Efficacy and Tolerability of Tauroursodeoxycholic Acid in Amyotrophic Lateral Sclerosis
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): tauroursodeoxycholic acid (TUDCA); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Oral route at the dose of 1 g b.i.d. (2 g daily) for 1 year; identical placebo by oral route at the same dosing schedule
Other intervention name(s): Ursodiol; Actigall; Generic; Oral route at the dose of 1 g b.i.d. (2 g daily) for 1 year
Intervention MeSH terms: Ursodoxicoltaurine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: ALS; Therapy; Tauroursodeoxycholic acid; TUDCA; antioxidant; antiapoptotic drug; neuroprotective drug