Tarek; Kneebone, Christopher; Fedulau, Aliaksandr; Mikhailova, Elena; Likhachev, Sergey; Naumova, Halina; Vande Gaer, Luc; Decoo, Danny; Sindic, Christian; Grgic, Sanja; Sinanovic, Osman; Suljic, Enra Mehmedika; Georgiev, Dimitar; Haralanov, Lyubomir; Ivanova, Sonyia; Minchev, Dimitar; Tournev, Ivailo; Stamenova, Paraskeva; Deleva, Nadezhda; Zahariev, Zahari; Manchev, Ivan; Vacheva, Elena; Bar-Or, Amit; Kremenchutzky, Marcelo; Veloso, Felix; Witt, Norbert; Blevins, Gregg; Parajeles Vindas, Alexander; Vargas Howell, Roberto; Soldo-Butković, Silva; Rudež, Josip; Habek, Mario; Vurdelja, Ranka Baraba; Havrdova, Eva; Doležil, David; Vaclavik, Daniel; Novak, Jiří; Gross-Paju, Katrin; Antsov, Katrin; Haldre, Sulev; Palu, Alla; Toomsoo, Toomas; Camu, William; Pelletier, Jean; Labauge, Pierre; Debouverie, Marc; Defer, Gilles; De Seze, Jérôme; Moreau, Thibault; Al Khedr, Abdullatif; Rumbach, Lucien; Daskalovska, Vera; Landefeld, Harald; Masri, Sabine; Schimrigk, Sebastian; Tackenberg, Björn; Eisensehr, Ilonka; Hoffmann, Frank; Kieseier, Bernd; Lüer, Wilfried; Benes, Heike; Paschen, Christine; Derfuß, Tobias; Sailer, Michael; Storch-Hagenlocher, Brigitte; Berthele, Achim; Oschmann, Patrick; Angnstwurm, Klemens; Hohlfeld, Reinhard; Reifschneider, Gerd; Tiel-Wilck, Klaus; Nelles, Gereon; Boldt, Hans-Jürgen; Emrich, Peter; Kallmann, Boris-Alexander; Feneberg, Wolfgang; Christopher, Angelika; Hüntemann, Reinhard; Spiegel-Meixensberger, Mechthild; Thomaides, Thomas; Vlaikidis, Nicholas; Karageorgiou, Clementine; Papathanasopoulos, Panagiotis; Mehndiratta, Man Mohan; Vijayan, Krishnan; Arjundas, Deepak; Srinivasa, Rangasetty; Ghosh, Amitabha; Kulkarni, Rahul Vitthal; Shah, Shalin Dipinkumar; Mukherji, Joy Dev; Nellikunja, Shankara; Behari, Madhuri; Singh, Gagandeep; Ghosh, Pahari; Ichaporia, Nasli Rustom; Sethi, Prahlad Kumar; Mehta, Neeta Abhay; Misra, Usha Kant; Singh, Maneesh Kumar; Khurana, Dheeraj; Salem, Abdu; Sweeney, Bernard; Gilad, Ronit; Shahien, Radi; Paegle, Anita; Punzo, Guillermo; Santos, Jose; Quiñones, Sandra; Macias, Miguel Angel; Estañol, Bruno; Escamilla, Juan; Lopez, Neyla; Renteria, Mariela; Delgado, Cesar; Odainic, Olesea; Groppa, Stanislav; Gavriliuc, Mihail; Timmings, Paul; Drozdowski, Wieslaw; Fryze, Waldemar; Kochanowicz, Jan; Kaminska, Anna; Selmaj, Krzysztof; Wajgt, Andrzej; Kleczkowska, Magdalena; Nowacki, Przemyslaw; Czlonkowska, Anna; Stelmasiak, Zbigniew; Podemski, Ryszard; Dorobek, Malgorzata; Hertmanowska, Hanka; Pierzchala, Krystyna; Zielinski, Tomasz; Szczudlik, Andrzej; Tutaj, Andrzej; Losy, Jacek; Potemkowski, Andrzej; Nyka, Walenty; Kapelusiak-Pielok, Magdalena; Ionescu-Dimancea, Valentin; Balasa, Rodica; Mihancea, Petru; Popescu, Cristian; Protosevici, Liviu Codrut; Vojinovic, Slobodan; Drakulić, Svetlana Miletić; Raicevic, Ranko; Nadj, Congor; Turčáni, Peter; Kahancová, Edita; Kurca, Egon; Lisý, Lubomir; Montalbán, Xavier; Izquierdo, Guillermo; Arroyo, Rafael; Prieto, Jose Maria; Fernández, Oscar; Oreja-Guevara, Celia; Sanchez Lopez, Fernando; Guijarro, Cristina; Voloshina, Nataliya; Pasyura, Igor; Palamar, Borys; Nehrych, Tetyana; Kobys, Tetyana; Lytvynenko, Nataliya; Goloborodko, Alla; Buchakchyyska, Nataliya; Lebedynets, Volodymyr; Ryabichenko, Tatyana; Kushnir, Grygory; Moskovko, Sergii; Chmyr, Galyna; Forester, Mary; Ayala, Ricardo; Voci, James; Krolczyk, Stanley; Glaun, Braeme; Smith, Robert; Crowell, Giles; Kinkel, Revere Philip; Patel, Malti; Miller, Tamara; Pardo, Gabriel; Asher, Stephen; LaGanke, Christopher; Ayres, Donald; Baker, Matthew; Williams, Mitzi; Sheremata, William; Vasquez, Alberto; Janicki, Mark; Garmany, George Jr; Hull, Richard; Steiner, David; Herbert, Joseph; Edwards, Keith; Fox, Robert; Khatri, Bhupendra; Levin, Michael; Mattson, David; Applebee, Angela; Phillips, Joseph Jr; Picone, Mary Ann; Felton, Warren 3rd; Fox, Edward; Apperson, Michelle; Gold, Scott; Kita, Mariko; Moses, Harold Jr; Shin, Robert; Rinker, John 2nd; Hutton, George; Krupp, Lauren; Fodor, Patricia; Foley, John; Gazda, Suzanne; Honeycutt, William; Mitchell, Galen; Sadiq, Saud; Steingo, Brian; Jacobs, Dina; Freedman, Steven; Weinstock-Guttman, Bianca; Lynch, Sharon; Vaishnav, Anand; Wray, Sibyl; Hunter, Samuel; Luzzio, Christopher; Huddlestone, John; Cohan, Stanley; Chinea, Angel; Giang, Daniel; Shubin, Richard; Negroski, Donald; Perel, Allan; Stein, Michael; Herskowitz, Allan; Warach, Jonathan; Mikol, Daniel; Bomprezzi, Roberto; Eubank, Geoffery; Licht, Jonathan; Sullivan, Herman; Rao, T Hemanth; Newman, Stephen; Silverman, Stuart; Gudesblatt, Mark; Sunter, William Jr; Minagar, Alireza; Rammohan, Kottil; Gottesman, Malcolm; Schaeffer, John; Carlini, Walter; Stein, Lee; Buckler, Richard; Azizi, S Ausim; Bauer, Brendan; Ford, Corey
BACKGROUND:BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate). METHODS:In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate. RESULTS:At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12. CONCLUSIONS:In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).
PMID: 22992072
ISSN: 1533-4406
CID: 5347972

Yet another flawed study of self-referral?

Hutchinson, Michael; Rowe, Elizabeth
PMID: 22915436
ISSN: 0361-803x
CID: 175796

Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS

Weinstock-Guttman, Bianca; Galetta, Steven L; Giovannoni, Gavin; Havrdova, Eva; Hutchinson, Michael; Kappos, Ludwig; O'Connor, Paul W; Phillips, J Theodore; Polman, Chris; Stuart, William H; Lynn, Frances; Hotermans, Christophe
Standard clinical endpoints in multiple sclerosis (MS) studies, such as disability progression defined by the expanded disability status scale (EDSS) and annualized relapse rate, may not fully reflect all aspects of therapeutic benefit experienced by patients. Pivotal studies showed that natalizumab is effective both as monotherapy (AFFIRM study) and in combination with interferon beta-1a (IFNbeta-1a) (SENTINEL study) in patients with relapsing MS. We present AFFIRM and SENTINEL data demonstrating the efficacy of natalizumab on prespecified tertiary endpoints, including extent of confirmed change in EDSS score from baseline, time to sustained progression to EDSS milestone scores, hospitalizations, corticosteroid use, and time to confirmed progression of cognitive deficits. Natalizumab significantly reduced changes in EDSS scores (P < 0.001) and proportion of patients progressing to an EDSS score >/=4.0 (P < 0.001) and >/=6.0 (P = 0.002) compared with placebo. Natalizumab + IFNbeta-1a significantly reduced changes in EDSS scores compared with placebo + IFNbeta-1a (P = 0.011). Based on 0.5 standard deviation change in paced auditory serial addition test-3 score, natalizumab treatment reduced the risk of confirmed progression of cognitive deficits by 43% compared with placebo (HR 0.57 [95% CI 0.37, 0.89], P = 0.013); however, no significant difference between groups was seen in SENTINEL. Natalizumab, both as monotherapy and in combination with IFNbeta-1a, significantly reduced the annualized rate of MS-related hospitalizations (by 64 and 61%, respectively) and the annualized rate of relapses severe enough to require steroid treatment (by 69 and 61%, respectively) compared with placebo and placebo + IFNbeta-1a (P < 0.001). These analyses underline beneficial effects of natalizumab therapy in relapsing MS patients.
PMID: 22008873
ISSN: 0340-5354
CID: 174712

At last, a gene therapy for Parkinson's disease? [Letter]

Hutchinson, Michael
PMID: 21419705
ISSN: 1474-4465
CID: 129322

Assessing disability progression with the Multiple Sclerosis Functional Composite

Rudick, R A; Polman, C H; Cohen, J A; Walton, M K; Miller, A E; Confavreux, C; Lublin, F D; Hutchinson, M; O'Connor, P W; Schwid, S R; Balcer, L J; Lynn, F; Panzara, M A; Sandrock, A W
BACKGROUND: The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event. OBJECTIVE: Evaluate a new method for analyzing disability progression using the MSFC. METHODS: MSFC progression was defined as worsening from baseline on scores of at least one MSFC component by 20% (MSFC Progression-20) or 15% (MSFC Progression-15), sustained for >or=3 months. Progression rates were determined using data from natalizumab clinical studies (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]). Correlations between MSFC progression and other clinical measures were determined, as was sensitivity to treatment effects. RESULTS: Substantial numbers of patients met MSFC progression criteria, with MSFC Progression-15 being more sensitive than MSFC Progression-20, at both 1 and 2 years. MSFC Progression-20 and MSFC Progression-15 were related significantly to Expanded Disability Status Scale (EDSS) score change, relapse rate, and the SF-36 Physical Component Summary (PCS) score change. MSFC Progression-20 and MSFC Progression-15 at 1 year were predictive of EDSS progression at 2 years. Both MSFC progression end points demonstrated treatment effects in AFFIRM, and results were replicated in SENTINEL. CONCLUSION: MSFC Progression-20 and MSFC Progression-15 are sensitive measures of disability progression; correlate with EDSS, relapse rates, and SF-36 PCS; and are capable of demonstrating therapeutic effects in randomized, controlled clinical studies.
PMID: 19667023
ISSN: 1352-4585
CID: 222462