The Physiological Effects of Human Ether-a-go-go-Related Gene (hERG)Blockade on Metabolism

NCT03868657 | Completed DMC

• 1 other identifier: H-1701307
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

The human ether-a-go-go-related gene HERG (encoding Kv11.1 potassium channels) is expressed in different parts of the body including the heart, pancreas and intestines. In the heart, Kv11.1 channels play a role in ending depolarization by causing repolarization. Loss-of-function mutations of HERG cause long QT syndrome, a condition of elongated QT interval that can lead to ventricular tachycardia, syncope and sudden death. Kv11.1 channels are also found in pancreatic α- and β-cells and intestinal L-cells, where they seem to play a role in the secretion of insulin, glucagon and Glucagon-Like Peptide-1 (GLP-1). Carriers of loss-of-function mutations in the HERG gene have showed increased insulin and incretin responses after glucose ingestion and decreased fasting levels of glucagon compared to matched control persons. Blockade of Kv11.1 has shown to augment glucose dependent insulin secretion and decrease low-glucose stimulated glucagon secretion in isolated α- and β- cells. The investigators of this study hypothesize that a blockade of Kv11.1 channels will increase incretin and β cell function and decrease α cell function and thus lead to lower glucose levels in humans after glucose intake. To investigate this, The investigators of this study will perform a randomized, cross sectional study of up to 40 healthy study participants who will serve as their own controls. The study participants will undergo two 6-hours oral glucose tolerance tests, one after intake of a known Kv11.1 blocker (moxifloxacin) and one control oral glucose tolerance test after intake of placebo. Prior to both tests the study participants will wear a continuous glucose monitor and on the day of the tests they will fill out a glucose questionnaire. Investigation of the physiological role of HERG in metabolism may provide a better insight on metabolic regulation.

Conditions

Long QT Syndrome; Hypoglycemia

Outcome Measures

Primary Outcomes (1)

• Insulin and GLP-1

  Change in serum insulin response (AUC/30 min) and GLP-1(AUC/30 min) to a 75 g oral glucose tolerance test between OGTT with and without Kv11.1 blocker (moxifloxacin).

  First and second test day

Secondary Outcomes (2)

• Glucose, Glucagon and GIP

  First and second test day

• Continuous Glucose Monitor

  First and second test day

Other Outcomes (4)

• Hypoglycemia questionnaires

  First and second test day

• Electrolytes

  First and second test day

• Gut microbiota

  Baseline, after first test day, after second test day and after 6 months

Study Arms (2)

Moxifloxacin

ACTIVE COMPARATOR

Per os, 800 mg, once daily for 4 days

Drug: Moxifloxacin

Placebo

PLACEBO COMPARATOR

Per os, 800 mg, once daily for 4 days

Drug: Placebo

Interventions

Moxifloxacin DRUG

Moxifloxacin is solely used to cause a known and for the drug well documented effect, namely blockade of the Kv11.1 channel.

Moxifloxacin

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 20 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy men and women
• Age ≥20 and ≤40 years
• BMI ≥18,5 and ≤27,5

You may not qualify if:

• Chronic diseases (cardiac, metabolic, liver) including a family history of congenital Long QT syndrome.
• QTc values \>440 ms (men) and \>450 ms (women)
• Clinical important and/or symptomatic bradycardia
• Regular medication (contraceptive pills allowed)
• Pregnancy and breastfeeding

Sponsors & Collaborators

• Signe Torekov: lead

Study Sites (1)

University of Copenhagen, Department of Biomedical Sciences

Copenhagen, 2200, Denmark

Location

MeSH Terms

Conditions

Long QT Syndrome; Hypoglycemia

Interventions

Moxifloxacin

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

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

Study Officials

• Signe S. Torekov, MSc, PhD

  University of Copenhagen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: January 27, 2019
• First Posted: March 11, 2019
• Study Start: January 28, 2019
• Primary Completion: August 19, 2019
• Study Completion: March 9, 2020
• Last Updated: April 14, 2022

Record last verified: 2022-04

Locations

DK (1)