Effect of tauroursodeoxycholic acid on survival and safety in amyotrophic lateral sclerosis: a retrospective population-based cohort study

Abstract

Background: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only.

Methods: This propensity score-matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients.

Findings: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000 mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7-93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7-41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA (HR 0.56; 95% CI 0.38-0.83; p = 0.0042) compared to both the control group and those with lower TUDCA dosages (defined as < 1000 mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae.

Interpretation: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug.

Funding: Emilia-Romagna Region.

Keywords: Amyotrophic lateral sclerosis; Propensity score matching; Real-world evidence; Survival; Tauroursodeoxycholic acid.

Fig. 1

Participant flow through study analysis. Cases and controls of the ERRALS study population are shown through the flowchart. 761 patients were diagnosed with ALS between January, 1st, 2015 and June, 30th, 2021 in the Emilia Romagna region and recorded in ERRALS. Last follow-up date was fixed on February 1st, 2022. All patients with ALS with insufficient baseline or follow-up data on the ERRALS registry were excluded from propensity score-matching analysis; TUDCA-exposed patients who took less than three consecutive months of therapy were similarly excluded. ALS: Amyotrophic Lateral Sclerosis; ERRALS: Emilia Romagna Region ALS registry; TUDCA: tauroursodeoxycholic acid.

Fig. 2

Tracheostomy-free/life survival from diagnosis of incident ALS cases based on TUDCA treatment. Kaplan–Meier survival plot displaying tracheostomy-free survival of patients with ALS in ERRALS study divided by controls (i.e., non-TUDCA-exposed patients, blue line), low-dose TUDCA-exposed patients (i.e., <1000 mg/daily dosage, red line), and high-dose TUDCA patients (≥1000 mg/daily dosage, green line). Survival was calculated by considering the time in months from symptom onset to death or tracheostomy (whichever occurred first) or the censoring date (the last day of follow-up, February 1st, 2022). The number of patients included in the analysis is presented every 20 months, with the number of censored patients between brackets. TUDCA: tauroursodeoxycholic acid.