Protein misfolding, amyotrophic lateral sclerosis and guanabenz: Protocol for a phase II RCT with futility design (ProMISe trial)

ED Bella, I Tramacere, Giovanni Antonini, G Borghero, M Capasso, C Caponnetto, A Chiò, Massimo Corbo, R Eleopra, M Filosto, Fabio Giannini, Enrico Granieri, Vincenzo La Bella, C Lunetta, Jessica Mandrioli, L Mazzini, S Messina, MR Monsurrò, G Mora, N Riva & 7 others R Rizzi, G Siciliano, V Silani, I Simone, G Sorarù, P Volanti, G Lauria

Research output: Contribution to journalArticle

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Abstract

Introduction Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS. Methods and analyses Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. Ethics and dissemination The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration. © Article autho (s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved.
Original languageEnglish
Article numbere015434
JournalBMJ Open
Volume7
Issue number8
DOIs
Publication statusPublished - 2017

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Guanabenz
Medical Futility
Amyotrophic Lateral Sclerosis
Proteins
Placebos
Translational Peptide Chain Initiation
Adrenergic alpha-2 Receptor Agonists
Biomarkers
Helsinki Declaration
Orphan Drug Production
Riluzole
Safety
Ethics Committees
Phase II Clinical Trials
Endoplasmic Reticulum Stress
Controlled Clinical Trials
Motor Neurons
Neuroprotective Agents
Heat-Shock Proteins
Ethics

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Protein misfolding, amyotrophic lateral sclerosis and guanabenz: Protocol for a phase II RCT with futility design (ProMISe trial). / Bella, ED; Tramacere, I; Antonini, Giovanni; Borghero, G; Capasso, M; Caponnetto, C; Chiò, A; Corbo, Massimo; Eleopra, R; Filosto, M; Giannini, Fabio; Granieri, Enrico; La Bella, Vincenzo; Lunetta, C; Mandrioli, Jessica; Mazzini, L; Messina, S; Monsurrò, MR; Mora, G; Riva, N; Rizzi, R; Siciliano, G; Silani, V; Simone, I; Sorarù, G; Volanti, P; Lauria, G.

In: BMJ Open, Vol. 7, No. 8, e015434, 2017.

Research output: Contribution to journalArticle

Bella, ED, Tramacere, I, Antonini, G, Borghero, G, Capasso, M, Caponnetto, C, Chiò, A, Corbo, M, Eleopra, R, Filosto, M, Giannini, F, Granieri, E, La Bella, V, Lunetta, C, Mandrioli, J, Mazzini, L, Messina, S, Monsurrò, MR, Mora, G, Riva, N, Rizzi, R, Siciliano, G, Silani, V, Simone, I, Sorarù, G, Volanti, P & Lauria, G 2017, 'Protein misfolding, amyotrophic lateral sclerosis and guanabenz: Protocol for a phase II RCT with futility design (ProMISe trial)', BMJ Open, vol. 7, no. 8, e015434. https://doi.org/10.1136/bmjopen-2016-015434
Bella, ED ; Tramacere, I ; Antonini, Giovanni ; Borghero, G ; Capasso, M ; Caponnetto, C ; Chiò, A ; Corbo, Massimo ; Eleopra, R ; Filosto, M ; Giannini, Fabio ; Granieri, Enrico ; La Bella, Vincenzo ; Lunetta, C ; Mandrioli, Jessica ; Mazzini, L ; Messina, S ; Monsurrò, MR ; Mora, G ; Riva, N ; Rizzi, R ; Siciliano, G ; Silani, V ; Simone, I ; Sorarù, G ; Volanti, P ; Lauria, G. / Protein misfolding, amyotrophic lateral sclerosis and guanabenz: Protocol for a phase II RCT with futility design (ProMISe trial). In: BMJ Open. 2017 ; Vol. 7, No. 8.
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AU - Bella, ED

AU - Tramacere, I

AU - Antonini, Giovanni

AU - Borghero, G

AU - Capasso, M

AU - Caponnetto, C

AU - Chiò, A

AU - Corbo, Massimo

AU - Eleopra, R

AU - Filosto, M

AU - Giannini, Fabio

AU - Granieri, Enrico

AU - La Bella, Vincenzo

AU - Lunetta, C

AU - Mandrioli, Jessica

AU - Mazzini, L

AU - Messina, S

AU - Monsurrò, MR

AU - Mora, G

AU - Riva, N

AU - Rizzi, R

AU - Siciliano, G

AU - Silani, V

AU - Simone, I

AU - Sorarù, G

AU - Volanti, P

AU - Lauria, G

PY - 2017

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N2 - Introduction Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS. Methods and analyses Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. Ethics and dissemination The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration. © Article autho (s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved.

AB - Introduction Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS. Methods and analyses Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. Ethics and dissemination The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration. © Article autho (s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved.

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DO - 10.1136/bmjopen-2016-015434

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JO - BMJ Open

JF - BMJ Open

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