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A new Phase III Clinical Trial for the use of TUDCA in ALS

About

The TUDCA-ALS Consortium spans seven countries in the EU and is formed by 10 partner organisations who are coming together to conduct this new Phase III clinical trial testing the safety and efficacy of Tauroursodeoxycholic acid (TUDCA) as a treatment to slow progression of amyotrophic lateral sclerosis (ALS).

TUDCA-ALS includes a double-blind, placebo-controlled, randomised (1:1 ratio), parallel-group study comparing riluzole plus TUDCA to riluzole plus placebo. The study will occur over an 18-month treatment period.

TUDCA-ALS embarked on its 4-year collaborative journey to conduct this new Phase III Clinical Trial in January 2018 and is supported by a grant provided by the European Commission’s Horizon 2020 research and innovation programme.

The project is coordinated by Professor Alberto Albanese of Humanitas University Clinical and Research Center (Humanitas Mirasole SpA) NeuroCenter Unit (Italy) and brings together a team of excellence that includes leading research scientists, laboratories and clinicians from Italy, France, Belgium, The Netherlands, Ireland, United Kingdom and Germany. They are working closely with a Small and Medium Enterprise (SME) Bruschettini srl, an independent company which manufactures and markets high quality pharmaceutical products, and the MND Association of England, Wales and Northern Ireland, one of the biggest ALS/MND charities in Europe.

 

At the moment, there is no cure for ALS and the few limited treatments currently available slow down disease progression by only a few months. An initial pilot study on 60 patients recently showed that TUDCA significantly delayed the degeneration of motor neurons in ALS patients by about one third, thus allowing for longer survival.

Professor Alberto Albanese

What is the TUDCA-ALS Project?

The primary goal is to demonstrate the clinical efficacy and safety of TUDCA, a drug with potentially protective effects on motor neurons, in reducing the progression of neurodegeneration in patients with ALS. This phase III placebo-controlled, double-blind, European multicentre randomized clinical trial is designed to demonstrate a decrease in rate of functional disability and progression with TUDCA as an add-on to the standard riluzole treatment, compared to riluzole alone.

The secondary goal is to correlate clinical outcomes with changes in biomarkers related to disease progression (neurofilaments, NF) or influenced by TUDCA protective activity (matrix metalloproteinase 9, MMP-9).

Measures of NF levels in the cerebrospinal fluid (CSF) and serum of people living with ALS will provide a biological measure of disease progression in patients treated with active compound (TUDCA) or placebo. Neuronal MMP-9 is a marker of cellular neurodegeneration. Measures of MMP-9 expression in serum will serve as a mirror for TUDCA neuronal protective action. The aims are (i) to provide a proof of mechanism for TUDCA and (ii) see how the people living with ALS who are taking the active drug are responding to the drug. Because of the already-proven neuroprotective agent in ALS (riluzole), we can assess the changes in CSF NF levels in people taking riluzole and TUDCA, and compare these to those on riluzole only. This design will help to assess the variation of biomarkers in patients receiving the reference and the experimental treatment, and also provide the opportunity to comparatively explore mechanisms underpinning disease activity and drug response.

Are you a person living with ALS?

Results from a small, short-term trial indicate that TUDCA could slow down the progression of ALS, but this needs to be verified in a larger trial and over a longer period of time. The TUDCA-ALS project will use a clinical trial to look at the safety and effectiveness of using TUDCA as a treatment alongside riluzole, the only currently available treatment in Europe. People who enrol into the TUDCA-ALS clinical trial will be randomly assigned (50% and 50%) to either taking TUDCA in capsule form (known as the active drug arm), or taking an identical capsule that will not contain TUDCA (known as a placebo arm). The TUDCA-ALS project will then follow the study participants and assess how well TUDCA is working by using biomarkers specific to ALS and TUDCA (chemicals in the blood and cerebrospinal fluid that will indicate any changes that are occurring over time).

At the end of the clinical trial, all study participants will have the opportunity to continue onto an open label phase of the study, where they will be given TUDCA regardless of whether they were in the TUDCA or placebo arm of the clinical trial.

TUDCA-ALS Partners, Independent Advisory Board (IAB) and Independent Ethic Board – Data Safety Monitoring Board (IEB-DSMB)

Partner 1 – Professor Alberto Albanese, Humanitas Clinical and Research Center (Humanitas Mirasole SpA) -NeruoCenter Unit, Milan, Italy (ICH)

Expertise in methodology in neurodegenerative diseases, ALS and biomarkers

As the Project Co-ordinator, ICH will be in charge of the implementation of the Clinical Trial and of the entire project. Moreover, ICH will lead Work Package 6 – Coordination and management working with the partners from UULM and KUL.

To ensure an effective and efficient coordination and management for the TUDCA-ALS consortium, in order to deliver the trial outcomes on time and within budget.

Partner 2 – Professor Albert Ludolph, Universität Ulm (UULM)

Expertise in ALS and biomarkers

Lead for Work Package 3 – Biomarkers of disease and treatment working with the partner from ICH.

To integrate biomarkers of neuronal damage, already used as prognostic indicators and for disease stratification in ALS, as well as new biomarkers potentially linked to drug action into the study design. This will establish a proof of concept and mechanism for the tested drug and help simplify future research efforts.

Partner 3 – Professor Christopher McDermott, University of Sheffield (USFD)

Expertise in ALS and Clinical Trials

Lead for Work Package 2 – Trial Implementation and monitoring working with partners from ICH, CHUT, KUL, UMCU, TCD and BRU

To run a randomized, double-blind, placebo controlled phase III clinical trial in compliance with Good Clinical Practice (GCP), Good Clinical Laboratory Practice (GCLP) and Good Manufacturing Practice (GMP) rules in order to demonstrate the clinical efficacy and safety of TUDCA.

Partner 4 – Professor Phillippe Corcia, Hôpital Universitaire de Tours (CHUT)

Expertise in methodology and ALS

Working on Work Package 1 – Trial Set-up and harmonisation with partners from UMCU, ICH, USFD, KUL and BRU; Work Package 2 – Trial Implementation and monitoring working with partners from USFD, ICH, KUL, UMCU, TCD and BRU and Work Package 5 – Dissemination, communication and exploitation with partners from MNDA, ICH, USFD, KUL and BRU.

Partner 5 – Professor Philip Van Damme, Katholieke Universiteit Leuven (KUL)

Expertise in ALS and clinical trials

Working on Work Package 1 – Trial Set-up and harmonisation with partners from UMCU, ICH, USFD, CHUT and BRU; Work Package 2 – Trial Implementation and monitoring working with partners from USFD, ICH, CHUT, UMCU, TCD and BRU; Work Package 5 – Dissemination, communication and exploitation with partners from MNDA, ICH, USFD, CHUT and BRU and Work Package 6 – Coordination and management working with the partners from ICH and UULM.

Partner 6 – Professor Leonard van den Berg, Universitair Medisch Centrum Utrecht (UMCU)

Expertise in ALS, clinical trials, TRICALS platform

Lead for Work Package 1 – Trial Set-up and harmonisation with partners from ICH, USFD, CHUT, KUL and BRU

To develop all essential documents, get approval from regulatory bodies and Institutional Review Boards (IRBs) and organize the preparation of Clinical Trial Centres (CTCs), clinical data collection, sample collection, banking and assays in a Good Clinical Practice (GCP) and Good Clinical Laboratory Practice (GCLP) compliant Phase III Randomized Clinical Trial (RCT) aiming at investigating the efficacy and safety of TUDCA.

Partner 7 – Professor Orla Hardiman, Trinity College Dublin (TCD)

Expertise in ALS, biomarkers, neurodegenerative diseases

Lead for Work Package 4 – Data Analysis with partners from BRU and ISS

To perform data analysis, correlation of clinical and biomarker results and stratification by relevant variables. TCD has a long standing clinical expertise on ALS.

Partner 8 – Dr Gilberto Rinaldi, Bruschettini srl (BRU)

Production of study drug, pharma development

Working on Work Package 1 – Trial Set-up and harmonisation with partners from UMCU, ICH, USFD, CHUT and KUL; Work Package 2 – Trial Implementation and monitoring working with partners from USFD, ICH, CHUT, UMCU, TCD and KUL; Work Package 4 – Data Analysis with partners from TCD and ISS and Work Package 5 – Dissemination, communication and exploitation with partners from MNDA, ICH, USFD, CHUT and KUL.

Partner 9 – Dr Nicola Vanacore, Istituto Superiore di Sanità (ISS)

Public Health, Epidemiology, statistics, clinical trial randomisation and data analysis

Working on Work Package 4 – Data Analysis with partners from TCD and BRU.

Partner 10 – Dr Brian Dickie, Motor Neurone Disease Association (MNDA)

Dissemination, ethics and PR liaison

Lead for Work Package 5 – Dissemination, communication and exploitation with partners from ICH, USFD, CHUT, KUL, BRU

To promote the study and ensure that the project results are widely disseminated, communicated and exploited and to ensure sustainability beyond the funding period.

Member of Independent Ethics Board – Data Safety Monitoring Board (IEB-DSMB) – Professor Heiner Fangerau

Department of the History, Philosophy and Ethics of Medicine, Heinrich-Heine-Universität Düsseldorf.

Researchs History of Science and Medicine and Medical Ethics.

Member of the Independent Ethics Board – Data Safety Monitoring (IEB-DSMB) – Professor Olivier Rascol

Neurologist specialized in Movement Disorders and Professor of Clinical Pharmacology at the Toulouse University Hospital.

Runs the Toulouse Clinical Investigation Centre since and the Toulouse European Space Clinic.

Coordinator of the Toulouse Expert Center for Parkinson Disease and of the French Reference Center for Multiple System Atrophy (Atypical Parkinsonism).

Chair of the NS-Park/F-CRIN Neurosciences Network on clinical research in Parkinson disease

Coordinating the National French Clinical Research Infrastructure Network F-CRIN.

Member of the Independent Advisory Board (IAB) – Professor Angela Genge, Montreal Neurological Institute Hospital

Director of both the Clinical Research Unit (CRU) and the internationally recognized multidisciplinary ALS-clinic at the Montreal Neurological Institute and Hospital (MNI/H) and co-director of the MNI/H biobank (C-BIG repository).

Over 20 years of experience in Clinical research and a passion for bringing much needed therapies to patients with neurological diseases, particularly in the rare disease space and actively involved as an advisor for both early and late-stage clinical programs for multiple small biotech and larger pharmaceutical companies.

Member of the Independent Advisory Board (IAB) – Professor Gunther Deuschl, Christian-Albrechts-University Kiel

Senior Professor at the Department of Neurology at the Christian-Albrechts-University in Kiel

Research interests are focused on the clinical features and treatment of Movement Disorders, Parkinson’s disease, essential and other tremors and deep Brain Stimulation. A special interest covers clinical studies on deep brain stimulation for Parkinson’s disease and the pathophysiology of movement disorders.

Honorary member of the International Movement Disorder, the Austrian Parkinson Society as well as the French, Moldavian and Rumanian Neurological Societies.

Founding president of the European Academy of Neurology.

Member of the Independent Advisory Board – Professor Magdalena Kuzma-Kozakiewicz, Medical University of Warsaw

Leader of Neurodegenerative Diseases Research Group, Medical University of Warsaw and Head of Laboratory of Biochemistry, Clinical Hospital, Warsaw

Board member of the European Network for the Cure for ALS (ENCALS)

ACTIVITY

See the Progress we are Making

As the TUDCA-ALS project continues, we will update this live progress chart with key highlights. This information is mainly for those researchers and clinicians involved in the trial. For more general updates, visit the news section.

Summary

  1. January 1st, 2018

    TUDCA-ALS started

  2. January 31st, 2018

    The Consortium secured intranet and management book (Deliverable 6.1) was submitted to the EC

     

  3. April 17th, 2018

    The Dissemination and Exploitation Plan (Devlierable 5.1) was submitted to the EC.

  4. June 1st, 2018

    The TUDCA-ALS website was launched.

  5. October 1st, 2018

    The Project Website Report (Deliverable 5.3) was submitted to the EC.

  6. October 10th, 2018

    The Dossier for regulatory submissions (Deliverable 1.1) was submitted to the EC.

  7. January, 2019

    First participant is recruited into the TUDCA-ALS Clinical Trial