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189 results on '"Dangond, Fernando"'

1. Clinical Meaningfulness in Alzheimer’s Disease Clinical Trials. A Report from the EU-US CTAD Task Force

Author

Angioni, D., Cummings, J., Lansdall, C. J., Middleton, L., Sampaio, C., Gauthier, S., Cohen, S., Petersen, R. C., Rentz, D. M., Wessels, A. M., Hendrix, S. B., Jessen, F., Carrillo, M. C., Doody, R. S., Irizarry, M., Andrews, J. S., Vellas, B., Aisen, P., Andrieu, Sandrine, Bateman, Randall, Batrla, Richard, Bell, Joanne, Bosson, Oskar, Bozeat, Sasha, Brooks, Dawn, Haeberlein, Samantha Budd, Buracchio, Teresa, Cho, Min, Choung, Matthew, Cook, Gavin, Crisitello, Darrin, Dangond, Fernando, de Santi, Susan, Dennehy, Ellen, Dhadda, Shobha, Dhillon, Harjeet, Dunn, Billy, Egan, Michael, Elwood, Fiona, Eriksson, Sven, Fagan, Tom, Fillit, Howard, Freskgard, Per-Ola, Gallagher, Diana, Gangi, Gopi, Granda, Carlos, Greeley, David, Gronblad, Anna-Kaija, Hampel, Harald, Hawthorne, Paul, Henley, David, Herring, Joe, Hersch, Steve, Holt, Bill, Iwatsubo, Takeshi, Jones, Daryl, Kahl, Anja, Kinney, Gene, Kolb, Hartmuth, Kramer, Lynn, Kulic, Luka, Kumar, Sanjay, Lannfelt, Lars, Lawson, John, Legrand, Valérie, Lenington, Rachel, Longo, Frank, Matthews, Brandy, Masterman, Donna, McLinden, Kristina, Mikels, Sarah, Miller, Michael, Mintun, Mark, Moebius, Hans, Monteiro, Cecilia, Morken, Mario, Murphy, Jennifer, Odergren, Tomas, Osswald, Gunilla, Parnas, Laura, Patru, Maria-Magdalena, Prazma, Charlene, Raman, Rema, Reyderman, Larisa, Rogers, Sharon, Roman, Lise, Romano, Gary, Roskey, Mark, Rubino, Ivana, Ryan, Laurie, Salloway, Stephen, Schindler, Rachel, Schneider, Lon, Scott, David, Sims, John, Skovronsky, Daniel, Soto, Marion, Sperling, Reisa, Steukers, Lennert, Stoops, Erik, Strittmatter, Stephen, Tahami, Amir, Tamagnan, Gilles, Tariot, Gilles, Toloue, Masoud, Touchon, Jacques, Vanmechelen, Eugeen, Walt, Len, Weinberg, Mark, Weiner, Michael, White, Anne, Wiesel, Iris, Wilson, David, Yarenis, Lisa, Zago, Wagner, and Zhou, Jin

Published
2024
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3. Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials

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Hermine, Olivier, Mariette, Xavier, Ravaud, Philippe, Bureau, Serge, Dougados, Maxime, Resche-Rigon, Matthieu, Tharaux, Pierre-Louis, Tibi, Annick, Azoulay, Elie, Cadranel, Jacques, Emmerich, Joseph, Fartoukh, Muriel, Guidet, Bertrand, Humbert, Marc, Lacombe, Karine, Mahevas, Matthieu, Pene, Frédéric, Porcher, Raphaël, Pourchet-Martinez, Valerie, Schlemmer, Frédéric, Yazdanpanah, Yazdan, Baron, Gabriel, Perrodeau, Elodie, Vanhoye, Damien, Kedzia, Cécile, Demerville, Lauren, Gysembergh-Houal, Anne, Bourgoin, Alexandre, Raked, Nabil, Mameri, Lakhdar, Montlahuc, Claire, Biard, Lucie, Alary, St.phanie, Hamiria, Samir, Bariz, Thinhinane, Semri, Hala, Hai, Dhiaa Meriem, Benafla, Moustafa, Belloul, Mohamed, Vauboin, Pernelle, Flamand, Saskia, Pacheco, Claire, Walter-Petrich, Anouk, Stan, Emilia, Benarab, Souad, Nyanou, Corine, Charreteur, Robin, Dupre, Céline, Cardet, Kévin, Lehmann, Blandine, Baghli, Kamyl, Madelaine, Claire, D'Ortenzio, Eric, Puéchal, Oriane, Semaille, Caroline, Savale, Laurent, Harrois, Anatole, Figueiredo, Samy, Duranteau, Jacques, Anguel, Nadia, Pavot, Arthur, Monnet, Xavier, Richard, Christian, Teboul, Jean-Louis, Durand, Philippe, Tissieres, Pierre, Jevnikar, Mitja, Montani, David, Pavy, Stephan, Nocturne, Gaétane, Bitoun, Samuel, Noel, Nicolas, Lambotte, Olivier, Escaut, Lelia, Jauréguiberry, Stephane, Baudry, Elodie, Verny, Christiane, Lefevre, Edouard, Zaidan, Mohamad, Molinari, Domitille, Leprun, Gaël, Fourreau, Alain, Cylly, Laurent, Grimaldi, Lamiae, Virlouvet, Myriam, Meftali, Ramdane, Fabre, Soléne, Licois, Marion, Mamoune, Asmaa, Boudali, Yacine, Le Tiec, Clotilde, Verstuyft, Céline, Roques, Anne-Marie, Georgin-Lavialle, Sophie, Senet, Patricia, Pialoux, Gilles, Soria, Angele, Parrot, Antoine, François, Helene, Rozensztajn, Nathalie, Blin, Emmanuelle, Choinier, Pascaline, Camuset, Juliette, Rech, Jean-Simon, Canellas, Antony, Rolland-Debord, Camille, Lemarié, Nadege, Belaube, Nicolas, Nadal, Marine, Siguier, Martin, Petit-Hoang, Camille, Chas, Julie, Drouet, Elodie, Lemoine, Matthieu, Phibel, Audrey, Aunay, Lucie, Bertrand, Eliane, Ravato, Sylviane, Vayssettes, Marie, Adda, Anne, Wilpotte, Celine, Thibaut, Pélagie, Fillon, Julie, Debrix, Isabelle, Fellahi, Soraya, Bastard, Jean-Philippe, Lefévre, Guillaume, Gottenberg, Jacques-Eric, Hansmann, Yves, Blanc, Frédéric, Ohlmann-Caillard, Sophie, Castelain, Vincent, Chatelus, Emmanuel, Chatron, Eva, Collange, Olivier, Danion, François, De Blay, Frédéric, Diemunsch, Pierre, Diemunsch, Sophie, Felten, Renaud, Goichot, Bernard, Greigert, Valentin, Guffroy, Aurelien, Heger, Bob, Kaeuffer, Charlotte, Kassegne, Loic, Korganow, Anne Sophie, Le Borgne, Pierrick, Lefebvre, Nicolas, Mertes, Paul-Michel, Noll, Eric, Oberlin, Mathieu, Poindron, Vincent, Pottecher, Julien, Ruch, Yvon, Weill, François, Meyer, Nicolas, Andres, Emmanuel, Demonsant, Eric, Tayebi, Hakim, Nisand, Gabriel, Brin, Stéphane, Sublon, Cédric, Becker, Guillaume, Hutt, Anne, Martin, Tristan, Bayer, Sophie, Metzger, Catherine, Mekinian, Arsene, Abisror, Noémie, Adedjouma, Amir, Bollens, Diane, Bonneton, Marion, Bourcicaux, Nathalie, Bourrier, Anne, Thibault Chiarabiani, Maria Chauchard, Chopin, Doroth.e, Cohen, Jonathan, Devred, Ines, Donadille, Bruno, Fain, Olivier, Hariri, Geoffrey, Jachiet, Vincent, Ingliz, Patrick, Garnier, Marc, Gatfosse, Marc, Ghrenassia, Etienne, Gobert, Delphine, Krause le Garrec, Jessica, Landman, Cecilia, Lavillegrand, Jean Remy, Lefebvre, Benedicte, Mahevas, Thibault, Mazerand, Sandie, Meynard, Jean Luc, Morgand, Marjolaine, Ouaz.ne, Zineb, Pacanowski, Jerome, Riviere, S.bastien, Seksik, Philippe, Sokol, Harry, Soliman, Heithem, Valin, Nadia, Urbina, Thomas, McAvoy, Chloé, Miranda, Maria Pereira, Aratus, Gladys, Berard, Laurence, Simon, Tabassome, Nguyen, Anne Daguenel, Girault, Elise, Mayala-Kanda, Cl.mentine, Antignac, Marie, Leplay, Céline, Arlet, Jean-Benoit, Diehl, Jean-Luc, Bellenfant, Florence, Blanchard, Anne, Buffet, Alexandre, Cholley, Bernard, Fayol, Antoine, Flamarion, Edouard, Godier, Anne, Gorget, Thomas, Hamada, Sophie-Rym, Hauw-Berlemont, Caroline, Hulot, Jean-Sébastien, Lebeaux, David, Livrozet, Marine, Michon, Adrien, Neuschwander, Arthur, Pennet, Marie-Aude, Planquette, Benjamin, Ranque, Brigitte, Sanchez, Olivier, Volle, Geoffroy, Briois, Sandrine, Cornic, Mathias, Elisee, Virginie, Denis, Jesuthasan, Djadi-Prat, Juliette, Jouany, Pauline, Junquera, Ramon, Henriques, Mickael, Kebir, Amina, Lehir, Isabelle, Meunier, Jeanne, Patin, Florence, Paquet, Val.rie, Tréhan, Anne, Vigna, Véronique, Sabatier, Brigitte, Bergerot, Damien, Jouve, Charléne, Knosp, Camille, Lenoir, Olivia, Mahtal, Nassim, Resmini, Léa, Lescure, Xavier, Ghosn, Jade, Bachelard, Antoine, Rachline, Anne, Isernia, Valentina, Bao-chau, Phung, Vallois, Dorothée, Sautereau, Aurelie, Neukrich, Catherine, Dossier, Antoine, Borie, Raphaël, Crestani, Bruno, Ducrocq, Gregory, Steg, Philippe Gabriel, Dieude, Philippe, Papo, Thomas, Marcault, Estelle, Chaudhry, Marhaba, Da Silveira, Charléne, Metois, Annabelle, Mahenni, Ismahan, Meziani, Meriam, Nilusmas, Cyndie, Le Gac, Sylvie, Ndiaye, Awa, Louni, Fran.oise, Chansombat, Malikhone, Julia, Zelie, Chalal, Solaya, Chalal, Lynda, Kramer, Laura, Le Grand, Jeniffer, Ouifiya, Kafif, Piquard, Valentine, Tubiana, Sarah, Nguyen, Yann, Honsel, Vasco, Weiss, Emmanuel, Codorniu, Anais, Zarrouk, Virginie, de Lastours, Victoire, Uzzan, Matthieu, Gamany, Naura, Claveirole, Agathe, Navid, Alexandre, Fouque, Tiffanie, Cohen, Yonathan, Lupo, Maya, Gilles, Constance, Rahli, Roza, Louis, Zeina, Boutboul, David, Galicier, Lionel, Amara, Yaël, Archer, Gabrielle, Benattia, Amira, Bergeron, Anne, Bondeelle, Louise, de Castro, Nathalie, Clément, Melissa, Darmon, Michaël, Denis, Blandine, Dupin, Clairelyne, Feredj, Elsa, Feyeux, Delphine, Joseph, Adrien, Lenglin, Etienne, Le Guen, Pierre, Liégeon, Geoffroy, Lorillon, Gwenaël, Mabrouki, Asma, Mariotte, Eric, Martin de Frémont, Grégoire, Mirouse, Adrien, Molina, Jean-Michel, Peffault de Latour, Régis, Oksenhendler, Eric, Saussereau, Julien, Tazi, Abdellatif, Tudesq, Jean-Jacques, Zafrani, Lara, Brindele, Isabelle, Bugnet, Emmanuelle, Lebras, Karine Celli, Chabert, Julien, Djaghout, Lamia, Fauvaux, Catherine, Jegu, Anne Lise, Kozakiewicz, Ewa, Meunier, Martine, Tremorin, Marie-Thérèse, Davoine, Claire, Madelaine, Isabelle, Caillat-Zucman, Sophie, Delaugerre, Constance, Morin, Florence, Sène, Damien, Burlacu, Ruxandra, Chousterman, Benjamin, Mégarbanne, Bruno, Richette, Pascal, Riveline, Jean-Pierre, Frazier, Aline, Vicaut, Eric, Berton, Laure, Hadjam, Tassadit, Vazquez-Ibarra, Miguel Alejandro, Jourdaine, Clément, Tran, Olivia, Jouis, Véronique, Jacob, Aude, Smati, Julie, Renaud, Stéphane, Pernin, Claire, Suarez, Lydia, Semerano, Luca, Abad, Sébastien, nainous, Ruben B., Bonnet, Nicolas, Comparon, Celine, Cohen, Yves, Cordel, Hugues, Dhote, Robin, Dournon, Nathalie, Duchemann, Boris, Ebstein, Nathan, Gille, Thomas, Giroux-Leprieur, Benedicte, Goupil de Bouille, Jeanne, Nunes, Hilario, Oziel, Johanna, Roulot, Dominique, Sese, Lucile, ClaireTantet, Uzunhan, Yurdagul, Bloch-Queyrat, Coralie, Levy, Vincent, Messani, Fadhila, Rahaoui, Mohammed, Petit, Myléne, Brahmi, Sabrina, Rathoin, Vanessa, Rigal, Marthe, Costedoat-Chalumeau, Nathalie, Luong, Liem Binh, Hamou, Zakaria Ait, Benghanem, Sarah, Blanche, Philippe, Carlier, Nicolas, Chaigne, Benjamin, Gauzit, Remy, Joumaa, Hassan, Jozwiak, Mathieu, Lachétre, Marie, Lafoeste, Hélène, Launay, Odie, Legendre, Paul, Marey, Jonathan, Morbieu, Caroline, Palmieri, Lola-Jade, Szwebel, Tali-Anne, Abdoul, Hendy, Bruneau, Alexandra, Beclin-Clabaux, Audrey, Larrieu, Charly, Montanari, Pierre, Dufour, Eric, Clarke, Ada, Le Bourlout, Catherine, Marin, Nathalie, Menage, Nathalie, Saleh-Mghir, Samira, Cisse, Mamadou Salif, Cheref, Kahina, Guerin, Corinne, Zerbit, Jérémie, Michel, Marc, Gallien, Sébastien, Crickx, Etienne, Le Vavasseur, Benjamin, Kempf, Emmanuelle, Jaffal, Karim, Vindrios, William, Oniszczuk, Julie, Guillaud, Constance, Lim, Pascal, Fois, Elena, Melica, Giovanna, Matignon, Marie, Jalabert, Maud, Lelièvre, Jean-Daniel, Schmitz, David, Bourhis, Marion, Belazouz, Sylia, Languille, Laetitia, Boucle, Caroline, Cita, Nelly, Didier, Agnés, Froura, Fahem, Ledudal, Katia, Sadaoui, Thiziri, Thiemele, Alaki, Le Febvre De Bailly, Delphine, Verlinde, Muriel Carvhalo, Mayaux, Julien, Cacoub, Patrice, Saadoun, David, Vautier, Mathieu, Bugaut, Héléne, Benveniste, Olivier, Allenbach, Yves, Leroux, Gaëlle, Rigolet, Aude, Guillaume-Jugnot, Perrine, Domont, Fanny, Desbois, Anne Claire, Comarmond, Chloé, Champtiaux, Nicolas, Toquet, Segolene, Ghembaza, Amine, Vieira, Matheus, Maalouf, Georgina, Boleto, Goncalo, Ferfar, Yasmina, Corvol, Jean-Christophe, Louapre, C.line, Sambin, Sara, Mariani, Louise-Laure, Karachi, Carine, Tubach, Florence, Estellat, Candice, Gimeno, Linda, Martin, Karine, Bah, Aicha, Keo, Vixra, Ouamri, Sabrine, Messaoudi, Yasmine, Yelles, Nessima, Faye, Pierre, Cavelot, Sebastien, Larcheveque, Cecile, Annonay, Laurence, Benhida, Jaouad, Zahrate-Ghoul, Aida, Hammal, Soumeya, Belilita, Ridha, Charbonnier, Fanny, Aguilar, Claire, Alby-Laurent, Fanny, Burger, Carole, Campos-Vega, Clara, Chavarot, Nathalie, Fournier, Benjamin, Rouzaud, Claire, Vimpére, Damien, Elie, Caroline, Bakouboula, Prissile, Choupeaux, Laure, Granville, Sophie, Issorat, Elodie, Broissand, Christine, Alyanakian, Marie-Alexandra, Geri, Guillaume, Derridj, Nawal, Sguiouar, Naima, Meddah, Hakim, Djadel, Mourad, Chambrin-Lauvray, Héléne, Duclos-vallée, Jean-Charles, Saliba, Faouzi, Sacleux, Sophie-Caroline, Kounis, Ilias, Tamazirt, Sonia, Rudant, Eric, Michot, Jean-Marie, Stoclin, Annabelle, Colomba, Emeline, Pommeret, Fanny, Willekens, Christophe, Da Silva, Rosa, Dejean, Valérie, Mekid, Yasmina, Ben-Mabrouk, Ines, Netzer, Florence, Pradon, Caroline, Drouard, Laurence, Camara-Clayette, Valérie, Morel, Alexandre, Garcia, Gilles, Mohebbi, Abolfazl, Berbour, Férial, Dehais, Mélanie, Pouliquen, Anne-Lise, Klasen, Alison, Soyez-Herkert, Loren, London, Jonathan, Keroumi, Younes, Guillot, Emmanuelle, Grailles, Guillaume, El amine, Younes, Defrancq, Fanny, Fodil, Hanane, Bouras, Chaouki, Dautel, Dominique, Gambier, Nicolas, Dieye, Thierno, Bienvenu, Boris, Lancon, Victor, Lecomte, Laurence, Beziriganyan, Kristina, Asselate, Belkacem, Allanic, Laure, Kiouris, Elena, Legros, Marie-Héléne, Lemagner, Christine, Martel, Pascal, Provitolo, Vincent, Ackermann, Félix, Le Marchand, Mathilde, Chan Hew Wai, Aurélie, Fremont, Dimitri, Coupez, Elisabeth, Adda, Mireille, Duée, Frédéric, Bernard, Lise, Gros, Antoine, Henry, Estelle, Courtin, Claire, Pattyn, Anne, Guinot, Pierre-Grégoire, Bardou, Marc, Maurer, Agnes, Jambon, Julie, Cransac, Amélie, Pernot, Corinne, Mourvillier, Bruno, Marquis, Eric, Benoit, Philippe, Roux, Damien, Gernez, Coralie, Yelnik, Cécile, Poissy, Julien, Nizard, Mandy, Denies, Fanette, Gros, Helene, Mourad, Jean-Jacques, Sacco, Emmanuelle, Renet, Sophie, Ader, F., Yazdanpanah, Y., Mentre, F., Peiffer-Smadja, N., Lescure, F.X., Poissy, J., Bouadma, L., Timsit, J.F., Lina, B., Morfin-Sherpa, F., Bouscambert, M., Gaymard, A., Peytavin, G., Abel, L., Guedj, J., Andrejak, C., Burdet, C., Laouenan, C., Belhadi, D., Dupont, A., Alfaiate, T., Basli, B., Chair, A., Laribi, S., Level, J., Schneider, M., Tellier, M.C., Dechanet, A., Costagliola, D., Terrier, B., Ohana, M., Couffin-Cadiergues, S., Esperou, H., Delmas, C., Saillard, J., Fougerou, C., Moinot, L., Wittkop, L., Cagnot, C., Le Mestre, S., Lebrasseur-Longuet, D., Petrov-Sanchez, V., Diallo, A., Mercier, N., Icard, V., Leveau, B., Tubiana, S., Hamze, B., Gelley, A., Noret, M., D’Ortenzio, E., Puechal, O., Semaille, C., Welte, T., Paiva, J.A., Halanova, M., Kieny, M.P., Balssa, E., Birkle, C., Gibowski, S., Landry, E., Le Goff, A., Moachon, L., Moins, C., Wadouachi, L., Paul, C., Levier, A., Bougon, D., Djossou, F., Epelboin, L., Dellamonica, J., Marquette, C.H., Robert, C., Gibot, S., Senneville, E., Jean-Michel, V., Zerbib, Y., Chirouze, C., Boyer, A., Cazanave, C., Gruson, D., Malvy, D., Andreu, P., Quenot, J.P., Terzi, N., Faure, K., Chabartier, C., Le Moing, V., Klouche, K., Ferry, T., F, Valour, Gaborit, B., Canet, E., Le Turnier, P., Boutoille, D., Bani-Sadr, F., Benezit, F., Revest, M., Cameli, C., Caro, A., Um Tegue, MJ Ngo, Le Tulzo, Y., Laviolle, B., Laine, F., Thiery, G., Meziani, F., Hansmann, Y., Oulehri, W., Tacquard, C., Vardon-Bounes, F., Riu-Poulenc, B., Murris-Espin, M., Bernard, L., Garot, D., Hinschberger, O., Martinot, M., Bruel, C., Pilmis, B., Bouchaud, O., Loubet, P., Roger, C., Monnet, X., Figueiredo, S., Godard, V., Mira, J.P., Lachatre, M., Kerneis, S., Aboab, J., Sayre, N., Crockett, F., Lebeaux, D., Buffet, A., Diehl, J.L., Fayol, A., Hulot, J.S., Livrozet, M., Dessap, A Mekontso, Ficko, C., Stefan, F., Le Pavec, J., Mayaux, J., Ait-Oufella, H., Molina, J.M., Pialoux, G., Fartoukh, M., Textoris, J., Brossard, M., Essat, A., Netzer, E., Riault, Y., Ghislain, M., Beniguel, L., Genin, M., Gouichiche, L., Betard, C., Belkhir, L., Altdorfer, A., Centro, V Fraipont, Braz, S., Ribeiro, JM Ferreira, Alburqueque, R Roncon, Berna, M., Alexandre, M., Lamprecht, B., Egle, A., Greil, R., Joannidis, M., Patterson, Thomas F., Ponce, Philip O., Taylor, Barbara S., Patterson, Jan E., Bowling, Jason E., Javeri, Heta, Kalil, Andre C., Larson, LuAnn, Hewlett, Angela, Mehta, Aneesh K., Rouphael, Nadine G., Saklawi, Youssef, Scanlon, Nicholas, Traenkner, Jessica J., Trible, Ronald P., Jr., Walter, Emmanuel B., Ivey, Noel, Holland, Thomas L., Ruiz-Palacios, Guillermo M., Ponce de León, Alfredo, Rajme, Sandra, Hsieh, Lanny, Amin, Alpesh N., Watanabe, Miki, Lee, Helen S., Kline, Susan, Billings, Joanne, Noren, Brooke, Kim, Hyun, Bold, Tyler D., Tapson, Victor, Grein, Jonathan, Sutterwala, Fayyaz, Iovine, Nicole, Beattie, Lars K., Wakeman, Rebecca Murray, Shaw, Matthew, Jain, Mamta K., Mocherla, Satish, Meisner, Jessica, Luque, Amneris, Sweeney, Daniel A., Benson, Constance A., Ali, Farhana, Atmar, Robert L., El Sahly, Hana M., Whitaker, Jennifer, Falsey, Ann R., Branche, Angela R., Rozario, Cheryl, Pineda, Justino Regalado, Martinez-Orozco, José Arturo, Lye, David Chien, Ong, Sean WX., Chia, Po Ying, Young, Barnaby E., Sandkovsky, Uriel, Berhe, Mezgebe, Haley, Clinton, Dishner, Emma, Cantos, Valeria D., Kelley, Colleen F., Rebolledo Esteinou, Paulina A., Kandiah, Sheetal, Doernberg, Sarah B., Crouch, Pierre-Cedric B., Jang, Hannah, Luetkemeyer, Anne F., Dwyer, Jay, Cohen, Stuart H., Thompson, George R., 3rd, Nguyen, Hien H., Finberg, Robert W., Wang, Jennifer P., Perez-Velazquez, Juan, Wessolossky, Mireya, Jackson, Patrick E.H., Bell, Taison D., West, Miranda J., Taiwo, Babafemi, Krueger, Karen, Perez, Johnny, Pearson, Triniece, Paules, Catharine I., Julian, Kathleen G., Ahmad, Danish, Hajduczok, Alexander G., Arguinchona, Henry, Arguinchona, Christa, Erdmann, Nathaniel, Goepfert, Paul, Ahuja, Neera, Frank, Maria G., Wyles, David, Young, Heather, Oh, Myoung-don, Park, Wan Beom, Kang, Chang Kyung, Marconi, Vincent, Moanna, Abeer, Cribbs, Sushma, Harrison, Telisha, Kim, Eu Suk, Jung, Jongtak, Song, Kyoung-Ho, Kim, Hong Bin, Tan, Seow Yen, Shafi, Humaira, Chien, Jaime, Fong, Raymond KC., Murray, Daniel D., Lundgren, Jens, Nielsen, Henrik, Jensen, Tomas, Zingman, Barry S., Grossberg, Robert, Riska, Paul F., Yang, Otto O., Ahn, Jenny, Arias, Rubi, Rapaka, Rekha R., Hauser, Naomi, Campbell, James D., Short, William R., Tebas, Pablo, Baron, Jillian T., McLellan, Susan L.F., Blanton, Lucas S., Seashore, Justin B., Creech, C. Buddy, Rice, Todd W., Walker, Shannon, Thomsen, Isaac P., Lopez de Castilla, Diego, Van Winkle, Jason W., Riedo, Francis X., Pada, Surinder Kaur, Wang, Alvin DY., Lin, Li, Harkins, Michelle, Mertz, Gregory, Sosa, Nestor, Ann Chai, Louis Yi, Tambyah, Paul Anantharajah, Tham, Sai Meng, Archuleta, Sophia, Yan, Gabriel, Lindholm, David A., Markelz, Ana Elizabeth, Mende, Katrin, Mularski, Richard, Hohmann, Elizabeth, Torres-Soto, Mariam, Jilg, Nikolaus, Maves, Ryan C., Utz, Gregory C., George, Sarah L., Hoft, Daniel F., Brien, James D., Paredes, Roger, Mateu, Lourdes, Loste, Cora, Kumar, Princy, Thornton, Sarah, Mohanraj, Sharmila, Hynes, Noreen A., Sauer, Lauren M., Colombo, Christopher J., Schofield, Christina, Colombo, Rhonda E., Chambers, Susan E., Novak, Richard M., Wendrow, Andrea, Gupta, Samir K., Lee, Tida, Lalani, Tahaniyat, Holodniy, Mark, Chary, Aarthi, Huprikar, Nikhil, Ganesan, Anuradha, Ohmagari, Norio, Mikami, Ayako, Price, D. Ashley, Duncan, Christopher J.A., Dierberg, Kerry, Neumann, Henry J., Taylor, Stephanie N., Lacour, Alisha, Masri, Najy, Swiatlo, Edwin, Widmer, Kyle, Neaton, James D., Bessesen, Mary, Stephens, David S., Burgess, Timothy H., Uyeki, Timothy M., Walker, Robert, Marks, G. Lynn, Osinusi, Anu, Cao, Huyen, Cardoso, Anabela, de Bono, Stephanie, Schlichting, Douglas E., Chung, Kevin K., Ferreira, Jennifer L., Green, Michelle, Makowski, Mat, Wierzbicki, Michael R., Conrad, Tom M., El-Khorazaty, Jill Ann, Hill, Heather, Bonnett, Tyler, Gettinger, Nikki, Engel, Theresa, Lewis, Teri, Wang, Jing, Beigel, John H., Tomashek, Kay M., Ghazaryan, Varduhi, Beresnev, Tatiana, Nayak, Seema, Dodd, Lori E., Dempsey, Walla, Nomicos, Effie, Lee, Marina, Pikaart-Tautges, Rhonda, Elsafy, Mohamed, Jurao, Robert, Koo, Hyung, Proschan, Michael, Yokum, Tammy, Arega, Janice, Florese, Ruth, Voell, Jocelyn D., Davey, Richard, Serrano, Ruth C., Wiley, Zanthia, Phadke, Varun K., Goepfert, Paul A., Gomez, Carlos A., Sofarelli, Theresa A., Certain, Laura, Imlay, Hannah N., Wolfe, Cameron R., Ko, Emily R., Engemann, John J., Felix, Nora Bautista, Wan, Claire R., Elmor, Sammy T., Bristow, Laurel R., Harkins, Michelle S., Iovine, Nicole M., Elie-Turenne, Marie-Carmelle, Tapson, Victor F., Choe, Pyoeng Gyun, Mularski, Richard A., Rhie, Kevin S., Hussein, Rezhan H., Ince, Dilek, Winokur, Patricia L., Takasaki, Jin, Saito, Sho, McConnell, Kimberly, Wyles, David L., Sarcone, Ellen, Grimes, Kevin A., Perez, Katherine, Janak, Charles, Whitaker, Jennifer A., Rebolledo, Paulina A., Gharbin, John, Lambert, Allison A., Zea, Diego F., Bainbridge, Emma, Hostler, David C., Hostler, Jordanna M., Shahan, Brian T., Ling, Evelyn, Go, Minjoung, Hubbard, Fleesie A., Chakrabarty, Melony, Laguio-Vila, Maryrose, Walsh, Edward E., Guirgis, Faheem, Marconi, Vincent C., Madar, Christian, Borgetti, Scott A., Levine, Corri, Nock, Joy, Candiotti, Keith, Rozman, Julia, Dangond, Fernando, Hyvert, Yann, Seitzinger, Andrea, Cross, Kaitlyn, Pettibone, Stephanie, Nayak, Seema U., Deye, Gregory A., Siempos, Ilias I., Belhadi, Drifa, Veiga, Viviane Cordeiro, Cavalcanti, Alexandre Biasi, Branch-Elliman, Westyn, Papoutsi, Eleni, Gkirgkiris, Konstantinos, Xixi, Nikoleta A., and Kotanidou, Anastasia

Published
2024
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4. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial

Author

Kalil, Andre C, Mehta, Aneesh K, Patterson, Thomas F, Erdmann, Nathaniel, Gomez, Carlos A, Jain, Mamta K, Wolfe, Cameron R, Ruiz-Palacios, Guillermo M, Kline, Susan, Pineda, Justino Regalado, Luetkemeyer, Anne F, Harkins, Michelle S, Jackson, Patrick EH, Iovine, Nicole M, Tapson, Victor F, Oh, Myoung-don, Whitaker, Jennifer A, Mularski, Richard A, Paules, Catharine I, Ince, Dilek, Takasaki, Jin, Sweeney, Daniel A, Sandkovsky, Uriel, Wyles, David L, Hohmann, Elizabeth, Grimes, Kevin A, Grossberg, Robert, Laguio-Vila, Maryrose, Lambert, Allison A, de Castilla, Diego Lopez, Kim, EuSuk, Larson, LuAnn, Wan, Claire R, Traenkner, Jessica J, Ponce, Philip O, Patterson, Jan E, Goepfert, Paul A, Sofarelli, Theresa A, Mocherla, Satish, Ko, Emily R, de Leon, Alfredo Ponce, Doernberg, Sarah B, Atmar, Robert L, Maves, Ryan C, Dangond, Fernando, Ferreira, Jennifer, Green, Michelle, Makowski, Mat, Bonnett, Tyler, Beresnev, Tatiana, Ghazaryan, Varduhi, Dempsey, Walla, Nayak, Seema U, Dodd, Lori, Tomashek, Kay M, Beigel, John H, members, ACTT-3 study group, Hewlett, Angela, Taylor, Barbara S, Bowling, Jason E, Serrano, Ruth C, Rouphael, Nadine G, Wiley, Zanthia, Phadke, Varun K, Certain, Laura, Imlay, Hannah N, Engemann, John J, Walter, Emmanuel B, Meisner, Jessica, Rajme, Sandra, Billings, Joanne, Kim, Hyun, Martinez-Orozco, Jose A, Felix, Nora Bautista, Elmor, Sammy T, Bristow, Laurel R, Mertz, Gregory, Sosa, Nestor, Bell, Taison D, West, Miranda J, Elie-Turenne, Marie-Carmelle, Grein, Jonathan, Sutterwala, Fayyaz, Choe, Pyoeng Gyun, Kang, Chang Kyung, Sahly, Hana M El, Rhie, Kevin S, Hussein, Rezhan H, Winokur, Patricia L, Mikami, Ayako, Saito, Sho, Benson, Constance A, McConnell, Kimberly, Berhe, Mezgebe, Dishner, Emma, Frank, Maria G, Sarcone, Ellen, Crouch, Pierre-Cedric B, Jang, Hannah, and Jilg, Nikolaus

Subjects
Rehabilitation, Clinical Trials and Supportive Activities, Lung, Clinical Research, Infectious Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Adenosine Monophosphate, Adult, Aged, Alanine, Antiviral Agents, Double-Blind Method, Female, Humans, Interferon beta-1a, Japan, Male, Mexico, Middle Aged, Oxygen, Oxygen Saturation, Republic of Korea, SARS-CoV-2, Singapore, Treatment Outcome, United States, COVID-19 Drug Treatment, ACTT-3 study group members, Clinical Sciences, Public Health and Health Services, Other Medical and Health Sciences
Abstract

BackgroundFunctional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.MethodsWe did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475.FindingsBetween Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.InterpretationInterferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.FundingThe National Institute of Allergy and Infectious Diseases (USA).

Published
2021

5. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study

Author

Freedman, Mark S, Leist, Thomas P, Comi, Giancarlo, Cree, Bruce AC, Coyle, Patricia K, Hartung, Hans-Peter, Vermersch, Patrick, Damian, Doris, and Dangond, Fernando

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurodegenerative, Brain Disorders, Clinical Trials and Supportive Activities, Autoimmune Disease, Multiple Sclerosis, Neurosciences, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Cladribine tablets, McDonald 2010 criteria, clinically isolated syndrome, conversion to clinically definite multiple sclerosis, early multiple sclerosis, efficacy, Epidemiology, Health services and systems
Abstract

BackgroundMultiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria.ObjectiveThe objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS.MethodsA post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted.ResultsCladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p

Published
2017

6. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-blind, randomised, placebo-controlled, phase 3 trial

Author

Hewlett, Angela, Taylor, Barbara S, Bowling, Jason E, Serrano, Ruth C, Rouphael, Nadine G, Wiley, Zanthia, Phadke, Varun K, Certain, Laura, Imlay, Hannah N, Engemann, John J, Walter, Emmanuel B, Meisner, Jessica, Rajme, Sandra, Billings, Joanne, Kim, Hyun, Martinez-Orozco, Jose A, Bautista Felix, Nora, Elmor, Sammy T, Bristow, Laurel R, Mertz, Gregory, Sosa, Nestor, Bell, Taison D, West, Miranda J, Elie-Turenne, Marie-Carmelle, Grein, Jonathan, Sutterwala, Fayyaz, Gyun Choe, Pyoeng, Kyung Kang, Chang, El Sahly, Hana M, Rhie, Kevin S, Hussein, Rezhan H, Winokur, Patricia L, Mikami, Ayako, Saito, Sho, Benson, Constance A, McConnell, Kimberly, Berhe, Mezgebe, Dishner, Emma, Frank, Maria G, Sarcone, Ellen, Crouch, Pierre-Cedric B, Jang, Hannah, Jilg, Nikolaus, Perez, Katherine, Janak, Charles, Cantos, Valeria D, Rebolledo, Paulina A, Gharbin, John, Zingman, Barry S, Riska, Paul F, Falsey, Ann R, Walsh, Edward E, Branche, Angela R, Arguinchona, Henry, Arguinchona, Christa, Van Winkle, Jason W, Zea, Diego F, Jung, Jongtak, Song, Kyoung-Ho, Kim, Hong Bin, Dwyer, Jay, Bainbridge, Emma, Hostler, David C, Hostler, Jordanna M, Shahan, Brian T, Hsieh, Lanny, Amin, Alpesh N, Watanabe, Miki, Short, William R, Tebas, Pablo, Baron, Jillian T, Ahuja, Neera, Ling, Evelyn, Go, Minjoung, Yang, Otto O, Ahn, Jenny, Arias, Rubi, Rapaka, Rekha R, Hubbard, Fleesie A, Campbell, James D, Cohen, Stuart H, Thompson, George R, 3rd, Chakrabarty, Melony, Taylor, Stephanie N, Masri, Najy, Lacour, Alisha, Lee, Tida, Lalani, Tahaniyat, Lindholm, David A, Markelz, Ana Elizabeth, Mende, Katrin, Colombo, Christopher J, Schofield, Christina, Colombo, Rhonda E, Guirgis, Faheem, Holodniy, Mark, Chary, Aarthi, Bessesen, Mary, Hynes, Noreen A, Sauer, Lauren M, Marconi, Vincent C, Moanna, Abeer, Harrison, Telisha, Lye, David C, Ong, Sean W X, Ying Chia, Po, Huprikar, Nikhil, Ganesan, Anuradha, Madar, Christian, Novak, Richard M, Wendrow, Andrea, Borgetti, Scott A, George, Sarah L, Hoft, Daniel F, Brien, James D, McLellan, Susan L F, Levine, Corri, Nock, Joy, Yen Tan, Seow, Shafi, Humaira, Chien, Jaime M F, Candiotti, Keith, Finberg, Robert W, Wang, Jennifer P, Wessolossky, Mireya, Utz, Gregory C, Chambers, Susan E, Stephens, David S, Burgess, Timothy H, Rozman, Julia, Hyvert, Yann, Seitzinger, Andrea, Osinusi, Anu, Cao, Huyen, Chung, Kevin K, Conrad, Tom M, Cross, Kaitlyn, El-Khorazaty, Jill A, Hill, Heather, Pettibone, Stephanie, Wierzbicki, Michael R, Gettinger, Nikki, Engel, Theresa, Lewis, Teri, Wang, Jing, Deye, Gregory A, Nomicos, Effie, Pikaart-Tautges, Rhonda, Elsafy, Mohamed, Jurao, Robert, Koo, Hyung, Proschan, Michael, Davey, Richard, Yokum, Tammy, Arega, Janice, Florese, Ruth, Kalil, Andre C, Mehta, Aneesh K, Patterson, Thomas F, Erdmann, Nathaniel, Gomez, Carlos A, Jain, Mamta K, Wolfe, Cameron R, Ruiz-Palacios, Guillermo M, Kline, Susan, Regalado Pineda, Justino, Luetkemeyer, Anne F, Harkins, Michelle S, Jackson, Patrick E H, Iovine, Nicole M, Tapson, Victor F, Oh, Myoung-don, Whitaker, Jennifer A, Mularski, Richard A, Paules, Catharine I, Ince, Dilek, Takasaki, Jin, Sweeney, Daniel A, Sandkovsky, Uriel, Wyles, David L, Hohmann, Elizabeth, Grimes, Kevin A, Grossberg, Robert, Laguio-Vila, Maryrose, Lambert, Allison A, Lopez de Castilla, Diego, Kim, EuSuk, Larson, LuAnn, Wan, Claire R, Traenkner, Jessica J, Ponce, Philip O, Patterson, Jan E, Goepfert, Paul A, Sofarelli, Theresa A, Mocherla, Satish, Ko, Emily R, Ponce de Leon, Alfredo, Doernberg, Sarah B, Atmar, Robert L, Maves, Ryan C, Dangond, Fernando, Ferreira, Jennifer, Green, Michelle, Makowski, Mat, Bonnett, Tyler, Beresnev, Tatiana, Ghazaryan, Varduhi, Dempsey, Walla, Nayak, Seema U, Dodd, Lori, Tomashek, Kay M, and Beigel, John H

Published
2021
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15. Cladribine tablets added to IFN-β in active relapsing MS: The ONWARD study

Author

Montalban, Xavier, Leist, Thomas P., Cohen, Bruce A., Moses, Harold, Campbell, Jackie, Hicking, Christine, Dangond, Fernando, Comi, Giancarlo, Gallo, Paolo, Pozzilli, Carlo, Gasperini, Claudio, Morra, Vincenzo Brescia, Boyko, Alexey N, Amelina, Olga, Kotov, Sergey V, Novikova, Lilia, Patrusheva, Olga, Zavalishin, Igor, Khabirov, Farid, Maslova, Natalia, Malkova, Nadezda, Poverennova, Irina E, Montalban, Xavier, Martinez Yelamos, Sergio, Izquierdo, Guillermo, Fernandez, Oscar, Rodriguez-Antiguedad, Alfredo, Sempere, Angel Perez, Arroyo, Rafael, Casanova, Bonaventura, Arias, Manual, Cascione, Mark, Cohen, Bruce Arnold, Fox, Edward, Berkovich, Regina, Kaufman, Michael, Leist, Thomas, Jacobs, Dina, Miller, Tamara, Moses, Harold, Racke, Michael, Hutton, George, Singer, Barry, Kresa-Reahl, Kiren, Pharr, Emily, Carter, Jonathan L, Wendt, Jeanette, Tandan, Rup, Bomprezzi, Roberto, Ford, Corey, Kamin, Stephen, Pless, Misha, Garmany, George P, Gazda, Suzanne, English, Jeffrey, Green, Barbara, Garwacki, Dennis, Gould, Jeffrey, and LaGanke, Chris

Published
2018
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27. Determination of a clinically effective evobrutinib dose: Exposure–response analyses of a phase II relapsing multiple sclerosis study.

Author

Papasouliotis, Orestis, Mitchell, David, Girard, Pascal, Dangond, Fernando, and Dyroff, Martin

Subjects
BRUTON tyrosine kinase, FINGOLIMOD, MULTIPLE sclerosis
Abstract

The pharmacometric analysis of the double‐blind, randomized, phase II study (NCT02975349) investigating the safety and efficacy of evobrutinib, explored exposure–response relationships and suitable dosing regimens of evobrutinib for relapsing multiple sclerosis. Population pharmacokinetic (PK)/pharmacodynamic modeling was applied to data collected in fasted patients treated with placebo or evobrutinib (25 mg once‐daily [q.d.], 75 mg q.d., or 75 mg twice‐daily [b.i.d.]) for 24 weeks, followed by a 24‐week blinded extension (placebo patients switched to 25 mg q.d.). Model‐based exposures for PK and Bruton's tyrosine kinase occupancy (BTKO) were used for exposure–response analyses (maximum 207 patients). PK, BTKO profiles, and annualized relapse rate (ARR) after 48 weeks of treatment under alternative dosing regimens were simulated. Exposure–response modeling identified a relationship between evobrutinib exposure and clinical response for total number of T1 Gd+ and new/enlarging T2 lesions at weeks 12–24, and ARR at week 48. Area under the concentration–time curve over 24 h at steady‐state (AUC0–24,SS) of 468 and ≥400 ng/ml h was associated with T1 Gd+/T2 lesion reduction and ARR improvement, respectively. These exposures were associated with steady‐state (SS) predose BTKO ≥95%. Based on PK and BTKO profile simulations, evobrutinib 75 mg b.i.d. while fasted is predicted to maintain SS predose BTKO >95% in 92% of patients. Evobrutinib 45 mg b.i.d. with food is predicted to achieve similar exposure as 75 mg b.i.d. while fasted (predose BTKO >95% in 93% of patients). Evobrutinib 45 mg b.i.d. with food is predicted to have comparable exposure and BTKO to 75 mg b.i.d. without food (phase II) and will be pharmacologically effective and appropriate for clinical use in phase III multiple sclerosis studies. [ABSTRACT FROM AUTHOR]

Published
2022
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33. Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies.

Author

De Stefano, Nicola, Sormani, Maria Pia, Giovannoni, Gavin, Rammohan, Kottil, Leist, Thomas, Coyle, Patricia K, Dangond, Fernando, Keller, Birgit, Alexandri, Nektaria, and Galazka, Andrew

Subjects
MULTIPLE sclerosis, PLACEBOS, DISEASE relapse, PATIENTS
Abstract

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment. Objective: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension. Methods: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT (n = 433) and placebo (n = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension (n = 98). Results: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p < 0.0001), and qualifying or all severe relapses (all p < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment. Conclusion: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis. CLARITY: NCT00213135; CLARITY Extension: NCT00641537 [ABSTRACT FROM AUTHOR]

Published
2022
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37. Comparative injection-site pain and tolerability of subcutaneous serum-free formulation of interferonβ-1a versus subcutaneous interferonβ-1b: results of the randomized, multicenter, Phase IIIb REFORMS study

Author

Singer Barry, Bandari Daniel, Cascione Mark, LaGanke Christopher, Huddlestone John, Bennett Randy, and Dangond Fernando

Subjects
Randomized controlled trial, Interferonβ-1a, Interferonβ-1b, Relapsing–remitting multiple sclerosis, Subcutaneous injections, Injection-site pain, Pain measurement, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background In patients with relapsing–remitting multiple sclerosis (RRMS), subcutaneous (sc) interferon (IFN)β-1a and IFNβ-1b have been shown to reduce relapse rates. A formulation of IFNβ-1a has been produced without fetal bovine serum and without human serum albumin as an excipient (not currently approved for use in the US). The objectives of this study were to evaluate tolerability, injection-site redness, subject-reported satisfaction with therapy, and clinical safety and efficacy of the serum-free formulation of IFNβ-1a versus IFNβ-1b in IFNβ-treatment-naïve patients with RRMS. The objectives of the extension phase were to evaluate long-term safety and tolerability of IFNβ-1a. Methods This randomized, parallel-group, open-label study was conducted at 27 clinical sites in the US. Eligible patients aged 18–60 years were randomized to receive either IFNβ-1a, titrated to 44 μg sc three times weekly (tiw) (n = 65), or IFNβ-1b, titrated to 250 μg sc every other day (n = 64) over 12 weeks. Following this, all patients received IFNβ-1a 44 μg tiw for 82–112 weeks. Primary endpoint was mean change in patient-reported pain, as assessed by visual analog scale (VAS) diary pain score (from 0 mm [no pain] to 100 mm [worst possible pain]) at the injection site, from pre-injection to 30 min post-injection over the first 21 full-dose injections. Secondary assessments included proportion of patients pain-free as recorded by VAS diary and the Short-Form McGill Pain questionnaire VAS. Results A total of 129 patients were included in the intent-to-treat analysis. Mean (standard deviation) change in VAS diary pain score was not significantly different between groups, although numerically lower with IFNβ-1a versus IFNβ-1b from pre-injection to immediately post-injection (1.46 [2.93] vs. 4.63 [10.57] mm), 10 min post-injection (0.70 [1.89] vs. 1.89 [5.75] mm), and 30 min post-injection (0.67 [2.32] vs. 1.14 [4.94] mm). Proportion of patients pain-free at all time periods post-injection was also not significantly different between groups. Adverse events were consistent with the known safety profiles of these treatments. Conclusions In IFNβ-treatment-naïve patients with RRMS, both the serum-free formulation of IFNβ-1a and IFNβ-1b treatments were generally accompanied by low-level injection-site pain and were well tolerated. Trial registration ClinicalTrials.gov NCT00428584

Published
2012
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38. Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis.

Author

Oh, Jiwon, Walker, Bryan, Giovannoni, Gavin, Jack, Dominic, Dangond, Fernando, Nolting, Axel, Aldridge, Julie, Lebson, Lori A, and Leist, Thomas P

Subjects
TERMINATION of treatment, MULTIPLE sclerosis, THERAPEUTICS, PLACEBOS, LYMPHOPENIA
Abstract

Background: Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets. Objective: To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies. Methods: This post hoc analysis of CLARITY and ORACLE-MS safety populations assessed the incidence of TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation in patients receiving cladribine tablets or placebo within 2, 6, and 12 weeks after treatment initiation. Results: By Week 12, 61.3% of patients treated with cladribine tablets 3.5 mg/kg and 55.2% treated with placebo experienced a TEAE. More patients receiving cladribine tablets versus placebo experienced a drug-related TEAE by Week 12 (34.7% vs. 23.2%). The most common TEAEs reported with cladribine tablets were: headache (7.2%), lymphopenia (6.8%), and nausea (6.0%). Patients receiving cladribine tablets and placebo reported similar proportions of serious TEAEs (2.2% vs. 1.7%) and TEAEs leading to treatment discontinuation (1.6% vs. 1.4%). Conclusion: Cladribine tablets were well tolerated during the first 12 weeks as evidenced by a low incidence of TEAEs leading to treatment discontinuation. [ABSTRACT FROM AUTHOR]

Published
2021
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39. Efficacy of cladribine tablets in high disease activity patients with relapsing multiple sclerosis: post hoc analysis of subgroups with and without prior disease-modifying drug treatment.

Author

Vermersch, Patrick, Galazka, Andrew, Dangond, Fernando, Damian, Doris, Wong, Schiffon L., Jack, Dominic, and Harty, Gerard

Subjects
NATALIZUMAB, MAGNETIC resonance imaging, MULTIPLE sclerosis, DISEASE relapse, SUBGROUP analysis (Experimental design), THERAPEUTICS
Abstract

Relapsing–remitting multiple sclerosis (RRMS) patients with high disease activity (HDA) experience more severe disease than those without HDA. This analysis describes the efficacy of cladribine tablets 3.5 mg/kg in HDA patient subgroups that were either treated with disease-modifying drugs (DMDs) prior to study entry or were treatment naïve. Post hoc analysis of the 96 week Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study compared cladribine tablets 3.5 mg/kg to placebo in subgroups of patients meeting the high relapse activity plus disease activity on treatment definition of HDA. Patients were categorized into either prior DMD treatment or DMD treatment-naïve subgroups. Endpoints included annualized relapse rate (ARR), time to first relapse, time to disability progression and magnetic resonance imaging (MRI) outcomes. No inferential statistical analyses were conducted between subgroups. The DMD-naïve cohort (n = 187) was larger than the prior-DMD cohort (n = 102). In both the DMD-naïve and prior-DMD cohorts, cladribine tablets were associated with a reduction in ARR (rate ratio [RR]: 0.26; 95% confidence interval [CI]: 0.16–0.42; p <.0001 and RR: 0.55; 95% CI: 0.32–0.95; p =.0324, respectively). In both subgroups, cladribine tablets increased the time to relapse versus placebo (hazard ratio [HR]: 0.36; 95% CI: 0.21–0.62; p =.0002 for DMD-naïve cohort and HR: 0.50; 95% CI: 0.24–1.02; p =.0557 for prior-DMD cohort). Significant differences were observed for all assessed disability and MRI outcomes independently of previous treatment. Post hoc evidence suggests consistent treatment benefits of cladribine tablets 3.5 mg/kg during the 96 week CLARITY study among HDA-RRMS patients who were either previously treated with DMDs or were treatment naïve. [ABSTRACT FROM AUTHOR]

Published
2021
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40. Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

Author

Freedman, Mark S., Coyle, Patricia K., Comi, Giancarlo, Scarberry, Susan L., Damian, Doris, Hyvert, Yann, Dangond, Fernando, Galazka, Andrew, Jack, Dominic, Lebson, Lori A., and Leist, Thomas P.

Subjects
MULTIPLE sclerosis, MAGNETIC resonance imaging
Abstract

Background: In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE). Objective: To determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI). Methods: This post hoc analysis assessed the effect of cladribine tablets versus placebo in ORACLE-MS on secondary MRI endpoints including T1 gadolinium-enhancing (Gd+), new or enlarging T2 lesions, and combined unique active lesions assessed on MRI scans performed at screening and every 3 months thereafter. Results: Compared to placebo, cladribine tablets 3.5 mg/kg treatment appeared to lead to a trend of reductions in the mean number of T1 Gd+ lesions by Week 13 (first post-baseline scan: 0.37 vs. 1.00), new or enlarging T2 (0.20 vs. 1.01) and combined unique active (0.29 vs. 1.91) lesions by Week 24. Low lesion counts were maintained with cladribine tablets throughout 96weeks. Similar results were observed with the 5.25 mg/kg dosage. Conclusion: In participants with an FCDE, cladribine tablets appeared to reduce lesion numbers within 13 weeks (time of first evaluation). [ABSTRACT FROM AUTHOR]

Published
2021
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42. Effects of cladribine tablets on heart rate, atrio‐ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis.

Author

Hermann, Robert, Litwin, Jeffrey S., Friberg, Lena E., Dangond, Fernando, and Munafo, Alain

Subjects
HEART beat, MULTIPLE sclerosis, CARDIAC patients, HEART conduction system, NATALIZUMAB, ALEMTUZUMAB, THERAPEUTICS, BODY weight
Abstract

Aims: Cladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune‐mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: CLARITY was a 96‐week, double‐blind, placebo‐controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post‐dose ECGs. ECG data were collected 15 minutes pre‐dose and between 0.5 and 3 hours post‐dose at pre‐study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52. Results: For cladribine tablets 3.5 mg/kg, the maximum change in placebo‐adjusted post‐dose QTcF vs. visit‐baseline (BL) was −0.42 ms (90% CI: −3.61–4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: −0.08–6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post‐dose QTcF vs. study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53–11.44) and 8.74 ms (90% CI: 3.18–14.31), respectively. No significant changes were observed in T‐wave morphology in either treatment group. Conclusions: Cladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization. [ABSTRACT FROM AUTHOR]

Published
2019
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43. Efficacy of Cladribine Tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study.

Author

Giovannoni, Gavin, Soelberg Sorensen, Per, Cook, Stuart, Rammohan, Kottil W, Rieckmann, Peter, Comi, Giancarlo, Dangond, Fernando, Hicking, Christine, and Vermersch, Patrick

Subjects
MAGNETIC resonance imaging, MULTIPLE sclerosis
Abstract

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis. Objective: Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population. Methods: Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to study entry while on therapy with other DMDs and ⩾1 T1 Gd+ or ⩾9 T2 lesions). Results: In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo. A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA. There were consistent results for other efficacy endpoints. The safety profile in HDA patients was consistent with the overall CLARITY population. Conclusion: Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population. [ABSTRACT FROM AUTHOR]

Published
2019
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49. Safety and efficacy of cladribine tablets in patients with relapsing–remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.

Author

Giovannoni, Gavin, Soelberg Sorensen, Per, Cook, Stuart, Rammohan, Kottil, Rieckmann, Peter, Comi, Giancarlo, Dangond, Fernando, Adeniji, Abidemi K., and Vermersch, Patrick

Subjects
MULTIPLE sclerosis, MAGNETIC resonance imaging, LYMPHOPENIA, DEOXYADENOSINE, NEUTROPHILS
Abstract

Background: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing–remitting multiple sclerosis (MS). Objective: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. Methods: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. Results: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0–1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. Conclusion: Cladribine tablets treatment for 2 years followed by 2 years’ placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting. [ABSTRACT FROM AUTHOR]

Published
2018
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50. Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets.

Author

De Stefano, Nicola, Giorgio, Antonio, Battaglini, Marco, De Leucio, Alessandro, Hicking, Christine, Dangond, Fernando, Giovannoni, Gavin, and Sormani, Maria Pia

Subjects
MULTIPLE sclerosis treatment, CEREBRAL atrophy, DISEASE relapse, DISABILITIES, MAGNETIC resonance imaging of the brain
Abstract

Background: Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage. Methods: In the CLARITY study (ClinicalTrials.gov NCT00213135), the effect of 2 years' treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS). Results: Compared with placebo (-0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (-0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (-0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p < 0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at 2 years and vice versa. Conclusions: Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates. [ABSTRACT FROM AUTHOR]

Published
2018
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