Key result
Naloxegol does not prolong the QTc interval compared to placebo in healthy men.
Why the study?
Naloxegol is in clinical development for opioid-induced constipation, and its effect on cardiac repolarization needed characterization according to ICH E14 guidelines.
Does naloxegol prolong the QT/QTc interval in healthy men?
RCT (n=52)
Placebo-controlled
Williams Latin square design
Does naloxegol prolong the QT/QTc interval in healthy men?
Effect estimate: mean increase <5 msec (95% CI upper limit <10 msec (90% CI))
Naloxegol at therapeutic and supratherapeutic doses does not cause clinically relevant QT/QTc interval prolongation in healthy men.
Naloxegol can be used without QT monitoring concerns; confirms cardiac safety in this dedicated RCT.
BACKGROUND: Opioid-induced constipation (OIC) is a common adverse effect associated with opioid use. Naloxegol is a PEGylated derivative of naloxone in clinical development as a once-daily oral treatment of OIC. OBJECTIVES: A thorough QT/QTc study was conducted, according to International Conference on Harmonisation E14 guidelines, to characterize the effect of naloxegol on cardiac repolarization. METHODS: In this randomized, positive- and placebo-controlled crossover study, healthy men received a single dose of naloxegol 25 mg (therapeutic dose), naloxegol 150 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), or placebo in 1 of 4 sequences (Williams Latin square design). The washout time between treatment periods was at least 5 days. Digital 12-lead ECGs were recorded at baseline and at 10 time points over 24 hours after dosing in each treatment period. QT intervals were corrected for heart rate using the Fridericia formula (QTcF) and the Bazett formula (QTcB). RESULTS: A total of 52 subjects were enrolled (mean age, 28 years), and 45 received all 4 treatments. The placebo-corrected, baseline-adjusted, mean increases in QTcF with naloxegol 25 and 150 mg were both <5 msec at each time point, and all upper limits of the 2-sided 90% CI were <10 msec. Similar findings were observed using QTcB; the upper limits of the 2-sided 90% CI were <10 msec at all time points after dosing with naloxegol 25 or 150 mg. With moxifloxacin 400 mg, mean QTcF was increased by a maximum of 11.1 msec (90% CI, 9.3-12.9 msec), supporting assay sensitivity. CONCLUSION: Naloxegol at 25 and 150 mg was not associated with QT/QTc interval prolongation in these healthy men, and at the proposed therapeutic dose of 25 mg/d, naloxegol is not expected to have a clinically relevant effect on cardiac repolarization in patients with OIC. ClinicalTrials.gov identifier: NCT01325415.
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Gottfridsson et al. (2013) conducted an RCT in Healthy volunteers (n=52). Naloxegol vs. Placebo and moxifloxacin 400 mg was evaluated on Placebo-corrected, baseline-adjusted mean increase in QTcF (mean increase <5 msec, 95% CI upper limit <10 msec (90% CI)). Naloxegol at 25 mg and 150 mg did not prolong the QT/QTc interval in healthy men, with placebo-corrected mean increases in QTcF <5 msec and upper 90% CI limits <10 msec.
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