title: Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.
authors.affiliation: 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.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Haïk
authors.affiliation: IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy; DSMB, University of Udine, Udine, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marcon
authors.affiliation: AP-HP, Unité de Recherche Clinique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Mallet
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Tettamanti
authors.affiliation: AP-HP, Cellule Nationale de Référence des maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Arlette
authors.initials: A
authors.lastname: Welaratne
authors.affiliation: IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
authors.affiliation: AP-HP, Département de la Recherche Clinique et du Développement (DRCD), Hôpital Saint Louis, Paris, France.
authors.forename: Shohreh
authors.initials: S
authors.lastname: Azimi
authors.affiliation: Department of Neurosciences, Neurology Unit, University of Parma, Parma, Italy.
authors.forename: Vladimiro
authors.initials: V
authors.lastname: Pietrini
authors.affiliation: AP-HP, Agence Générale des Equipements et Produits de Santé (AGEPS), Paris, France.
authors.forename: Jean-Roch
authors.initials: JR
authors.lastname: Fabreguettes
authors.affiliation: Neurology Unit, Prion Disease Regional Center DOMP, Maria Vittoria Hospital, Torino, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Imperiale
authors.affiliation: AP-HP, Service de Neurologie, Hôpital Henri-Mondor, Créteil, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cesaro
authors.affiliation: Neurology Unit, Prion Disease Regional Center DOMP, Maria Vittoria Hospital, Torino, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Buffa
authors.affiliation: AP-HP, Département de la Recherche Clinique et du Développement (DRCD), Hôpital Saint Louis, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Aucan
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Lucca
authors.affiliation: 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.
authors.forename: Laurène
authors.initials: L
authors.lastname: Peckeu
authors.affiliation: IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Suardi
authors.affiliation: Service de Neurologie, Hôpital de Hautepierre, Strasbourg et FMTS, Université de Strasbourg, Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.affiliation: Department of Neurology, Clinical Dementia Center, Medical Center Georg-August University, Göttingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
authors.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Houillier
authors.affiliation: IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Redaelli
authors.affiliation: Service de Neurologie, Centre Hospitalier Universitaire de Nancy, Nancy, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Vespignani
authors.affiliation: IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Campanella
authors.affiliation: Service de Neurologie, Hôpital Pasteur, Colmar et Inserm U 1118, Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Sellal
authors.affiliation: Department of Neurology, Clinical Dementia Center, Medical Center Georg-August University, Göttingen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Krasnianski
authors.affiliation: 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.
authors.forename: Danielle
authors.initials: D
authors.lastname: Seilhean
authors.affiliation: Department of Neurology, Clinical Dementia Center, Medical Center Georg-August University, Göttingen, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Heinemann
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 4, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Sedel
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Canovi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Fede
authors.affiliation: AP-HP, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière et Université Paris Descartes, Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pocchiari
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: 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.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brandel
authors.affiliation: IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy. Electronic address: ftagliavini@istituto-besta.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: D000368:Aged; D007562:Creutzfeldt-Jakob Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D004311:Double-Blind Method; D004318:Doxycycline / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D008297:Male; D018447:Medical Futility; D008875:Middle Aged; D017211:Treatment Failure
chemical_list: D004318:Doxycycline