100 80 tsn 60 e i t a p % 40 20 0 Oral UDCA Placebo 10 20 30 40 50 60 Months Fig. 2. Kaplan-Meier survival curves, using a change of 20 points on the Appel ALS total score as the end point. Time to 20 points progression was estimated by assum- ing a linearity of the change in the Appel ALS total score. In two patients whose slope was not above zero (zero in one, and -0.33 point/month in the other, both treated with oral solubilized UDCA), the time to 20 point progression was estimated to be 60 months, i.e., 1 point/3 month. score as the end point which was reported to represent a clini- cally meaningful lifestyle change. However, because of the short study period of this trial, the time to reach this endpoint had to be estimated in all patients, and was calculated by assuming that the slope of AALSRS would be linear from the start of treatment through the endpoint. As for the PP’ datasets, the time to a 20- points progression in the AALSRS total score was estimated to be delayed by 14.9 months in oral solubilized UDCA-treated group compared to placebo-treated group (22.5 vs 7.6 months, 95% CI for difference 2.97-26.8 months, P = 0.018) (Fig. 2). Additionally, we compared clinical features between 60 patients who dropped out and 53 patients who completed at least one part of the study. At baseline, sex, age at onset, age at enrollment, disease duration from symptom onset to diagnosis, onset region, severity, and level of diagnostic certainty were not significantly different be- tween two groups (all, P > 0.05). Safety data from each period of study were pooled to provide a whole picture of the adverse event profile. The population for safety analysis consisted of 74 patients who took oral solubilized UDCA, and 70 patients who took placebo (Table 3). Not included for safety analysis were the patien ts who did not take the study drug or placebo at all, 6 pa- tients assigned to oral solubilized UDCA and 10 patients to pla- cebo. A total of 25 occasions of adverse events were reported in 17 patients (23.0%) treated with oral solubilized UDCA, and 12 oc- casions in 10 patients (14.3%) treated with placebo. Except for the expected complications of ALS such as dyspnea and dys- phagia, adverse events that could be possibly attributed to the study drug or placebo were reported in 12 patients (16.2%, 16 occasions) treated with oral solubilized UDCA, and in 6 patients 204 http://jkms.org Min J-H, et al. • Oral Ursodeoxycholic Acid Therapy in Amyotrophic Lateral Sclerosis Table 3. Incidence of adverse events Symptoms/signs (Pnla=ce7b0o) Oral so(lnub=ili7ze4d) UDCA Ophthalmic 1 1 Cataract 1 1 Gastrointestinal* 6 18 Abdominal pain 0 5 (1) Anorexia 0 2 (1) Dyphagia 1 (1) 1 Diarrhea 1 5 Dyspepsia 2 1 Nausea 0 1 Vomiting 2 3 (1) Neurological 2 2 Dizziness 1 0 Headache 1 2 Respiratory 3 4 Dyspnea 3 (2) 4 (3) Total* 12 25 Data are numbers of events (number of serious adverse events). *P < 0.05, chi-square test. (8.6%, 7 occasions) treated with placebo. Gastrointestinal adverse events were significantly more common in patients treated with oral solubilized UDCA (P < 0.05), but serious events were re- ported in only one patient who discontinued the drug due to abdominal pain, anorexia and vomiting. None of the 80 patients who were randomized died during the 8-month period of study, with tracheostomy performed in 2 patients. DISCUSSION The results of this study suggest that oral solubilized UDCA ther- apy may have a beneficial effect on the rate of functional decline in patients with ALS. As for the slope of AALSRS, the difference between oral solubilized UDCA and placebo was 1.17 and 1.63 points per month on the average for the PP and PP’ datasets, re- spectively, which correspond to 34% and 42% relative slowing of the rate of deterioration in this scale. Although estimated, the time to a 20-points progression in the AALSRS also showed that oral solubilized UDCA treatment could delay this endpoint by more than 1 yr compared to placebo. Although it was not statis- tically significant, the efficacy data in the other outcomes also showed a trend favoring oral solubilized UDCA. Although gas- trointestinal adverse events developed more frequently in pa- tients treated with oral solubilized UDCA, these were mostly tolerable and oral high dose solubilized UDCA was well tolerated in vast majority of patients. Taken together, this study suggests a therapeutic potential and acceptable safety profile of oral solu- bilized UDCA in ALS patients. However, no firm conclusion cannot be made on the efficacy of oral solubilized UDCA because of several critical problems and limitations of this study which should be acknowledged herein. First of all, the major problem was the large drop-out rate in this trial. In fact, only about a fourth of the initially ran- http://dx.doi.org/10.3346/jkms.2012.27.2.200