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3. Designing an exploratory phase 2b platform trial in NASH with correlated, co-primary binary endpoints

Author

Meyer, Elias Laurin, Mesenbrink, Peter, Di Prospero, Nicholas A., Pericàs, Juan M., Glimm, Ekkehard, Ratziu, Vlad, Sena, Elena, and König, Franz

Subjects
Statistics - Applications
Abstract

Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and a disease with high unmet medical need. Platform trials provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. In this article, we describe some of the activities of the EU-PEARL consortium (EU Patient-cEntric clinicAl tRial pLatforms) regarding the use of platform trials in NASH, in particular the proposed trial design, decision rules and simulation results. For a set of assumptions, we present the results of a simulation study recently discussed with two health authorities and the learnings from these meetings from a trial design perspective. Since the proposed design uses co-primary binary endpoints, we furthermore discuss the different options and practical considerations for simulating correlated binary endpoints.

Published
2022
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4. CohortPlat: Simulation of cohort platform trials investigating combination therapies

Author

Meyer, Elias Laurin, Mesenbrink, Peter, Dunger-Baldauf, Cornelia, Glimm, Ekkehard, and König, Franz

Subjects
Statistics - Applications
Abstract

Platform trials have gained a lot of attention recently as a possible remedy for time-consuming classical two-arm randomized controlled trials, especially in early phase drug development. This short article illustrates how to use the CohortPlat R package to simulate a cohort platform trial, where each cohort consists of a combination treatment and the respective monotherapies and standard-of-care. The endpoint is always assumed to be binary. The package offers extensive flexibility with respect to both platform trial trajectories, as well as treatment effect scenarios and decision rules. As a special feature, the package provides a designated function for running multiple such simulations efficiently in parallel and saving the results in a concise manner. Many illustrations of code usage are provided.

Published
2022

5. On model-based time trend adjustments in platform trials with non-concurrent controls

Author

Roig, Marta Bofill, Krotka, Pavla, Burman, Carl-Fredrik, Glimm, Ekkehard, Gold, Stefan M., Hees, Katharina, Jacko, Peter, Koenig, Franz, Magirr, Dominic, Mesenbrink, Peter, Viele, Kert, and Posch, Martin

Subjects
Statistics - Methodology
Abstract

Platform trials can evaluate the efficacy of several treatments compared to a control. The number of treatments is not fixed, as arms may be added or removed as the trial progresses. Platform trials are more efficient than independent parallel-group trials because of using shared control groups. For arms entering the trial later, not all patients in the control group are randomised concurrently. The control group is then divided into concurrent and non-concurrent controls. Using non-concurrent controls (NCC) can improve the trial's efficiency, but can introduce bias due to time trends. We focus on a platform trial with two treatment arms and a common control arm. Assuming that the second treatment arm is added later, we assess the robustness of model-based approaches to adjust for time trends when using NCC. We consider approaches where time trends are modeled as linear or as a step function, with steps at times where arms enter or leave the trial. For trials with continuous or binary outcomes, we investigate the type 1 error (t1e) rate and power of testing the efficacy of the newly added arm under a range of scenarios. In addition to scenarios where time trends are equal across arms, we investigate settings with trends that are different or not additive in the model scale. A step function model fitted on data from all arms gives increased power while controlling the t1e, as long as the time trends are equal for the different arms and additive on the model scale. This holds even if the trend's shape deviates from a step function if block randomisation is used. But if trends differ between arms or are not additive on the model scale, t1e control may be lost. The efficiency gained by using step function models to incorporate NCC can outweigh potential biases. However, the specifics of the trial, plausibility of different time trends, and robustness of results should be considered

Published
2021
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6. Pseudo-domains in imaging data improve prediction of future disease status in multi-center studies

Author

Perkonigg, Matthias, Mesenbrink, Peter, Goehler, Alexander, Martic, Miljen, Ba-Ssalamah, Ahmed, and Langs, Georg

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning
Abstract

In multi-center randomized clinical trials imaging data can be diverse due to acquisition technology or scanning protocols. Models predicting future outcome of patients are impaired by this data heterogeneity. Here, we propose a prediction method that can cope with a high number of different scanning sites and a low number of samples per site. We cluster sites into pseudo-domains based on visual appearance of scans, and train pseudo-domain specific models. Results show that they improve the prediction accuracy for steatosis after 48 weeks from imaging data acquired at an initial visit and 12-weeks follow-up in liver disease, Comment: Accepted at Medical Imaging Meets NeurIPS 2021

Published
2021

7. Decision rules for identifying combination therapies in open-entry, randomized controlled platform trials

Author

Meyer, Elias Laurin, Mesenbrink, Peter, Dunger-Baldauf, Cornelia, Glimm, Ekkehard, Li, Yuhan, and König, Franz

Subjects
Statistics - Applications
Abstract

Platform trials have become increasingly popular for drug development programs, attracting interest from statisticians, clinicians and regulatory agencies. Many statistical questions related to designing platform trials - such as the impact of decision rules, sharing of information across cohorts, and allocation ratios on operating characteristics and error rates - remain unanswered. In many platform trials, the definition of error rates is not straightforward as classical error rate concepts are not applicable. For an open-entry, exploratory platform trial design comparing combination therapies to the respective monotherapies and standard-of-care, we define a set of error rates and operating characteristics and then use these to compare a set of design parameters under a range of simulation assumptions. When setting up the simulations, we aimed for realistic trial trajectories, such that e.g. a priori we do not know the exact number of treatments that will be included over time in a specific simulation run as this follows a stochastic mechanism. Our results indicate that the method of data sharing, exact specification of decision rules and a priori assumptions regarding the treatment efficacy all strongly contribute to the operating characteristics of the platform trial. Furthermore, different operating characteristics might be of importance to different stakeholders. Together with the potential flexibility and complexity of a platform trial, which also impact the achieved operating characteristics via e.g. the degree of efficiency of data sharing, this implies that utmost care needs to be given to evaluation of different assumptions and design parameters at the design stage.

Published
2021
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8. Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Author

Sánchez-Montalva, Adrian, Estevez, Ana Belén, Sánchez, Àlex, Sanjuan, Anna, Sena, Elena, Granados, Emma, Arévalo de Andrés, Esther, Nuñez, Fátima, Arteaga, Gara, Fuentes Ruiz, Gabriela Perez, Fernández, Guillermo, Rivera-Esteban, Jesus, Comella, Joan, Ramos-Quiroga, Josep Antoni, Genescà, Joan, Espinosa, Juan, Pericàs, Juan Manuel, Murcia, Lada, Cash-Gibson, Lucinda, de Valles Silvosa, Maria, Barroso de Sousa, María Fernanda, Sánchez-Maroto Carrizo, Olga, Ibañez-Jiménez, Pol, Augustin, Salvador, Perez-Hoyos, Santiago, Rodríguez-Navarro, Sarai, Muñoz-Martínez, Sergio, Serres, Silvia, Kalko, Susana, Michon, Amelie, Ussi, Anton, Lydall, Ben, van de Ketterij, Edwin, Quiles, Ignacio, Carapina, Tamara, Kumaus, Constantin, Ramazanova, Dariga, Meyer, Elias Laurin, Koenig, Franz, Roig, Marta Bofill, Brunner, Martin, Posch, Martin, Krotka, Pavla, Zehetmayer, Sonja, Carton, Charlotte, Legius, Eric, Begum, Amina, Pariante, Carmine, Worrell, Courtney, Lombardo, Giulia, Sforzini, Luca, Brown, Mollie, Gullet, Nancy, Amasi-Hartoonian, Nare, Ferner, Rosalie, Kose, Melisa, Spitaleri, Andrea, Ghodousi, Arash, Di Serio, Clelia, Cirillo, Daniela, Cugnata, Federica, Saluzzo, Francesca, Benedetti, Francesco, Scarale, Maria Giovanna, Zini, Michela, Rancoita, Paola Maria, Alagna, Riccardo, Poletti, Sara, Dhaenens, Britt, Van Der Lei, Johan, de Steenwinkel, Jurriaan, Moinat, Maxim, Oostenbrink, Rianne, Hoogendijk, Witte, Hölscher, Michael, Heinrich, Norbert, Otte, Christian, Potratz, Cornelia, Zocholl, Dario, Kulakova, Eugenia, Tacke, Frank, Brasanac, Jelena, Leubner, Jonas, Krajewska, Maja, Freitag, Michaela Maria, Gold, Stefan, Zoller, Thomas, Chae, Woo Ri, Daniel, Christel, Kara, Leila, Vaterkowski, Morgan, Griffon, Nicolas, Wolkenstein, Pierre, Pais, Raluca, Ratziu, Vlad, Voets, David, Maes, Christophe, Kalra, Dipak, Thienpoint, Geert, Deckerck, Jens, Lea, Nathan, Singleton, Peter, Viele, Kert, Jacko, Peter, Berry, Scott, Parke, Tom, Aydin, Burç, Kubiak, Christine, Demotes, Jacques, Ueda, Keiko, Matei, Mihaela, Contrino, Sergio, Röhl, Claas, Cordero, Estefania, Greenhalgh, Fiona, Jarke, Hannes, Angelova, Juliana, Boudes, Mathieu, Dressler, Stephan, Strammiello, Valentina, Anstee, Quentin, Gutierrez-Ibarluzea, Iñaki, Otte, Maximilian, Heimbach, Natalie, Hofner, Benjamin, Burgwinkel, Cora, Kaestel, Hue, Hees, Katharina, Nguyen, Quynh, Prieto-Alhambra, Daniel, Tan, Eng Hooi (Cheryl), Raviglione, Mario, de Colombani, Pierpaolo, Villa, Simone, Maron, Eduard, Evans, Gareth, Savitz, Adam J., Van Dessel, Ann, Duca, Anna, Kaminski, Anne, Wouters, Bie, Porter, Brandon, Charron, Catherine, Spiertz, Cecile, Zizzamia, Christopher, Millar, Daniel, Hasselbaink, Danny, Orr, David, Kesters, Divya, Hubin, Ellen, Davies, Emma, Didden, Eva-Maria, Guz, Gabriela, Verstraete, Evelyn, Mao, Gary, Capuano, George, Martynowicz, Heddie, De Smedt, Heidi, Larsson, Ingela, Bruegelmans, Ines, Coste, Isabelle, Gonzalez Moreno, Jesus Maria, Niewczas, Julia, Xu, Jiajun, Rombouts, Karin, Woo, Katherine, Wuyts, Kathleen, Hersh, Kathryn, Oldenburg, Khrista, Zhang, Lingjiao, Schmidt, Mark, Szuch, Mark, Todorovic, Marija, Mangelaars, Maartje, Grewal, Melissa, Sandor, Molli, Di Prospero, Nick, Van Houten, Pamela, Minnick, Pansy, Bastos, Polyana, Patrizi, Robert, Morello, Salvatore, De Wilde, Severijn, Sun, Tao, Kline, Timothy, de Marez, Tine, Mielke, Tobias, Reijns, Tom, Popova, Vanina, Flossbach, Yanina, Tymofyeyev, Yevgen, De Groote, Zeger, Sverdlov, Alex, Bobirca, Alexandra, Krause, Annekatrin, Bobrica, Catalin, Heintz, Daniela, Magirr, Dominic, Glimm, Ekkehard, Baffert, Fabienne, Castiglione, Federica, Caruso, Franca, Patalano, Francesco, Bretz, Frank, Heimann, Guenter, Carbarns, Ian, Rodríguez, Ignacio, Ratescu, Ioana, Hampson, Lisa, Pedrosa, Marcos, Hark, Mareile, Mesenbrink, Peter, Penna, Sabina Hernandez, Bergues-Lang, Sarah, Baltes-Engler, Susanne, Arsiwala, Tasneem, Mondragon, Valeria Jordan, Guo, Hua, Da Costa, Jose Leite, Burman, Carl-Fredrik, Kirk, George, Aaes-Jørgensen, Anders, Dirach, Jorgen, Kjær, Mette Skalshøi, Martin, Alexandra, Hristov, Diyan, Rousseaux, Florent, Hittel, Norbert, Dornheim, Robert, Evans, Daniel, Sykes, Nick, Couvert, Camille, Leuven, Catherine, Notelet, Loïc, Gidh-Jain, Madhavi, Jouannin, Mathieu, Ammour, Nadir, Pierre, Suzanne, Haufe, Volker, Dong, Yingwen, Dubanchet, Catherine, de Préville, Nathalie, Baltauss, Tania, Jian, Zhu, Shnider, Sara, Bar-El, Tal, Bakker, Annette, Nievo, Marco, Iloeje, Uche, Conradie, Almari, Auffarrth, Ece, Lombard, Leandra, Benhayoun, Majda, Olugbosi, Morounfolu, Seidel, Stephanie S., Gumí, Berta, Guzmán, Claudia García, Molero, Eva, Pairó, Gisela, Machin, Núria, Cardelús, Raimon, Ramasastry, Saira, Pelzer, Saskia, Kremer, Andreas, Lindfors, Erno, Lynch, Chris, Spiertz, Cécile, Machín, Núria, and Pericàs, Juan M.

Published
2024
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10. Platform Trial Designs

Author

Sverdlov, Oleksandr, Glimm, Ekkehard, Mesenbrink, Peter, Choodari-Oskooei, Babak, Section editor, Parmar, Mahesh, Section editor, Meinert, Curtis L., Section editor, Piantadosi, Steven, Section editor, Piantadosi, Steven, editor, and Meinert, Curtis L., editor

Published
2022
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12. Regulatory Issues of Platform Trials: Learnings from EU‐PEARL

Author

Nguyen, Quynh Lan, primary, Hees, Katharina, additional, Hernandez Penna, Sabina, additional, König, Franz, additional, Posch, Martin, additional, Bofill Roig, Marta, additional, Meyer, Elias Laurin, additional, Freitag, Michaela Maria, additional, Parke, Tom, additional, Otte, Maximilian, additional, Dauben, Hans‐Peter, additional, Mielke, Tobias, additional, Spiertz, Cecile, additional, Mesenbrink, Peter, additional, Gidh‐Jain, Madhavi, additional, Pierre, Suzanne, additional, Morello, Salvatore, additional, and Hofner, Benjamin, additional

Published
2024
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13. Machine learning approaches to enhance diagnosis and staging of patients with MASLD using routinely available clinical information

Author

Mcteer, Matthew, Applegate, Douglas, Mesenbrink, Peter, Ratziu, Vlad, Schattenberg, Joern M., Bugianesi, Elisabetta, Geier, Andreas, Gomez, Manuel Romero, Dufour, Jean-Francois, Ekstedt, Mattias, Francque, Sven, Yki-Jarvinen, Hannele, Allison, Michael, Valenti, Luca, Miele, Luca, Pavlides, Michael, Cobbold, Jeremy, Papatheodoridis, Georgios, Holleboom, Adriaan G., Tiniakos, Dina, Brass, Clifford, Anstee, Quentin M., Missier, Paolo, Mcteer, Matthew, Applegate, Douglas, Mesenbrink, Peter, Ratziu, Vlad, Schattenberg, Joern M., Bugianesi, Elisabetta, Geier, Andreas, Gomez, Manuel Romero, Dufour, Jean-Francois, Ekstedt, Mattias, Francque, Sven, Yki-Jarvinen, Hannele, Allison, Michael, Valenti, Luca, Miele, Luca, Pavlides, Michael, Cobbold, Jeremy, Papatheodoridis, Georgios, Holleboom, Adriaan G., Tiniakos, Dina, Brass, Clifford, Anstee, Quentin M., and Missier, Paolo

Abstract

Aims Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints.Methods Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test. This data was used to train predictive models using supervised machine learning (ML) algorithm XGBoost, alongside missing imputation technique MICE and class balancing algorithm SMOTE. Shapley Additive exPlanations (SHAP) were added to determine relative importance for each clinical variable.Results Analysing nine biopsy-derived MASLD outcomes of cohort size ranging between 5385 and 6673 subjects, we were able to predict individuals at training set AUCs ranging from 0.719-0.994, including classifying individuals who are At-Risk MASH at an AUC = 0.899. Using two further feature combinations of 26-variables and 35-variables, which included composite scores known to be good indicators for MASLD endpoints and advanced specialist tests, we found predictive performance did not sufficiently improve. We are also able to present local and global explanations for each ML model, offering clinicians interpretability without the expense of worsening predictive performance.Conclusions This study developed a series of ML models of accuracy ranging from 71.9-99.4% using only easily extractable and readily available information in predicting MASLD outcomes which are usually determined through highly invasive means., Funding Agencies|Newcastle University; Red Hat UK; LITMUS project - Innovative Medicines Initiative 2 Joint Undertaking [777377]; European Union's Horizon 2020 research and innovation programme; EFPIA; Newcastle NIHR Biomedical Research Centre.

Published
2024
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15. Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Author

Koenig, Franz, primary, Spiertz, Cécile, additional, Millar, Daniel, additional, Rodríguez-Navarro, Sarai, additional, Machín, Núria, additional, Van Dessel, Ann, additional, Genescà, Joan, additional, Pericàs, Juan M., additional, Posch, Martin, additional, Sánchez-Montalva, Adrian, additional, Estevez, Ana Belén, additional, Sánchez, Àlex, additional, Sanjuan, Anna, additional, Sena, Elena, additional, Granados, Emma, additional, Arévalo de Andrés, Esther, additional, Nuñez, Fátima, additional, Arteaga, Gara, additional, Fuentes Ruiz, Gabriela Perez, additional, Fernández, Guillermo, additional, Rivera-Esteban, Jesus, additional, Comella, Joan, additional, Ramos-Quiroga, Josep Antoni, additional, Espinosa, Juan, additional, Pericàs, Juan Manuel, additional, Murcia, Lada, additional, Cash-Gibson, Lucinda, additional, de Valles Silvosa, Maria, additional, Barroso de Sousa, María Fernanda, additional, Sánchez-Maroto Carrizo, Olga, additional, Ibañez-Jiménez, Pol, additional, Augustin, Salvador, additional, Perez-Hoyos, Santiago, additional, Muñoz-Martínez, Sergio, additional, Serres, Silvia, additional, Kalko, Susana, additional, Michon, Amelie, additional, Ussi, Anton, additional, Lydall, Ben, additional, van de Ketterij, Edwin, additional, Quiles, Ignacio, additional, Carapina, Tamara, additional, Kumaus, Constantin, additional, Ramazanova, Dariga, additional, Meyer, Elias Laurin, additional, Koenig, Franz, additional, Roig, Marta Bofill, additional, Brunner, Martin, additional, Krotka, Pavla, additional, Zehetmayer, Sonja, additional, Carton, Charlotte, additional, Legius, Eric, additional, Begum, Amina, additional, Pariante, Carmine, additional, Worrell, Courtney, additional, Lombardo, Giulia, additional, Sforzini, Luca, additional, Brown, Mollie, additional, Gullet, Nancy, additional, Amasi-Hartoonian, Nare, additional, Ferner, Rosalie, additional, Kose, Melisa, additional, Spitaleri, Andrea, additional, Ghodousi, Arash, additional, Di Serio, Clelia, additional, Cirillo, Daniela, additional, Cugnata, Federica, additional, Saluzzo, Francesca, additional, Benedetti, Francesco, additional, Scarale, Maria Giovanna, additional, Zini, Michela, additional, Rancoita, Paola Maria, additional, Alagna, Riccardo, additional, Poletti, Sara, additional, Dhaenens, Britt, additional, Van Der Lei, Johan, additional, de Steenwinkel, Jurriaan, additional, Moinat, Maxim, additional, Oostenbrink, Rianne, additional, Hoogendijk, Witte, additional, Hölscher, Michael, additional, Heinrich, Norbert, additional, Otte, Christian, additional, Potratz, Cornelia, additional, Zocholl, Dario, additional, Kulakova, Eugenia, additional, Tacke, Frank, additional, Brasanac, Jelena, additional, Leubner, Jonas, additional, Krajewska, Maja, additional, Freitag, Michaela Maria, additional, Gold, Stefan, additional, Zoller, Thomas, additional, Chae, Woo Ri, additional, Daniel, Christel, additional, Kara, Leila, additional, Vaterkowski, Morgan, additional, Griffon, Nicolas, additional, Wolkenstein, Pierre, additional, Pais, Raluca, additional, Ratziu, Vlad, additional, Voets, David, additional, Maes, Christophe, additional, Kalra, Dipak, additional, Thienpoint, Geert, additional, Deckerck, Jens, additional, Lea, Nathan, additional, Singleton, Peter, additional, Viele, Kert, additional, Jacko, Peter, additional, Berry, Scott, additional, Parke, Tom, additional, Aydin, Burç, additional, Kubiak, Christine, additional, Demotes, Jacques, additional, Ueda, Keiko, additional, Matei, Mihaela, additional, Contrino, Sergio, additional, Röhl, Claas, additional, Cordero, Estefania, additional, Greenhalgh, Fiona, additional, Jarke, Hannes, additional, Angelova, Juliana, additional, Boudes, Mathieu, additional, Dressler, Stephan, additional, Strammiello, Valentina, additional, Anstee, Quentin, additional, Gutierrez-Ibarluzea, Iñaki, additional, Otte, Maximilian, additional, Heimbach, Natalie, additional, Hofner, Benjamin, additional, Burgwinkel, Cora, additional, Kaestel, Hue, additional, Hees, Katharina, additional, Nguyen, Quynh, additional, Prieto-Alhambra, Daniel, additional, Tan, Eng Hooi (Cheryl), additional, Raviglione, Mario, additional, de Colombani, Pierpaolo, additional, Villa, Simone, additional, Maron, Eduard, additional, Evans, Gareth, additional, Savitz, Adam J., additional, Duca, Anna, additional, Kaminski, Anne, additional, Wouters, Bie, additional, Porter, Brandon, additional, Charron, Catherine, additional, Spiertz, Cecile, additional, Zizzamia, Christopher, additional, Hasselbaink, Danny, additional, Orr, David, additional, Kesters, Divya, additional, Hubin, Ellen, additional, Davies, Emma, additional, Didden, Eva-Maria, additional, Guz, Gabriela, additional, Verstraete, Evelyn, additional, Mao, Gary, additional, Capuano, George, additional, Martynowicz, Heddie, additional, De Smedt, Heidi, additional, Larsson, Ingela, additional, Bruegelmans, Ines, additional, Coste, Isabelle, additional, Gonzalez Moreno, Jesus Maria, additional, Niewczas, Julia, additional, Xu, Jiajun, additional, Rombouts, Karin, additional, Woo, Katherine, additional, Wuyts, Kathleen, additional, Hersh, Kathryn, additional, Oldenburg, Khrista, additional, Zhang, Lingjiao, additional, Schmidt, Mark, additional, Szuch, Mark, additional, Todorovic, Marija, additional, Mangelaars, Maartje, additional, Grewal, Melissa, additional, Sandor, Molli, additional, Di Prospero, Nick, additional, Van Houten, Pamela, additional, Minnick, Pansy, additional, Bastos, Polyana, additional, Patrizi, Robert, additional, Morello, Salvatore, additional, De Wilde, Severijn, additional, Sun, Tao, additional, Kline, Timothy, additional, de Marez, Tine, additional, Mielke, Tobias, additional, Reijns, Tom, additional, Popova, Vanina, additional, Flossbach, Yanina, additional, Tymofyeyev, Yevgen, additional, De Groote, Zeger, additional, Sverdlov, Alex, additional, Bobirca, Alexandra, additional, Krause, Annekatrin, additional, Bobrica, Catalin, additional, Heintz, Daniela, additional, Magirr, Dominic, additional, Glimm, Ekkehard, additional, Baffert, Fabienne, additional, Castiglione, Federica, additional, Caruso, Franca, additional, Patalano, Francesco, additional, Bretz, Frank, additional, Heimann, Guenter, additional, Carbarns, Ian, additional, Rodríguez, Ignacio, additional, Ratescu, Ioana, additional, Hampson, Lisa, additional, Pedrosa, Marcos, additional, Hark, Mareile, additional, Mesenbrink, Peter, additional, Penna, Sabina Hernandez, additional, Bergues-Lang, Sarah, additional, Baltes-Engler, Susanne, additional, Arsiwala, Tasneem, additional, Mondragon, Valeria Jordan, additional, Guo, Hua, additional, Da Costa, Jose Leite, additional, Burman, Carl-Fredrik, additional, Kirk, George, additional, Aaes-Jørgensen, Anders, additional, Dirach, Jorgen, additional, Kjær, Mette Skalshøi, additional, Martin, Alexandra, additional, Hristov, Diyan, additional, Rousseaux, Florent, additional, Hittel, Norbert, additional, Dornheim, Robert, additional, Evans, Daniel, additional, Sykes, Nick, additional, Couvert, Camille, additional, Leuven, Catherine, additional, Notelet, Loïc, additional, Gidh-Jain, Madhavi, additional, Jouannin, Mathieu, additional, Ammour, Nadir, additional, Pierre, Suzanne, additional, Haufe, Volker, additional, Dong, Yingwen, additional, Dubanchet, Catherine, additional, de Préville, Nathalie, additional, Baltauss, Tania, additional, Jian, Zhu, additional, Shnider, Sara, additional, Bar-El, Tal, additional, Bakker, Annette, additional, Nievo, Marco, additional, Iloeje, Uche, additional, Conradie, Almari, additional, Auffarrth, Ece, additional, Lombard, Leandra, additional, Benhayoun, Majda, additional, Olugbosi, Morounfolu, additional, Seidel, Stephanie S., additional, Gumí, Berta, additional, Guzmán, Claudia García, additional, Molero, Eva, additional, Pairó, Gisela, additional, Machin, Núria, additional, Cardelús, Raimon, additional, Ramasastry, Saira, additional, Pelzer, Saskia, additional, Kremer, Andreas, additional, Lindfors, Erno, additional, and Lynch, Chris, additional

Published
2024
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19. Time to onset of antifracture efficacy and year‐by‐year persistence of effect of zoledronic acid in women with osteoporosis

Author

Boonen, Steven, Eastell, Richard, Su, Guoqin, Mesenbrink, Peter, Cosman, Felicia, Cauley, Jane A, Reid, Ian R, Claessens, Frank, Vanderschueren, Dirk, Lyles, Kenneth W, and Black, Dennis M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Osteoporosis, Aging, Clinical Trials and Supportive Activities, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Aged, Aged, 80 and over, Algorithms, Bone Density, Bone Density Conservation Agents, Diphosphonates, Double-Blind Method, Female, Humans, Imidazoles, Osteoporosis, Postmenopausal, Osteoporotic Fractures, Placebos, Proportional Hazards Models, Risk, Time Factors, Zoledronic Acid, FRACTURES, POSTMENOPAUSAL OSTEOPOROSIS, REACTION TIME, ZOLEDRONIC ACID, BONE MINERAL DENSITY, Biological Sciences, Engineering, Medical and Health Sciences, Anatomy & Morphology, Biological sciences, Biomedical and clinical sciences
Abstract

Oral bisphosphonates reduce fracture risk in osteoporotic patients but are often associated with poor compliance, which may impair their antifracture effects. This post hoc analysis assessed the time to onset and persistence of the antifracture effect of zoledronic acid, a once-yearly bisphosphonate infusion, in women with osteoporosis. Data from 9355 women who were randomized in two placebo-controlled pivotal trials were included. Endpoints included reduction in the rate of any clinical fracture at 6, 12, 18, 24, and 36 months in the zoledronic acid group compared with placebo, and the year-by-year incidence of all clinical fractures over 3 years. Cox proportional hazards regression was used to determine the timing of onset of antifracture efficacy. A generalized estimating equation model was used to assess fracture reduction for the 3 consecutive years of treatment, thereby evaluating persistence of effect. Safety results from women in the two studies were collated. Zoledronic acid reduced the risk of all clinical fractures at 12 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.61-0.92, p = 0.0050) with significant reductions maintained at all subsequent time points. Year-by-year analysis showed that zoledronic acid reduced the risk for all clinical fractures compared with the placebo group in each of the 3 years (year 1: odds ratio [OR] = 0.74, 95% CI 0.60-0.91, p = 0.0044; year 2: OR = 0.53, 95% CI 0.42-0.66, p < 0.0001; year 3: OR = 0.61, 95% CI 0.48-0.77, p < 0.0001). This antifracture effect was persistent over 3 years, with the reductions in years 2 and 3 slightly larger than in year 1 (p = 0.097). This analysis shows that zoledronic acid offered significant protection from clinical fractures as early as 12 months. When administered annually, its beneficial effects persisted for at least 3 years.

Published
2012

20. Lessons for the setting of an international integrated research platform to conduct adaptive trials in non-alcoholic steatohepatitis: results of the EU-PEARL project

Author

Pericàs, Juan M, primary, de Sena, Elena, additional, Tacke, Frank, additional, Anstee, Quentin, additional, Di Prospero, Nicholas, additional, Kjaer, Mette, additional, Mesenbrink, Peter, additional, Koenig, Franz, additional, Genescà, Joan, additional, Ratziu, Vlad, additional, and Martínez, Sergio Muñoz, additional

Published
2023
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22. Longitudinal ALT trajectories are generally stable among patients with non-alcoholic fatty liver disease (NAFLD): an investigation using artificial recurrent neural networks

Author

Fried, Michael, primary, Munoz, Breda, additional, Wu, Jamie, additional, Cusi, Kenneth, additional, Wong, Vincent Wai-Sun, additional, Mesenbrink, Peter, additional, Pedrosa, Marcos, additional, Mospan, Andrea, additional, Vos, Miriam, additional, Loomba, Rohit, additional, and Sanyal, Arun, additional

Published
2022
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23. On model-based time trend adjustments in platform trials with non-concurrent controls

Author

Roig, Marta Bofill, Krotka, Pavla, Burman, Carl-Fredrik, Glimm, Ekkehard, Gold, Stefan M., Hees, Katharina, Jacko, Peter, Koenig, Franz, Magirr, Dominic, Mesenbrink, Peter, Viele, Kert, Posch, Martin, Roig, Marta Bofill, Krotka, Pavla, Burman, Carl-Fredrik, Glimm, Ekkehard, Gold, Stefan M., Hees, Katharina, Jacko, Peter, Koenig, Franz, Magirr, Dominic, Mesenbrink, Peter, Viele, Kert, and Posch, Martin

Abstract

Background: Platform trials can evaluate the efficacy of several experimental treatments compared to a control. The number of experimental treatments is not fixed, as arms may be added or removed as the trial progresses. Platform trials are more efficient than independent parallel group trials because of using shared control groups. However, for a treatment entering the trial at a later time point, the control group is divided into concurrent controls, consisting of patients randomised to control when that treatment arm is in the platform, and non-concurrent controls, patients randomised before. Using non-concurrent controls in addition to concurrent controls can improve the trial’s efficiency by increasing power and reducing the required sample size, but can introduce bias due to time trends. Methods: We focus on a platform trial with two treatment arms and a common control arm. Assuming that the second treatment arm is added at a later time, we assess the robustness of recently proposed model-based approaches to adjust for time trends when utilizing non-concurrent controls. In particular, we consider approaches where time trends are modeled either as linear in time or as a step function, with steps at time points where treatments enter or leave the platform trial. For trials with continuous or binary outcomes, we investigate the type 1 error rate and power of testing the efficacy of the newly added arm, as well as the bias and root mean squared error of treatment effect estimates under a range of scenarios. In addition to scenarios where time trends are equal across arms, we investigate settings with different time trends or time trends that are not additive in the scale of the model. Results: A step function model, fitted on data from all treatment arms, gives increased power while controlling the type 1 error, as long as the time trends are equal for the different arms and additive on the model scale. This holds even if the shape of the time trend deviates from

Published
2022

24. Designing an exploratory phase 2b platform trial in NASH with correlated, co-primary binary endpoints.

Author

Meyer, Elias Laurin, Mesenbrink, Peter, Di Prospero, Nicholas A., Pericàs, Juan M., Glimm, Ekkehard, Ratziu, Vlad, Sena, Elena, and König, Franz

Subjects
*NON-alcoholic fatty liver disease, *CONSORTIA, *DRUG development
Abstract

Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and a disease with high unmet medical need. Platform trials provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. In this article, we describe some of the activities of the EU-PEARL consortium (EU Patient-cEntric clinicAl tRial pLatforms) regarding the use of platform trials in NASH, in particular the proposed trial design, decision rules and simulation results. For a set of assumptions, we present the results of a simulation study recently discussed with two health authorities and the learnings from these meetings from a trial design perspective. Since the proposed design uses co-primary binary endpoints, we furthermore discuss the different options and practical considerations for simulating correlated binary endpoints. [ABSTRACT FROM AUTHOR]

Published
2023
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29. Decision rules for identifying combination therapies in open‐entry, randomized controlled platform trials.

Author

Meyer, Elias Laurin, Mesenbrink, Peter, Dunger‐Baldauf, Cornelia, Glimm, Ekkehard, Li, Yuhan, and König, Franz

Subjects
*ERROR rates, *GOVERNMENT agencies, *RATE setting, *DRUG development, *INFORMATION sharing
Abstract

Platform trials have become increasingly popular for drug development programs, attracting interest from statisticians, clinicians and regulatory agencies. Many statistical questions related to designing platform trials—such as the impact of decision rules, sharing of information across cohorts, and allocation ratios on operating characteristics and error rates—remain unanswered. In many platform trials, the definition of error rates is not straightforward as classical error rate concepts are not applicable. For an open‐entry, exploratory platform trial design comparing combination therapies to the respective monotherapies and standard‐of‐care, we define a set of error rates and operating characteristics and then use these to compare a set of design parameters under a range of simulation assumptions. When setting up the simulations, we aimed for realistic trial trajectories, such that for example, a priori we do not know the exact number of treatments that will be included over time in a specific simulation run as this follows a stochastic mechanism. Our results indicate that the method of data sharing, exact specification of decision rules and a priori assumptions regarding the treatment efficacy all strongly contribute to the operating characteristics of the platform trial. Furthermore, different operating characteristics might be of importance to different stakeholders. Together with the potential flexibility and complexity of a platform trial, which also impact the achieved operating characteristics via, for example, the degree of efficiency of data sharing this implies that utmost care needs to be given to evaluation of different assumptions and design parameters at the design stage. [ABSTRACT FROM AUTHOR]

Published
2022
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30. Incidence of osteonecrosis of the jaw in women with posemenopausal osteoporosis in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial

Author

Grbic, John T., Landesberg, Regina, Lin, Shou-Qing, Mesenbrink, Peter, Reid, Ian R., Leung, Ping-Cheung, Casas, Noemi, Recknor, Christopher P., Hua, Ye, Delmas, Pierre D., and Eriksen, Erik F.

Subjects
Postmenopausal women -- Health aspects, Jaw diseases -- Distribution, Zoledronic acid -- Usage, Bones -- Necrosis, Bones -- Distribution, Company distribution practices, Health
Abstract

A total of 7,714 women with postmenopausal osteoporosis were given placebo or intravenous zoledronic acid to determine the incidence of osteonecrosis of the jaw. The occurrence of osteonecrosis of the jaw in the sample was low, and healing of lesions can occur over three years.

Published
2008

32. Zoledronic acid and clinical fractures and mortality after hip fracture

Author

Lyles, Kenneth W., Colon-Emeric, Cathleen S., Magaziner, Jay S., Adachi, Jonathan D., Pieper, Carl F., Mautalen, Carlos, Hyldstrup, Lars, Recknor, Chris, Nordsletten, Lars, Moore, Kathy A., Lavecchia, Catherine, Jie Zhang, Mesenbrink, Peter, Hodgson, Patricia K., Abrams, Ken, Orloff, John J., Horowitz, Zebulun, Eriksen, Erik Fink, and Boonen, Steven

Subjects
Zoledronic acid -- Patient outcomes, Zoledronic acid -- Research, Hip joint -- Fractures, Hip joint -- Drug therapy, Hip joint -- Care and treatment, Hip joint -- Prevention
Abstract

The effectiveness of zoledronic acid in prevention of new clinical fractures, to patients undergone hip fracture surgery is studied. Results concluded yearly infusion of zoledronic acid within 90 days of hip fracture surgery reduced risk of new clinical fractures raising survival rate.

Published
2007

33. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis

Author

Black, Dennis M., Delmas, Pierre D., Eastell, Richard, Reid, Ian R., Boonen, Steven, Cauley, Jane A., Cosman, P.H. Felicia, Lakatos, Peter, Ping Chung Leung, Man, Zulema, Mautalen, Carlos, Mesenbrink, Peter, Huilin Hi, Caminis, John, Tong, Karen, Rosario-Jansen, Theresa, Krasnow, Joel, Hue, Trisha F., Sellmeyer, Deborah, Eriksen, Erik Fink, and Cummings, Steven R.

Subjects
Osteoporosis -- Drug therapy, Postmenopausal women -- Health aspects, Zoledronic acid -- Dosage and administration, Zoledronic acid -- Complications and side effects
Abstract

The effects of annual infusion of zoledronic acid in postmenopausal women are assessed. This dose was found to improve the bone density and reduce the risk of osteoporotic fractures over a period of three years.

Published
2007

34. Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease

Author

Reid, Ian R., Connell, William Fraser, Mesenbrink, Peter, Zelenakas, Ken, Richardson, Peter, Miller, Paul, Lyles, Kenneth, Brown, Jacques P., Saidi, Youssef, Guoqin Su, Pak, Judy, Luchi, Monica, and Hosking, David

Subjects
Risedronate -- Dosage and administration, Zoledronic acid -- Dosage and administration, Osteitis deformans -- Drug therapy
Abstract

The comparison of a single 15-minute infusion of 5 mg of zoledronic acid with 60 days of oral risedronate (30 mg per day) for treating Paget's disease is presented. The results show that a single infusion of zoledronic acid produces more rapid, more complete, and more sustained responses in Paget's disease than does daily treatment with risedronate.

Published
2005

35. Attribution of Nonalcoholic Steatohepatitis as an Etiology of Cirrhosis for Clinical Trials Eligibility: Recommendations From the Multi-stakeholder Liver Forum

Author

Noureddin, Mazen, primary, Chan, Jean L., additional, Barradas, Katherine, additional, Dimick-Santos, Lara, additional, Schabel, Elmer, additional, Omokaro, Stephanie O., additional, Anania, Frank A., additional, Myers, Robert P., additional, Miller, Veronica, additional, Sanyal, Arun J., additional, Chalasani, Naga, additional, Bajaj, Jasmohan, additional, Berzigotti, Annalisa, additional, Birman, Pascal, additional, Bosch, Jaime, additional, Brower, Ashley, additional, Calboli, Dania, additional, Charlton, William, additional, Dickinson, Klara, additional, Filozof, Claudia, additional, Forsgren, Mikael F., additional, Fuchs, Michael, additional, Garcia-Tsao, Guadalupe, additional, Gonzalez-Abraldes, Juan, additional, Gruss, Hans-Juergen, additional, Hansen, Morten, additional, Hosman, Suneil, additional, Imperial, Joanne, additional, Jones, David, additional, Lalazar, Gadi, additional, Leinhard, Olof Dahlqvist, additional, Lyons, Erica, additional, McColgan, Brian, additional, Mehta, Ruby, additional, Mesenbrink, Peter, additional, Myers, Rob, additional, Noureddin, Mazen, additional, Pei, Veronica, additional, Ratziu, Vlad, additional, Regev, Arie, additional, Riccio, Robert, additional, Sanyal, Arun, additional, Seo, Suna, additional, Smith, Alastair, additional, Szitanyi, Peter, additional, and Traber, Peter, additional

Published
2020
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37. Factors to Consider in Development of Drugs for Pediatric Nonalcoholic Fatty Liver Disease

Author

Vos, Miriam B., primary, Dimick-Santos, Lara, additional, Mehta, Ruby, additional, Omokaro, Stephanie O., additional, Taminiau, Johannes, additional, Schabel, Elmer, additional, Kleiner, David E., additional, Szitanyi, Peter, additional, Socha, Piotr, additional, Schwimmer, Jeffrey B., additional, Noviello, Stephanie, additional, Silberg, Debra G., additional, Torstenson, Richard, additional, Miller, Veronica, additional, Lavine, Joel E., additional, Adda, Nathalie, additional, Baldyga, William, additional, Banerjee, Rajarshi, additional, Behling, Cynthia, additional, Boulos, Sherif, additional, Burgess, Gary, additional, Calboli, Dania, additional, Charles, Edgar, additional, Christian, Rose, additional, Cohen-Bacrie, Claude, additional, Cosma-Roman, Doina, additional, Danzer, Claus-Peter, additional, Delaet, Ingrid, additional, Delegge, Mark, additional, DiProspero, Nicholas, additional, Donohue, Kathleen, additional, Fischer, Laurent, additional, Fitzpatrick, Emer, additional, Fried, Michael, additional, Hagerty, David, additional, Hale, Paula, additional, Hildick, Keri, additional, Hum, Dean, additional, Jamil, Khurram, additional, Jiang, Lijuan, additional, Karpen, Saul, additional, Kelly, Matt, additional, Kohli, Rohit, additional, Kordy, Kattayoun, additional, Krieger, Nancy, additional, Lavine, Joel, additional, Lee, Lois, additional, Lefebvre, Eric, additional, Lopez, Patricia, additional, Lyons, Erica, additional, Malahias, Laura, additional, Megnien, Sophie, additional, Mesenbrink, Peter, additional, Minnick, Pansy, additional, Murray, Christine, additional, Nghiem, Tien, additional, Nicholson, Nikki, additional, Pang, Wenjie, additional, Percival, Lisa, additional, Peres, Dan, additional, Powell, Margaret, additional, Roman, Dragos, additional, Root, Mark, additional, Sampson, Claire, additional, Sanyal, Arun, additional, Schwarz, Kathleen, additional, Seyedkazemi, Star, additional, Shapiro, David, additional, Shringarpure, Reshma, additional, Silberg, Debra, additional, Smith, Edward, additional, Squires, Robert, additional, Treem, William, additional, Vig, Pamela, additional, Vos, Miriam, additional, Yamashita, Mason, additional, and Zemel, Michael, additional

Published
2019
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42. Systematic review of available software for multi-arm multi-stage and platform clinical trial design.

Author

Meyer, Elias Laurin, Mesenbrink, Peter, Mielke, Tobias, Parke, Tom, Evans, Daniel, König, Franz, and EU-PEARL (EU Patient-cEntric clinicAl tRial pLatforms) Consortium

Subjects
*EXPERIMENTAL design, *INTEGRATED software, *SOFTWARE architecture, *COMPUTER software
Abstract

Background: In recent years, the popularity of multi-arm multi-stage, seamless adaptive, and platform trials has increased. However, many design-related questions and questions regarding which operating characteristics should be evaluated to determine the potential performance of a specific trial design remain and are often further complicated by the complexity of such trial designs.Methods: A systematic search was conducted to review existing software for the design of platform trials, whereby multi-arm multi-stage trials were also included. The results of this search are reported both on the literature level and the software level, highlighting the software judged to be particularly useful.Results: In recent years, many highly specialized software packages targeting single design elements on platform studies have been released. Only a few of the developed software packages provide extensive design flexibility, at the cost of limited access due to being commercial or not being usable as out-of-the-box solutions.Conclusions: We believe that both an open-source modular software similar to OCTOPUS and a collaborative effort will be necessary to create software that takes advantage of and investigates the impact of all the flexibility that platform trials potentially provide. [ABSTRACT FROM AUTHOR]

Published
2021
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44. Золедроновая кислота в профилактике потери костной ткани у женщин постменопаузального возраста с остеопенией

Author

Mcclung, Michael, Miller, Paul, Recknor, Chris, Mesenbrink, Peter, Bucci-rechtweg, Christina, and Benhamou, Claude-laurent

Abstract

Профилактика остеопоротических переломов, особенно бедренной кости и позвонков, это важная проблема здравоохранения. Подобные переломы сопровождаются повышенным риском осложнений и смерти, поэтому эффективная стратегия их профилактики может оказать значительное влияние на заболеваемость и несколько меньшее, но существенное влияние на смертность пожилых людей. 1-3 Хотя у женщин с остепенией риск развития переломов ниже, чем у женщин того же возраста с остеопорозом, тем не менее, при отсутствии лечения у них высока вероятность развития остеопороза. Более того, большинство переломов регистрируют у пациенток с остеопенией. 4 В последних рекомендациях женщинам постменопаузального возраста с остеопенией и со средним или высоким риском переломов (оценивают с помощью валидированных методов, таких как FRAX) предлагается назначать лекарственные средства, предназначенные для лечения остеопороза. 5 Пероральные бисфосфонаты предупреждают потерю костной ткани после наступления менопаузы у женщин более молодого и старшего возраста 6-8 Однако в клинической практике многие пациентки плохо выполняют рекомендации врача и принимают пероральные бисфосфонаты в течение не более нескольких месяцев. 9 В связи с этим важное значение имеет применение эффективного препарата, обеспечивающего высокую приверженность пациенток. В клинических исследованиях доказано, что ежегодные инфузии золедроновой кислоты в дозе 5 мг в течение 3 лет снижают риск переломов позвонков, бедренной кости и внепозвоночных переломов и увеличивают МПК поясничных позвонков и бедренной кости у женщин с постменопаузальным остеопорозом. 10 Кроме того, препарат снижал риск повторных клинически явных переломов у мужчин и женщин, недавно перенесших остеопоротический перелом бедренной кости. 11 Целью данного исследования было изучение эффективности и переносимости внутривенных инфузий золедроновой кислоты в дозе 5 мг у женщин постменопаузального возраста с остеопенией. В 2-летнем исследовании изучали эффективность двух и одной инфузии препарата, чтобы оценить возможность сокращения числа инфузий для профилактики потери костной ткани.

Published
2011

45. Subgroup Variations in Bone Mineral Density Response to Zoledronic Acid After Hip Fracture

Author

Magaziner, Jay S, primary, Orwig, Denise L, additional, Lyles, Kenneth W, additional, Nordsletten, Lars, additional, Boonen, Steven, additional, Adachi, Jonathan D, additional, Recknor, Chris, additional, Colón‐Emeric, Cathleen S, additional, Mesenbrink, Peter, additional, Bucci‐Rechtweg, Christina, additional, Su, Guoqin, additional, Johnson, Rasheeda, additional, and Pieper, Carl F, additional

Published
2014
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46. Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density.

Author

UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service de rhumatologie, Eastell, Richard, Black, Dennis M, Boonen, Steven, Adami, Silvano, Felsenberg, Dieter, Lippuner, Kurt, Cummings, Steven R, Delmas, Pierre D, Palermo, Lisa, Mesenbrink, Peter, Cauley, Jane A, Devogelaer, Jean-Pierre, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service de rhumatologie, Eastell, Richard, Black, Dennis M, Boonen, Steven, Adami, Silvano, Felsenberg, Dieter, Lippuner, Kurt, Cummings, Steven R, Delmas, Pierre D, Palermo, Lisa, Mesenbrink, Peter, Cauley, Jane A, and Devogelaer, Jean-Pierre

Abstract

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk.

Published
2009

47. Antifracture efficacy and reduction of mortality in relation to timing of the first dose of zoledronic acid after hip fracture

Author

Eriksen, Erik Fink, Lyles, Kenneth W, Colón-Emeric, Cathleen S, Pieper, Carl F, Magaziner, Jay S, Adachi, Jonathan D, Hyldstrup, Lars, Recknor, Chris, Nordsletten, Lars, Lavecchia, Catherine, Hu, Huilin, Boonen, Steven, Mesenbrink, Peter, Eriksen, Erik Fink, Lyles, Kenneth W, Colón-Emeric, Cathleen S, Pieper, Carl F, Magaziner, Jay S, Adachi, Jonathan D, Hyldstrup, Lars, Recknor, Chris, Nordsletten, Lars, Lavecchia, Catherine, Hu, Huilin, Boonen, Steven, and Mesenbrink, Peter

Abstract

Udgivelsesdato: 2009-Jul, Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow-up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was approximately 6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2-wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low-trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality.

Published
2009

48. Zoledronic acid and clinical fractures and mortality after hip fracture.

Author

Lyles, Kenneth W, Colón-Emeric, Cathleen S, Magaziner, Jay S, Adachi, Jonathan D, Pieper, Carl F, Mautalen, Carlos, Hyldstrup, Lars, Recknor, Chris, Nordsletten, Lars, Moore, Kathy A, Lavecchia, Catherine, Zhang, Jie, Mesenbrink, Peter, Hodgson, Patricia K, Abrams, Ken, Orloff, John J, Horowitz, Zebulun, Eriksen, Erik Fink, Boonen, Steven, NN, NN, Lyles, Kenneth W, Colón-Emeric, Cathleen S, Magaziner, Jay S, Adachi, Jonathan D, Pieper, Carl F, Mautalen, Carlos, Hyldstrup, Lars, Recknor, Chris, Nordsletten, Lars, Moore, Kathy A, Lavecchia, Catherine, Zhang, Jie, Mesenbrink, Peter, Hodgson, Patricia K, Abrams, Ken, Orloff, John J, Horowitz, Zebulun, Eriksen, Erik Fink, Boonen, Steven, and NN, NN

Abstract

BACKGROUND: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].). Udgivelsesdato: 2007-Nov-1, BACKGROUND: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].).

Published
2007

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