Food and Insulin Effect on QT/QTC Interval of ECG (C11035)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Richmond Pharmacology Limited
ClinicalTrials.gov Identifier:
NCT01642485
First received: June 19, 2012
Last updated: June 4, 2013
Last verified: June 2013
  Purpose

The aims of the study are 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 will be done be giving different treatments on separate days which will include intravenous insulin, a high carbohydrate breakfast [>70%], and a calorie reduced low carbohydrate American FDA standard breakfast. Moxifloxacin 400 mg will be used as a positive control and will be given with and without food to Caucasian and Japanese volunteers to investigate racial differences.


Condition Intervention Phase
Effects of Different Meals on the QT/QTc Interval
Insulin Effects on the QT/QTc Interval
C Peptide Effects on the QT/QTc Interval
Moxifloxacin ECG Profile Fed and Fasted
Japanese Caucasian TQT Comparison
Drug: Placebo
Other: FDA breakfast
Other: Continental breakfast
Drug: Moxifloxacin with food
Drug: Moxifloxacin fasted
Procedure: Insulin Clamp
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: An Open-label, Randomised, Placebo-controlled, Crossover Study to Evaluate the Effect of Different Foods, Carbohydrate Meal, and a Euglycaemic Insulin Clamp on the QT/QTc Interval of the ECG Using a Single 400 mg Dose of Moxifloxacin as a Positive Control in Non-elderly Healthy Male and Female, Caucasian and Japanese Volunteers

Resource links provided by NLM:


Further study details as provided by Richmond Pharmacology Limited:

Primary Outcome Measures:
  • To thoroughly evaluate the effect of glucose, insulin, c-peptide compared to placebo and moxifloxacin on the mean QT/QTc interval of the ECG. [ Time Frame: Up to 6 hours ] [ Designated as safety issue: Yes ]
    Recording of 12 Lead ECG will be done at specified time-points during the study, after the subjects have been resting in a supine position for at least 10 minutes. At each time-point, the ECG will be recorded in triplicate, to reduce variance and improve the precision of measurement. The triplicates will be performed at approximately one-minute intervals. Each ECG recording (trace) will last ten seconds.


Secondary Outcome Measures:
  • To assess the effects of different meal compositions (carbohydrate rich versus standard FDA breakfast) on the QT/QTc interval. [ Time Frame: Up to 6 hours ] [ Designated as safety issue: No ]
    The primary baseline corrections will be 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) will be used to calculate ΔQTc for each study period.

  • To assess the effect of food on the Moxifloxacin QT/QTc effect. [ Time Frame: Up to 6 hours ] [ Designated as safety issue: Yes ]
    The primary baseline corrections will be 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) will be used to calculate ΔQTc for each study period.

  • To confirm the magnitude of effect seen in a previous study which found an effect of food on QT/QTc. [ Time Frame: Up to 6 hours ] [ Designated as safety issue: No ]
    The food effect on QT/QTc in this study will be compared with a previous study (Taubel et al, 2011) which found an effect of food on QT/QTc.

  • To compare 12-lead holter versus bed-side ECG acquisition [ Time Frame: Up to 6 hours ] [ Designated as safety issue: No ]
    To determine whether automated 12-lead bedside measurement is necessary to provide large enough sample sizes to overcome this experimental noise as previously shown (Taubel et al, 2011).

  • To describe and compare the number and the rates of adverse events (AEs) under each treatment. [ Time Frame: Up to 2 weeks or longer if AE not resolved ] [ Designated as safety issue: Yes ]
    The number and frequency of adverse events will be recorded throughout the study and analysed at the end of the study relative to treatment

  • To compare moxifloxacin 400 mg (single dose) to placebo on the mean QT/QTc interval. [ Time Frame: Up to 6 hours ] [ Designated as safety issue: Yes ]
    The best heart rate correction method will be used - in order to assess the ability of the study to detect differences of clinical significance.

  • To describe the pharmacodynamic (PD) profiles of insulin, glucose and C-Peptide. [ Time Frame: Up to 6 hours ] [ Designated as safety issue: No ]
    Plots of the differences with 90% CIs between insulin, glucose and C-Peptide and placebo as well as moxifloxacin and placebo over time will be produced for all analyses.

  • Area under plasma concentration versus time curve (AUC) of moxifloxacin, insulin, glucose and C-peptide [ Time Frame: Up to 6 hours ] [ Designated as safety issue: Yes ]
    PK parameters will be analysed descriptively: AUC0-t, Cmax, tmax will be summarised with arithmetic mean, geometric mean, minimum, median, maximum, standard deviation, standard error, CVb(%) and 95% confidence limits of the means for each dose group. Log-transformed AUC0-t, AUC0-∞, Cmax and t½ values will be summarised with geometric mean, standard deviation of the logs, 95% confidence limits and CVb(%).

  • Peak plasma concentration (Cmax) of moxifloxacin, insulin, glucose and C-peptide [ Time Frame: Up to 6 hours ] [ Designated as safety issue: Yes ]
    Insulin, glucose and C-Peptide concentrations will be listed for each individual subject by treatment and summarised at each time point by treatment group using the following descriptive statistics: n (the number of subjects), arithmetic mean, SD (standard deviation), geometric mean, CV (coefficient of variation), median, minimum and maximum.


Enrollment: 32
Study Start Date: July 2011
Study Completion Date: September 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Fasted Drug: Placebo
Subjects receiving placebo or drug (moxifloxacin) fasted overnight for 10 hours.
Active Comparator: Moxifloxacin 400 mg single oral dose fasting Drug: Moxifloxacin fasted
One single dose of 400mg moxifloxacin after fasting - This is the standard probe for the assessment of assay sensitivity in Thorough QT (TQT) studies.
Experimental: Calorie-reduced FDA standard breakfast Other: FDA breakfast
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.
Experimental: Carbohydrate rich (Continental style) breakfast Other: Continental breakfast
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.
Experimental: Euglycaemic Insulin Clamp Procedure: Insulin Clamp
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.
Experimental: Moxifloxacin 400 mg single oral dose fed Drug: Moxifloxacin with food
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.

Detailed Description:

This study will be performed initially 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 will be based on the standard deviation of the ECG intervals observed in the first 24 volunteers. This analysis will be performed by an independent statistician under blinded conditions.

Each volunteer will participate in 2 periods. Each period will consist of 1 baseline day (D-1) followed by 3 study days (D1 - D3) when the various food effect and drug treatments or placebo will be administered. All volunteers will receive all treatments. Moxifloxacin is always given on D3 to prevent any carryover effect and there will be 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) are tolerated by the volunteers will be assessed and any side effects noted.

We will compare the effects of the various treatments between Caucasian and Japanese volunteers.

Moxifloxacin and placebo will be given to volunteers by mouth, i.e. they will be asked to swallow them with water. The different types of breakfast will be provided which volunteers will be asked to eat. Insulin and glucose will be administered intravenously (Insulin/glucose clamp). Hence the study will be performed as an open-label design.

This study is being conducted as a single site study at Richmond Pharmacology/ St George's University of London.

  Eligibility

Ages Eligible for Study:   20 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy male or female subjects aged between 20 and 45 years (inclusive) at screening.
  2. Signed informed consent in the local language prior to any study-mandated procedure.
  3. Japanese subjects defined as a person carrying a Japanese passport, who is a descendant of four Japanese grandparents and has not been outside Japan for more than five years prior to screening.
  4. The Caucasian subjects should be distinguished especially by very light to brown skin pigmentation and straight to wavy or curly hair, and should be indigenous to Europe, northern Africa, western Asia, and India. Therefore, the study may as well include Caucasian subjects from North America, Australia and South Africa
  5. No clinically significant findings on the physical examination at screening and at admission on Day −2.
  6. Body mass index (BMI) between 18 and 25 kg/m2 (inclusive) at screening and at admission on Day −2, body weight at least 48 kg.
  7. Systolic blood pressure (SBP) 90-145 mmHg, diastolic blood pressure (DBP) 40-90 mmHg, and heart rate (HR) 40-90 bpm (all inclusive), measured on the left arm, after 10 minutes in the supine position at screening and at admission on Day -2.
  8. Triplicate 12 lead ECG without clinically relevant abnormalities measured after ten minutes in the supine position at screening and on admission on Day -2.
  9. 24 hour 12 lead Holter ECG or an equivalent assessment and/or submaximal exercise test without clinically relevant abnormalities measured at screening.
  10. Haematology, biochemistry and urinalysis test results not deviating from the normal range to a clinically relevant extent at screening and at admission.
  11. Subjects 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 (appendectomy and herniotomy allowed, cholecystectomy not allowed).
  2. History of clinically significant syncope.
  3. Family history of sudden death.
  4. Family history of premature cardiovascular death.
  5. Clinically significant history or family history of congenital long QT syndrome (e.g. Romano-Ward syndrome, Jervell and Lange-Nielson syndrome) or Brugada's syndrome.
  6. History of clinically significant arrhythmias and ischemic heart disease (especially ventricular arrhythmias, atrial fibrillation (AF), recent conversion from AF or coronary spasm).
  7. Conditions predisposing the volunteer to electrolyte imbalances (e.g. altered nutritional states, chronic vomiting, anorexia nervosa, bulimia nervosa).
  8. ECG abnormalities in the standard 12-lead ECG (at screening and Day -2) and 24-hour 12 lead Holter ECG or an equivalent assessment and/or submaximal exercise test (at screening) which in the opinion of the Investigator will interfere with the ECG analysis.
  9. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc interval changes. This includes subjects with any of the following (at screening and Day -2 of Period 1):

    • 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.

    Subject with borderline deviations from these criteria may be included if the deviations do not pose a safety risk, and if agreed between the appointed Cardiologist and the PI.

  10. Subjects with an abnormal blood glucose result, (blood glucose >7.8mmol/l) after oral glucose tolerance test at screening, that in the opinion of the investigator is considered to be clinically significant.
  11. Subjects with significant family history of diabetes mellitus as considered by the investigator.
  12. Subjects with elevated fasting blood glucose level at screening considered clinically significant by Investigator
  13. Signs and/or symptoms of a clinically relevant acute illness in the four-week period prior to screening.
  14. Veins unsuitable for intravenous puncture or cannulation on either arm (e.g. veins that are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture).
  15. Known hypersensitivity to any medicines administered in the trial.
  16. Treatment with any prescribed medication during the two weeks prior to first baseline day.
  17. Treatment with any over-the-counter (OTC) medications during the two 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 four weeks prior to dosing or having participated in more than three investigational drug studies within one year prior to dosing.
  20. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids, opiates, barbiturates and methadone) or from the alcohol breath test at screening and on Day −2.
  21. History or clinical evidence of alcoholism or drug abuse. Alcohol abuse is defined as regular weekly intake of more than 14 units if female and 21 units if male; drug abuse is defined as 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, defined as ≥800 mg per day at screening (800 mg = 7 cups of coffee or 16 cups of tea).
  23. Smoking within three months prior to screening or during the screening period.
  24. Loss of 250 mL or more blood within three months prior to screening.
  25. Positive results from the hepatitis serology, except for vaccinated subjects, at screening.
  26. Positive results from the HIV serology at screening.
  27. Any circumstances or conditions, which, in the opinion of the Investigator, may affect full participation in the study or compliance with the protocol.
  28. Legal incapacity or limited legal capacity at screening.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01642485

Locations
United Kingdom
Richmond Pharmacology Ltd
London, Tooting, United Kingdom, SW17 0RE
Sponsors and Collaborators
Richmond Pharmacology Limited
Investigators
Principal Investigator: Ulrike Lorch, MD FRCA FFPM Richmond Pharmacology Limited
  More Information

Additional Information:
Publications:
Responsible Party: Richmond Pharmacology Limited
ClinicalTrials.gov Identifier: NCT01642485     History of Changes
Other Study ID Numbers: RPL-01-11, 2011-002423-17
Study First Received: June 19, 2012
Last Updated: June 4, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Richmond Pharmacology Limited:
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

Additional relevant MeSH terms:
Insulin, Globin Zinc
Insulin
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents

ClinicalTrials.gov processed this record on August 01, 2014