Stéphane Haïk1, Gabriella Marcon2, Alain Mallet3, Mauro Tettamanti4, Arlette Welaratne5, Giorgio Giaccone6, Shohreh Azimi7, Vladimiro Pietrini8, Jean-Roch Fabreguettes9, Daniele Imperiale10, Pierre Cesaro11, Carlo Buffa10, Christophe Aucan7, Ugo Lucca4, Laurène Peckeu12, Silvia Suardi6, Christine Tranchant13, Inga Zerr14, Caroline Houillier15, Veronica Redaelli6, Hervé Vespignani16, Angela Campanella6, François Sellal17, Anna Krasnianski14, Danielle Seilhean18, Uta Heinemann14, Frédéric Sedel19, Mara Canovi4, Marco Gobbi4, Giuseppe Di Fede6, Jean-Louis Laplanche20, Maurizio Pocchiari21, Mario Salmona4, Gianluigi Forloni4, Jean-Philippe Brandel12, Fabrizio Tagliavini22. 1. Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CR ICM), UMRS 975, Equipe Maladie d'Alzheimer-Maladies à Prions, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; AP-HP, Cellule Nationale de Référence des maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; CNRS, UMR 7225, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; AP-HP, Laboratoire de Neuropathologie R Escourolle, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Inserm, U 975, Paris, France. 2. IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy; DSMB, University of Udine, Udine, Italy. 3. AP-HP, Unité de Recherche Clinique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 4. IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. 5. AP-HP, Cellule Nationale de Référence des maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 6. IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy. 7. AP-HP, Département de la Recherche Clinique et du Développement (DRCD), Hôpital Saint Louis, Paris, France. 8. Department of Neurosciences, Neurology Unit, University of Parma, Parma, Italy. 9. AP-HP, Agence Générale des Equipements et Produits de Santé (AGEPS), Paris, France. 10. Neurology Unit, Prion Disease Regional Center DOMP, Maria Vittoria Hospital, Torino, Italy. 11. AP-HP, Service de Neurologie, Hôpital Henri-Mondor, Créteil, France. 12. Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CR ICM), UMRS 975, Equipe Maladie d'Alzheimer-Maladies à Prions, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; AP-HP, Cellule Nationale de Référence des maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; CNRS, UMR 7225, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Inserm, U 975, Paris, France. 13. Service de Neurologie, Hôpital de Hautepierre, Strasbourg et FMTS, Université de Strasbourg, Strasbourg, France. 14. Department of Neurology, Clinical Dementia Center, Medical Center Georg-August University, Göttingen, Germany. 15. Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CR ICM), UMRS 975, Equipe Maladie d'Alzheimer-Maladies à Prions, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; CNRS, UMR 7225, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Inserm, U 975, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France. 16. Service de Neurologie, Centre Hospitalier Universitaire de Nancy, Nancy, France. 17. Service de Neurologie, Hôpital Pasteur, Colmar et Inserm U 1118, Strasbourg, France. 18. Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CR ICM), UMRS 975, Equipe Maladie d'Alzheimer-Maladies à Prions, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; CNRS, UMR 7225, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; AP-HP, Laboratoire de Neuropathologie R Escourolle, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Inserm, U 975, Paris, France. 19. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 4, Paris, France. 20. AP-HP, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière et Université Paris Descartes, Paris, France. 21. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy. 22. IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy. Electronic address: ftagliavini@istituto-besta.it.
Abstract
BACKGROUND:Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. METHODS: We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. FINDINGS:From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. INTERPRETATION:Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. FUNDING: Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.
RCT Entities:
BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prionencephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. METHODS: We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. FINDINGS: From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. INTERPRETATION:Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. FUNDING: Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.
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