Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03868657 |
| Other study ID # |
H-1701307 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 28, 2019 |
| Est. completion date |
March 9, 2020 |
Study information
| Verified date |
April 2022 |
| Source |
University of Copenhagen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
Background and significance:
The human ether-a-go-go-related gene (HERG) encodes Kv11.1 voltage-gated potassium channels
throughout different parts of the human body including the heart, pancreas and intestine.
Potassium channels are important for ending the depolarization by causing repolarization in
cells.
Hence, various mutations in HERG have effects on cardiac and metabolic functions. One known
example in the case of loss-of-function mutations in HERG is a reduced outward flow of
potassium during repolarization of the heart, leading to an elongated QT interval that can
lead to ventricular tachycardia, cardiac syncope and sudden death - known as the long-QT
syndrome (LQTS) (1, 2). LQTS caused by HERG mutations is the second most common type of LQTS
(1).
With regards to metabolism, blockade of Kv11.1 has shown to augment glucose dependent insulin
secretion (3-5) and decrease low-glucose stimulated glucagon secretion (4) in isolated β and
α cells and to augment insulin secretion and reduce blood glucose in living mice(3).
A study of 11 patients with LQTS caused by HERG mutations showed that during a 6-hour OGTT,
the mutation carriers experienced increased levels of insulin, GLP-1 and Gastric Inhibitory
Polypeptide (GIP), decreased levels of glucose and lower fasting levels of glucagon compared
to matched control persons(6).
In this study the investigators wish to investigate the effects of Kv11.1 blockade on
incretin and insulin secretion and blood glucose levels after oral glucose intake in humans.
Research question Study hypothesis The investigators of this study hypothesize that Kv11.1
blockade will increase the metabolic response of serum insulin and GLP-1 (AUC/30 min) to a
6-hour 75 g oral glucose tolerance test (OGTT) in healthy individuals.
Objective To investigate the hypothesis, the investigators of this study want to examine the
metabolic responses of up to 40 healthy test subjects to a 6-hours 75 g OGTT. The test
subjects will serve as their own controls in a double-blinded crossover trial where they will
undergo two 6-hours OGTTs separated by a 3 weeks washout period. During one OGTT they will
have received moxifloxacin (800 mg/day), which is a known blocker of the Kv11.1 channel, and
during the other OGTT they will have received placebo. Prior to and after the test the
subjects will wear a continuous glucose monitor (CGM) and at the day of the test they will
fill out a glucose questionnaire.
Moxifloxacin is solely used to cause a known and for the drug well documented effect, namely
blockade of the Kv11.1 channel.
Study design:
A randomized controlled double-blinded crossover trial with up to 40 healthy participants,
who will serve as their own controls. Study design is outlined in figure 1.
Screening visit (V0): At the screening visit, participants will:
- Be screened to assess their eligibility (anamnesis, weight/height measurements and
12-lead electrocardiography (ECG)). If found eligible:
- Be instructed to have a CGM monitor placed 4 days prior to test visit 1 (V1) for up to 7
days.
- Be randomized to either group A or B by a qualified unblinded person from the Department
of Biomedical Sciences, University of Copenhagen:
- Group A will first receive the active drug known to have Kv11.1 blockade effects
(Moxifloxacin, 800 mg/day) 3 days prior to test visit 1 and then - after a 3 weeks
wash-out period - receive a placebo drug prior to test visit 2.
- Group B will first receive the placebo drug 3 days prior to test visit 1 and then -
after a 3 weeks wash-out period - receive the active drug prior to test visit 2.
Receive the drug for test visit 1 (Kv11.1 blocker or placebo) and be instructed to
orally administer the drug every morning at 6.00 AM 3 days prior to and at the same
morning as the test visit (V1). The unblinded person will make sure to provide the
right drug to the participants.
Test visit 1 (V1): Participants will meet fasting since 10.00 PM the previous evening at 8.00
AM at the Department for Biomedical Sciences, University of Copenhagen.
- The participants will hand in a urine and fecal sample.
- A 75 g 6-hours oral glucose tolerance test (OGTT) will be performed. Crushed
paracetamol, 1 g is added to the glucose mixture. Blood samples and ECGs will be drawn
and collected together. Blood samples of 8 ml will be drawn at -20, -10, -0 minutes
before and at 8, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 210, 240, 270, 300,
330, and 360 minutes after the glucose intake. All blood samples will be analyzed for
hormones, glucose, electrolytes, plasma paracetamol, proteomics and metabolomics and
from the -20 minutes sample DNA material will be extracted and used for genome analysis
(not an extensive genome sequencing). The samples will be tested for mutations in genes
associated with glucose metabolism in relation to obesity, diabetes and cardiovascular
disease. HbA1c and lipids will be measured.
- Glucose questionnaires. Wash-out period: There will be a wash-out period of 3 weeks.
- Participants will come in and have a CGM monitor placed 4 days prior to test visit 2
(V2) for up to 7 days
- Participants will receive the drug (Kv11.1 blocker or placebo) and start to orally
administer the drug every morning at the same time3 days prior to and at the same
morning as the test visit 2.
Test visit 2 (V2): Same examinations as described for Visit 1.
Criteria for when tests can be performed:
- Participants have to have orally administered the study medication 3 days prior to and
at the same morning as the test visits at the same time.
- Participants have to be fasting from 10hours before test visits. This includes foods,
liquids, smoking, alcohol and medication (except Kv11.1 blocker and a small amount of
water used for administration hereof)
- Participants are not allowed to perform any exercise the day before as well as the same
morning as the test visit.
- Participant are not allowed to take paracetamol 24 hours before test visits. Unblinding:
The randomization list will be stored on site at the Department of Biomedical Sciences
at the University of Copenhagen. Subject number of the trial participant is matched with
the list, which reveals to what group the participant is randomized. The unblinded
person will perform any unblinding of the trial participants after Last Patient Last
Visit.
Data Data management: The subject and the biological material obtained from the subject will
be identified by subject number and trial identification number. Appropriate measures such as
encryption or deletion will be enforced to protect the identity of human subjects in all
presentations and publications as required by national requirements. Laboratory data will be
transferred electronically from the laboratory performing clinical analyses and will be
archived in secured hard drives with backup options. The electronic data will be considered
source data. In cases where laboratory data is transferred via non-secure electronic
networks, data will be encrypted during transfer. Data is saved for 20 years.
Source data: Source documents will be kept at the Department of Biomedical Sciences,
University of Copenhagen. Source data registered directly in the Case Report Form (CRF)
include anamnesis, weight and height measurements, ECG.
Evaluability for subjects for analysis: Withdrawn subjects will be replaced. Rescreening is
allowed within the recruitment period, at the Investigator's discretion.
Statistical considerations Data analysis plan: To investigate whether Kv11.1 blockade
significantly effects fasting and glucose-stimulated values of serum insulin and plasma
glucagon, GLP-1, potassium and GIP concentrations, an ANOVA will be performed using age and
sex as covariate, randomization group as independent variable and AUC change in serum insulin
and plasma glucagon, GLP-1, potassium and GIP concentrations as dependent variables to
examine if mean differences exist on study participants after intake of Kv11.1 blocker and
without Kv11.1 blocker.
