Food and Insulin Effect on QT/QTC Interval of ECG
Condition: 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
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Moxifloxacin 400 mg fasted; FDA breakfast; Continental breakfast; Moxifloxacin 400 mg fed; Insulin Clamp; Placebo
Intervention type(s): Drug; Other; Other; Drug; Procedure; Drug
Intervention description(s): 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.; 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
Other intervention name(s): Moxifloxacin; Moxifloxacin
Intervention MeSH terms: Moxifloxacin; Norgestimate, ethinyl estradiol drug combination
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
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