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

Eleonora Dalla Bella, Irene Tramacere, Giovanni Antonini, Giuseppe Borghero, Margherita Capasso, Claudia Caponnetto, Adriano Chiò, Massimo Corbo, Roberto Eleopra, Massimiliano Filosto, Fabio Giannini, Enrico Granieri, Vincenzo La Bella, Christian Lunetta, Jessica Mandrioli, Letizia Mazzini, Sonia Messina, Maria Rosaria Monsurrò, Gabriele Mora, Nilo RivaRomana Rizzi, Gabriele Siciliano, Vincenzo Silani, Isabella Simone, Gianni Sorarù, Paolo Volanti, Giuseppe Lauria

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere015434
JournalBMJ Open
Volume7
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

Fingerprint

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

Keywords

  • amyotrophic lateral sclerosis
  • motor neurone disease
  • neuromuscular disease
  • randomized clinical trial guanabenz
  • unfolded protein response

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Protein misfolding, amyotrophic lateral sclerosis and guanabenz : Protocol for a phase II RCT with futility design (ProMISe trial). / Bella, Eleonora Dalla; Tramacere, Irene; Antonini, Giovanni; Borghero, Giuseppe; Capasso, Margherita; Caponnetto, Claudia; Chiò, Adriano; Corbo, Massimo; Eleopra, Roberto; Filosto, Massimiliano; Giannini, Fabio; Granieri, Enrico; Bella, Vincenzo La; Lunetta, Christian; Mandrioli, Jessica; Mazzini, Letizia; Messina, Sonia; Monsurrò, Maria Rosaria; Mora, Gabriele; Riva, Nilo; Rizzi, Romana; Siciliano, Gabriele; Silani, Vincenzo; Simone, Isabella; Sorarù, Gianni; Volanti, Paolo; Lauria, Giuseppe.

In: BMJ Open, Vol. 7, No. 8, e015434, 01.08.2017.

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, Bella, VL, 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, Eleonora Dalla ; Tramacere, Irene ; Antonini, Giovanni ; Borghero, Giuseppe ; Capasso, Margherita ; Caponnetto, Claudia ; Chiò, Adriano ; Corbo, Massimo ; Eleopra, Roberto ; Filosto, Massimiliano ; Giannini, Fabio ; Granieri, Enrico ; Bella, Vincenzo La ; Lunetta, Christian ; Mandrioli, Jessica ; Mazzini, Letizia ; Messina, Sonia ; Monsurrò, Maria Rosaria ; Mora, Gabriele ; Riva, Nilo ; Rizzi, Romana ; Siciliano, Gabriele ; Silani, Vincenzo ; Simone, Isabella ; Sorarù, Gianni ; Volanti, Paolo ; Lauria, Giuseppe. / 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.
@article{8a1eed6e899b49c4903d45be1c9cbc67,
title = "Protein misfolding, amyotrophic lateral sclerosis and guanabenz: Protocol for a phase II RCT with futility design (ProMISe trial)",
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.",
keywords = "amyotrophic lateral sclerosis, motor neurone disease, neuromuscular disease, randomized clinical trial guanabenz, unfolded protein response",
author = "Bella, {Eleonora Dalla} and Irene Tramacere and Giovanni Antonini and Giuseppe Borghero and Margherita Capasso and Claudia Caponnetto and Adriano Chi{\`o} and Massimo Corbo and Roberto Eleopra and Massimiliano Filosto and Fabio Giannini and Enrico Granieri and Bella, {Vincenzo La} and Christian Lunetta and Jessica Mandrioli and Letizia Mazzini and Sonia Messina and Monsurr{\`o}, {Maria Rosaria} and Gabriele Mora and Nilo Riva and Romana Rizzi and Gabriele Siciliano and Vincenzo Silani and Isabella Simone and Gianni Sorar{\`u} and Paolo Volanti and Giuseppe Lauria",
year = "2017",
month = "8",
day = "1",
doi = "10.1136/bmjopen-2016-015434",
language = "English",
volume = "7",
journal = "BMJ Open",
issn = "2044-6055",
publisher = "BMJ Publishing Group",
number = "8",

}

TY - JOUR

T1 - Protein misfolding, amyotrophic lateral sclerosis and guanabenz

T2 - Protocol for a phase II RCT with futility design (ProMISe trial)

AU - Bella, Eleonora Dalla

AU - Tramacere, Irene

AU - Antonini, Giovanni

AU - Borghero, Giuseppe

AU - Capasso, Margherita

AU - Caponnetto, Claudia

AU - Chiò, Adriano

AU - Corbo, Massimo

AU - Eleopra, Roberto

AU - Filosto, Massimiliano

AU - Giannini, Fabio

AU - Granieri, Enrico

AU - Bella, Vincenzo La

AU - Lunetta, Christian

AU - Mandrioli, Jessica

AU - Mazzini, Letizia

AU - Messina, Sonia

AU - Monsurrò, Maria Rosaria

AU - Mora, Gabriele

AU - Riva, Nilo

AU - Rizzi, Romana

AU - Siciliano, Gabriele

AU - Silani, Vincenzo

AU - Simone, Isabella

AU - Sorarù, Gianni

AU - Volanti, Paolo

AU - Lauria, Giuseppe

PY - 2017/8/1

Y1 - 2017/8/1

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.

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.

KW - amyotrophic lateral sclerosis

KW - motor neurone disease

KW - neuromuscular disease

KW - randomized clinical trial guanabenz

KW - unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=85027400225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027400225&partnerID=8YFLogxK

U2 - 10.1136/bmjopen-2016-015434

DO - 10.1136/bmjopen-2016-015434

M3 - Article

AN - SCOPUS:85027400225

VL - 7

JO - BMJ Open

JF - BMJ Open

SN - 2044-6055

IS - 8

M1 - e015434

ER -