• Stéphane Haïk, Gabriella Marcon, Alain Mallet, Mauro Tettamanti, Arlette Welaratne, Giorgio Giaccone, Shohreh Azimi, Vladimiro Pietrini, Jean-Roch Fabreguettes, Daniele Imperiale, Pierre Cesaro, Carlo Buffa, Christophe Aucan, Ugo Lucca, Laurène Peckeu, Silvia Suardi, Christine Tranchant, Inga Zerr, Caroline Houillier, Veronica Redaelli, Hervé Vespignani, Angela Campanella, François Sellal, Anna Krasnianski, Danielle Seilhean, Uta Heinemann, Frédéric Sedel, Mara Canovi, Marco Gobbi, Giuseppe Di Fede, Jean-Louis Laplanche, Maurizio Pocchiari, Mario Salmona, Gianluigi Forloni, Jean-Philippe Brandel, and Fabrizio Tagliavini.
• 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.
• Lancet Neurol. 2014 Feb 1; 13 (2): 150-8.

BackgroundCreutzfeldt-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.MethodsWe 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.FindingsFrom 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.InterpretationDoxycycline 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.FundingAgenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.Copyright © 2014 Elsevier Ltd. All rights reserved.

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