CLINICAL TRIAL: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, CROSS-OVER, ACTIVE-CONTROL

这个子项目是利用这些资源的众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Urea cycle disorders (UCDs) are inborn errors of metabolism that can result from decreased or absent activity of any of the following enzymes: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase (ARG). These disorders prevent the conversion of waste nitrogen into urea and result in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Most patients with UCDs are managed chronically either by diet alone or by dietary nitrogen restriction plus oral doses of Buphenyl¿ (sodium phenylbutyrate) with citrulline or arginine. Although an effective treatment, Buphenyl¿ has some disadvantages, such as a high pill burden (approximately 40 tablets [20 g] per day for an adult or 4 tsp of powder for a 20 kg child), unpleasant taste, and high sodium content. There is some evidence from clinical trials of PBA for other indications that the high pill burden may decrease the likelihood of compliance with the treatment regimen. Glyceryl tri (4-phenylbutyrate) (GT4P or HPN-100), a prodrug of phenylbutyrate (PBA) (Buphenyl¿) and a pre-prodrug of the active compound phenylacetate (PAA), is under development as an alternative therapy to Buphenyl¿ in patients with UCDs. HPN-100 is expected to provide similar nitrogen-scavenging ability while eliminating the current issues of bad taste, odor, sodium content, and pill burden. This second clinical trial of HPN-100 in adults with urea cycle disorders is a randomized, active-controlled, double-blind, cross-over study. Subjects will be randomly assigned to receive either HPN-100 + NaPBA placebo or NaPBA + HPN 100 placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks. I. HYPOTHESIS HPN-100 is as effective a medication for the treatment of urea cycle disorders as sodium phenylbutyrate (NaPBA) as assessed by venous ammonia levels. II. SPECIFIC AIMS The primary specific aim of this study is to establish the non-inferiority of HPN-100 to sodium phenylbutyrate (NaPBA) as assessed by venous ammonia.