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Effect of Glucose on QTc Interval in Type 1 Diabetes

Information source: Richmond Pharmacology Limited
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Diabetes

Intervention: Moxifloxacin (Drug); hyper-glycaemic clamp (Other)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: Richmond Pharmacology Limited

Official(s) and/or principal investigator(s):
Ulrike Lorch, MD FRCA FFPM, Principal Investigator, Affiliation: Richmond Pharmacology Limited

Overall contact:
Ulrike Lorch, MD FRCA FFPM, Phone: +44 20 8664 5200, Email: u.lorch@richmondpharmacology.com

Summary

High blood glucose levels (hyperglycaemia) and Moxifloxacin (a commonly used antibiotic) have both been shown independently to affect heart activity in healthy volunteers as recorded by ECG. i. e. Both cause prolongation of the QTc interval which is a measure of the time between the start of the Qwave and the end of the Twave during a heartbeat cycle. In this study, the investigators want to find out whether moxifloxacin and hyperglycaemia cause QTc prolongation in Type 1 diabetic patients. The investigators also want to assess whether C-peptide (a fragment if insulin normally found in the blood but not present in not present in the blood of Type 1 diabetics) which has the opposite effect on heart activity i. e it shortens the QTc interval will reverse the effect of QTc prolongation in Type 1 diabetes as this may be useful for preventing 'dead in bed' syndrome also known as 'Sudden Cardiac Death' which is more common in diabetic patients compared to healthy volunteers.

Clinical Details

Official title: A Crossover Study to Evaluate the Effect of Glucose on Cardiac Repolarisation Using a Glucose Clamp and a Single 400 mg Dose of Moxifloxacin as a Positive Control in Male and Female Patients With Type I Diabetes

Study design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science

Primary outcome: ECG Analysis

Secondary outcome:

Pharmacokinetics

Pharmacodynamic analysis

Detailed description: The investigators previous research (Taubel et al., 2013) has shown that in healthy individuals glucose by itself can prolong (with C-peptide antagonising the effects) the QT interval, which has long been used as a clinical index of the duration of ventricular repolarisation. This observation warrants serious attention because it suggests that high glucose levels by themselves may be pro-arrhythmogenic. To investigate whether glucose has an effect on cardiac repolarisation, it would be advantageous to test this in an environment uncomplicated by C-peptide. In order to elucidate the effects of glucose on the QTc in the absence of C-peptide, the investigators will use diabetic patients who are no longer able to release endogenous C-peptide. This will allow better understanding to whether (1) the well established QTc prolongation caused by moxifloxacin is exaggerated by elevated levels of blood glucose, which would be important for evaluating the risk in diabetic patients using an IKr blocking drug such as moxifloxacin, and (2) to investigate whether C-peptide substitution will reverse or attenuate the effect in the presence of moxifloxacin. Using the conditions of a formal TQT study, the investigators would also want to confirm the QTc prolonging effects described in Gordin et al. (2008) and whether in this setting C-Peptide substitution will reverse or attenuate the glucose effect on QTc. This will be a phase I, single centre, randomised, placebo-controlled, open-label, crossover study designed to evaluate the effect of glucose and C-peptide on cardiac repolarisation using a hyperglycaemic clamp and a single 400 mg dose of moxifloxacin as a positive control in non-elderly male and female patients with type I diabetes. The results from this study will form the basis for decisions for future studies. This study will be performed in compliance with the protocol, ICH GCP and applicable regulatory requirements including EU GMP requirements for investigational medicinal product(s) (IMPs).

Eligibility

Minimum age: 20 Years. Maximum age: 64 Years. Gender(s): Both.

Criteria:

Inclusion Criteria A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Subject is a male or female with a confirmed diagnosis of Type 1 diabetes mellitus,

20 - 64 years of age (inclusive) at screening.

2. Signed informed consent in the local language prior to any study-mandated procedure. 3. No clinically significant findings on the physical examination at screening and at admission on Day −1. 4. Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) at screening and at admission on Day −1, body weight at least 48 kg. 5. Systolic blood pressure (SBP) 90-160 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 - 1.

6. Triplicate 12 lead ECG without clinically relevant abnormalities measured after ten

minutes in the supine position at screening and on admission on Day - 1.

7. 24 hour 12 lead Holter ECG or an equivalent assessment and/or submaximal exercise test without clinically relevant abnormalities measured at screening. 8. Haematology, biochemistry and urinalysis test results not deviating from the normal range to a clinically relevant extent at screening and at admission. 9. Subjects must agree to use acceptable methods of contraception: Male subjects Male subjects must use medically acceptable methods of contraception if their female partner(s) is (are) pregnant or lactating from the time of the first administration of treatment or study medication until three months following administration of the last treatment or dose of study medication. Acceptable methods include:

- Condom used with spermicidal foam/gel/film/cream/suppository

- If the subject has undergone surgical sterilisation (vasectomy with

documentation of azoospermia) a condom with spermicidal foam/gel/film/cream/suppository must be used. Use acceptable methods of contraception if the male subject's partner could become pregnant from the time of the first administration of treatment or study medication until three months following administration of the last treatment or dose of study medication. The acceptable methods of contraception are as follows:

- Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal

foam/gel/film/cream/suppository;

- Surgical sterilisation (vasectomy with documentation of azoospermia) and a

barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);

- The female partner uses oral contraceptives (combination oestrogen/progesterone

pills), injectable progesterone or subdermal implants and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);

- The female partner uses medically prescribed topically-applied transdermal

contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);

- The female partner has undergone documented tubal ligation (female

sterilisation). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) must be used;

- The female partner has undergone documented placement of an IUD or IUS and the

use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);

- True abstinence: When this is in line with the preferred and usual lifestyle of

the subject. (Periodic abstinence [e. g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). Female subjects Female subjects of childbearing potential must use medically acceptable methods of contraception from the time of the first administration of treatment or study medication until three months following administration of the last treatment or dose of study medication. Acceptable methods include:

- A documented placement of an intrauterine device (IUD) or intrauterine system

(IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);

- Documented tubal ligation (female sterilisation). In addition, a barrier method

(condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used;

- Double barrier method: Condom and occlusive cap (diaphragm or cervical/vault

caps) with spermicidal foam/gel/film/cream/suppository;

- Oral contraceptive pill in addition, a barrier method (condom or occlusive cap

[diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used;

- True abstinence: When this is in line with the preferred and usual lifestyle of

the subject. (Periodic abstinence [e. g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). 10. Ability to communicate well with the Investigator in the local language, and to understand and comply with the requirements of the study. 11. Subject has a stable diabetic treatment regimen. Exclusion Criteria A subject will not be eligible for inclusion in this study if any of the following criteria apply: 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 or clinical evidence of microvascular disease including chronic kidney failure, macular degeneration or any other disease attributed to the microvascular system, that in the Investigator's opinion may affect the outcome of the study. 3. Recent hospitalisation due to hypoglycaemia or hyperglycaemia within the past one month. 4. History of clinically significant syncope. 5. Family history of sudden death. 6. 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. 7. History of clinically significant arrhythmias and ischemic heart disease (especially ventricular arrhythmias, atrial fibrillation (AF), recent conversion from AF or coronary spasm). 8. Conditions predisposing the volunteer to electrolyte imbalances other than Type 1 diabetes (e. g. altered nutritional states, chronic vomiting, anorexia nervosa, bulimia nervosa).

9. ECG abnormalities in the standard 12-lead ECG (at screening and Day - 1) 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. 10. 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 - 1 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. 11. Signs and/or symptoms of a clinically relevant acute illness in the four-week period prior to screening. 12. 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). 13. Known hypersensitivity to any medicines administered in the trial. 14. Treatment with any over-the-counter (OTC) medications during the two weeks prior to admission. 15. You have taken antibiotics 7 days prior to the admission for the study or plan to take antibiotics during the study. 16. Treatment with vitamins and/or minerals within 48 hours prior to admission. 17. 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. 18. 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 −1. 19. 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. 20. Excessive caffeine consumption, defined as ≥800 mg per day at screening (800 mg = 7 cups of coffee or 16 cups of tea). 21. Smoking within three months prior to screening or during the screening period. 22. Loss of 250 mL or more blood within three months prior to screening. 23. Positive results from the hepatitis serology, except for vaccinated subjects, at screening. 24. Positive results from the HIV serology at screening. 25. Any circumstances or conditions, which, in the opinion of the Investigator, may affect full participation in the study or compliance with the protocol. 26. Legal incapacity or limited legal capacity at screening.

Locations and Contacts

Ulrike Lorch, MD FRCA FFPM, Phone: +44 20 8664 5200, Email: u.lorch@richmondpharmacology.com

Richmond Pharmacology Ltd. Croydon University Hospital Thornton Wing, 530, London Road, London, Croydon CR7 7YE, United Kingdom; Not yet recruiting
Keith Berelowitz, PhD
Ulrike Lorch, MD FRCA FFPM, Principal Investigator
Additional Information

Clincal Research Organisation

Related publications:

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.

Taubel J, Naseem A, Shakeri-Nejad K, Dingemanse J, Ferber G and Camm A. J. Comparison of digital 12-lead ECG and digital 12-lead holter ECG recordings in healthy male subjects. Clinical Pharmacology and Therapeutics / 89:Supplement 1 (2011) / S11.

Starting date: March 2014
Last updated: November 14, 2013

Page last updated: August 23, 2015

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