Effect of Glucose on QTc Interval in Type 1 Diabetes

NCT01984827 | Completed Phase 1

• 3 other identifiers: RPL-01-122013-001612-30C12061
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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 the blood of Type 1 diabetics) 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.

Conditions

Diabetes

Keywords

Hyperglycaemia; Moxifloxacin; QTc prolongation; C-peptide; Dead in bed syndrome

Outcome Measures

Primary Outcomes (1)

• ECG Analysis

  * The paired PK and QTc interval parameters pre-dose compared to post-administration of glucose. Clinically significant ECG morphology and interval changes from baseline. * The effect on QTc will be calculated using concentration-effect analysis.

  1, 2, 3 Days

Secondary Outcomes (1)

• Proportion of Participants with Adverse Events

  1, 2, 3 Days

Study Arms (3)

hyper-glycaemic clamp:

EXPERIMENTAL

hyper-glycaemic clamp: intra-venous Glucose as an initial bolus of 250mg/kg followed by a variable maintenance infusion for 4 hours

Other: hyper-glycaemic clamp

Moxifloxacin

EXPERIMENTAL

Single oral dose of 400 mg Moxifloxacin

Drug: Moxifloxacin

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Moxifloxacin

Interventions

Moxifloxacin DRUG

1. a single oral dose of 400mg Moxifloxacin plus a hyper-glycaemic clamp for 4 hours 2. a single oral dose of 400mg Moxifloxacin plus C-peptide 3. a single oral dose of 400mg Moxifloxacin 4. placebo Oral doses of placebo and moxifloxacin will be administered by a Research Physician or Pharmacy staff member between 08:00 a.m. and 10:00 a.m.

Also known as: Avelox®

Moxifloxacin; Placebo

hyper-glycaemic clamp OTHER

a hyper-glycaemic clamp only for 2 hours followed by a hyper-glycaemic clamp plus C-peptide for 2 hours

Also known as: glucose infusion, glucose clamp

hyper-glycaemic clamp:

Eligibility Criteria

• Age: 20 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Subject is a male or female with a confirmed diagnosis of C-peptide deficiency Type 1 diabetes mellitus, HbA1c levels of ≤ 60 mmol/mol and 20 - 64 years of age (inclusive) at screening.
• Healthy (apart from the confirmed diagnosis of C-peptide deficiency Type 1 diabetes mellitus) on the physical examination at screening and at admission on Day -1.
• Body mass index (BMI) between 18 and 30 kg/m2 (inclusive) at screening and at admission on Day -1, body weight at least 48 kg.
• Haematology, biochemistry and urinalysis test results within the normal range to a clinically relevant extent at screening and at admission.
• Female subjects who are either:
• Non-childbearing potential, e.g. post-menopausal (as defined as amenorrhoea for at least 12 months with no alternative medical cause) or permanently sterile (permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) OR
• Childbearing potential AND (if heterosexually active) agree to use one or more forms of highly effective contraception as defined below, starting at least one menstrual cycle before first study drug administration and continuing until at least 3 months after the end of the systemic exposure of the study drug.
• Highly effective contraceptive methods for females are as follows:
• Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation as follows:
• Oral
• Intravaginal
• Transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation as follows:
• Oral
• Injectable

You may not qualify if:

• History or clinical evidence of Type 1 diabetes mellitus related secondary complications in particular autonomic neuropathy, rhythm disturbances, post medical history of syncope and potassium abnormalities.
• 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).
• 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.
• Recent hospitalisation due to hypoglycaemia or hyperglycaemia within the past one month.
• History of clinically significant syncope.
• Family history of sudden death.
• 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.
• History of clinically significant arrhythmias and ischemic heart disease (especially ventricular arrhythmias, atrial fibrillation (AF), recent conversion from AF or coronary spasm).
• Conditions predisposing the volunteer to electrolyte imbalances other than Type 1 diabetes (e.g. altered nutritional states, chronic vomiting, anorexia nervosa, bulimia nervosa).
• ECG abnormalities in the standard 12-lead ECG (at screening, Day -1 or pre-dose of 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.
• 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, Day-1 or pre-dose of Day 1):
• Sinus node dysfunction.
• Clinically significant PR (PQ) interval prolongation.
• Intermittent second or third degree AV block.
• Incomplete or complete bundle branch block.

Sponsors & Collaborators

• Richmond Research Institute: lead
• Richmond Pharmacology Limited: collaborator

Study Sites (1)

Richmond Pharmacology Ltd. 1a Newcomen St, London Bridge

London, SE1 1YR, United Kingdom

Location

Related Publications (3)

• 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 BACKGROUND

• 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.

  BACKGROUND

• Taubel J, Pimenta D, Cole ST, Graff C, Kanters JK, Camm AJ. Effect of hyperglycaemia in combination with moxifloxacin on cardiac repolarization in male and female patients with type I diabetes. Clin Res Cardiol. 2022 Oct;111(10):1147-1160. doi: 10.1007/s00392-022-02037-8. Epub 2022 May 21.

  PMID: 35596784 DERIVED

Related Links

• Clincal Research Organisation

MeSH Terms

Conditions

Diabetes Mellitus; Hyperglycemia

Interventions

Moxifloxacin; Glucose Clamp Technique

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Jorg Taubel, MD FFPM

  Richmond Pharmacology Limited

  PRINCIPAL INVESTIGATOR

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: November 8, 2013
• First Posted: November 15, 2013
• Study Start: February 10, 2019
• Primary Completion: December 31, 2020
• Study Completion: December 31, 2020
• Last Updated: May 5, 2021

Record last verified: 2021-04

Locations

GB (1)