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Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS (TUDCA-ALS)

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ClinicalTrials.gov Identifier: NCT03800524
Recruitment Status : Recruiting
First Posted : January 11, 2019
Last Update Posted : July 15, 2019
Sponsor:
Collaborators:
University of Ulm
University of Sheffield
University Hospital, Tours
KU Leuven
UMC Utrecht
University of Dublin, Trinity College
Information provided by (Responsible Party):
Humanitas Mirasole SpA

Brief Summary:
This is a Phase III, multi-centre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate Safety and Efficacy of Tauroursodeoxycholic (TUDCA) as add-on Treatment in Patients Affected by Amyotrophic Lateral Sclerosis (ALS).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis (ALS) Drug: Tauroursodeoxycholic Acid Drug: Placebo Phase 3

Detailed Description:

Enrolled patients will be randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The randomization will be performed in a ratio one to one for the two arms.

TUDCA will be administered orally at the dose of 1 g twice daily (2 g daily) for 18 months. Patients will be taking also riluzole at the dose of 50 mg twice daily (100 mg daily).

Patient randomization will take place after a screening (lead-in) period of 12 weeks (3 months) with 3 assessments at 6-week intervals. Clinical assessments during the trial phase will be performed every three months. This will allow measuring the progression rate before and after starting treatment (either active or placebo).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 440 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Tauroursodeoxycholic (TUDCA) as add-on Treatment in Patients Affected by Amyotrophic Lateral Sclerosis (ALS)
Actual Study Start Date : February 22, 2019
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2021


Arm Intervention/treatment
Experimental: Tauroursodeoxycholic acid (TUDCA)
  • Tauroursodeoxycholic acid (TUDCA) 250 mg capsules
  • Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal
  • Mode of administration: orally
  • Duration: 18 months
Drug: Tauroursodeoxycholic Acid
  • Tauroursodeoxycholic acid (TUDCA) 250 mg capsules
  • Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal
  • Mode of administration: orally
  • Duration: 18 months
Other Names:
  • TUDCA
  • Tudcabil
  • Taurolite

Placebo Comparator: Reference therapy
  • Placebo capsules identical to active compound
  • Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal
  • Mode of administration: orally
  • Duration: 18 months
Drug: Placebo
  • Placebo 250 mg capsules
  • Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal
  • Mode of administration: orally
  • Duration: 18 months




Primary Outcome Measures :
  1. Number of responder patients [ Time Frame: 18 months ]
    Identification of the responder patients defined as those showing an improvement of at least 20% in the ALSFRS-R slope


Secondary Outcome Measures :
  1. Survival time [ Time Frame: 18 months ]
    Survival time measured by death or respiratory insufficiency

  2. ALS disease functional rating scale - revised version (ALSFRS-R) [ Time Frame: 18 months ]
    Difference in change from baseline in ALSFRS-R. Each task of the scale is rated on a five-point scale from 0 = can't do, to 4 = normal ability. Individual item scores are summed to produce a reported score ranging from 0 = worst to 48 = best.

  3. ALS Assessment Questionnaire‐40 (ALSAQ-40) [ Time Frame: 18 months ]
    Difference in change from baseline in ALSAQ-40. The instrument contains 40 statements that measure five dimensions of health state: Physical Mobility (10 statements), Activities of Daily Living and Independence (10 statements), Eating and Drinking (5 statements), Communication (5 statements), Emotional Functioning (10 statements). The patient must indicate how often (Never, Rarely, Sometimes, Often, or Always) the statement have been true. Dimension scores are coded on a likert scale, ranging from 0 (best health as assessed by the scale) to 100 (worse health as assessed by the measure).

  4. Forced Vital Capacity [ Time Frame: 18 months ]
    Difference in change from baseline in Forced Vital Capacity

  5. EuroQol 5‐Dimension-5 Levels (EQ-5D-5L) scale [ Time Frame: 18 months ]
    Difference in change from baseline in EQ-5D-5L scale. The EQ-5D-5L descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). Each dimension has 5 levels: 1.no problems, 2.slight problems, 3.moderate problems, 4.severe problems, 5.extreme problems. The patient is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number expressing the level selected for that dimension. The digits for 5 dimensions can be combined in a 5-digit number describing the patient health state. Numbers 1-5 have no arithmetic properties and should not be used as a cardinal score.

  6. Medical Research Council (MRC) scale [ Time Frame: 18 months ]
    Difference in change from baseline in muscle force assessed by the MRC scale. The scale rates muscle strength of 6 muscles (3 at the upper and 3 at the lower limbs), bilaterally. Each muscle is graded from 0 = no movement, to 5 = normal strength, giving a total sum-score that ranges from 0 (total paralysis) to 60 (normal strength).

  7. Neurofilaments levels [ Time Frame: 18 months ]
    Effect of TUDCA on Neurofilament levels in comparison to placebo

  8. MMP-9 levels [ Time Frame: 18 months ]
    Effect of TUDCA on MMP-9 expression in comparison to placebo



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Probable laboratory-supported, probable, or definite ALS, as defined by El Escorial Revised ALS diagnostic criteria 34
  • Disease duration ≤ 18 months
  • No swallowing difficulty (4 at ALSFRS-R swallowing subscore)
  • Able to perform reproducible pulmonary function tests
  • Forced vital capacity ≥70% of normal
  • Stable on riluzole treatment for 3 months in the lead-in period
  • Able to perform reproducible pulmonary function tests
  • Signed informed consent

Exclusion Criteria:

  • Treatment with edaravone
  • Other causes of neuromuscular weakness
  • Presence of other neurodegenerative diseases
  • Significant cognitive impairment, clinical dementia or psychiatric illness
  • Severe cardiac or pulmonary disease
  • Other diseases precluding functional assessments
  • Other life-threatening diseases
  • At the time of screening, any use of non-invasive ventilation (e.g. continuous positive airway pressure, non-invasive bi-level positive airway pressure or non-invasive volume ventilation) for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation
  • Gastrointestinal disorder that is likely to impair absorption of study drug from the gastrointestinal tract
  • Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dosing
  • Any clinically significant laboratory abnormality
  • Other concurrent investigational medications
  • Active peptic ulcer
  • Previous surgery or infections of small intestine
  • Patients unable to easily swallow the treatment pills at time of enrolment
  • Occurrence of frequent biliary colic, biliary infections, severe pancreatic abnormalities
  • Subjects who weigh 88 lbs (40 kg) or less at screening
  • Aspartate aminotransferase or alanine aminotransferase concentrations more than 3 times the upper limit of normal
  • Creatinine clearance 50 ml/min or less
  • Previous exposure to bile acids
  • Any clinically significant neurological, haematological, autoimmune, endocrine, cardiovascular, neoplastic, renal, gastrointestinal, or other disorder that, in the Investigator's opinion, could interfere with the subject's participation in the study, place the subject at increased risk, or confound interpretation of study results
  • Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive TUDCA or that the subject is unable or unlikely to comply with the dosing schedule or study evaluations
  • The patient is sexually active and is not willing to use highly effective contraception during the study and up to 90 days after the day of last dose

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03800524


Contacts
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Contact: Alberto Albanese, MD +39-0282246418 alberto.albanese@humanitas.it
Contact: Paolo Tornese, PhD +39-0282246422 paolo.tornese@humanitas.it

Locations
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Belgium
Katholieke Universiteit Leuven Not yet recruiting
Leuven, Belgium
Principal Investigator: Philip Van Damme, MD         
France
Centre Hospitalier Universitaire de Bordeaux Not yet recruiting
Bordeaux, France
Principal Investigator: Gwendal Lemasson, MD         
Centre Hospitalier Universitaire Limoges Not yet recruiting
Limoges, France
Principal Investigator: Philippe Couratier, MD         
Centre Hospitalier Universitaire de Montpellier Not yet recruiting
Montpellier, France
Principal Investigator: William Camu, MD         
Centre Hospitalier Regional Universitaire de Tours Not yet recruiting
Tours, France
Principal Investigator: Philippe Corcia, MD         
Germany
Charité - Universitätsmedizin Berlin Not yet recruiting
Berlin, Germany
Principal Investigator: Thomas Meyer, MD         
Universitätsklinikum Carl Gustav Carus Dresden Not yet recruiting
Dresden, Germany
Principal Investigator: Andreas Hermann, MD         
Alfried Krupp Krankenhaus Rüttenscheid Not yet recruiting
Essen, Germany
Principal Investigator: Torsten Grehl, MD         
Medizinische Hochschule Hannover Not yet recruiting
Hannover, Germany
Principal Investigator: Susanne Petri, MD         
Universitätsklinikum Jena Not yet recruiting
Jena, Germany
Principal Investigator: Julian Grosskreutz, MD         
Universität Ulm Not yet recruiting
Ulm, Germany
Principal Investigator: Albert C Ludolph, MD         
Ireland
Trinity College Dublin Not yet recruiting
Dublin, Ireland
Principal Investigator: Orla Hardiman, MD         
Italy
IRCCS Istituto Auxologico Italiano Recruiting
Milano, Italy
Principal Investigator: Vincenzo Silani, MD         
NEuroMuscular Omnicentre. Fondazione Serena Onlus Recruiting
Milano, Italy
Principal Investigator: Christian Lunetta, MD         
AOU Università degli Studi della Campania "Luigi Vanvitelli" Not yet recruiting
Napoli, Italy
Principal Investigator: Gioacchino Tedeschi, MD         
IRCCS Istituto Clinico Humanitas Recruiting
Rozzano, Italy
Contact: Alberto Albanese, MD    +39-0282246418    alberto.albanese@humanitas.it   
Contact: Paolo Tornese, PhD    +39-0282246418    paolo.tornese@humanitas.it   
Principal Investigator: Alberto Albanese, MD         
Azienda Ospedaliera Santa Maria di Terni Not yet recruiting
Terni, Italy
Principal Investigator: Carlo Colosimo, MD         
AOU Città della Salute e della Scienza di Torino Not yet recruiting
Torino, Italy
Principal Investigator: Adriano Chiò, MD         
Netherlands
Universitair Medisch Centrum Utrecht Not yet recruiting
Utrecht, Netherlands
Principal Investigator: Leonard H van den Berg, MD         
United Kingdom
The Walton Centre NHS Foundation Trust Not yet recruiting
Liverpool, United Kingdom
Principal Investigator: Carolyn Young, MD         
Plymouth Hospitals NHS Trust Not yet recruiting
Plymouth, United Kingdom
Principal Investigator: Oliver Hanemann, MD         
Lancashire Teaching Hospitals NHS Foundation Trust Not yet recruiting
Preston, United Kingdom
Principal Investigator: Suresh Chhetri, MD         
Salford Royal NHS Foundation Trust Not yet recruiting
Salford, United Kingdom
Principal Investigator: Amina Chaouch, MD         
University of Sheffield Not yet recruiting
Sheffield, United Kingdom
Principal Investigator: Christopher J McDermott, MD         
Sponsors and Collaborators
Humanitas Mirasole SpA
University of Ulm
University of Sheffield
University Hospital, Tours
KU Leuven
UMC Utrecht
University of Dublin, Trinity College
Investigators
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Study Chair: Alberto Albanese, MD Humanitas Mirasole SpA

Additional Information:
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Responsible Party: Humanitas Mirasole SpA
ClinicalTrials.gov Identifier: NCT03800524     History of Changes
Other Study ID Numbers: 755094
First Posted: January 11, 2019    Key Record Dates
Last Update Posted: July 15, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Once the dataset has been analysed, a complete, cleaned, anonymized copy of the final data used in conducting the final analyses will be made available to be used in further studies by the research partners or by other research groups and clinicians.

To prevent misuse and misinterpretation, relevant study metadata (such as the study protocol, case report forms, documentation providing information about the methodology and procedures used to collect the data, definition of variables and statistical code) will be shared in a data repository with a stable URL. Patient anonymity and legal compliance will be assured throughout all the steps of data transfer.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Three months after the data-entry process and final data curation
Access Criteria: Data will be made available only to qualified designated persons (methodologists, biostatisticians) from other academic institutions, on request. User registration will be required in order to access files.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Sclerosis
Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Tauroursodeoxycholic acid
Taurochenodeoxycholic Acid
Antiviral Agents
Anti-Infective Agents
Cholagogues and Choleretics
Gastrointestinal Agents