Efficacy and Tolerability of Tauroursodeoxycholic Acid in Amyotrophic Lateral Sclerosis
NCT ID: NCT00877604
Last Updated: 2014-11-26
Study Results
Results available
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE2
Total Enrollment
34 participants
Study Classification
INTERVENTIONAL
Study Start Date
2008-06-30
Study Completion Date
2012-04-30
Brief Summary
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The preclinical rationale for tauroursodeoxycholic acid (TUDCA) use in treating patients with amyotrophic lateral sclerosis (ALS) stems from the demonstration of antioxidant, antiapoptotic and neuroprotective properties of TUDCA in the central nervous system (CNS), both in vitro and in vivo models.
This protocol is meant for assessing if the addition of TUDCA to the conventional therapy can improve the therapeutic outcome in patients affected by ALS.
Safety will be assessed for all subjects, for the entire duration of the study. 30 patients affected by ALS with site of onset in the limbs will be recruited.
All enrolled subjects will continue receiving riluzole at the same regimen as before entering the trial. Based on an appropriate random code, subjects will be divided into two groups of equal size treated, after a lead-in period of 3 months, by oral route with TUDCA at the dose 2 g daily for 1 year or with identical placebo by oral route at the same dosing schedule, under double-blind conditions.
Every concomitant and/or supportive therapy will be admitted.
Evaluation criteria:
Efficacy. The proportion of responder patients in the two treatment groups was the primary outcome measure of the study. Responder patients were defined as those subjects showing an improvement of at least 15% in the ALSFRS-R (2) slope during the treatment period as compared to the lead-in period. This threshold was chosen based according to the consensus conference on designing and implementing clinical trials in ALS (3).
Other parameters will include ALSFRS-R at study end, FVC%, the SF-36 quality of life rating scale, time to tracheotomy from starting of study medication dosing (if appropriate), survival Time from starting of study medication dosing (if appropriate), Medical Research Council scores for right and left muscle groups.
Safety. Incidence, severity and type of adverse events; changes in clinical laboratory findings.
This protocol is meant for assessing if the addition of TUDCA to the conventional therapy can improve the therapeutic outcome in patients affected by ALS.
Safety will be assessed for all subjects, for the entire duration of the study. 30 patients affected by ALS with site of onset in the limbs will be recruited.
All enrolled subjects will continue receiving riluzole at the same regimen as before entering the trial. Based on an appropriate random code, subjects will be divided into two groups of equal size treated, after a lead-in period of 3 months, by oral route with TUDCA at the dose 2 g daily for 1 year or with identical placebo by oral route at the same dosing schedule, under double-blind conditions.
Every concomitant and/or supportive therapy will be admitted.
Evaluation criteria:
Efficacy. The proportion of responder patients in the two treatment groups was the primary outcome measure of the study. Responder patients were defined as those subjects showing an improvement of at least 15% in the ALSFRS-R (2) slope during the treatment period as compared to the lead-in period. This threshold was chosen based according to the consensus conference on designing and implementing clinical trials in ALS (3).
Other parameters will include ALSFRS-R at study end, FVC%, the SF-36 quality of life rating scale, time to tracheotomy from starting of study medication dosing (if appropriate), survival Time from starting of study medication dosing (if appropriate), Medical Research Council scores for right and left muscle groups.
Safety. Incidence, severity and type of adverse events; changes in clinical laboratory findings.
Detailed Description
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Amyotrophic lateral sclerosis (ALS), or motor neuron disease (MND), is a rapidly progressive, fatal neurodegenerative condition characterized by loss of upper and lower motor neurons in the brain and spinal cord. The terms ALS and MND are often used inter-changeably to cover the different clinical syndromes, which include upper and lower motor neuron disorder, progressive bulbar palsy, and pseudo-polyneuritic form.
Degeneration of lower motor neurons (LMN) in the anterior horns of spinal cord and brainstem leads to progressive muscular atrophy and eventually to death within a few years due to respiratory insufficiency. During the course of the disease, the involvement of tongue and pharynx muscles causes swallowing impairment with marked drooling, need of parenteral or enteral feeding, and finally gastrostomy. Denervation of laryngeal muscles causes loss of speech. Cramps and fasciculation typically occur from the early phases of the disease. Degeneration of upper motor neurons (UMN) in the brain cortex causes pyramidal tract dysfunctions including clonus, Babinski sign, hypertonia, and loss of dexterity that further limit patients' daily activities.
The incidence of ALS varies from 0.2 to 2.5 cases per 100,000 per year, although estimates vary between countries, likely reflecting a combination of availability of medical services, diagnostic accuracy, and demo-graphic characteristics of the area. Increasing life expectancy and improvements in standards of treatment and care will also result in an increased incidence of ALS. Globally, the overall rate is approximately 2 per 100,000. Its prevalence is approximately of 7 per 100,000. In Italy, the reported incidence of ALS is 2.2 cases/100,000/year.
There is currently no cure for ALS. Despite initial positive results in preclinical and early clinical studies, large-scale clinical trials with all agents except riluzole failed to demonstrate a clinically meaningful therapeutic effect in patients with ALS. Riluzole at the dose of 100 mg/day showed a significant difference on survival (6.4%; gain of 3 months) and slowed deterioration in muscle strength.
Primary involvement of apoptotic mechanisms has important implications in selecting drug candidates for therapy in ALS. Recent preclinical studies have demonstrated that TUCA is endowed with antioxidant, antiapoptotic and neuroprotective activities. In particular, TUDCA can cross the blood-brain-barrier and has been shown to exert a significant therapeutic effect in a model of HD mice.
Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is normally produced endogenously in humans at very low levels. TUDCA is synthesized in the liver by conjugation of taurine to ursodeoxycholic acid (UDCA), which is commonly used as a bile acid replacement therapy for the treatment of certain cholestatic syndromes.
The main pharmacological activity of TUDCA consists in its ability in increasing the cholesterol solubilising activity of bile, thus transforming "lithogenic" bile in "non-lithogenic" or "litholytic" bile.
TUDCA inhibits mitochondrial-associated apoptosis via many pathways: 1) it inhibits the mitochondrial permeability transition (MPT) and cytochrome C release, 2) it inhibits mitochondrial membrane depolarization, and 3) it antagonizes Bax translocation from the mitochondria and caspase activation in hepatocytes and brain. TUDCA may also ease oxidative stress.Study relevant TUDCA pharmacology consists in its antioxidant, antiapoptotic and neuroprotective activities evidenced in preclinical studies.
Recent reports have shown that hydrophilic bile acids, such as UDCA and TUDCA, can prevent hepatic cytotoxicity through several mechanisms. For example, TUDCA prevents the production of reactive oxygen species and thus acts as an antioxidant. Additionally, TUDCA mitigates mitochondrial insufficiency and toxicity, and prevents apoptosis, in part, by inhibiting Bax translocation from cytosol to the mitochondria. In hepatocytes, this inhibition results in reduced mitochondrial membrane perturbation, release of cytochrome c, and activation of downstream caspases. TUDCA reduced cytotoxicity in neurons through similar mechanisms, as well as mitochondrial pathways that are independent of the permeability transition. TUDCA prevented striatal degeneration and ameliorated locomotor and cognitive deficits in the in vivo 3-nitropropionic acid (3-NP) rat model of HD. Intracellular inclusions were significantly reduced, and the TUDCA-treated mice showed improved locomotor and sensorimotor abilities.
In addition, the antiapoptotic and cytoprotective effects of TUDCA have been tested in models of acute stroke. The possibility that TUDCA exerts an antiapoptotic action by ameliorating mitochondrial function raises the issue whether other neurological disorders, including Friedreich's ataxia, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease, can benefit by the administration of TUDCA. This drug is a candidate neuroprotective agent for a variety of chronic neurodegenerative conditions.
Degeneration of lower motor neurons (LMN) in the anterior horns of spinal cord and brainstem leads to progressive muscular atrophy and eventually to death within a few years due to respiratory insufficiency. During the course of the disease, the involvement of tongue and pharynx muscles causes swallowing impairment with marked drooling, need of parenteral or enteral feeding, and finally gastrostomy. Denervation of laryngeal muscles causes loss of speech. Cramps and fasciculation typically occur from the early phases of the disease. Degeneration of upper motor neurons (UMN) in the brain cortex causes pyramidal tract dysfunctions including clonus, Babinski sign, hypertonia, and loss of dexterity that further limit patients' daily activities.
The incidence of ALS varies from 0.2 to 2.5 cases per 100,000 per year, although estimates vary between countries, likely reflecting a combination of availability of medical services, diagnostic accuracy, and demo-graphic characteristics of the area. Increasing life expectancy and improvements in standards of treatment and care will also result in an increased incidence of ALS. Globally, the overall rate is approximately 2 per 100,000. Its prevalence is approximately of 7 per 100,000. In Italy, the reported incidence of ALS is 2.2 cases/100,000/year.
There is currently no cure for ALS. Despite initial positive results in preclinical and early clinical studies, large-scale clinical trials with all agents except riluzole failed to demonstrate a clinically meaningful therapeutic effect in patients with ALS. Riluzole at the dose of 100 mg/day showed a significant difference on survival (6.4%; gain of 3 months) and slowed deterioration in muscle strength.
Primary involvement of apoptotic mechanisms has important implications in selecting drug candidates for therapy in ALS. Recent preclinical studies have demonstrated that TUCA is endowed with antioxidant, antiapoptotic and neuroprotective activities. In particular, TUDCA can cross the blood-brain-barrier and has been shown to exert a significant therapeutic effect in a model of HD mice.
Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is normally produced endogenously in humans at very low levels. TUDCA is synthesized in the liver by conjugation of taurine to ursodeoxycholic acid (UDCA), which is commonly used as a bile acid replacement therapy for the treatment of certain cholestatic syndromes.
The main pharmacological activity of TUDCA consists in its ability in increasing the cholesterol solubilising activity of bile, thus transforming "lithogenic" bile in "non-lithogenic" or "litholytic" bile.
TUDCA inhibits mitochondrial-associated apoptosis via many pathways: 1) it inhibits the mitochondrial permeability transition (MPT) and cytochrome C release, 2) it inhibits mitochondrial membrane depolarization, and 3) it antagonizes Bax translocation from the mitochondria and caspase activation in hepatocytes and brain. TUDCA may also ease oxidative stress.Study relevant TUDCA pharmacology consists in its antioxidant, antiapoptotic and neuroprotective activities evidenced in preclinical studies.
Recent reports have shown that hydrophilic bile acids, such as UDCA and TUDCA, can prevent hepatic cytotoxicity through several mechanisms. For example, TUDCA prevents the production of reactive oxygen species and thus acts as an antioxidant. Additionally, TUDCA mitigates mitochondrial insufficiency and toxicity, and prevents apoptosis, in part, by inhibiting Bax translocation from cytosol to the mitochondria. In hepatocytes, this inhibition results in reduced mitochondrial membrane perturbation, release of cytochrome c, and activation of downstream caspases. TUDCA reduced cytotoxicity in neurons through similar mechanisms, as well as mitochondrial pathways that are independent of the permeability transition. TUDCA prevented striatal degeneration and ameliorated locomotor and cognitive deficits in the in vivo 3-nitropropionic acid (3-NP) rat model of HD. Intracellular inclusions were significantly reduced, and the TUDCA-treated mice showed improved locomotor and sensorimotor abilities.
In addition, the antiapoptotic and cytoprotective effects of TUDCA have been tested in models of acute stroke. The possibility that TUDCA exerts an antiapoptotic action by ameliorating mitochondrial function raises the issue whether other neurological disorders, including Friedreich's ataxia, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease, can benefit by the administration of TUDCA. This drug is a candidate neuroprotective agent for a variety of chronic neurodegenerative conditions.
Conditions
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Amyotrophic Lateral Sclerosis
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
SINGLE_GROUP
Primary Study Purpose
TREATMENT
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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TUDCA
tauroursodeoxycholic acid di-hydrate
Group Type
EXPERIMENTAL
tauroursodeoxycholic acid (TUDCA)
Intervention Type
DRUG
Oral route at the dose of 1 g b.i.d. (2 g daily) for 1 year
placebo
excipient lactose
Group Type
PLACEBO_COMPARATOR
Placebo
Intervention Type
DRUG
identical placebo by oral route at the same dosing schedule
Interventions
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tauroursodeoxycholic acid (TUDCA)
Oral route at the dose of 1 g b.i.d. (2 g daily) for 1 year
Intervention Type
DRUG
Placebo
identical placebo by oral route at the same dosing schedule
Intervention Type
DRUG
Other Intervention Names
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Ursodiol
Actigall
Generic
Oral route at the dose of 1 g b.i.d. (2 g daily) for 1 year
Eligibility Criteria
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Inclusion Criteria
* Caucasian male or female out-patients;
* aged 18 to 75 years inclusive;
* diagnosis of "probable" or "definite" amyotrophic lateral sclerosis according to the El Escorial revised criteria (1);
* first symptoms of ALS by no more than 1.5 years;
* in treatment with steady regimen of riluzole for a minimum of 3 months before study entry, and desiring its continuation;
* FVC ≥ 75% of predicted;
* no conditions known to be contraindications to the use of TUDCA;
* written informed consent.
* aged 18 to 75 years inclusive;
* diagnosis of "probable" or "definite" amyotrophic lateral sclerosis according to the El Escorial revised criteria (1);
* first symptoms of ALS by no more than 1.5 years;
* in treatment with steady regimen of riluzole for a minimum of 3 months before study entry, and desiring its continuation;
* FVC ≥ 75% of predicted;
* no conditions known to be contraindications to the use of TUDCA;
* written informed consent.
Exclusion Criteria
* subjects who underwent tracheostomy;
* subjects who underwent resection of gall bladder;
* subjects with signs of conduction blocks of motor nerves, sensory nerves or both on nerve conduction study;
* subjects with clinical signs of dementia;
* subjects with active peptic ulcer;
* subjects with active malignancy;
* subjects with bulbar onset;
* female subjects who are pregnant or lactating
* subjects who have received an experimental drug or have participated in a clinical trial within 3 months prior to screening
* employees of the investigator or study centre with direct involvement in the proposed study or other studies under the direction of that investigator or study centre.
* subjects who underwent resection of gall bladder;
* subjects with signs of conduction blocks of motor nerves, sensory nerves or both on nerve conduction study;
* subjects with clinical signs of dementia;
* subjects with active peptic ulcer;
* subjects with active malignancy;
* subjects with bulbar onset;
* female subjects who are pregnant or lactating
* subjects who have received an experimental drug or have participated in a clinical trial within 3 months prior to screening
* employees of the investigator or study centre with direct involvement in the proposed study or other studies under the direction of that investigator or study centre.
Minimum Eligible Age
18 Years
Maximum Eligible Age
75 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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University of Palermo
OTHER
Sponsor Role
collaborator
Federico II University
OTHER
Sponsor Role
collaborator
Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
OTHER
Sponsor Role
lead
Responsible Party
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Alberto Albanese
Professor
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Alberto Albanese, MD
Role: PRINCIPAL_INVESTIGATOR
Fondazione IRCCS Istituto neurologico Carlo Besta
Locations
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Fondazione IRCCS Istituto neurologico Carlo Besta
Milan, Milan, Italy
Site Status
Countries
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Italy
References
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Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. doi: 10.1080/146608200300079536. No abstract available.
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Leigh PN, Swash M, Iwasaki Y, Ludolph A, Meininger V, Miller RG, Mitsumoto H, Shaw P, Tashiro K, Van Den Berg L. Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Jun;5(2):84-98. doi: 10.1080/14660820410020187.
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Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10671-6. doi: 10.1073/pnas.162362299. Epub 2002 Jul 29.
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Benz C, Angermuller S, Otto G, Sauer P, Stremmel W, Stiehl A. Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis in primary human hepatocytes. Eur J Clin Invest. 2000 Mar;30(3):203-9. doi: 10.1046/j.1365-2362.2000.00615.x.
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BACKGROUND
Schoemaker MH, Conde de la Rosa L, Buist-Homan M, Vrenken TE, Havinga R, Poelstra K, Haisma HJ, Jansen PL, Moshage H. Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways. Hepatology. 2004 Jun;39(6):1563-73. doi: 10.1002/hep.20246.
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BACKGROUND
Miller SD, Greene CM, McLean C, Lawless MW, Taggart CC, O'Neill SJ, McElvaney NG. Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha-1 antitrypsin via inhibition of Bad. Hepatology. 2007 Aug;46(2):496-503. doi: 10.1002/hep.21689.
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BACKGROUND
Rodrigues CM, Sola S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry. 2003 Mar 18;42(10):3070-80. doi: 10.1021/bi026979d.
Reference Type
BACKGROUND
Ramalho RM, Ribeiro PS, Sola S, Castro RE, Steer CJ, Rodrigues CM. Inhibition of the E2F-1/p53/Bax pathway by tauroursodeoxycholic acid in amyloid beta-peptide-induced apoptosis of PC12 cells. J Neurochem. 2004 Aug;90(3):567-75. doi: 10.1111/j.1471-4159.2004.02517.x.
Reference Type
BACKGROUND
Rodrigues CM, Sola S, Nan Z, Castro RE, Ribeiro PS, Low WC, Steer CJ. Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6087-92. doi: 10.1073/pnas.1031632100. Epub 2003 Apr 29.
Reference Type
BACKGROUND
Ramalho RM, Borralho PM, Castro RE, Sola S, Steer CJ, Rodrigues CM. Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer's disease mutant neuroblastoma cells. J Neurochem. 2006 Sep;98(5):1610-8. doi: 10.1111/j.1471-4159.2006.04007.x.
Reference Type
BACKGROUND
Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B. Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem. 2005 Dec 30;280(52):42655-42668. doi: 10.1074/jbc.M505910200. Epub 2005 Oct 19.
Reference Type
BACKGROUND
Sola S, Castro RE, Laires PA, Steer CJ, Rodrigues CM. Tauroursodeoxycholic acid prevents amyloid-beta peptide-induced neuronal death via a phosphatidylinositol 3-kinase-dependent signaling pathway. Mol Med. 2003 Sep-Dec;9(9-12):226-34. doi: 10.2119/2003-00042.rodrigues.
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BACKGROUND
Rudolph G, Kloeters-Plachky P, Sauer P, Stiehl A. Intestinal absorption and biliary secretion of ursodeoxycholic acid and its taurine conjugate. Eur J Clin Invest. 2002 Aug;32(8):575-80. doi: 10.1046/j.1365-2362.2002.01030.x.
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BACKGROUND
Keene CD, Rodrigues CM, Eich T, Linehan-Stieers C, Abt A, Kren BT, Steer CJ, Low WC. A bile acid protects against motor and cognitive deficits and reduces striatal degeneration in the 3-nitropropionic acid model of Huntington's disease. Exp Neurol. 2001 Oct;171(2):351-60. doi: 10.1006/exnr.2001.7755.
Reference Type
BACKGROUND
Castro RE, Sola S, Ramalho RM, Steer CJ, Rodrigues CM. The bile acid tauroursodeoxycholic acid modulates phosphorylation and translocation of bad via phosphatidylinositol 3-kinase in glutamate-induced apoptosis of rat cortical neurons. J Pharmacol Exp Ther. 2004 Nov;311(2):845-52. doi: 10.1124/jpet.104.070532. Epub 2004 Jun 9.
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BACKGROUND
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Miller RG, Munsat TL, Swash M, Brooks BR. Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology committee on Research. J Neurol Sci. 1999 Oct 31;169(1-2):2-12. doi: 10.1016/s0022-510x(99)00209-9.
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Elia AE, Lalli S, Monsurro MR, Sagnelli A, Taiello AC, Reggiori B, La Bella V, Tedeschi G, Albanese A. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol. 2016 Jan;23(1):45-52. doi: 10.1111/ene.12664. Epub 2015 Feb 9.
Reference Type
DERIVED
Other Identifiers
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EudraCT No.: 2007-001592-10
Identifier Type: -
Identifier Source: secondary_id
TUDCA200701
Identifier Type: -
Identifier Source: org_study_id