Doxycycline in Creutzfeldt-Jakob disease: A phase 2, randomised, double-blind, placebo-controlled trial

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 RedaelliHervé 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, Fabrizio Tagliavini

Research output: Contribution to journalArticle

81 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)150-158
Number of pages9
JournalThe Lancet Neurology
Volume13
Issue number2
DOIs
Publication statusPublished - Feb 2014

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Creutzfeldt-Jakob Syndrome
Doxycycline
Placebos
Random Allocation
Prions
Italy
France
Survival
Medical Futility
Therapeutics
Inborn Genetic Diseases
Health
Brain Diseases
Rare Diseases
Double-Blind Method
Caregivers
Observational Studies
Referral and Consultation

ASJC Scopus subject areas

  • Clinical Neurology

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Doxycycline in Creutzfeldt-Jakob disease : A phase 2, randomised, double-blind, placebo-controlled trial. / Haïk, Stéphane; Marcon, Gabriella; Mallet, Alain; Tettamanti, Mauro; Welaratne, Arlette; Giaccone, Giorgio; Azimi, Shohreh; Pietrini, Vladimiro; Fabreguettes, Jean Roch; Imperiale, Daniele; Cesaro, Pierre; Buffa, Carlo; Aucan, Christophe; Lucca, Ugo; Peckeu, Laurène; Suardi, Silvia; Tranchant, Christine; Zerr, Inga; Houillier, Caroline; Redaelli, Veronica; Vespignani, Hervé; Campanella, Angela; Sellal, François; Krasnianski, Anna; Seilhean, Danielle; Heinemann, Uta; Sedel, Frédéric; Canovi, Mara; Gobbi, Marco; Di Fede, Giuseppe; Laplanche, Jean Louis; Pocchiari, Maurizio; Salmona, Mario; Forloni, Gianluigi; Brandel, Jean Philippe; Tagliavini, Fabrizio.

In: The Lancet Neurology, Vol. 13, No. 2, 02.2014, p. 150-158.

Research output: Contribution to journalArticle

Haïk, S, Marcon, G, Mallet, A, Tettamanti, M, Welaratne, A, Giaccone, G, Azimi, S, Pietrini, V, Fabreguettes, JR, Imperiale, D, Cesaro, P, Buffa, C, Aucan, C, Lucca, U, Peckeu, L, Suardi, S, Tranchant, C, Zerr, I, Houillier, C, Redaelli, V, Vespignani, H, Campanella, A, Sellal, F, Krasnianski, A, Seilhean, D, Heinemann, U, Sedel, F, Canovi, M, Gobbi, M, Di Fede, G, Laplanche, JL, Pocchiari, M, Salmona, M, Forloni, G, Brandel, JP & Tagliavini, F 2014, 'Doxycycline in Creutzfeldt-Jakob disease: A phase 2, randomised, double-blind, placebo-controlled trial', The Lancet Neurology, vol. 13, no. 2, pp. 150-158. https://doi.org/10.1016/S1474-4422(13)70307-7
Haïk, Stéphane ; Marcon, Gabriella ; Mallet, Alain ; Tettamanti, Mauro ; Welaratne, Arlette ; Giaccone, Giorgio ; Azimi, Shohreh ; Pietrini, Vladimiro ; Fabreguettes, Jean Roch ; Imperiale, Daniele ; Cesaro, Pierre ; Buffa, Carlo ; Aucan, Christophe ; Lucca, Ugo ; Peckeu, Laurène ; Suardi, Silvia ; Tranchant, Christine ; Zerr, Inga ; Houillier, Caroline ; Redaelli, Veronica ; Vespignani, Hervé ; Campanella, Angela ; Sellal, François ; Krasnianski, Anna ; Seilhean, Danielle ; Heinemann, Uta ; Sedel, Frédéric ; Canovi, Mara ; Gobbi, Marco ; Di Fede, Giuseppe ; Laplanche, Jean Louis ; Pocchiari, Maurizio ; Salmona, Mario ; Forloni, Gianluigi ; Brandel, Jean Philippe ; Tagliavini, Fabrizio. / Doxycycline in Creutzfeldt-Jakob disease : A phase 2, randomised, double-blind, placebo-controlled trial. In: The Lancet Neurology. 2014 ; Vol. 13, No. 2. pp. 150-158.
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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.",
author = "St{\'e}phane Ha{\"i}k and Gabriella Marcon and Alain Mallet and Mauro Tettamanti and Arlette Welaratne and Giorgio Giaccone and Shohreh Azimi and Vladimiro Pietrini and Fabreguettes, {Jean Roch} and Daniele Imperiale and Pierre Cesaro and Carlo Buffa and Christophe Aucan and Ugo Lucca and Laur{\`e}ne Peckeu and Silvia Suardi and Christine Tranchant and Inga Zerr and Caroline Houillier and Veronica Redaelli and Herv{\'e} Vespignani and Angela Campanella and Fran{\cc}ois Sellal and Anna Krasnianski and Danielle Seilhean and Uta Heinemann and Fr{\'e}d{\'e}ric Sedel and Mara Canovi and Marco Gobbi and {Di Fede}, Giuseppe and Laplanche, {Jean Louis} and Maurizio Pocchiari and Mario Salmona and Gianluigi Forloni and Brandel, {Jean Philippe} and Fabrizio Tagliavini",
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TY - JOUR

T1 - Doxycycline in Creutzfeldt-Jakob disease

T2 - A phase 2, randomised, double-blind, placebo-controlled trial

AU - Haïk, Stéphane

AU - Marcon, Gabriella

AU - Mallet, Alain

AU - Tettamanti, Mauro

AU - Welaratne, Arlette

AU - Giaccone, Giorgio

AU - Azimi, Shohreh

AU - Pietrini, Vladimiro

AU - Fabreguettes, Jean Roch

AU - Imperiale, Daniele

AU - Cesaro, Pierre

AU - Buffa, Carlo

AU - Aucan, Christophe

AU - Lucca, Ugo

AU - Peckeu, Laurène

AU - Suardi, Silvia

AU - Tranchant, Christine

AU - Zerr, Inga

AU - Houillier, Caroline

AU - Redaelli, Veronica

AU - Vespignani, Hervé

AU - Campanella, Angela

AU - Sellal, François

AU - Krasnianski, Anna

AU - Seilhean, Danielle

AU - Heinemann, Uta

AU - Sedel, Frédéric

AU - Canovi, Mara

AU - Gobbi, Marco

AU - Di Fede, Giuseppe

AU - Laplanche, Jean Louis

AU - Pocchiari, Maurizio

AU - Salmona, Mario

AU - Forloni, Gianluigi

AU - Brandel, Jean Philippe

AU - Tagliavini, Fabrizio

PY - 2014/2

Y1 - 2014/2

N2 - 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.

AB - 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.

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