Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01185119 |
| Other study ID # |
H80-CP-O015 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
August 18, 2010 |
| Last updated |
March 21, 2011 |
| Start date |
June 2010 |
| Est. completion date |
March 2011 |
Study information
| Verified date |
March 2011 |
| Source |
University of Aarhus |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Denmark: The Regional Committee on Biomedical Research EthicsDenmark: Danish Dataprotection Agency |
| Study type |
Interventional
|
Clinical Trial Summary
10 healthy men will be PET-scanned (CNS) twice in random order with infusions of placebo or
Native GLP-1 during hyperglycemic clamp to uncover the metabolic effects of GLP-1 in
perspectives of intervention of macrovascular late diabetic pathology such as stroke and
AMI. Earlier studies have revealed tendencies towards steady glucose metabolism in the CNS
despite fluctuations in blood sugar when infusing native GLP-1.
Description:
Background Type 2 diabetes (T2D) is epidemically increasing throughout the world. T2D is
frequently associated with multiple complications, where particularly the macrovascular
complications in the form of myocardial infarction with its possible complication of death
or heart failure, cerebral infarction and limb amputation are responsible for a vast
increase in morbidity and mortality in this group of patients. Apart from the individual
burden on the patient, T2D puts massive pressure on national health economies.
It is well established that blood glucose lowering drugs, antihypertensive as well as lipid
lowering drugs all play a pivotal role in the treatment of the type 2 diabetic subjects.
Regarding glycemia, there are frequently side effects with the 'classic' drugs such as
hypoglycemia, weight gain, heart failure, and so forth. Another important caveat is that
employing the anti-hyperglycemic drugs either as monotherapy or in combination does not
lower blood glucose to the targets as defined by the ADA. In other words novel anti-diabetic
drugs are urgently required. However, the incretin concept has recently been inaugurated in
the pharmacological scenario.
Glucagon-like peptide-1-receptors (GLP-1R) are abundant on alpha- and beta-cells in the
pancreas, but are also present in the heart and CNS, especially in hypothalamic and
hippocampal regions. A wide range of extrapancreatic effects of GLP-1 have been observed
such as slowed gastric emptying and satiety-stimulating effects through hypothalamic
mechanisms. Recent studies have showed interesting results regarding protection of the heart
during ischemia, and protection of the brain in the acute phases of stroke have been
proposed. Over-all GLP-1 seems to display effects in heart, brain, vessels, kidneys, muscles
and liver(7).
To our knowledge, our group has in a very recent study been the first, by sophisticated
metabolic techniques, together with Positron Emission Tomography (PET), to demonstrate that
GLP-1 per se reduces cerebral glucose transport in total cerebral grey matter as well as
individual grey matter regions, thereby suggesting that GLP-1 may protect the brain by
limiting intracerebral glucose fluctuation when plasma glucose is increased. In other words,
GLP-1 regulates blood brain barrier (BBB) glucose transfer at normal glycemia and presumably
also during hyperglycemia(19).
Glucagon-like-peptide-1 (GLP-1): T2D is characterized by several hormonal and metabolic
abnormalities such as dysfunction of insulin secretion, glucagon excess, impaired
Glucagon-like-peptide-1 (GLP-1) secretion, and insulin resistance.
GLP-1 is an incretin hormone with numerous documented effects on the glycemic response. It
is one of the most potent insulinotropic agents known and is secreted from L-cells in the
gut mucosa in response to food ingestion. Effects on the islet-cells are (I) Amplification
of glucose dependent stimulation of insulin secretion (II) Inhibition of glucagon secretion.
In animal and cellular studies GLP-1 stimulates β-cell neogenesis, growth and
differentiation, and in vitro inhibition of β-cell apoptosis is observed. Thus GLP-1 is also
a β-cell growth factor. For now, treatment with GLP-1 has seldom caused hypoglycaemia in
type 2 diabetic patients.
Hypotheses Based on the findings in the above-mentioned study, we hypothesize that Native
GLP-1 during hyperglycemia will protect the brain in healthy men from hyperglycemia by
reducing blood-brain-barrier glucose transport and brain glucose metabolism.
Aim: With well established methodology, to compare the effect of native GLP-1 and placebo,
respectively, on the consumption of glucose in the CNS assessed by uptake of
18-fluro-deoxy-glucose (FDG) monitored by PET-scan of healthy young men during hyperglycemic
pituitary-pancreatic clamp in the perspective of future prevention of macrovascular
complications of diabetes and possibly other diseases such as Alzheimer's disease and other
neurodegenerative and cardiac diseases.
The primary endpoint of the project: steady glucose metabolism in the brain during
hyperglycemia with native GLP-1 infusion compared to placebo.
Design: Randomized, double-blinded crossover design. Every participant will be
CNS-PET-scanned twice in random order with GLP-1 and placebo-infusions interrupted by a 3-4
week wash-out period between study days.
The study will be performed similarly to our previously conducted FDG/PET-study(21) and
pancreatic clamp as done by Nielsen et al.(22)
Methods
GLP-1 is a natural peptide hormone that is degraded by the enzyme DPPIV after few minutes in
the circulation. The remaining hormones utilized in this study, are used as tools in the
investigational design and will not be used as medical compounds themselves.
Hormone doses
- Somatostatin (Ferring) 300 μg/hour(22)
- Insulin Actrapid (NOVO Nordisk) 0,12 mU/kg/minute (22)
- Glucagon (NOVO Nordisk, Glucagen) 0.6 ng/kg/minute(22)
- Growth hormone (NOVO Nordisk) 2 ng/kg/minute(22)
- Native GLP-1 (PolyPeoptide) 1,2 pmol/kg/minute (23) Pancreatic and hyperglycemic clamp
Somatostatin is administered to inhibit endogenous production of GLP-1, insulin,
glucagon, and growth hormone. Insulin, glucagon, and growth hormone are administered to
achieve basal hormone levels. 20% glucose is infused to achieve hyperglycemic clamp
with plasma glucose at 9 mM which is by experience the highest level of hyperglycemia
possible while still avoiding breakthrough of natural counterregulatory hormones.
Ethics: Apart from its documented effect on glycemic control, GLP-1 has potential protective
impact in the brain. Patients with type-2 diabetes carry a significantly increased risk of
ischemic heart disease and stroke that has not been substantially reduced by current
treatments. Preliminary data suggest that clinical use of GLP-1 can lead to improved
prophylaxis against late diabetic complications, which can be achieved in this patient group
in addition to improved glycemic control. This project is conducted to map the physiology of
GLP-1 in heathy during hyperglycemia.
We believe the current study will provide deeper insight into the extra-pancreatic effects
of GLP-1, with the particular aim to develop efficient prophylaxis against late diabetic
cerebrovascular and cardiovascular complications, which outweighs the known adverse effects
of the elements of the study.
The study will be conducted in accordance with the principles described in the Helsinki
Declaration II and will not be initiated before acceptance is granted from the local Ethics
Committee.
Written consent from participants is required before studies can be commenced, and all
participants are covered by insurance according to "Bekendtgørelse af lov om
patientforsikring" and "Lov om erstatning for lægemiddelskader".
Informed consent All participants will receive written and oral information about the
purpose and the expected scientific value of the project as well as detailed description of
all procedures and risks involved. Specifically, the participant will be told that
participation is completely voluntary, and withdrawal is accepted at any stage during the
investigation.
The project coordinator, Dr. Michael Gejl Jensen, will provide oral information and hand out
written material including the general information brochure "Before you decide….." ("Før du
beslutter dig…"). The participant is allowed an accompanying person for the duration of the
meeting.
Written consent is collected after a minimum of 24 hours for further consideration. Both the
responsible physician and the participant sign the consent, and the latter will be provided
a copy.
Data management Source data (original documentation of clinical findings, printouts, lab
results, and other details necessary to completely reconstruct each study) are stored in
case report forms and a common database. All personal information is locked away and
inaccessible to all but the investigators. Screening ID, randomization ID, and initials in
the database identify participants. The initials will be erased from the database after
completion of the study to ensure anonymity. A separate chart containing screening ID,
randomization ID, initials, and personal data will be stored at another location to allow
re-identification of source data. Social security numbers (Danish: CPR-numbers) are present
on electronical charts, which are kept in the individual electronical patient charts on the
hospital server. This information will only be accessible to personnel in the study-group
and not to doctors treating the patients in any future hospitalization. Data will
automatically be erased from the server after 15 years. The study will be disclosed to the
local Data Monitoring Board.
Financial aspects Each participant will receive dkr 2400 as compensation.
The applicant will provide the needed work in accordance with present rules and contracts
concerning research fellows at Institute of Pharmacology, University of Aarhus and the
Research Unit, Department of Endocrinology (M), Aarhus University Hospital.
