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C11035
Evaluation of the Effect of Different Foods, Carbohydrate Meal, and a Euglycaemic Insulin Clamp on the QT/QTc Interval Using a Single Dose of Moxifloxacin as a Positive Control in Healthy Male and Female, Caucasian and Japanese Volunteers
Sponsor study identifier
Secondary identifiers
EUDRACT_NUMBER
interventional
32
1 country
1
Study Start
July 2011
Date type not reportedThis date has not been verified as actual or estimated.
Primary Completion
September 2011
Actual (reported)Study Completion
September 2011
Actual (reported)Moxifloxacin is routinely used as a probe to confirm assay sensitivity in thorough electrocardiogram (ECG) studies. It has been shown that a meal shortens the QT interval, which may affect pharmacokinetics (PK) and/or pharmacodynamics (PD) of the study drug. However, there is no published data clarifying this issue. There is also a paucity of data investigating ethnic differences of the effects of medicines on QTc. The aims of the study were to compare the effect of different food contents to placebo on the changes in ECG and to demonstrate the effect of insulin, C-peptide and glucose on the ECG. This was done by giving different treatments on separate days, which included intravenous insulin, a high carbohydrate breakfast \[\>70%\], and a calorie reduced low carbohydrate American FDA standard breakfast. Moxifloxacin 400 mg was used as a positive control and was given with and without food to Caucasian and Japanese volunteers to investigate racial differences.
Registry-reported information. Elapsed time and enrollment totals alone do not measure study progress or recruitment pace.
September 2011
Actual (reported)Click on a node to explore related trials.
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Dates and qualifiers reported by the registry. Estimated dates do not confirm that a milestone has occurred.
July 2011
Date type not reportedThis date has not been verified as actual or estimated.
September 2011
Actual (reported)September 2011
Actual (reported)June 19, 2012
Actual (reported)July 17, 2012
Actual (reported)August 20, 2014
Actual (reported)The Effect of Food (Fasted and Fed State) on the Degree of QT Prolongation Caused by Moxifloxacin
The primary baseline corrections were calculated using averaged QTc baseline values (the mean of all median readings recorded for each time-point on the baseline Day -1). This single value (QTcbaselineAV) was used to calculate ΔQTc for each study period.
0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
The Food Effects (Calorie Reduced FDA Breakfast and Carbohydrate Rich Continental Style) on QTcF
0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
Moxifloxacin 400 mg (Single Dose) Compared to Placebo on the Mean QT/QTc Interval.
Moxifloxacin 400 mg fasted was administered on Day 3. For Day 1 and 2, there were 4 different sequences: Placebo and Insulin Clamp; Insulin Clamp and Continental breakfast; Continental breakfast and FDA breakfast; FDA breakfast and Placebo. Additionally, Caucasian vs Japanese subjects were analysed.
Moxifloxacin 400 mg fed was administered on Day 3 after Continental breakfast. For Day 1 and 2, there were 4 different sequences: Placebo and Insulin Clamp; Insulin Clamp and Continental breakfast; Continental breakfast and FDA breakfast; FDA breakfast and Placebo. Additionally, Caucasian vs Japanese subjects were analysed.
Subjects receiving drug (400 mg moxifloxacin),having fasted overnight for 10 hours. This is the standard probe for the assessment of assay sensitivity in Thorough QT (TQT) studies.
Calorie reduced FDA standard breakfast (58% fat, low carbohydrates)- On the assumption that increases in C-peptide levels are responsible for the QTc shortening observed after a meal, a lesser effect on QTc compared to a carbohydrate rich breakfast should be observed.
Richmond Pharmacology Ltd
London, Tooting, SW17 0RE, United Kingdom
Taubel J, Wong AH, Naseem A, Ferber G, Camm AJ. Shortening of the QT interval after food can be used to demonstrate assay sensitivity in thorough QT studies. J Clin Pharmacol. 2012 Oct;52(10):1558-65. doi: 10.1177/0091270011419851. Epub 2011 Nov 8.
Scott EM, Greenwood JP, Vacca G, Stoker JB, Gilbey SG, Mary DA. Carbohydrate ingestion, with transient endogenous insulinaemia, produces both sympathetic activation and vasodilatation in normal humans. Clin Sci (Lond). 2002 May;102(5):523-9.
Our findings based on the confirmatory and concentration-effect analysis suggest that any difference between ethnicities was most likely attributable to differences in plasma concentrations and not differences in sensitivity to moxifloxacin.
Ulrike Lorch, MD FRCA FFPM
Richmond Pharmacology Limited
32 participants (actual enrollment reported by the registry).
First Submitted
June 19, 2012
First Posted
July 17, 2012
Study Start
July 2011
Date type not reportedThis date has not been verified as actual or estimated.
0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
Insulin, Glucose and C-Peptide Effects on the QT/QTc Interval
0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
The QTcF Profile of Oral Moxifloxacin (400 mg) in Healthy Japanese Versus Caucasian Subjects
0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
High carbohydrate breakfast (\>70% carbohydrates)- On the assumption that increases in C-peptide levels are responsible for the QTc shortening observed after a meal, a greater effect on QTc compared to a low carbohydrate breakfast (FDA standard breakfast) should be observed.
Currently, there is no published data showing the effects of a single 400 mg oral dose of moxifloxacin on the ECG/QT/QTc after food.
A euglycaemic/hyperinsulinaemic clamp, (DeFronzo, 1979) involves acutely raising the plasma insulin levels to a steady state and maintaining a state of euglycaemia with a glucose infusion, thereby effectively stopping endogenous insulin and C-peptide release. This technique will confirm whether hyperinsulinaemia has any effect on the QT/QTc interval.
Comparison of different meals effect on Moxifloxacin PK profile
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Contact the study team to confirm eligibility.
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214-23. doi: 10.1152/ajpendo.1979.237.3.E214.
Taubel J, Ferber G, Lorch U, Batchvarov V, Savelieva I, Camm AJ. Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects. Br J Clin Pharmacol. 2014 Jan;77(1):170-9. doi: 10.1111/bcp.12168.
Taubel J, Lorch U, Ferber G, Singh J, Batchvarov VN, Savelieva I, Camm AJ. Insulin at normal physiological levels does not prolong QT(c) interval in thorough QT studies performed in healthy volunteers. Br J Clin Pharmacol. 2013 Feb;75(2):392-403. doi: 10.1111/j.1365-2125.2012.04376.x.
Primary Completion
September 2011
Actual (reported)Study Completion
September 2011
Actual (reported)Last Updated
August 20, 2014
Results First Posted
August 20, 2014
Record last verified: 2014-08
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