title: An adaptive first in man dose-escalation study of NGX267: statistical, clinical, and operational considerations.
abstract: The primary objective of the dose-escalation trial for NGX267 was to estimate the maximally tolerated dose (MTD) and to gather detailed clinical and pharmacokinetic observations near the MTD. The MTD was defined based on the weighted average of moderate and severe adverse events. An adaptive design was employed to concentrate dosage assignments at or near the MTD. Favoring the acquisition of data near the MTD, at the expense of information at lower dosage levels, resulted in a shorter trial and no loss of the type of information required to inform subsequent studies where larger normal volunteer or patient samples are evaluated.
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7420, USA. aivanova@bios.unc.edu
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.forename: Michael
authors.initials: M
authors.lastname: Murphy
mesh_terms: D000328:Adult; D000465:Algorithms; D017321:Clinical Trials, Phase I as Topic; D015331:Cohort Studies; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D018721:Muscarinic Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D012107:Research Design; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D018721:Muscarinic Agonists; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D013141:Spiro Compounds; D013844:Thiazoles; C470586:(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one