Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis

A E Elia, S Lalli, M R Monsurrò, A Sagnelli, A C Taiello, B Reggiori, V La Bella, G Tedeschi, A Albanese, A E Elia, S Lalli, M R Monsurrò, A Sagnelli, A C Taiello, B Reggiori, V La Bella, G Tedeschi, A Albanese

Abstract

Background and purpose: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS).

Methods: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events.

Results: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01).

Conclusions: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.

Trial registration: ClinicalTrials.gov NCT00877604.

Keywords: amyotrophic lateral sclerosis; cholic acids; tauroursodeoxycholic acid.

© 2015 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

Figures

Figure 1
Figure 1
Random assignments to treatment, withdrawals during the lead‐in phase, completion of the trial, and requests for open‐label treatment. The number of patients who died during the treatment phase is also reported.
Figure 2
Figure 2
Linear regression analysis of ALSFFRS‐R mean scores over time for the TUDCA (circles, slope −0.388) and placebo groups (triangles, slope −0.262).
Figure 3
Figure 3
Kaplan–Meier estimates of the probability of survival in the placebo and TUDCA groups (P = 0.092; log‐rank test).

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