Min J-H, et al. • Oral Ursodeoxycholic Acid Therapy in Amyotrophic Lateral Sclerosis from being delivered through systemic circulation, for example, to the central nervous system at potentially therapeutic concen- trations (18). UDCA capsules or tablets, for instance, contain acid crystals with a very low solubility at pH < 7, and after adminis- tration of the pharmacological dose (10-15 mg/kg/day) UDCA is absorbed through passive non-ionic diffusion, which is large- ly limited by dilution mostly in the small intestine (18). More- over, a large proportion of UDCA taken up from the portal blood is conjugated with glycine or taurine during its first hepatic pas- sage, and actively secreted into the bile (18). A new UDCA formula, oral solubilized UDCA (Yoo’s solution; US patent 6251428, 7166299, 7303768 with PTC), was developed to broaden its therapeutic targets beyond the liver and biliary tracts eluding those pharmacokinetic limitations such as the enterohepatic circulation and high first-pass metabolism. The new formula contains intact UDCA molecules and soluble starch conversion product that enables UDCA to remain in solution. The product is highly soluble in water with a solubility of 80 mg/ mL, and stable from pH 1 to 14 without producing precipitate (19, 20). It can deliver therapeutically effective amounts of solu- bilized intact UDCA to the systemic circulation with a Cmax of 20.4 μg/mL at a Tmax of 15 min in human blood after oral admin- istration of single dose containing 500 mg of UDCA (20). More- over, a preliminary study showed that UDCA can be effectively delivered to the central nervous system (cerebrospinal fluid, CSF) with oral administration of solubilized UDCA (described in the methods). The present study was performed to evaluate the efficacy and safety of oral solubilized UDCA treatment in patients with ALS. MATERIALS AND METHODS Study design, patients and treatment The study was a double-blind, placebo-controlled, randomized, cross-over, single center, phase III trial. Inclusion started in March 2005, and the final patient completed the study in July 2007. Pa- tients with definite or probable sporadic ALS, according the re- vised El Escorial criteria, were enrolled (21). They had to be at or above 20 yr of age, and have disease duration of less than 60 months. The Appel ALS rating scale (AALSRS) total score had to be between 40 and 120 at baseline (22). Patients who had a forced vital capacity of less than 30%, those with signs of major psychi- atric disorders and/or dementia, and acute cholecystitis or oc- clusion of bile duct, or patients who had another concomitant conditions likely to interfere with drug compliance and outcome assessment were excluded. Additional exclusion criteria were pregnancy and participation to other clinical trials. Eligibility was assessed by two of the authors , and the eligible patients who gave informed consents were randomly assigned to one of the two treatment groups according to a randomiza- tion schedule prepared by Prime Pharm Tech, Corp (Suwon, http://dx.doi.org/10.3346/jkms.2012.27.2.200 Korea). There was no stratification of patients according to the onset region, age or respiratory function, since all the patients enrolled were supposed to receive both treatments (oral solubi- lized UDCA and placebo) sequentially in this cross-over trial. After a run-in period of 1 month, one group received oral solubi- lized UDCA (UDCA 3.5 g/140 mL q.d., Prime Pharm Tech, Corp.) for 3 months, while the other group received placebo (identi- cally-appearing, equal amount of solution q.d., Prime Pharm Tech, Corp.). Subsequently, the two groups switched to receive the other treatment for another 3 months during the second period of study. To eliminate a possible carry-over effect of oral solubilized UDCA, a wash-out period of 1 month was set at the beginning of the second period. To ensure blinding, placebo was made to be identical to oral solubilized UDCA in viscosity as well as appearance (color, packaging and labeling), and to be similar in bitter taste (by adding quinine hydrochloride in pla- cebo). A preliminary study was performed to test if UDCA can be effectively delivered to the central nervous system with oral ad- ministration of solubilized UDCA. Seven patients were all treated with oral solubilized UDCA with informed consents. After the first 3 months of treatment, pure UDCA was detected with con- centrations ranging from 0.75 to 1.72 μM/L in CSF of these pa- tients (JASCO Bile Acid Analysis System, Japan Spectroscopic Co., Ltd., Tokyo; data not shown). Efficacy and safety evaluation Patients were scheduled to visit for outcome assessment at month 1, 4, 5, and 8 throughout the 8-month study period. The prima- ry outcome measure was the rate of progression, measured by the AALSRS, i.e., the slope of AALSRS (22, 23). Secondary out- come measures were the deterioration rates, assessed by the revised ALS functional rating scale (ALSFRS-R) and forced vital capacity (FVC, % of predicted value) (24, 25). To preserve blind- ing, efficacy measures were assessed by two independent inves- tigators, who were not otherwise involved in the care of patients throughout the trial. Treatment adherence was checked monthly by a pharmacist, and noncompliant patients who took the study medications less than 80% of the given were considered to have violated the treatment protocol. Standard laboratory tests in- cluding blood counts, chemistry, renal and liver function, and electrocardiogram were performed at baseline and at the post- treatment discontinuation visit. Safety was evaluated as the in- cidence and severity of adverse events, and their relationship to treatment which were based on the results of laboratory tests, patients’ reports and the investigator’s judgements. Statistical analysis We hypothesized that oral solubilized UDCA therapy slows the deterioration of function in patients with ALS, as assessed by comparing the slopes of AALSRS while the patients were treated http://jkms.org 201