The objective of these studies is to identify the primary mechanisms of GC-induced dysmetabolic effects in humans and to find biomarkers that reflect these side effects of GC treatment and which can be followed during therapy and in future clinical…
ID
Source
Brief title
Condition
- Other condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Therapeutic and nontherapeutic effects (excl toxicity)
Synonym
Health condition
Metabole effecten van behandeling met prednisolon
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
In PANTHEON-I, various aspects of beta-cell function will be studied after
intravenous (combined eu- and hyperglycemic clamp with subsequent arginine
stimulation) and orally (mixed-meal test) administered glucose.
In PANTHEON-II, GC-induced changes in hepatic and peripheral insulin
sensitivity and subsequent changes in intermediary metabolism/metabolic fluxes,
such as rate of endogenous glucose production, lipolysis and proteolysis, and
the underlying molecular mechanism, will be studied.
Secondary outcome
Secundary outcomes of PANTHEON-I:
1. circulating biomarkers (plasma)
2. Microvascular function
3. Blood pressure
4. Molecular mechanisms
Secundaire uitkomsten van PANTHEON-II betreffen de effecten van bovengenoemde
interventie met prednisolon op:
1. circulating biomarkers (plasma)
2. Body composition
3. Blood pressure
4. body fat distribution
5. Molecular mechanisms
Background summary
Glucocorticoids, such as prednisolone, are the most frequently prescribed
anti-inflammatory and immunosuppressive medication. Although GCs display
excellent efficacy in a great number of (auto-immune) diseases, the side-effect
profile often limits their therapeutical benefit. Major side effects associated
with GC treatment include changes in glucose, lipid and protein metabolism,
leading amongst others, to insulin resistance, glucose intolerance, muscle
wasting and dyslipidemia. The current development of *dissociated
glucocorticoid receptor activators*, which seem to lack these deleterious
effects, while preserving its immunomodulatory effects, and the recently
identified role of cortisol in the development of the metabolic syndrome (MetS)
and type 2 diabetes (T2DM) , have led to a renewed interest in the mechanisms
of these diabetogenic effects.
In this Top Institute Pharma (TIP) study group is, in addition to cooperation
between a number of pre-clinical and clinical groups, NV Organon involved,
which is currently developing dissociated glucocorticoid receptor agonists.
The results of these trials may support the development of the above-named
compounds, which may become of great importance for the millions of people
world-wide that require GC-treatment and who suffering daily from their
dysmetabolic side effects.
Study objective
The objective of these studies is to identify the primary mechanisms of
GC-induced dysmetabolic effects in humans and to find biomarkers that reflect
these side effects of GC treatment and which can be followed during therapy and
in future clinical trials.
Study design
The PANTHEON studies are randomized, placebo controlled, dubbel-blind,
dose-response, parallelgroup intervention studies.
It concerns a monocenter studie (VUmc) and in total 124 participants will be
included.
32 Healthy males in PANTHEON-I
32 Subjects with the metabolic syndrome in PANTHEON-I
30 Healthy males in PANTHEON-II
30 Subjects with the metabolic syndrome in PANTHEON-II
Intervention
Participants will be randomized to one of the following groups: placebo,
prednisolone 7.5 mg/daily or prednisolone 30 mg /daily.
Treatment duration is 14 days.
Study burden and risks
We are well aware of the possible demand that may be imposed on the
participants. Overall, participants will travel 7 times to the study location.
The duration of these visits ranges between 30 minutes (control visit) and
8hours (stable isotope test). A total amount of 500 mL blood will be withdrawn
in both PANTHEON-I and PANTHEON-II.
nomen. The maximum amount of blood to be collected during one visit is 130 mL.
All possible measures will be taken to minimize the discomfort for the
participants. During the clamps, meal tests and stable isotopes tests, patients
will assume a semirecumbent position, to alleviate discomfort, and will be
allowed to read or watch TV/video. Following the tests, all participants will
be presented with a meal and coffee/tea. During the clamps (a restricted
regimen of) water intake is allowed. Subjects with claustrophobia are excluded
from MRI-scans. The amount of radiation used during a DEXA-scan is 1/10 of a
standard CXR. Lidocaine will be used as a local anesthetic during the biopsy
procedures. Pressure bandages will be used to reduce the change of the
development of a hematoma. Our current experience indicates that no harm is
being done by performing these biopsies and that the small incision heals very
quickly. The medication in this study, prednisolone, is a regular orally
administered pharmacological compound, registered for the treatment of a wide
range of (auto-immune) diseases. Since prednisolone has been used extensively,
its potential, clinically relevant side-effects are well documented. Aside from
the development of transient impairment of insulin sensitivity and subsequent
short-lived metabolic adaptations (i.e. our study goals), we do not expect to
find other adverse effects in our short treatment period with low- to
medium-doses of prednisolone. In a recent study in healthy males, using an
identical intervention as in our study, it was shown that GC-induced insulin
resistance was quickly resolved after cessation of therapy. Glucose levels were
not changed during the study, and the increased levels of C-peptide and
pro-insulin (signs of insulin resistance) had returned to baseline after
one-week of follow-up. Furthermore, no participants had to discontinue the
study due to health problems, and no serious adverse events were reported (NV
Organon, unpublished data).
De Boelelaan 1117
1081 HV Amsterdam
NL
De Boelelaan 1117
1081 HV Amsterdam
NL
Listed location countries
Age
Inclusion criteria
For all participants:
1. signed informed consent
2. caucasian male
3. normal day-and night rythm
For healthy volunteers:
1. Good health (from history, physical exams, blood tests)
2. fasting glucose < 5.6 mmol/L
3. 20 < BMI< 25.
4. 20 < age < 55 jaar.
For subjects with the metabolic syndrome:
1. metabolic syndrome (according to IDF criteria). Waist > 93 cm and at least 3 of the following criteria:
- triglycerides > 1.7 mmol/L
- HDL cholesterol < 1.03 mmol/L
- blood pressure > 130/85 mmHg
- disturbed glucose tolerance (definded as: fasting glucose between 5.6 en 6.1 mmol/L en 2 hr plasma glucose after oral glucose tolerance test < 11.0 mmol/L).
Exclusion criteria
For all participants:
1. allergy for prednisolone
2. any other contra-indication for prednisolone use.
3. use of glucocorticoids in the past 3 months
4. Recent participation in a clinical trial
5. Blood donation in the past 3 months
6. (history of) alcohol or drugs abuse.
7. Not willing or able to sign the informed consent or not being able to understand the study information
8. smoking
for healthy males:
1. any present disorder
2. any medication use, except for incidental use of analgesic agents
3. 1ste degree relative with type 2 diabetes
4. intensive physical activity (sport) > 2x/week.
For males with the metabolic syndrome:
1. serious (pulmonary, liver, kidney) diseases
2. history of cardiovascular disease (such as MI or CVA)
3. psychiatric disorder
4. depression
5. any condition that interferes with the HPA axis
6. malignancy
7. other condition or usage of medication that may interfere with study endpoints of hypothesis. Eligibility will be assessed in each individual case by the research physician and internist.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-002597-57-NL |
| Other | ISRTCN78149983 (PANTHEON-I) en ISRTCN83991850 (PANTHEON-II) |
| CCMO | NL17711.029.07 |