Food and Insulin Effect on QT/QTC Interval of ECG

NCT01642485 | Completed Phase 1 Results

• 2 other identifiers: RPL-01-112011-002423-17
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• The Effect of Food (Fasted and Fed State) on the Degree of QT Prolongation Caused by Moxifloxacin

  The primary baseline corrections were 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) was used to calculate ΔQTc for each study period.

  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 (4)

• The Food Effects (Calorie Reduced FDA Breakfast and Carbohydrate Rich Continental Style) on QTcF

  0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose

• Moxifloxacin 400 mg (Single Dose) Compared to Placebo on the Mean QT/QTc Interval.

  0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose

• Insulin, Glucose and C-Peptide Effects on the QT/QTc Interval

  0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose

• The QTcF Profile of Oral Moxifloxacin (400 mg) in Healthy Japanese Versus Caucasian Subjects

  0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 and 6 hours post-dose

Study Arms (2)

Moxifloxacin 400 mg fasted

ACTIVE COMPARATOR

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.

Drug: Moxifloxacin 400 mg fasted; Other: FDA breakfast; Other: Continental breakfast; Procedure: Insulin Clamp; Drug: Placebo

Moxifloxacin 400 mg fed

EXPERIMENTAL

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.

Other: FDA breakfast; Other: Continental breakfast; Drug: Moxifloxacin 400 mg fed; Procedure: Insulin Clamp; Drug: Placebo

Interventions

Moxifloxacin 400 mg fasted DRUG

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.

Also known as: Moxifloxacin

Moxifloxacin 400 mg fasted

FDA breakfast OTHER

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.

Moxifloxacin 400 mg fasted; Moxifloxacin 400 mg fed

Continental breakfast OTHER

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.

Moxifloxacin 400 mg fasted; Moxifloxacin 400 mg fed

Moxifloxacin 400 mg fed DRUG

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.

Also known as: Moxifloxacin

Moxifloxacin 400 mg fed

Insulin Clamp PROCEDURE

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.

Moxifloxacin 400 mg fasted; Moxifloxacin 400 mg fed

Placebo DRUG

Comparison of different meals effect on Moxifloxacin PK profile

Moxifloxacin 400 mg fasted; Moxifloxacin 400 mg fed

Eligibility Criteria

• Age: 20 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male or female, 20 - 45 years old
• Signed ICF
• 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
• 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
• No clinical findings on the physical examination
• Body mass index (BMI) = 18 - 25 kg/m2, body weight at least 48 kg.
• Systolic blood pressure 90-145 mmHg, diastolic blood pressure 40-90 mmHg, and heart rate 40-90 bpm
• Triplicate 12 lead ECG without clinically relevant abnormalities
• hour 12 lead Holter ECG without clinically relevant abnormalities
• Haematology, biochemistry and urinalysis within the normal range
• Must agree to use acceptable methods of contraception

You may not qualify if:

• 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
• History of clinically significant syncope.
• Family history of sudden death.
• Family history of premature cardiovascular death.
• Family history of congenital long QT syndrome or Brugada's syndrome.
• History of arrhythmias and ischemic heart disease
• Conditions predisposing to electrolyte imbalances (e.g. altered nutritional states, chronic vomiting, anorexia nervosa, bulimia nervosa).
• Abnormal ECG in the standard 12-lead ECG and 24-hour 12 lead Holter ECG
• 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.

Sponsors & Collaborators

• Richmond Pharmacology Limited: lead

Study Sites (1)

Richmond Pharmacology Ltd

London, Tooting, SW17 0RE, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 22067197 BACKGROUND

• 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.

  PMID: 11980571 BACKGROUND

• 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.

  PMID: 382871 BACKGROUND

• 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.

  PMID: 23713767 RESULT

• 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.

  PMID: 22775199 RESULT

Related Links

• The FIRST to obtain MHRA Standard and Supplementary Accreditation for two hospital based clinical trial units.

MeSH Terms

Conditions

Insulin Resistance; Fasting; Lecithin Cholesterol Acyltransferase Deficiency

Interventions

Moxifloxacin

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Feeding Behavior; Behavior; Hypoalphalipoproteinemias; Hypolipoproteinemias; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Dyslipidemias; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Our findings based on the confirmatory and concentration-effect analysis suggest that any difference between ethnicities was most likely attributable to differences in plasma concentrations and not differences in sensitivity to moxifloxacin.

Results Point of Contact

• Title: Dr Jorg Taubel
• Organization: Richmond Pharmacology Ltd

j.taubel@richmondpharmacology.com

+44(0)2086645200

Study Officials

• Ulrike Lorch, MD FRCA FFPM

  Richmond Pharmacology Limited

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2012
• First Posted: July 17, 2012
• Study Start: July 1, 2011
• Primary Completion: September 1, 2011
• Study Completion: September 1, 2011
• Last Updated: August 20, 2014
• Results First Posted: August 20, 2014

Record last verified: 2014-08

Locations

GB (1)