Clinical trial NCT01642485: Food and Insulin Effect on QT/QTC Interval of ECG
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Richmond Pharmacology Limited
Sponsor class: INDUSTRY
First posted: 2012-07-17
Enrollment: 32
Sex: ALL
Minimum age (years): 20
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: The Effect of Food (Fasted and Fed State) on the Degree of QT Prolongation Caused by Moxifloxacin
timeFrame: 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 outcomes:
measure: The Food Effects (Calorie Reduced FDA Breakfast and Carbohydrate Rich Continental Style) on QTcF
timeFrame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
measure: Moxifloxacin 400 mg (Single Dose) Compared to Placebo on the Mean QT/QTc Interval.
timeFrame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
measure: Insulin, Glucose and C-Peptide Effects on the QT/QTc Interval
timeFrame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
measure: The QTcF Profile of Oral Moxifloxacin (400 mg) in Healthy Japanese Versus Caucasian Subjects
timeFrame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Richmond Pharmacology Ltd
state: Tooting
Study officials:
affiliation: Richmond Pharmacology Limited
name: Ulrike Lorch, MD FRCA FFPM
role: PRINCIPAL_INVESTIGATOR
References:
citation: Taubel J, Wong AH, Naseem A, Ferber G, Camm AJ. Shortening of the QT interval after food can be used to demonstrate assay sensitivity in thorough QT studies. J Clin Pharmacol. 2012 Oct;52(10):1558-65. doi: 10.1177/0091270011419851. Epub 2011 Nov 8.
citation: Scott EM, Greenwood JP, Vacca G, Stoker JB, Gilbey SG, Mary DA. Carbohydrate ingestion, with transient endogenous insulinaemia, produces both sympathetic activation and vasodilatation in normal humans. Clin Sci (Lond). 2002 May;102(5):523-9.
citation: DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214-23. doi: 10.1152/ajpendo.1979.237.3.E214.
citation: Taubel J, Ferber G, Lorch U, Batchvarov V, Savelieva I, Camm AJ. Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects. Br J Clin Pharmacol. 2014 Jan;77(1):170-9. doi: 10.1111/bcp.12168.
citation: Taubel J, Lorch U, Ferber G, Singh J, Batchvarov VN, Savelieva I, Camm AJ. Insulin at normal physiological levels does not prolong QT(c) interval in thorough QT studies performed in healthy volunteers. Br J Clin Pharmacol. 2013 Feb;75(2):392-403. doi: 10.1111/j.1365-2125.2012.04376.x.