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17. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial

Author

Selim, Magdy, Foster, Lydia D, Moy, Claudia S, Xi, Guohua, Hill, Michael D, Morgenstern, Lewis B, Greenberg, Steven M, James, Michael L, Singh, Vineeta, Clark, Wayne M, Norton, Casey, Palesch, Yuko Y, Yeatts, Sharon D, Investigators, i-DEF, Dolan, Monica, Yeh, Erlinda, Sheth, Kevin, Kunze, Kimberly, Muehlschlegel, Susanne, Nieto, Iryna, Claassen, Jan, Falo, Cristina, Huang, David, Beckwith, Anne, Messe, Steven, Yates, Melissa, O'Phelan, Kristine, Escobar, Andrea, Becker, Kyra, Tanzi, Patricia, Gonzales, Nicole, Tremont, Chad, Venkatasubramanian, Chitra, Thiessen, Rosita, Save, Supriya, Verrault, Steven, Collard, Karin, DeGeorgia, Michael, Cwiklinski, Valerie, Thompson, Bradford, Wasilewski, Lesley, Andrews, Charles, Burfeind, Robert, Torbey, Michel, Hamed, Mohammad, Butcher, Kenneth, Sivakumar, Leka, Varelas, Nicolaou, Mays-Wilson, Kathleen, Leira, Enrique, Olalde, Heena, Silliman, Scott, Calhoun, Rhonda, Dangayach, Neha, Renvill, Ricardo, Malhotra, Rishi, Kordesch, Kristina, Lord, Aaron, Calahan, Thomas, Geocadin, Romergryko, Parish, Michelle, Frey, James, Harrigan, Mary, Leifer, Dana, Mathias, Ryna, Schneck, Michael, Bernier, Tara, Gonzales-Arias, Sergio, Elysee, Josette, Lopez, George, Volgi, Josephine, Brown, Robert, Jasak, Sara, Phillips, Stephen, Jarrett, Judith, Gomes, Joao, McBride, Moneen, Aldrich, Francois, Aldrich, Charlene, Kornbluth, Joshua, Bettle, Michelle, Goldstein, Joshua, Tirrell, Gregory, Shaw, Qaisar, and Jonczak, Karin

Subjects
Neurosciences, Clinical Research, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, Cerebral Hemorrhage, Deferoxamine, Double-Blind Method, Female, Humans, Infusions, Intravenous, Iron Chelating Agents, Male, Medical Futility, Middle Aged, Negative Results, Prospective Studies, Risk Assessment, Treatment Outcome, i-DEF Investigators, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundIron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial.MethodsWe did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed.FindingsWe recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related.InterpretationDeferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile.FundingUS National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

Published
2019

23. Contributors

Author

Adams, Harold P., primary, Adeoye, Opeolu, additional, Albers, Gregory W., additional, Alexandrov, Andrei V., additional, Amin-Hanjani, Sepideh, additional, An, Hongyu, additional, Anderson, Craig S., additional, Anrather, Josef, additional, Aparicio, Hugo J., additional, Arai, Ken, additional, Aronowski, Jaroslaw, additional, Atchaneeyasakul, Kunakorn, additional, Audebert, Heinrich, additional, Auer, Roland N., additional, Awad, Issam A., additional, Ay, Hakan, additional, Baltan, Selva, additional, Balu, Ramani, additional, Behbahani, Mandana, additional, Benavente, Oscar R., additional, Bershad, Eric M., additional, Berthaud, Jimmy V., additional, Blackburn, Spiros L., additional, Bonati, Leo H., additional, Bösel, Julian, additional, Bousser, Marie Germaine, additional, Broderick, Joseph P., additional, Brown, Martin M., additional, Brown, Wendy, additional, Brust, John C.M., additional, Bushnell, Cheryl, additional, Canhão, Patrícia, additional, Caplan, Louis R., additional, Carrión-Penagos, Julián, additional, Castellanos, Mar, additional, Caunca, Michelle R., additional, Chabriat, Hugues, additional, Chamorro, Angel, additional, Chen, Jieli, additional, Chen, Jun, additional, Chopp, Michael, additional, Christorforids, Greg, additional, Connolly, E. Sander, additional, Cramer, Steven C., additional, Cucchiara, Brett L., additional, Czap, Alexandra L., additional, Dannenbaum, Mark J., additional, Davis, Patricia H., additional, Dawson, Ted M., additional, Dawson, Valina L., additional, Day, Arthur L., additional, De Silva, T. Michael, additional, de Sousa, Diana Aguiar, additional, Del Brutto, Victor J., additional, del Zoppo, Gregory J., additional, Derdeyn, Colin P., additional, Di Tullio, Marco R., additional, Diener, Hans Christoph, additional, Diringer, Michael N., additional, Dobkin, Bruce H., additional, Dzialowski, Imanuel, additional, Elkind, Mitchell S.V., additional, Elm, Jordan, additional, Feigin, Valery L., additional, Ferro, José Manuel, additional, Field, Thalia S., additional, Fischer, Marlene, additional, Fornage, Myriam, additional, Furie, Karen L., additional, Garcia-Bonilla, Lidia, additional, Giannotta, Steven L., additional, Gobin, Y. Pierre, additional, Goldberg, Mark P., additional, Goldstein, Larry B., additional, Gonzales, Nicole R., additional, Greer, David M., additional, Grotta, James C., additional, Guo, Ruiming, additional, Gutierrez, Jose, additional, Harmel, Peter, additional, Howard, George, additional, Howard, Virginia J., additional, Hwang, Jee-Yeon, additional, Iadecola, Costantino, additional, Jahan, Reza, additional, Jickling, Glen C., additional, Joutel, Anne, additional, Kasner, Scott E., additional, Katan, Mira, additional, Kellner, Christopher P., additional, Khan, Muhib, additional, Kidwell, Chelsea S., additional, Kim, Helen, additional, Kim, Jong S., additional, Kircher, Charles E., additional, Krings, Timo, additional, Krishnamurthi, Rita V., additional, Kurth, Tobias, additional, Lansberg, Maarten G., additional, Levy, Elad I., additional, Liebeskind, David S., additional, Liew, Sook-Lei, additional, Lin, David J., additional, Lisle, Benjamin, additional, Lo, Eng H., additional, Lyden, Patrick D., additional, Maki, Takakuni, additional, Maragkos, Georgios A., additional, Marosfoi, Miklos, additional, McCullough, Louise D., additional, Meckler, Jason M., additional, Meschia, James Frederick, additional, Messé, Steven R., additional, Mocco, J, additional, Mokin, Maxim, additional, Mooney, Michael A., additional, Morgenstern, Lewis B., additional, Moskowitz, Michael A., additional, Mullen, Michael T., additional, Nägel, Steffen, additional, Nedergaard, Maiken, additional, Neira, Justin A., additional, Newman, Sarah, additional, Nicholson, Patrick J., additional, Norrving, Bo, additional, O’Donnell, Martin, additional, Ofengeim, Dimitry, additional, Ogata, Jun, additional, Ogilvy, Christopher S., additional, Orrù, Emanuele, additional, Ortega-Gutiérrez, Santiago, additional, Padrick, Matthew Maximillian, additional, Parsha, Kaushik, additional, Parsons, Mark, additional, Patel, Neil V., additional, Patel, Virendra I., additional, Pawlikowska, Ludmila, additional, Pérez, Adriana, additional, Perez-Pinzon, Miguel A., additional, Picard, John M., additional, Polster, Sean P., additional, Powers, William J., additional, Puetz, Volker, additional, Putaala, Jukka, additional, Rabinovich, Margarita, additional, Ransom, Bruce R., additional, Roa, Jorge A., additional, Rosenberg, Gary A., additional, Rossitto, Christina P., additional, Rundek, Tatjana, additional, Russin, Jonathan J., additional, Sacco, Ralph L., additional, Safouris, Apostolos, additional, Samaniego, Edgar A., additional, Sansing, Lauren H., additional, Satani, Nikunj, additional, Sattenberg, Ronald J., additional, Saver, Jeffrey L., additional, Savitz, Sean I., additional, Schmidt, Christian, additional, Seshadri, Sudha, additional, Sharma, Vijay K., additional, Sharp, Frank R., additional, Sheth, Kevin N., additional, Siddiqi, Omar K., additional, Singhal, Aneesh B., additional, Sobey, Christopher G., additional, Sommer, Clemens J., additional, Spetzler, Robert F., additional, Stapleton, Christopher J., additional, Strickland, Ben A., additional, Su, Hua, additional, Suarez, José I., additional, Takayama, Hiroo, additional, Tarsia, Joseph, additional, Tatlisumak, Turgut, additional, Thomas, Ajith J., additional, Thompson, John W., additional, Tsivgoulis, Georgios, additional, Tournier-Lasserve, Elizabeth, additional, Vidal, Gabriel, additional, Wakhloo, Ajay K., additional, Weksler, Babette B., additional, Willey, Joshua Z., additional, Wintermark, Max, additional, Wong, Lawrence K.S., additional, Xi, Guohua, additional, Xu, Jinchong, additional, Yaghi, Shadi, additional, Yamaguchi, Takenori, additional, Yang, Tuo, additional, Yasaka, Masahiro, additional, Zahuranec, Darin B., additional, Zhang, Feng, additional, Zhang, John H., additional, Zheng, Zhitong, additional, Zukin, R. Suzanne, additional, and Zweifler, Richard M., additional

Published
2022
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28. Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.

Author

Karuppagounder, Saravanan, Alim, Ishraq, Khim, Soah, Bourassa, Megan, Sleiman, Sama, John, Roseleen, Thinnes, Cyrille, Yeh, Tzu-Lan, Demetriades, Marina, Neitemeier, Sandra, Cruz, Dana, Gazaryan, Irina, Killilea, David, Morgenstern, Lewis, Xi, Guohua, Keep, Richard, Schallert, Timothy, Tappero, Ryan, Zhong, Jian, Cho, Sunghee, Maxfield, Frederick, Holman, Theodore, Culmsee, Carsten, Fong, Guo-Hua, Su, Yijing, Ming, Guo-li, Song, Hongjun, Cave, John, Schofield, Christopher, Colbourne, Frederick, Coppola, Giovanni, and Ratan, Rajiv

Subjects
Activating Transcription Factor 4, Animals, Brain, Cell Death, Cells, Cultured, Disease Models, Animal, Gene Expression Regulation, Genes, Reporter, Hemin, Hypoxia-Inducible Factor 1, alpha Subunit, Intracranial Hemorrhages, Iron, Iron Chelating Agents, Mice, Molecular Targeted Therapy, Neurons, Neuroprotective Agents, Oxygen, Procollagen-Proline Dioxygenase, Protein Domains, Protein Isoforms, Rats, Recovery of Function
Abstract

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.

Published
2016

34. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial

Author

Dolan, Monica, Yeh, Erlinda, Sheth, Kevin, Kunze, Kimberly, Muehlschlegel, Susanne, Nieto, Iryna, Claassen, Jan, Falo, Cristina, Huang, David, Beckwith, Anne, Messe, Steven, Yates, Melissa, O'Phelan, Kristine, Escobar, Andrea, Becker, Kyra, Tanzi, Patricia, Gonzales, Nicole, Tremont, Chad, Venkatasubramanian, Chitra, Thiessen, Rosita, Save, Supriya, Verrault, Steven, Collard, Karin, DeGeorgia, Michael, Cwiklinski, Valerie, Thompson, Bradford, Wasilewski, Lesley, Andrews, Charles, Burfeind, Robert, Torbey, Michel, Hamed, Mohammad, Butcher, Kenneth, Sivakumar, Leka, Varelas, Nicolaou, Mays-Wilson, Kathleen, Leira, Enrique, Olalde, Heena, Silliman, Scott, Calhoun, Rhonda, Dangayach, Neha, Renvill, Ricardo, Malhotra, Rishi, Kordesch, Kristina, Lord, Aaron, Calahan, Thomas, Geocadin, Romergryko, Parish, Michelle, Frey, James, Harrigan, Mary, Leifer, Dana, Mathias, Ryna, Schneck, Michael, Bernier, Tara, Gonzales-Arias, Sergio, Elysee, Josette, Lopez, George, Volgi, Josephine, Brown, Robert, Jasak, Sara, Phillips, Stephen, Jarrett, Judith, Gomes, Joao, McBride, Moneen, Aldrich, Francois, Aldrich, Charlene, Kornbluth, Joshua, Bettle, Michelle, Goldstein, Joshua, Tirrell, Gregory, Shaw, Qaisar, Jonczak, Karin, Selim, Magdy, Foster, Lydia D, Moy, Claudia S, Xi, Guohua, Hill, Michael D, Morgenstern, Lewis B, Greenberg, Steven M, James, Michael L, Singh, Vineeta, Clark, Wayne M, Norton, Casey, Palesch, Yuko Y, and Yeatts, Sharon D

Published
2019
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