Abstract
Background
MAP0004 is an orally inhaled investigational drug containing dihydroergotamine (DHE).
Although DHE has been used for 60 years with no reported cardiac arrhythmias, a thorough
QT study had not previously been performed with DHE.
Objective
The objective of this study was to assess the effects of MAP0004 on the QT interval
as required for regulatory approval of a new product.
Methods
This randomized, double-blind, placebo-controlled, 3-period crossover study enrolled
healthy volunteers. Subjects were assigned to receive, in randomized sequence, MAP0004
at a supratherapeutic dose (3-fold the clinically effective dose) (3.0 mg), moxifloxacin
400 mg, or inactive vehicle, each administered with 1 placebo capsule. Triplicate
ECGs were performed continuously at baseline (day 0), before dosing, and over 24 hours
after dosing in each treatment period. The effect on the QT interval was assessed
using the Fridericia (QTcF) and individualized (QTcI) correction formulas.
Results
Fifty-four healthy adults (20 men, 34 women; mean age, 28 years) completed the trial
and had measurable plasma levels of DHE after MAP0004 administration. The largest
observed mean difference in QTcI between MAP0004 and placebo was 0.08 msec, and the
largest 1-sided 95% upper confidence bound was 2.24 msec, both at 30 minutes after
dosing. In contrast, moxifloxacin increased the mean QTcI between 9.57 and 11.28 msec
relative to placebo, with a 1-sided lower 95% CL between 7.23 and 8.96 msec, confirming
that the assay sensitivity was sufficient to detect MAP0004-related effects. Nausea
(27.8%) was common following MAP0004 administration but apparently did not influence
the QTc interval.
Conclusions
A supratherapeutic dose of MAP0004 was not associated with prolonged QTc intervals.
At the proposed clinical dose (1.0 mg), MAP0004 is unlikely to affect the QT interval.
MAP0004 and its primary metabolite showed no evidence for prolongation of the QTc
interval in healthy subjects according to the criteria required from regulatory agencies.
ClinicalTrials.gov identifier: NCT01191723.
Key words
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Article info
Publication history
Published online: August 22, 2012
Accepted:
August 1,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
