Meta-analysis for cardiovascular effects of NRL001 after rectal application in healthy volunteers.
OBJECTIVE
NRL001 is a highly specific α1 -adrenoceptor agonist currently under evaluation for the treatment of faecal incontinence caused by a weak internal anal sphincter. The aim of this meta-analysis was to quantify the effect of NRL001 on cardiovascular parameters including heart rate, blood pressure and QT interval.


METHODS
Data from the four Phase I healthy volunteer studies SUM (NCT00857467), SURD (NCT01099670), SUSD (NCT00850590) and SAGE (NCT01099683) were pooled and analyses were performed on individual subject data. Mixed effects regression analysis was used to determine the effect of NRL001 on heart rate, blood pressure and QT intervals. A multivariate statistical model was used to determine the effect of covariates on heart rate.


RESULTS
Subjects given NRL001 experienced a dose related decrease in heart rate of up to 9.48 bpm compared with subjects in the placebo arms. No statistically significant evidence for a threshold effect was found. There was no clear evidence of dose effect of NRL001 on blood pressure. QT interval increased in all NRL001 subject as expected; QTC F also showed a statistically significant increase. However, QTC B was shortened with no significant treatment effect.


CONCLUSIONS
NRL001 was found to have a dose-dependent effect on heart rate; however clinically-relevant bradycardia was not reported, indicating the decrease in heart rate was not of clinical significance. Furthermore, no clinically-significant drug effect on blood pressure or mean arterial pressure was observed. QT intervals were affected by changes in heart rate. However, trends were dependant on the correction factor used. No consistent QT effect was observed, but a thorough QTC study will be required to confirm the effects of rectally applied NRL001.
Medical & Safety Services, ICON Clinical Research, Eastleigh, UK.
H J
HJ
Gruss
C
C
Pediconi
A
A
Jacobs
D000293:Adolescent; D058646:Adrenergic alpha-1 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects*; D017321:Clinical Trials, Phase I as Topic; D004361:Drug Tolerance; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008729:Methoxamine / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D015999:Multivariate Analysis; D013237:Stereoisomerism
D058646:Adrenergic alpha-1 Receptor Agonists; D008729:Methoxamine
NRL001; adrenoceptor; cardiovascular; faecal incontinence; heart rate; pharmacodynamic