Primary objectives:* To assess telmisartan target (i.e. receptor) specific binding in vivo* To assess receptor occupancy of telmisartan in vivo* To determine optimal scanning time in vivoSecondary objective:* To explore the effect of telmisartan on…
ID
Source
Brief title
Condition
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are dynamic PET data and images and radiation count
measurement, and free plasma concentrations of telmisartan and its metabolite
telmisartan-glucoronide.
Secondary outcome
The secondary study parameters are GFR and UACR.
Background summary
In clinical research as well as in clinical practice identical therapy is
prescribed for all patients. This one-size-fits-all approach may not be
optimal, as it is known that the response to a drug varies between individuals.
Furthermore, we have shown that many drugs used in patients with diabetes
affect multiple cardiovascular/renal risk markers. Again changes in these risk
markers vary between individuals. The mean group results of randomized
controlled trials guide clinical decision making, whereas the individual
variable effects of many drugs in multiple parameters far exceeds the mean drug
effects on a population level. This provides a clear rationale to pay more
attention to studying the individual and to explore the underlying mechanisms
in drug responsiveness in order to tailor optimal therapy for each individual
and unravel determinants of therapy resistance. The ultimate aim of this study
is to determine the underlying mechanisms and determinants of the variability
in drug response. This will lead to the identification of previously unknown
factors that determine therapy response and provide the potential to improve
the treatment of microvascular complications of type 2 diabetes in the future.
We hypothesize that the underlying mechanisms of the varying response in
multiple parameters within an individual can be attributed to variability in
the causal path between drug administration, drug tissue distribution, and
tissue receptor interaction. To test this hypothesis we have synthesized an 11C
PET radiotracer of the ARB telmisartan, retaining the original molecular
structure. This drug class was selected for several reasons. First, it
represents an established renal protective drug class and it is likely that in
the near future telmisartan will form the guideline recommended therapy for
diabetic kidney disease. Importantly, we have shown for ARB that these drugs
have effects on multiple renal risk markers and that individual patients show a
huge variability in response in these multiple renal risk markers (Schievink et
al. 2015). The radiotracer we use, 11C-telmisartan, is structurally identical
to the original compound and pharmacodynamic properties are therefore not
changed. The safety and feasibility of 11C-telmisartan has been shown in
healthy volunteers (Shimizu et al. 2012), although that study did not
specifically calculate an input function and specific binding of the tracer. In
this clinical feasibility study we will assess 11C-telmisartan pharmacokinetic
characteristics and determine specific receptor binding, receptor occupancy and
optimal scanning time in 9 selected patients with diabetes and urinary
albumin:creatinine ratio (UACR) >1.7 mg/mmol.
Study objective
Primary objectives:
* To assess telmisartan target (i.e. receptor) specific binding in vivo
* To assess receptor occupancy of telmisartan in vivo
* To determine optimal scanning time in vivo
Secondary objective:
* To explore the effect of telmisartan on estimated Glomerular filtration Rate
(GFR)
* To explore the effect of telmisartan on Urinary Albumin-creatinine ratio
(UACR)
* To explore differences in drug disposition between UACR-responders and
-non-responders to telmisartan
Study design
A randomized open label feasibility study will be conducted in subjects with
Type II diabetes and UACR >1.7 mg/mmol. The study will consist of a screening
visit, a 4-week run-in phase for subjects on ACEi/ARB treatment and 2 treatment
days.
On the first study day, after IV radiotracer administration, a baseline dynamic
PET scan will be taken to measure selective uptake and accumulation in the
region of interest (ROI; kidney, aorta and part of the liver ). On the second
study day, after 20, 80 or 120 mg oral telmisartan administration, a second IV
radiotracer dose will be administered followed by a second 90-minute dynamic
PET scan (post-drug). In this second scan, receptor binding sites are occupied
by telmisartan, hence the reduction of radiotracer uptake compared to the
baseline scan can be used to determine the receptor occupancy based on the
binding potentials obtained from both scans. In all patients arterial plasma
samples will be taken after radiotracer administration, to quantify radiation
measure and free plasma concentrations of telmisartan and its metabolite
telmisartan-glucoronide.
Study burden and risks
Patients will be subjected to physical examination by the principal
investigator or delegate before inclusion. This physical examination entails a
routine investigation of heart, lungs and abdomen. A pregnancy test will be
performed in female participants of the study. Blood pressure will be monitored
during screening and on both study days. Body weight will be measured during
screening and first study day.
On the first study day, a CT topogram will be performed to optimally position
the individual patient for the dynamic PET scan, e.g. with the kidney, aorta
and part of the liver inside the field of view. At time=0 hours, patients will
receive an intravenous (IV) diagnostic dose of 11C-telmisartan radiotracer
followed by a 90-minute dynamic PET scan (Shimizu et al. 2012). On the second
study day, a CT topogram will be performed to optimally position the individual
patient for the dynamic PET scan, and three dose groups will receive an oral
dose of 20, 80 or 120 mg telmisartan, respectively, at t=0 hours. At the
approximate time of maximal plasma telmisartan concentration (tmax, 1h) a
second IV radiotracer dose will be administered immediately followed by a
second 90-minute dynamic PET scan.
Patients are asked to collect their first morning urine void at three days
before day of screening for measurement of albuminuria. During the two
treatment periods, 24-hour urine will be collected.
At screening and on both study days (prior to dosing) a blood sample will be
drawn by venepuncture for laboratory measurement (10 mL each). During the two
study days, in all patients, arterial plasma samples (10 samples of ~50
microlitre) will be taken after radiotracer administration, to quantify
radiation measure of 11C-telmisartan and its metabolite
11C-telmisartan-glucoronide. For this procedure (after positive hand
functionality test)an anaesthesiologist will place an arterial cannula under
local lidocain anaesthesia. Also, on the second study day, plasma samples (10
samples of 4 mL) will be taken to quantify unlabelled plasma concentrations of
telmisartan and its metabolite telmisartan-glucoronide for the purpose of
determining the pharmacokinetic parameters (e.g clearance and volume of
distribution) for each subject. Over the entire duration of the study,
approximately 23 samples will be taken per subject, totalling up to 71 mL blood.
There is no direct benefit to the patient*s health be expected from this study.
Participation in the study is on a free-will base. Patients will receive
restitution of all costs of transportation. Patients will not receive priority
for treatment of other diseases in the clinic during this study. Participation
in the proposed study is accompanied with only minor risks, if any at all.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
Main inclusion criteria are;
- Type 2 diabetes
- urinary albumin:creatinine ratio (UACR)> 1.7 mg/mmol
- Age * 45 years * 70 years
- Written informed consent
Exclusion criteria
Main exclusion criteria are;
- Pregnant women and women of child-bearing potential who are not using reliable contraception;
- Cardiovascular disease: myocardial infarction, angina pectoris, percutanous transluminal coronary angioplasty, coronary artery bypass grafting, stroke, heart failure (NYHA I-IV) < 6 months before inclusion;
- History of renal artery stenosis;
- History of hypersensitivity to telmisartan;
- History of autonomic dysfunction (e.g. history of fainting or clinically significant orthostatic hypotension);
- Uncontrolled blood pressure (office blood pressure * 160/ 100 mmHg);
- Participation in any clinical investigation within 3 months prior to initial dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations.;
- Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing;
- History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of drug or alcohol abuse as indicated by the laboratory assays conducted during the screening;
- Lithium use;
- Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following:;
o Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
o Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months;
o Pancreatic injury or pancreatitis within the last six months;
o Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at inclusion visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-004236-11-NL |
| CCMO | NL63683.042.17 |