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Trial record 11 of 509 for:    MOXIFLOXACIN

Food and Insulin Effect on QT/QTC Interval of ECG (C11035)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01642485
Recruitment Status : Completed
First Posted : July 17, 2012
Results First Posted : August 20, 2014
Last Update Posted : August 20, 2014
Sponsor:
Information provided by (Responsible Party):
Richmond Pharmacology Limited

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Conditions Effects of Different Meals on the QT/QTc Interval
Insulin and Oral Hypoglycemic [Antidiabetic] Drugs Causing Adverse Effects in Therapeutic Use
C-Peptide Effects on the QT/QTc Interval
Moxifloxacin ECG Profile in Fed and Fasted State
Japanese vs. Caucasian TQT Comparison
Interventions Drug: Moxifloxacin 400 mg fasted
Other: FDA breakfast
Other: Continental breakfast
Drug: Moxifloxacin 400 mg fed
Procedure: Insulin Clamp
Drug: Placebo
Enrollment 32
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Sequence 1 Sequence 2 Sequence 3 Sequence 4 Sequence 5 Sequence 6 Sequence 7 Sequence 8
Hide Arm/Group Description

Period1:

Day 1: Placebo Day 2: Insulin Clamp Day 3: Moxiloxacin 400 mg fasted Washout period: 3 days

Period 2:

Day 1: Continental breakfast Day 2:FDA breakfast Day 3: Moxifloxacin 400 mg fed (with continental breakfast)

Period1:

Day 1: Insulin Clamp Day 2: Continental breakfast Day 3: Moxiloxacin 400 mg fasted Washout period: 3 days

Period 2:

Day 1: FDA breakfast Day 2: Placebo Day 3: Moxifloxacin 400 mg fed (with continental breakfast)

Period1:

Day 1: Continental breakfast Day 2: FDA breakfast Day 3: Moxiloxacin 400 mg fasted Washout period: 3 days

Period 2:

Day 1: Placebo Day 2: Insulin Clamp Day 3: Moxifloxacin 400 mg fed (with continental breakfast)

Period1:

Day 1: FDA breakfast Day 2: Placebo Day 3: Moxiloxacin 400 mg fasted Washout period: 3 days

Period 2:

Day 1: Insulin Clamp Day 2: Continental breakfast Day 3: Moxifloxacin 400 mg fed (with continental breakfast)

Period1:

Day 1: Placebo Day 2: Insulin Clamp Day 3: Moxiloxacin 400 mg fed (with continental breakfast) Washout period: 3 days

Period 2:

Day 1: Continental breakfast Day 2:FDA breakfast Day 3: Moxifloxacin 400 mg fasted

Period1:

Day 1: Insulin Clamp Day 2: Continental breakfast Day 3: Moxiloxacin 400 mg fed (with continental breakfast) Washout period: 3 days

Period 2:

Day 1: FDA breakfast Day 2: Placebo Day 3: Moxifloxacin 400 mg fasted

Period1:

Day 1: Continental breakfast Day 2: FDA breakfast Day 3: Moxiloxacin 400 mg fed (with continental breakfast) Washout period: 3 days

Period 2:

Day 1: Placebo Day 2: Insulin Clamp Day 3: Moxifloxacin 400 mg fasted

Period1:

Day 1: FDA breakfast Day 2: Placebo Day 3: Moxiloxacin 400 mg fed (with continental breakfast) Washout period: 3 days

Period 2:

Day 1: Insulin Clamp Day 2: Continental breakfast Day 3: Moxifloxacin 400 mg fasted

Period Title: Period 1, Day 1
Started 4 [1] 4 4 4 4 4 4 4
Completed 4 4 4 4 4 4 4 4
Not Completed 0 0 0 0 0 0 0 0
[1]
crossover so all subjects had this treatment
Period Title: Period 1, Day 2
Started 4 4 4 4 4 4 4 4
Completed 4 4 4 4 4 4 4 4
Not Completed 0 0 0 0 0 0 0 0
Period Title: Period 1, Day 3
Started 4 4 4 4 4 4 4 4
Completed 4 4 4 4 4 4 4 4
Not Completed 0 0 0 0 0 0 0 0
Period Title: Period 2, Day 1
Started 4 4 4 4 4 4 4 4
Completed 4 4 4 4 4 4 4 4
Not Completed 0 0 0 0 0 0 0 0
Period Title: Period 2, Day 2
Started 4 4 4 4 4 4 4 4
Completed 4 4 4 4 4 4 4 4
Not Completed 0 0 0 0 0 0 0 0
Period Title: Period 2, Day 3
Started 4 4 4 4 4 4 4 4
Completed 4 4 4 4 4 4 4 4
Not Completed 0 0 0 0 0 0 0 0
Arm/Group Title All Study Participants
Hide Arm/Group Description Subjects participating in the study attended for screening, two treatment periods (periods 1 and 2) of 4 assessment days each and a follow-up visit. Data obtained on study days 1 and 2 compared the ECG effects of different types of food and placebo. Each period consisted of a baseline ECG day (day –1) and treatment days (days 1–3). Moxifloxacin was given in fasted condition or with Continental breakfast, on day 3 of each study period. The two periods were separated by at least 3 days to allow for the effects of moxifloxacin to wash-out. No wash-out was required between the other treatments investigated. The ECG and samples for PK and PD analysis on the treatment days were taken at the corresponding clock time points as on the baseline days. Each subject received all treatments and all the comparisons between treatment effects were made intra-individually reducing the anticipated variability and thereby reducing the sample size.
Overall Number of Baseline Participants 32
Hide Baseline Analysis Population Description
The study population consisted of healthy non-smoking, subjects. Electrocardiograms in the placebo arm were recorded twice in fasted and fed condition.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 32 participants
Caucasian 25.6  (4.7)
Japanese 27.6  (3.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants
Female
14
  43.8%
Male
18
  56.3%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 32 participants
Caucasian 13
Japanese 19
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United Kingdom Number Analyzed 32 participants
32
Body Mass Index  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 32 participants
>18 kg/m^2 32
>25 kg/m^2 0
1.Primary Outcome
Title The Effect of Food (Fasted and Fed State) on the Degree of QT Prolongation Caused by Moxifloxacin
Hide Description 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.
Time Frame 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Since the baseline was used as a covariate in the analysis, using the standard deviation of the change from baseline, in the simple sample size formula is justified. Assuming a standard deviation of 7 msec for the single differences, sample sizes for the sum can therefore work with a standard deviation of 6.5 msec.
Arm/Group Title Fasted Group Fed Group
Hide Arm/Group Description:
This study was designed as an open-label, randomized, placebo-controlled, crossover trial that evaluated the effect of a 400 mg oral dose of moxifloxacin in fasted conditions to a baseline and a placebo treatment. Data obtained on study days 1 and 2 compared the ECG effects of different types of food and placebo. Each period consisted of a baseline ECG day (day –1) and treatment days (days 1–3). Moxifloxacin was given in either the fed or fasted condition, on day 3 of each study period. The two periods were separated by at least 3 days to allow for the effects of moxifloxacin to wash-out. The ECG and samples for PK and PD analysis on the treatment days were taken at the corresponding clock time points as on the baseline days. Each subject received all treatments and all the comparisons between treatment effects were made intra-individually reducing the anticipated variability and thereby reducing the sample size.
This study was designed as an open-label, randomized, placebo-controlled, crossover trial that evaluated the effect of a 400 mg oral dose of moxifloxacin in fed conditions to a baseline and a placebo treatment. Data obtained on study days 1 and 2 compared the ECG effects of different types of food and placebo. Each period consisted of a baseline ECG day (day –1) and treatment days (days 1–3). Moxifloxacin was given in either the fed or fasted condition, on day 3 of each study period. The two periods were separated by at least 3 days to allow for the effects of moxifloxacin to wash-out. The ECG and samples for PK and PD analysis on the treatment days were taken at the corresponding clock time points as on the baseline days. Each subject received all treatments and all the comparisons between treatment effects were made intra-individually reducing the anticipated variability and thereby reducing the sample size.
Overall Number of Participants Analyzed 32 32
Mean (90% Confidence Interval)
Unit of Measure: ms
14.4
(11.9 to 16.8)
11.6
(9.1 to 14.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Fasted Group
Comments The effect of insulin, C-peptide and glucose on QTcF was investigated using linear mixed effect concentration–response models with the double difference of QTcF (difference to time matched placebo of the change from average baseline) as dependent variable and up to two of the variables change from time matched placebo in insulin, C-peptide and glucose as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method t-test, 1 sided
Comments [Not Specified]
2.Secondary Outcome
Title The Food Effects (Calorie Reduced FDA Breakfast and Carbohydrate Rich Continental Style) on QTcF
Hide Description

Scott et al (2002) demonstrated an increase in the heart rate of 10bpm in some healthy subjects following ingestion of a carbohydrate meal. There was significant correlation between the resultant hyperinsulinaemia and an increase in skeletal muscle blood flow, and sympathetic activity, with a reduction in vascular resistance.

If postprandial insulinaemia is a significant influence on the QT interval, then carbohydrate rich meals would be expected to show greater effect. Therefore, to explore this on two separate days of the study subjects will be given one of two different types of breakfast:

  1. A high carbohydrate content breakfast, (>70% carbohydrate)
  2. A reduced calorie FDA standard breakfast, (58% fat, low carbohydrate content) to determine effect on QT interval.
Time Frame 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title FDA Breakfast Continental Breakfast Placebo at Baseline
Hide Arm/Group Description:
FDA breakfast: 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.

Continental breakfast: 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.

QTcF change from a baseline presented.

a baseline QTcF measured on Day -1 of each period
Overall Number of Participants Analyzed 32 32 32
Mean (90% Confidence Interval)
Unit of Measure: ms
-6.8
(-9.3 to -4.3)
-7.9
(-10.4 to -5.5)
412.4
(407.9 to 416.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FDA Breakfast, Continental Breakfast
Comments The relevant confirmatory null hypotheses could all be rejected on the 5% level (one sided), i.e. a difference in QTcF between continental breakfast and placebo; between FDA breakfast and placebo could be ascertained.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method t-test, 1 sided
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Continental Breakfast
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -7.9
Confidence Interval (2-Sided) 90%
-10.4 to -5.5
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection FDA Breakfast
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -6.8
Confidence Interval (2-Sided) 90%
-9.3 to -4.3
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Moxifloxacin 400 mg (Single Dose) Compared to Placebo on the Mean QT/QTc Interval.
Hide Description "Moxifloxacin 400mg Fasted" group is reporting the maximum change in QT/QTc interval from placebo treatment.
Time Frame 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Moxifloxacin 400 mg Fasted Placebo
Hide Arm/Group Description:
The highest change was at 2.5h time point, which is presented here.
Time matched absolute value for QTcF for placebo treatment.
Overall Number of Participants Analyzed 32 32
Mean (90% Confidence Interval)
Unit of Measure: ms
14.4
(11.9 to 16.8)
414.2
(409.6 to 418.8)
4.Secondary Outcome
Title Insulin, Glucose and C-Peptide Effects on the QT/QTc Interval
Hide Description The effect on QTc was investigated using linear mixed effect models with placebo corrected QTcF (change from average baseline) as a dependent variable and insulin, glucose and C-peptide (placebo corrected) as covariates for the data obtained under the euglycaemic clamp as well as for all data obtained under the clamp and the two types of breakfast.
Time Frame 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Insulin Clamp Glucose C-peptide
Hide Arm/Group Description:
A euglycaemic/hyperinsulinaemic clamp was used to stop any endogenous C-peptide and insulin production. The clamp acutely raised the plasma insulin concentrations to a steady-state and maintained glucose concentrations at/or slightly lower than the individual subjects baseline reading. For each subject two 18G cannulas were inserted, one in the antecubital fossa for insulin and glucose infusions, and one for pharmacokinetic (PK) and blood glucose sampling.
A euglycaemic/hyperinsulinaemic clamp was used to stop any endogenous C-peptide and insulin production. The clamp acutely raised the plasma insulin concentrations to a steady-state and maintained glucose concentrations at/or slightly lower than the individual subjects baseline reading. For each subject two 18G cannulas were inserted, one in the antecubital fossa for insulin and glucose infusions, and one for pharmacokinetic (PK) and blood glucose sampling.
A euglycaemic/hyperinsulinaemic clamp 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 glucose and insulin production, and as a result reducing the release of C-peptides. This technique will firstly test whether hyperinsulinaemia has an effect on QT interval, and secondly whether C-peptide levels play any role in the proposed effect on the QT interval.
Overall Number of Participants Analyzed 32 32 32
Median (95% Confidence Interval)
Unit of Measure: msec
-0.01
(-0.02 to 0.04)
-0.86
(-1.45 to -0.27)
-0.71
(-0.98 to -0.45)
5.Secondary Outcome
Title The QTcF Profile of Oral Moxifloxacin (400 mg) in Healthy Japanese Versus Caucasian Subjects
Hide Description [Not Specified]
Time Frame 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Caucasian Fasted Group Caucasian Fed Group Japanese Fasted Group Japanese Fed Group
Hide Arm/Group Description:
The results of concentration-effect analysis: the effect of moxifloxacin on QTcF (double difference of QTcF) at the time point of maximum mean concentrationof moxifloxacin (1h)
The results of concentration-effect analysis: the effect of moxifloxacin on QTcF (double difference of QTcF) at the time point of maximum mean concentrationof moxifloxacin (4h)
The results of concentration-effect analysis: the effect of moxifloxacin on QTcF (double difference of QTcF) at the time point of maximum mean concentrationof moxifloxacin (4h)
The results of concentration-effect analysis: the effect of moxifloxacin on QTcF (double difference of QTcF) at the time point of maximum mean concentrationof moxifloxacin (4h)
Overall Number of Participants Analyzed 13 13 19 19
Mean (95% Confidence Interval)
Unit of Measure: ms
9.0
(3.2 to 14.7)
13.7
(8.2 to 19.2)
17.3
(13.9 to 20.6)
10.1
(5.1 to 15.1)
Time Frame The AEs were recorded at screening: Days: -21 to -3, daily through Period 1 (from Day -2 to Day 3), washout period (3 days), daily through Period 2 (from Day -2 to Day 3) and at follow-up visit (7-14 days after the end of Period 2).
Adverse Event Reporting Description Regular safety assessments have been done by using the following methods: investigator assessment, blood pressure and ECG measurements (12 time points per day in-house), laboratory testing (biochemistry and urinalysis on Day 3 of each period).
 
Arm/Group Title Moxifloxacin 400 mg Fasted Moxifloxacin 400 mg Fed
Hide Arm/Group Description

Moxifloxacin fasted: One single dose of 400mg moxifloxacin after fasting - This is the standard probe for the assessment of assay sensitivity in Thorough QT (TQT) studies.

No significant other Adverse Events have been reported.

Moxifloxacin with food: 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.

No significant other Adverse Events have been reported.

All-Cause Mortality
Moxifloxacin 400 mg Fasted Moxifloxacin 400 mg Fed
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Moxifloxacin 400 mg Fasted Moxifloxacin 400 mg Fed
Affected / at Risk (%) Affected / at Risk (%)
Total   0/32 (0.00%)   0/32 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Moxifloxacin 400 mg Fasted Moxifloxacin 400 mg Fed
Affected / at Risk (%) Affected / at Risk (%)
Total   0/32 (0.00%)   0/32 (0.00%) 
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.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr Jorg Taubel
Organization: Richmond Pharmacology Ltd
Phone: +44(0)2086645200
EMail: j.taubel@richmondpharmacology.com
Layout table for additonal information
Responsible Party: Richmond Pharmacology Limited
ClinicalTrials.gov Identifier: NCT01642485     History of Changes
Other Study ID Numbers: RPL-01-11
2011-002423-17 ( EudraCT Number )
First Submitted: June 19, 2012
First Posted: July 17, 2012
Results First Submitted: June 6, 2014
Results First Posted: August 20, 2014
Last Update Posted: August 20, 2014