Clinical trial NCT01642485
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
Keywords: Insulin clamp Glucose clamp Moxifloxacin Fed Fasted QT/QTC interval TQT ECG Meal effects C Peptide Japanese Caucasian bridging TQT bridging FDA standard breakfast Adaptive study design
Sponsor: Richmond Pharmacology Limited
Start date: 2011-07-01; Completion date: 2011-09-01
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Moxifloxacin 400 mg fasted intervention 2: FDA breakfast intervention 3: Continental breakfast intervention 4: Moxifloxacin 400 mg fed intervention 5: Insulin Clamp intervention 6: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: 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. intervention 4: 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. intervention 5: 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. intervention 6: Comparison of different meals effect on Moxifloxacin PK profile

Protocol documents: