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Mikito Kawamata,1 Masako Iseki,2 Mamoru Kawakami,3 Shoji Yabuki,4 Takuma Sasaki,5 Mitsuhiro Ishida,5 Atsushi Nishiyori,5 Hideaki Hida,6 Shin-ichi Kikuchi4 1Department of Anesthesiology and Resuscitology, Shinshu University School of Medicine, Matsumoto, Japan; 2Department of Anesthesiology and Pain Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; 3Spine Care Center, Wakayama Medical University Kihoku Hospital, Wakayama, Japan; 4Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan; 5Clinical Development Department, Shionogi & Co. Ltd., Osaka, Japan; 6Biostatistics Center, Shionogi & Co. Ltd., Osaka, Japan Background: Oxycodone is one of the options for the management of CLBP in patients with an inadequate response to other analgesics. However, oxycodone is not yet approved for noncancer pain in Japan. Here, we assessed the efficacy and long-term safety of S-8117, a controlled-release oxycodone formulation, for the management of Japanese CLBP patients. Patients and methods: An initial enriched enrollment randomized withdrawal, double-blind, placebo-controlled, 5-week phase III trial was conducted across 54 centers in Japan to assess the efficacy of S-8117 vs placebo in moderate-to-severe CLBP patients. Subsequently, a 52-week, open-label, single-arm study was conducted across 53 centers in Japan to evaluate the long-term safety of S-8117. The primary endpoint was the time to inadequate analgesic response during 35 days of the double-blind period. Secondary endpoints were the percentages of patients with inadequate analgesic response, discontinuation rate due to inadequate analgesic effects or AEs, and changes in scores of BPI severity, BPI pain interference, SF-36, and Roland-Morris Disability Questionnaire. Safety was assessed as the incidence of AEs and ADRs. Results: Of the 189 patients enrolled in the double-blind study, 130 patients who completed the initial titration period were randomized 1:1 to receive either S-8117 (n=62) or placebo (n=68). Baseline characteristics were comparable across the study groups. The time to inadequate analgesic response was significantly longer in patients treated with S-8117 than placebo (P=0.0095). Secondary endpoints corroborated the efficacy of S-8117 vs placebo. Overall, 478 AEs were reported in 73/75 patients in the long-term study. The most frequent ADRs were somnolence, constipation, and nausea. No case of drug dependence was reported in the long-term study. Conclusion: Short-term efficacy vs placebo and long-term safety of S-8117 were demonstrated for the management of Japanese patients with moderate-to-severe CLBP. Keywords: chronic low back pain, opioids, oxycodone, RCT

The gene for ornithine transcarbamylase (OTC; EC 2.1.3.3), a urea cycle enzyme, is expressed almost exclusively in the liver and small intestine. To identify DNA elements regulating transcription of the OTC gene in the liver, transient expression analysis was carried out by using hepatoma (HepG2) and nonhepatic (CHO) cell lines. The 1.3-kilobase 5'-flanking region of the rat OTC gene directed expression of the fused chloramphenicol acetyltransferase gene in HepG2 cells much more efficiently than in CHO cells. Analysis of deletion mutants of the 5'-flanking region in HepG2 cells revealed that there are at least one negative and two positive regulatory elements within the about 220-base-pair immediate 5'-flanking region. DNase I footprint analysis showed the presence of factors binding to these regulatory elements in nuclear extracts of rat liver and brain, and footprint profiles at the two positive elements exhibited liver-specific features. Transient expression analysis also revealed the existence of an enhancer region located 11 kilobases upstream of the transcription start site. The OTC enhancer was able to activate both its own and heterologous promoters in HepG2 but not in CHO cells. The enhancer was delimited to an about 230-base-pair region, and footprint analysis of this region revealed four protected areas. Footprint profiles at two of the four areas exhibited liver-specific features, and gel shift competition analysis showed that a factor(s) binding to the two liver-specific sites is related to C/EBP. These results suggest that both liver-specific promoter and enhancer elements regulate expression of the OTC gene through interaction with liver-specific factors binding to these elements.