Safety Monitoring in a Phase 1 First-In-Human Study of the Anti-Viral Agent CMX001: A Novel Application of Wireless Capsule Endoscopy

Abstract

Purpose: Wireless Capsule Endoscopy (WCE) is used to diagnose small bowel disease however it has been utilized infrequently as a method of evaluating drug induced small bowel (SB) mucosal changes in healthy adults. In preclinical studies the dose limiting toxicity of CMX001, a drug being developed to treat small pox, was enteropathy including small bowel involvement. The aim of this study was to utilize WCE to monitor and evaluate the effects of CMX001 on the SB mucosa for the purposes of determining the safety of the medication. Methods: Healthy volunteers were pre-selected and divided into 6 person cohorts. Subjects with a history of significant GI disorders or recent NSAID use were excluded. Two of five planned cohorts have been enrolled and completed. In each cohort subjects were randomized to receive either a single dose of 25μg/kg or 50μg/kg CMX001 or a placebo in a 4(CMX001) to 2 (Placebo) ratio. The day prior to medication allocation each subject underwent a baseline WCE. In preparation for the WCE, a clear liquid diet was instituted following lunch on the day before each study and overnight fasting was required. No bowel cleansing agents were administered. On the third day following medication administration WCE was repeated. All the WCE videos were evaluated twice by 2 separate readers; the readers were blinded to both study drug versus placebo and pre- versus post- drug exposure. Following WCE evaluation the results were paired by patient and the Lewis Score was added as a quantitative method of scoring the results. Results: There were no significant interval changes in the SB findings between the pre- and post-dose WCEs. Several patients had pre-dose Lewis Scores that classified them as having existing mild inflammatory mucosal changes (< 134). Findings were noted in all pre- and post- dose studies in patients who received either study drug or placebo. None of these patients experienced a post-dose worsening of their Lewis Score. Of the 24 separate WCE performed findings included, 33.3% with erosions, 62.5% had petechia, and 33.3% had erythematous/red spots. Other findings included denudation and mucosal irregularities. Conclusion: In this on-going clinical pharmaceutical trial, the WCE has thus far successful demonstrated the lack of clinically significant change in the SB mucosa of healthy volunteers ingesting a single dose of 25μg/kg or 50μg/kg CMX001.