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2. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author

Mercuri, Eugenio Maria, Deconinck, N., Mazzone, Elena Stacy, Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, Giovanni, Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, Craig, Fontoura, P., Day, J. W., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Casteels, I., De Waele, L., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., Mcdonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Gidaro, T., Seferian, A., De Lucia, Sara Sofia, Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J. -B., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, Enrico Silvio, D'Amico, Adele, Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, Serafino, Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Masson, R., Bianchi Marzoli, Stefania, Santarsiero, Rocco Domenico, Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, Renata, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Beres, S., Duong, T., Gee, R., Dunaway Young, S., Mercuri E. (ORCID:0000-0002-9851-5365), Mazzone E. S., Baranello G., Martin C., De Lucia S., Bertini E., D'Amico A., Corti S., Bianchi Marzoli S., Santarsiero D., Zanin R., Amorelli G. M., D'Amico G., Orazi L., Coratti G. (ORCID:0000-0001-6666-5628), Mercuri, Eugenio Maria, Deconinck, N., Mazzone, Elena Stacy, Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, Giovanni, Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, Craig, Fontoura, P., Day, J. W., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Casteels, I., De Waele, L., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., Mcdonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Gidaro, T., Seferian, A., De Lucia, Sara Sofia, Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J. -B., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, Enrico Silvio, D'Amico, Adele, Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, Serafino, Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Masson, R., Bianchi Marzoli, Stefania, Santarsiero, Rocco Domenico, Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, Renata, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Beres, S., Duong, T., Gee, R., Dunaway Young, S., Mercuri E. (ORCID:0000-0002-9851-5365), Mazzone E. S., Baranello G., Martin C., De Lucia S., Bertini E., D'Amico A., Corti S., Bianchi Marzoli S., Santarsiero D., Zanin R., Amorelli G. M., D'Amico G., Orazi L., and Coratti G. (ORCID:0000-0001-6666-5628)

Abstract

Background: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. Methods: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2–25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing. Findings: Between Oct 9, 2017, and Sept 4, 2018, 180 patients were rand

Published
2022

4. Cardiac phenotype in ATP1A3-related syndromes A multicenter cohort study

Author

Balestrini, S, Mikati, MA, Alvarez-Garcia-Roves, R, Carboni, M, Hunanyan, AS, Kherallah, B, McLean, M, Prange, L, De Grandis, E, Gagliardi, A, Pisciotta, L, Stagnaro, M, Veneselli, E, Campistol, J, Fons, C, Pias-Peleteiro, L, Brashear, A, Miller, C, Samoes, R, Brankovic, V, Padiath, QS, Potic, A, Pilch, J, Vezyroglou, A, Bye, AME, Davis, AM, Ryan, MM, Semsarian, C, Hollingsworth, G, Scheffer, IE, Granata, T, Nardocci, N, Ragona, F, Arzimanoglou, A, Panagiotakaki, E, Carrilho, I, Zucca, C, Novy, J, Parowicz, M, Weckhuysen, S, Pons, R, Groppa, S, Sinden, DS, Pitt, GS, Tinker, A, Ashworth, M, Michalak, Z, Thom, M, Cross, JH, Vavassori, R, Kaski, JP, Sisodiya, SM, Dzieiyc, K, Mazurkiewicz-Beldzinska, M, Balestrini, S, Mikati, MA, Alvarez-Garcia-Roves, R, Carboni, M, Hunanyan, AS, Kherallah, B, McLean, M, Prange, L, De Grandis, E, Gagliardi, A, Pisciotta, L, Stagnaro, M, Veneselli, E, Campistol, J, Fons, C, Pias-Peleteiro, L, Brashear, A, Miller, C, Samoes, R, Brankovic, V, Padiath, QS, Potic, A, Pilch, J, Vezyroglou, A, Bye, AME, Davis, AM, Ryan, MM, Semsarian, C, Hollingsworth, G, Scheffer, IE, Granata, T, Nardocci, N, Ragona, F, Arzimanoglou, A, Panagiotakaki, E, Carrilho, I, Zucca, C, Novy, J, Parowicz, M, Weckhuysen, S, Pons, R, Groppa, S, Sinden, DS, Pitt, GS, Tinker, A, Ashworth, M, Michalak, Z, Thom, M, Cross, JH, Vavassori, R, Kaski, JP, Sisodiya, SM, Dzieiyc, K, and Mazurkiewicz-Beldzinska, M

Abstract

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Published
2020

23. Cardiac Phenotype In ATP1A3 Related-Syndromes: A Multicentre Study

Author

Balestrini, S., Mikati, M., Garcia-Roves, R. Alvarez, Carboni, M., Hunanyan, A., Kherallah, B., Mclean, M., Prange, L., Grandis, E., Gagliardi, A., Pisciotta, L., Stagnaro, M., Veneselli, E., Campistol, J., Fons, C., Brashear, A., Miller, C., Samoes, R., Brankovic, V., Padiath, Q., Potic, A., Pilch, J., Vezyroglou, K., Hollingsworth, G., Scheffer, I., Granata, T., Nardo NARDOCCI, Ragona, F., Arzimanoglou, A., Panagiotakaki, E., Carrilho, I., Zucca, C., Novy, J., Dziezyc, K., Parowicz, M., Mazurkiewicz-Beldzinska, M., Weckhuysen, S., Pons, R., Groppa, S., Sinden, D. S., Pitt, G., Tinker, A., Ashworth, M., Michalak, Z., Thom, M., Cross, J. H., Vavassori, R., Kaski, J. P., and Sisodiya, S. M.

24. The PURPLE N study: objective and perceived nutritional status in children and adolescents with cerebral palsy

Author

Andras, Fogarasi, Elisa, Fazzi, Ana R P, Smorenburg, Maria, Mazurkiewicz-Beldzinska, Argirios, Dinopoulos, Alena, Pobiecka, Dea, Schröder-van den Nieuwendijk, Josef, Kraus, Hasan, Tekgül, Maria, Koutsaki, Giovanni, Baranello, Simona, Bertoli, Elisa, Caramaschi, Duccio Maria, Cordelli, Ramona, De Amicis, Maria Luisa, Forchielli, Azzurra, Guerra, Althea, Lividini, Maddalena, Marchiò, Andrea, Rossi, Dea Schröder-van den, Nieuwendijk, Jędrzej, Fliciński, Barbara, Gurda, Anna, Lemska, Agnieszka, Matheisel, Zuzanna, Niwinska, Małgorzata, Pawłowicz, Agnieszka, Sawicka, Barbara, Steinborn, Marta, Szmuda, Anna, Winczewska-Wiktor, Marta, Zawadzka, Ebru, Arhan, Kursad, Aydin, Erhan, Bayram, Kursat Bora, Carman, Pinar, Edem, Deniz, Ertem, Özben Akıncı, Goktas, Serdal, Gungor, Goknur, Haliloglu, Aydan, Kansu, Mustafa, Kömür, Akmer, Mutlu, Ceyda Tuna, Kırsaçlıoğlu, Çetin, Okuyaz, Bilge, Özgör, Yesim, Ozturk, Safiye Gunes, Sager, Esra, Sarıgeçili, Mukadder Ayse, Selimoglu, Hepsen Mine Öztürk, Serin, Serap Tıraş, Teber, Gülten, Thomas, Dilsad, Turkdogan, Burcu, Volkan, Coşkun, Yarar, Sanem Keskin, Yilmaz, Fogarasi A., Fazzi E., Smorenburg A.R.P., Mazurkiewicz-Beldzinska M., Dinopoulos A., Pobiecka A., Schroder-van den Nieuwendijk D., Kraus J., Tekgul H, and the PUrple study group Giovanni Baranello, Simona Bertoli, Elisa Caramaschi, Duccio Maria Cordelli, Ramona De Amici, Maria Luisa Forchielli, Azzurra Guerra, Althea Lividini, Maddalena Marchi, Andrea Rossi, Dea Schr€oder-van den Nieuwendijk, JeR drzej Flicinsk, Barbara Gurda, Anna Lemska, Agnieszka Matheisel, Maria Mazurkiewicz-Beldzinska, Zuzanna Niwinska, Małgorzata Pawłowicz, Agnieszka Sawicka, Barbara Steinborn, Marta Szmuda, Anna Winczewska-Wiktor, Marta Zawadzka: Alena Pobiecka, Ebru Arhan, Erhan Bayram, Eskis ehir Osmangazi, Pinar Edem, Deniz Ertem, €Ozben Akı ncı Gokta, Serdal Gungor, Goknur Haliloglu, Aydan Kansu, Mustafa K€om€ur, Akmer Mutlu, Ceyda Tuna Kırsac lıoglu, Cetin Okuyaz, Bilge €Ozg€or, Yesim Ozturk, Safiye Gunes Sagel, Esra Sarıgec ili, Mukadder Ayse Selimoglu, Hepsen Mine €Ozt€urk, Serap Tı ras Teber, Hasan Tekg€ul, G€ulten Thoma, Dilsad Turkdogan, Burcu Volkan, Coskun Yarar, and Sanem Keskin Yilmaz.

Subjects
Gerontology, Body-Composition, System, Referral, genetic structures, Adolescent, Physical-Activity, Cerebral palsy, concerns, feeding, nutrition, perceived nutritional status, medicine.medical_treatment, Nutritional Status, Growth, Continuous variable, Gross Motor Function, Surveys and Questionnaires, medicine, Humans, Child, Ability, Rehabilitation, business.industry, Malnutrition, People, Gross Motor Function Classification System, Nutritional status, Anthropometry, medicine.disease, Reliability, Preschool-Aged Children, Clinical trial, Caregivers, concern, business, Classify
Abstract

Purpose: To obtain information on characteristics, management, current objective nutritional status and perception of nutritional status of children with cerebral palsy (CP) from healthcare professionals (HCPs) and caregivers. Materials and methods: A detailed survey of several items on eight main topics (general characteristics, motor function, comorbidities, therapies, anthropometry, feeding mode and problems and perceived nutritional status) was developed and tested for the study. Correlation between nutritional status and Gross Motor Function Classification System (GMFCS) levels was assessed using continuous variables (Z-scores for weight-for-age, height-for-age, weight-for-height, and body mass index-for-age), and categorical variables (being malnourished, stunted, or wasted). HCP and caregiver perceptions of the child's nutritional status as well as agreement between perceived and objective nutritional status and agreement between perceived nutritional status and concerns about the nutritional status were analyzed. Results: Data were available for 497 participants from eight European countries. Poorer nutritional status was associated with higher (more severe) GMFCS levels. There was minimal agreement between perceived and objective nutritional status, both for HCPs and caregivers. Agreement between HCP and caregiver perceptions of the child's nutritional status was weak (weighted kappa 0.56). However, the concerns about the nutritional status of the child were in line with the perceived nutritional status. Conclusions: The risk of poor nutritional status is associated with more severe disability in children and adolescents with CP. There is a mismatch between HCP and caregiver perceptions of participants' nutritional status as well as between subjective and objective nutritional status. Our data warrant the use of a simple and objective screening tool in daily practice to determine nutritional status in children and adolescents with CP., Danone Nutricia Research, Utrecht, the Netherlands; Nutricia Advanced Medical Nutrition in Czech Republic; Nutricia Advanced Medical Nutrition in Greece; Nutricia Advanced Medical Nutrition in Hungary; Nutricia Advanced Medical Nutrition in Italy; Nutricia Advanced Medical Nutrition in Poland; Nutricia Advanced Medical Nutrition in Slovakia; Nutricia Advanced Medical Nutrition in The Netherlands; Nutricia Advanced Medical Nutrition in Turkey; Danone Nutricia Research, This study was sponsored by Danone Nutricia Research, Utrecht, the Netherlands. Local financial support was provided by the local business units of Nutricia Advanced Medical Nutrition in Czech Republic, Greece, Hungary, Italy, Poland, Slovakia, The Netherlands, and Turkey. Medical writing support was provided by Tim Kelly, Medi-Kelsey Limited, funded by Danone Nutricia Research.

Published
2022

25. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial

Author

Riccardo Masson, Maria Mazurkiewicz-Bełdzińska, Kristy Rose, Laurent Servais, Hui Xiong, Edmar Zanoteli, Giovanni Baranello, Claudio Bruno, John W Day, Nicolas Deconinck, Andrea Klein, Eugenio Mercuri, Dmitry Vlodavets, Yi Wang, Angela Dodman, Muna El-Khairi, Ksenija Gorni, Birgit Jaber, Heidemarie Kletzl, Eleni Gaki, Paulo Fontoura, Basil T Darras, Joseph J Volpe, John Posner, Ulrich Kellner, Rosaline Quinlivan, Marianne Gerber, Omar Khwaja, Renata S Scalco, Timothy Seabrook, Armin Koch, Irina Balikova, Inge Joniau, Geraldine Accou, Valentine Tahon, Sylvia Wittevrongel, Elke De Vos, Rodrigo de Holanda Mendonça, Ciro Matsui Jr, Ana Letícia Fornazieri Darcie, Cleide Machado, Maria Kiyoko Oyamada, Joyce Martini, Graziela Polido, Juliana Rodrigues Iannicelli, Juliana Caires de Oliveira Achili Ferreira, Chaoping Hu, Xiaomei Zhu, Chen Qian, Li Shen, Hui Li, Yiyun Shi, Shuizhen Zhou, Ying Xiao, Zhenxuan Zhou, Sujuan Wang, Tian Sang, Cuijie Wei, Hui Dong, Yiwen Cao, Jing Wen, Wenzhu Li, Lun Qin, Nina Barisic, Ivan Celovec, Martina Galiot Delic, Petra Kristina Ivkic, Nenad Vukojevic, Ivana Kern, Boris Najdanovic, Marin Skugor, Josipa Tomas, Odile Boespflug-Tanguy, Silvana De Lucia, Andrea Seferian, Emmanuel Barreau, Nabila Mnafek, Helene Peche, Allison Grange, Diem Trang Nguyen, Darko Milascevic, Shotaro Tachibana, Emanuela Pagliano, Stefania Bianchi Marzoli, Diletta Santarsiero, Myriam Garcia Sierra, Gemma Tremolada, Maria Teresa Arnoldi, Marta Vigano, Claudia Dosi, Riccardo Zanin, Veronica Schembri, Noemi Brolatti, Giuseppe Rao, Elisa Tassara, Simone Morando, Paola Tacchetti, Marina Pedemonte, Enrico Priolo, Lorenza Sposetti, Giacomo Pietro Comi, Alessandra Govoni, Silvia Gabriella Osnaghi, Valeria Minorini, Francesca Abbati, Federica Fassini, Michaela Foa, Amalia Lopopolo, Marika Pane, Concetta Palermo, Maria Carmela Pera, Giulia Maria Amorelli, Costanza Barresi, Guglielmo D'Amico, Lorenzo Orazi, Giorgia Coratti, Daniela Leone, Antonaci Laura, Roberto De Sanctis, Beatrice Berti, Naoki Kimura, Yasuhiro Takeshima, Hideki Shimomura, Tomoko Lee, Fumi Gomi, Takanobu Morimatsu, Toru Furukawa, Urszula Stodolska-Koberda, Agnieszka Waskowska, Jagoda Kolendo, Agnieszka Sobierajska-Rek, Sandra Modrzejewska, Anna Lemska, Evgenia Melnik, Svetlana Artemyeva, Natalya Leppenen, Nataliya Yupatova, Anastasya Monakhova, Yulia Papina, Olga Shidlovsckaia, Elena Litvinova, Cornelia Enzmann, Elea Galiart, Konstantin Gugleta, Christine Wondrusch Haschke, Haluk Topaloglu, Ibrahim Oncel, Nesibe Eroglu Ertugrul, Bahadir Konuskan, Bora Eldem, Sibel Kadayifçilar, Ipek Alemdaroglu, Seher Sari, Neslihan Bilgin, Aynur Ayse Karaduman, Fatma Gokcem Yildiz Sarikaya, Robert J Graham, Partha Ghosh, David Casavant, Alexis Levine, Rachael Titus, Amanda Engelbrekt, Lucia Ambrosio, Anne Fulton, Anna Maria Baglieri, Courtney Dias, Elizabeth Maczek, Amy Pasternak, Shannon Beres, Tina Duong, Richard Gee, Sally Young, Masson, R., Mazurkiewicz-Beldzinska, M., Rose, K., Servais, L., Xiong, H., Zanoteli, E., Baranello, G., Bruno, C., Day, J. W., Deconinck, N., Klein, A., Mercuri, E., Vlodavets, D., Wang, Y., Dodman, A., El-Khairi, M., Gorni, K., Jaber, B., Kletzl, H., Gaki, E., Fontoura, P., Darras, B. T., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Gerber, M., Khwaja, O., Scalco, R. S., Seabrook, T., Koch, A., Balikova, I., Joniau, I., Accou, G., Tahon, V., Wittevrongel, S., De Vos, E., de Holanda Mendonca, R., Matsui Jr, C., Fornazieri Darcie, A. L., Machado, C., Kiyoko Oyamada, M., Martini, J., Polido, G., Rodrigues Iannicelli, J., Caires de Oliveira Achili Ferreira, J., Hu, C., Zhu, X., Qian, C., Shen, L., Li, H., Shi, Y., Zhou, S., Xiao, Y., Zhou, Z., Wang, S., Sang, T., Wei, C., Dong, H., Cao, Y., Wen, J., Li, W., Qin, L., Barisic, N., Celovec, I., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Tomas, J., Boespflug-Tanguy, O., De Lucia, S., Seferian, A., Barreau, E., Mnafek, N., Peche, H., Grange, A., Trang Nguyen, D., Milascevic, D., Tachibana, S., Pagliano, E., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Dosi, C., Zanin, R., Schembri, V., Brolatti, N., Rao, G., Tassara, E., Morando, S., Tacchetti, P., Pedemonte, M., Priolo, E., Sposetti, L., Comi, G. P., Govoni, A., Osnaghi, S. G., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Pane, M., Palermo, C., Pera, M. C., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., Leone, D., Laura, A., De Sanctis, R., Berti, B., Kimura, N., Takeshima, Y., Shimomura, H., Lee, T., Gomi, F., Morimatsu, T., Furukawa, T., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Modrzejewska, S., Lemska, A., Melnik, E., Artemyeva, S., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Litvinova, E., Enzmann, C., Galiart, E., Gugleta, K., Wondrusch Haschke, C., Topaloglu, H., Oncel, I., Ertugrul, N. E., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Sari, S., Bilgin, N., Karaduman, A. A., Sarikaya, F. G. Y., Graham, R. J., Ghosh, P., Casavant, D., Levine, A., Titus, R., Engelbrekt, A., Ambrosio, L., Fulton, A., Baglieri, A. M., Dias, C., Maczek, E., Pasternak, A., Beres, S., Duong, T., Gee, R., and Young, S.

Subjects
Muscular Atrophy, Spinal, Settore MED/26 - NEUROLOGIA, Pyrimidines, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Settore MED/48 - SCIENZE INFERMIERISTICHE E TECNICHE NEURO-PSICHIATRICHE E RIABILITATIVE, Humans, Infant, Neurology (clinical), Spinal Muscular Atrophies of Childhood, Azo Compounds, spinal muscular atrophy
Abstract

Background: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. Methods: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. Findings: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p

Published
2022

26. Genotype-phenotype correlations in Polish patients with SCN8A-related epilepsy: A multicentre observational study.

Author

Paprocka J, Steinborn B, Krygier M, Winczewska-Wiktor A, Przyslo L, Hutny M, Hoffman-Zacharska D, Mazurkiewicz H, Kochanowska I, Zebrowska J, Zawadzka M, Piasecki L, and Mazurkiewicz-Beldzinska M

Subjects
Humans, Male, Female, Poland, Child, Preschool, Infant, Child, Mutation, Electroencephalography, Phenotype, Adolescent, Magnetic Resonance Imaging, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders physiopathology, NAV1.6 Voltage-Gated Sodium Channel genetics, Epilepsy genetics, Epilepsy physiopathology, Genetic Association Studies
Abstract

Background: Voltage-gated sodium channels are involved in the initial depolarisation of neurones. As such, they play important roles in neurotransmission. Variants in the genes encoding these channels may lead to altered functionality and neurodevelopmental disorders. Pathogenic variants of SCN8A, which encodes the voltage-gated Na+ channel Nav1.6, have been associated with various encephalopathies characterised by developmental delay and epileptic seizures. Herein, we discuss the genotype-phenotype associations in a group of 17 novel Polish patients with SCN8A mutations, further expanding the molecular and phenotypic spectrum of SCN8A-related diseases., Methods: The participants were recruited from five clinical centres in Poland. Pathogenic and likely pathogenic SCN8A variants were identified using a next-generation sequencing (NGS) panel and exome sequencing, respectively. Magnetic resonance imaging (MRI) and electroencephalography (EEG) recordings were performed to obtain relevant clinical data on brain malformations and epileptic seizures., Results: Three phenotypes were observed in the study group: developmental and epileptic encephalopathy, early onset epileptic encephalopathy, and neurodevelopmental disorders without epilepsy. Patients in the first two phenotypic subgroups presented with epileptic seizures within the first few months of life. Their semiology evolved with age, comprising mostly tonic, clonic, and tonic-clonic seizures, with eyelid myoclonia, myoclonic seizures, and epileptic spasms. The most prevalent neurological feature was developmental delay. Alterations in muscle tone were more frequent than in previous reports., Conclusions: Seventeen patients with 11 novel mutations in SCN8A had alterations in muscular tone accompanied by typical features of SCN8A-related encephalopathies (i.e., developmental delay and a wide range of seizures)., Competing Interests: Declaration of competing interest The Authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Published
2024
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27. The PURPLE N study: objective and perceived nutritional status in children and adolescents with cerebral palsy.

Author

Fogarasi A, Fazzi E, Smorenburg ARP, Mazurkiewicz-Beldzinska M, Dinopoulos A, Pobiecka A, Schröder-van den Nieuwendijk D, Kraus J, Tekgül H, Kraus J, Dinopoulos A, Koutsaki M, Fogarasi A, Baranello G, Bertoli S, Caramaschi E, Cordelli DM, De Amicis R, Fazzi E, Forchielli ML, Guerra A, Lividini A, Marchiò M, Rossi A, Nieuwendijk DSD, Fliciński J, Gurda B, Lemska A, Matheisel A, Mazurkiewicz-Beldzinska M, Niwinska Z, Pawłowicz M, Sawicka A, Steinborn B, Szmuda M, Winczewska-Wiktor A, Zawadzka M, Pobiecka A, Arhan E, Aydin K, Bayram E, Carman KB, Edem P, Ertem D, Goktas ÖA, Gungor S, Haliloglu G, Kansu A, Kömür M, Mutlu A, Kırsaçlıoğlu CT, Okuyaz Ç, Özgör B, Ozturk Y, Sager SG, Sarıgeçili E, Selimoglu MA, Serin HMÖ, Teber ST, Tekgül H, Thomas G, Turkdogan D, Volkan B, Yarar C, and Yilmaz SK

Subjects
Child, Adolescent, Humans, Nutritional Status, Caregivers, Surveys and Questionnaires, Cerebral Palsy, Malnutrition diagnosis
Abstract

Purpose: To obtain information on characteristics, management, current objective nutritional status and perception of nutritional status of children with cerebral palsy (CP) from healthcare professionals (HCPs) and caregivers., Materials and Methods: A detailed survey of several items on eight main topics (general characteristics, motor function, comorbidities, therapies, anthropometry, feeding mode and problems and perceived nutritional status) was developed and tested for the study. Correlation between nutritional status and Gross Motor Function Classification System (GMFCS) levels was assessed using continuous variables (Z-scores for weight-for-age, height-for-age, weight-for-height, and body mass index-for-age), and categorical variables (being malnourished, stunted, or wasted). HCP and caregiver perceptions of the child's nutritional status as well as agreement between perceived and objective nutritional status and agreement between perceived nutritional status and concerns about the nutritional status were analyzed., Results: Data were available for 497 participants from eight European countries. Poorer nutritional status was associated with higher (more severe) GMFCS levels. There was minimal agreement between perceived and objective nutritional status, both for HCPs and caregivers. Agreement between HCP and caregiver perceptions of the child's nutritional status was weak (weighted kappa 0.56). However, the concerns about the nutritional status of the child were in line with the perceived nutritional status., Conclusions: The risk of poor nutritional status is associated with more severe disability in children and adolescents with CP. There is a mismatch between HCP and caregiver perceptions of participants' nutritional status as well as between subjective and objective nutritional status. Our data warrant the use of a simple and objective screening tool in daily practice to determine nutritional status in children and adolescents with CP. Clinical trial registration: ClinicalTrials.gov Identifier: NCT03499288 (https://clinicaltrials.gov/ct2/show/NCT03499288). IMPLICATIONS FOR REHABILITATIONUse of the ESPGHAN recommendations and simple screening tools in daily practice is needed to improve nutritional care for individuals with CP.Attention should be paid to the differences in the perception of nutritional status of individuals with CP between professionals and caregivers to improve appropriate referral for nutritional support.Objective measures rather than the professional's perception need to be used to define the nutritional status of individuals with CP.

Published
2022
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28. Recommendations for treatment strategies in people with epilepsy during times of shortage of antiseizure medications

Author

Asadi-Pooya AA, Patel AA, Trinka E, Mazurkiewicz-Beldzinska M, Cross JH, and Welty TE

Subjects
Anticonvulsants therapeutic use, Carbamazepine therapeutic use, Humans, Oxcarbazepine, Epilepsy drug therapy, Epilepsy, Generalized drug therapy
Abstract

In times of severe antiseizure medication (ASM) shortage due to emergency situations (e.g., disasters, conflicts, sudden disruption to international supply chains), management of people with epilepsy with available ASMs can be difficult. A group of experts was brought together by the International League Against Epilepsy (ILAE) to formulate recommendations for such circumstances. Every effort was made to base these recommendations on direct published literature or extrapolations from basic information available about ASMs. Actual published literature in this area is, however, limited, and at times, assumptions were made by the experts to generate these recommendations. During times of shortage of ASMs, switching between different ASMs (e.g., oxcarbazepine and carbamazepine) can occasionally be considered as a mitigation procedure. However, for many ASMs, the option of an overnight switch to another drug does not exist. Switching from brand to generic or between generic products has often been shown to be safe, if required. Finally, when supplies of benzodiazepines or equipment to administer medications intravenously are not available, rectal administration of some ASMs may be an emergency alternative route for treating serial seizures and status epilepticus. Decision-making with regard to treatment and possible options should be driven by what is best for the patient.

Published
2022
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29. Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials.

Author

Privitera M, Bhathal H, Wong M, Cross JH, Wirrell E, Marsh ED, Mazurkiewicz-Beldzinska M, Villanueva V, Checketts D, Knappertz V, and VanLandingham K

Subjects
Adolescent, Adult, Child, Child, Preschool, Double-Blind Method, Female, Humans, Male, Middle Aged, Seizures etiology, Seizures therapy, Time Factors, Young Adult, Anticonvulsants therapeutic use, Cannabidiol therapeutic use, Lennox Gastaut Syndrome drug therapy, Treatment Outcome
Abstract

Objective: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome., Methods: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated., Results: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients., Significance: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2021
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30. Delayed-Release Dimethyl Fumarate Safety and Efficacy in Pediatric Patients With Relapsing-Remitting Multiple Sclerosis.

Author

Alroughani R, Huppke P, Mazurkiewicz-Beldzinska M, Blaschek A, Valis M, Aaen G, Pultz J, Peng X, and Beynon V

Abstract

Background: Pediatric multiple sclerosis (MS) is rare: only 1.5-5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS. Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13-17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR). Results: Twenty participants [median (range) age, 17 (14-18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16-24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0-6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction ( n = 20; 95% confidence interval: 66.8-92.8; p < 0.0001) vs. the year before DMF initiation. Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment., Competing Interests: RA reports receiving personal compensation for serving on speaker/advisory boards for Bayer, Biogen, Merck, Novartis, Roche, and Sanofi, and receiving research support from Biogen, Merck, Novartis, and Roche for the establishment of regional multiple sclerosis registries and the conduct of clinical trials. PH reports receiving speaker/consulting fees from Bayer, Merck, and Novartis. AB reports receiving speaker/consulting fees from AveXis, Biogen, Genzyme, and Merck. MV reports receiving speaker/consulting fees from Biogen, Genzyme, Merck, Novartis, Roche, and Teva. JP is a contractor for Biogen. XP and VB are employees of and hold stock/stock options in Biogen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alroughani, Huppke, Mazurkiewicz-Beldzinska, Blaschek, Valis, Aaen, Pultz, Peng and Beynon.)

Published
2021
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31. Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

Author

Thiele E, Marsh E, Mazurkiewicz-Beldzinska M, Halford JJ, Gunning B, Devinsky O, Checketts D, and Roberts C

Subjects
Adolescent, Adult, Cannabidiol administration & dosage, Cannabidiol adverse effects, Child, Child, Preschool, Double-Blind Method, Female, Humans, Male, Middle Aged, Seizures prevention & control, Treatment Outcome, Young Adult, Cannabidiol therapeutic use, Lennox Gastaut Syndrome drug therapy
Abstract

Objective: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial., Methods: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit., Results: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale., Significance: In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures., (© 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Published
2019
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32. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.

Author

Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, and Sommerville K

Subjects
Adolescent, Adult, Child, Child, Preschool, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Lennox Gastaut Syndrome complications, Male, Middle Aged, Seizures etiology, Treatment Outcome, Young Adult, Anticonvulsants therapeutic use, Cannabidiol therapeutic use, Lennox Gastaut Syndrome drug therapy, Seizures drug therapy
Abstract

Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients., Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690., Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment., Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial., Funding: GW Pharmaceuticals., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2018
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