Min J-H, et al. • Oral Ursodeoxycholic Acid Therapy in Amyotrophic Lateral Sclerosis UDCA and 15 of 23 (65.2%) patients treated with placebo com- pleted the study. All patients who completed the first period switched to receive the other treatment in the second period. The patients who dropped out during the first period of study were also scheduled to enter the second period of study after originally planned three months had passed with the other treat- ment given for the second period. Thus, 31 of 40 (77.5%) random- ized to oral solubilized UDCA and 19 of 23 (82.6%) randomized to placebo for the first period switched to receive placebo and oral solubilized UDCA, respectively, for the second period of study. During the second period, 6 of 19 (31.6%) treated with oral solubilized UDCA and 13 of 31 (41.9%) treated with place- Table 1. Baseline characteristics of patients Oral solubilized Placebo group Parameters UDCA group P value (n = 28) (n = 25) Women 10 (40%) 8 (28.6%) NS Age at onset (yr) 50.1 (2.2) 48.3 (1.7) NS Time from symptom onset to 12.6 (1.8) 14.6 (4.3) NS enrollment (month) Onset region NS Bulbar 3 3 Mixed 3 2 Limb 19 23 Appel ALS total score at baseline 69.3 (3.3) 70.4 (2.9) NS ALSFRS-R at baseline 39.6 (0.8) 39.9 (0.7) NS FVC (%) at baseline 72.9 (5.9) 69.4 (4.7) NS Certainty of diagnosis NS Definite 5 8 Probable 20 20 Data above are from the patients who completed either the first or second period of study. Baseline refers to the last measurement before the start of treatment during each period of study. ALSFRS-R and FVC (%) at baseline are from the first PP dataset on the corresponding outcome variable. Values are No. (%) or mean (standard error). UDCA, ursodeoxycholic acid; ALS, amyotrophic lateral sclerosis; ALSFRS-R, amyotrophic lateral sclerosis functional rating scale-revised; FVC, forced vital capacity. Table 2. Results of efficacy analysis Variables Oral solubilized UDCA Placebo bo completed the study. Drop-out rates were higher during the second period (62%) than the first (46%), and also higher whilst on oral solubilized UDCA (57.6%) than placebo (48.1%). Only 16 out of 63 enrolled patients completed the entire cross-over trial of 8-month, receving both treatments. Missed visits was the most common reason for drop-out (62%), followed by lost to fol- low-up (18%), discontinuation due to adverse events (12%) and a rapid progression (8%). The demographic and clinical characteristics of patients treat- ed with either oral solubilized UDCA or placebo are outlined in Table 1. The patients treated with oral solubilized UDCA and placebo were comparable to each other at baseline with respect to sex, age at onset, disease duration from symptom onset to di- agnosis, onset region, severity, and level of diagnostic certainty. We constructed the dataset for efficacy analysis separately for each outcome, because the AALSRS and FVC measures were missing more frequently than the ALSFRS-R. The results of effi- cacy analysis for each outcome were summarized in Table 2. As for the PP datasets, the slope of AALSRS was 1.17 points/month lower while the patients were treated with oral solubilized UDCA than with placebo (2.3 vs 3.47 points/month, 95% CI for differ- ence 0.08-2.26, P = 0.037). However, the slope of neither ALS- FRS-R nor FVC (%) did not show any significant differences between treatments. Efficacy analysis from the PP’ datasets re- vealed the same results as from the PP datasets. The slope of AALSRS was 1.63 points/month slower while the patients were treated with oral solubilized UDCA than with placebo (2.24 vs 3.88 points/month, 95% CI for difference 0.60-2.68, P = 0.004), whereas the ALSFRS-R and FVC (%) deteriorated without signif- icant differences between the two treatments. To infer the clini- cal meaning from the slope data, Kaplan-Meier estimation was performed using a 20-points progression in the AALSRS total LSM Difference (Placebo-Oral solubilized UDCA) Mean 95 % CI P value PP datasets Appel ALS total score n = 25 n = 28 Adjusted slope 2.30 (0.41) 3.47 (0.30) 1.17 0.08 to 2.26 0.037 ALSFRS-R n = 48 n = 44 Adjusted slope -1.04 (0.28) -1.61 (0.28) -0.57 -1.37 to 0.23 0.16 FVC (%) n = 17 n = 16 Adjusted slope -1.76 (1.03) -2.52 (1.02) -0.76 -4.04 to 2.52 0.62 PP’ datasets Appel ALS total score N = 16 Adjusted slope 2.24 (0.34) 3.88 (0.34) 1.63 0.60 to 2.68 0.004 ALSFRS-R N = 35 Adjusted slope -0.97 (0.32) -1.54 (0.32) -0.72 -1.64 to 0.2 0.22 FVC (%) N = 11 Adjusted slope -0.76 (1.23) -1.90 (1.23) -1.13 -5.07 to 2.8 0.53 Least square means (LSM) of slope and p-values were obtained from the analysis of covariance model with change from baseline (slope) as the dependent variable, treatment (Oral solubilized UDCA vs placebo) as factor, and the period and sequence as covariates. Values in paresthesis are standard errors of LSM. Efficacy was analyzed separately for each outcome without imputation for missing data, and definitions of the PP and PP’ datasets were as followings: PP datasets, the data from the patients (n) who completed ei- ther the first or second period of study; PP’ datasets, the data from the patients (N) who completed both the first and second periods of study. http://dx.doi.org/10.3346/jkms.2012.27.2.200 http://jkms.org 203