Food and Insulin Effect on QT/QTC Interval of ECG

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
This study was initially performed in 24 healthy Caucasian and Japanese volunteers with an option to increase the sample size to up to 54 volunteers. The decision to increase the sample size to 32 was based on the standard deviation of the ECG intervals observed in the first 24 volunteers. This analysis was performed by an independent statistician under blinded conditions. Each volunteer participated in 2 periods. Each period consisted of 1 baseline day (D-1) followed by 3 study days (D1 - D3) when the various food effect and drug treatments or placebo were administered. All volunteers received all treatments. Moxifloxacin was always given on D3 to prevent any carryover effect and there was a minimum washout period of 3 days in between the 2 periods. How well the treatments (insulin/glucose, high carbohydrate breakfast, calorie reduced breakfast and moxifloxacin) were tolerated by the volunteers was assessed and any side effects noted. We compared the effects of the various treatments between Caucasian and Japanese volunteers. Moxifloxacin and placebo were given to volunteers by mouth, i.e. they were asked to swallow them with water. The different types of breakfast were provided which volunteers were asked to eat. Insulin and glucose were administered intravenously (Insulin/glucose clamp). Hence, the study was performed as an open-label design. This study was conducted as a single site study at Richmond Pharmacology/ St George's University of London.

Official Title
-----------------
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

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

Intervention / Treatment
-----------------
* Drug: Moxifloxacin 400 mg fasted
* Other: FDA breakfast
* Other: Continental breakfast
* Drug: Moxifloxacin 400 mg fed
* Procedure: Insulin Clamp
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male or female, 20 - 45 years old Signed ICF Japanese - a descendant of four Japanese grandparents, carrying a Japanese passport and has not been outside Japan for more than 5 years prior to screening The Caucasian - light to brown skin pigmentation; straight to wavy or curly hair; indigenous to Europe, northern Africa, western Asia, and India. The study may also include Caucasians from North America, Australia and South Africa No clinical findings on the physical examination Body mass index (BMI) = 18 - 25 kg/m2, body weight at least 48 kg. Systolic blood pressure 90-145 mmHg, diastolic blood pressure 40-90 mmHg, and heart rate 40-90 bpm Triplicate 12 lead ECG without clinically relevant abnormalities 24 hour 12 lead Holter ECG without clinically relevant abnormalities Haematology, biochemistry and urinalysis within the normal range Must agree to use acceptable methods of contraception Exclusion Criteria: History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug History of clinically significant syncope. Family history of sudden death. Family history of premature cardiovascular death. Family history of congenital long QT syndrome or Brugada's syndrome. History of arrhythmias and ischemic heart disease Conditions predisposing to electrolyte imbalances (e.g. altered nutritional states, chronic vomiting, anorexia nervosa, bulimia nervosa). Abnormal ECG in the standard 12-lead ECG and 24-hour 12 lead Holter ECG Abnormal rhythm, conduction or morphology of resting ECG, such as: Sinus node dysfunction. Clinically significant PR (PQ) interval prolongation. Intermittent second or third degree AV block. Incomplete or complete bundle branch block. Abnormal T wave morphology. Prolonged QTcB >450 msec or shortened QTcB < 350 msec or family history of long QT syndrome. Abnormal blood glucose result (blood glucose >7.8mmol/l) Significant family history of diabetes mellitus. Significantly elevated fasting blood glucose level Signs and/or symptoms of acute illness in the four-week period prior to screening. Veins unsuitable for intravenous puncture or cannulation on either arm Known hypersensitivity to any medicines administered in the trial. Treatment with any prescribed medication during the 2 weeks prior to first baseline day. Treatment with any over-the-counter (OTC) medications during the 2 weeks prior to first baseline day. Treatment with vitamins and/or minerals within 48 hours prior to the first baseline day. Treatment with another investigational drug within 4 weeks prior to dosing or having participated in more than 3 investigational drug studies within a year prior to dosing. Positive urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids, opiates, barbiturates and methadone) or the alcohol breath test History or clinical evidence of alcoholism (regular weekly alcohol intake of more than 14 units if female and 21 units if male) or drug abuse (compulsive, repetitive and/or chronic use of drugs or other substances with or without problems related to their use and/or where stopping or a reduction in dose will lead to withdrawal symptoms) Excessive caffeine consumption (≥800 mg per day) Smoking within 3 months prior to screening Loss of 250 mL or more blood within 3 months prior to screening. Positive results from the hepatitis serology, except for vaccinated subjects. Positive results from the HIV serology. Any circumstances or conditions, which may affect full participation in the study or compliance with the protocol. Legal incapacity or limited legal capacity.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Moxifloxacin 400 mg fasted<br>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. | Drug: Moxifloxacin 400 mg fasted<br>* 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.<br>* Other names: Moxifloxacin;Other: FDA breakfast<br>* 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.<br>Other: Continental breakfast<br>* 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.<br>Procedure: Insulin Clamp<br>* 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.<br>Drug: Placebo<br>* Comparison of different meals effect on Moxifloxacin PK profile<br>|
| Experimental: Moxifloxacin 400 mg fed<br>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. | Other: FDA breakfast<br>* 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.<br>Other: Continental breakfast<br>* 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.<br>Drug: Moxifloxacin 400 mg fed<br>* 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.<br>* Other names: Moxifloxacin;Procedure: Insulin Clamp<br>* 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.<br>Drug: Placebo<br>* Comparison of different meals effect on Moxifloxacin PK profile<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Food Effects (Calorie Reduced FDA Breakfast and Carbohydrate Rich Continental Style) on QTcF | 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: A high carbohydrate content breakfast, (>70% carbohydrate) A reduced calorie FDA standard breakfast, (58% fat, low carbohydrate content) to determine effect on QT 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 | 
| Moxifloxacin 400 mg (Single Dose) Compared to Placebo on the Mean QT/QTc Interval. | Moxifloxacin 400mg Fasted group is reporting the maximum change in QT/QTc interval from placebo treatment. | 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 | 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. | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TQT, Insulin clamp, Glucose clamp, Moxifloxacin, Fed, Fasted, QT/QTC interval, ECG, Meal effects, C Peptide, Japanese Caucasian bridging, TQT bridging, FDA standard breakfast, Adaptive study design