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
Intervention: Moxifloxacin 400 mg fasted; FDA breakfast; Continental breakfast; Moxifloxacin 400 mg fed; Insulin Clamp; Placebo
Intervention description: 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
Intervention MeSH terms: Moxifloxacin; Norgestimate, ethinyl estradiol drug combination
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 20 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
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

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Healthy male or female, 20 - 45 years old

          2. Signed ICF

          3. 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

          4. 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

          5. No clinical findings on the physical examination

          6. Body mass index (BMI) = 18 - 25 kg/m2, body weight at least 48 kg.

          7. Systolic blood pressure 90-145 mmHg, diastolic blood pressure 40-90 mmHg, and heart
             rate 40-90 bpm

          8. Triplicate 12 lead ECG without clinically relevant abnormalities

          9. 24 hour 12 lead Holter ECG without clinically relevant abnormalities

         10. Haematology, biochemistry and urinalysis within the normal range

         11. Must agree to use acceptable methods of contraception

        Exclusion Criteria:

          1. 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

          2. History of clinically significant syncope.

          3. Family history of sudden death.

          4. Family history of premature cardiovascular death.

          5. Family history of congenital long QT syndrome or Brugada's syndrome.

          6. History of arrhythmias and ischemic heart disease

          7. Conditions predisposing to electrolyte imbalances (e.g. altered nutritional states,
             chronic vomiting, anorexia nervosa, bulimia nervosa).

          8. Abnormal ECG in the standard 12-lead ECG and 24-hour 12 lead Holter ECG

          9. 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.

         10. Abnormal blood glucose result (blood glucose >7.8mmol/l)

         11. Significant family history of diabetes mellitus.

         12. Significantly elevated fasting blood glucose level

         13. Signs and/or symptoms of acute illness in the four-week period prior to screening.

         14. Veins unsuitable for intravenous puncture or cannulation on either arm

         15. Known hypersensitivity to any medicines administered in the trial.

         16. Treatment with any prescribed medication during the 2 weeks prior to first baseline
             day.

         17. Treatment with any over-the-counter (OTC) medications during the 2 weeks prior to
             first baseline day.

         18. Treatment with vitamins and/or minerals within 48 hours prior to the first baseline
             day.

         19. 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.

         20. Positive urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids,
             opiates, barbiturates and methadone) or the alcohol breath test

         21. 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)

         22. Excessive caffeine consumption (≥800 mg per day)

         23. Smoking within 3 months prior to screening

         24. Loss of 250 mL or more blood within 3 months prior to screening.

         25. Positive results from the hepatitis serology, except for vaccinated subjects.

         26. Positive results from the HIV serology.

         27. Any circumstances or conditions, which may affect full participation in the study or
             compliance with the protocol.

         28. Legal incapacity or limited legal capacity.