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van CCT (UK)

van CCT (UK)

Grasping the Underlying Mechanisms of drug Disposition and Receptor Occupancy by Positron-emission tomography Studies (GUMDROPS)

- candidate number28203
- NTR NumberNTR6823
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR14-nov-2017
- Secondary IDs201700716 2017-004236-11
- Public TitleGrasping the Underlying Mechanisms of drug Disposition and Receptor Occupancy by Positron-emission tomography Studies (GUMDROPS)
- Scientific TitleA feasibility study for the use of 11C-telmisartan to quantify individual differences in target-site exposure in diabetes patients
- hypothesisWe 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.
In this clinical feasibility study we will assess radiolabeled telmisartan pharmacokinetic characteristics and determine specific receptor binding, receptor occupancy and optimal scanning time in patients with diabetes and microvascular complications. The main objectives are;
To assess telmisartan target (i.e. receptor) specific binding in vivo
To assess receptor occupancy of telmisartan in vivo
- Healt Condition(s) or Problem(s) studiedDiabetes Mellitus Type 2 (DM type II), Microvascular complications
- Inclusion criteria- Type 2 diabetes - urinary albumin:creatinine ratio (UACR) >3.4 mg/mmol - Age ≥ 40 years <70 years - Written informed consent
- Exclusion criteria- Pregnant women and women of child-bearing potential who are not using reliable contraception
- Use of an ACE inhibitor or angiotensine receptor blocker
- 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)
- Active malignancy
- History of autonomic dysfunction (e.g. history of fainting or clinically significant orthostatic hypotension)
- 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 such 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
- mec approval receivedno
- multicenter trialno
- randomisedyes
- masking/blindingNone
- controlNot applicable
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-jan-2018
- planned closingdate1-jan-2019
- Target number of participants9
- InterventionsOn 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
- Primary outcomeThe 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 outcomeThe secondary study parameters are Glomerular Filtration Rate and Urine Albumin:Creatinine Ratio.
- TimepointsDuring the two study days, for all patients, arterial plasma samples (4 mL) will be taken obtained by an automated sampler after radiotracer drug administration (at time= 0, 5, 10, 15, 20, 35, 50, 65, 80 and 120 minutes), for radiation measurement and PK assessment
24-hour urine will be collected for the measurement of 24-h protein, albumin, sodium, potassium, creatinine, and urea excretion.
- Trial web site
- status[default]
- Sponsor/Initiator University Medical Center Groningen (UMCG)
- Funding
(Source(s) of Monetary or Material Support)
European Foundation for the study of Diabetes (EFSD)
- Publications
- Brief summaryIntervention in the renin-angiotensin-aldosterone-system is a cornerstone treatment to slow renal function decline in diabetes. Accordingly, the guideline suggests that all patients should be treated with an Angiotensin-Converting-Enzym-inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB). Yet, a significant proportion of patients does not respond to ACEi or ARB therapy both in terms of its surrogates like albuminuria and hard renal outcomes. Consequently, a considerable proportion of patients remain at high risk of progressive renal function loss. We hypothesize that the variability in drug response between individuals is the result of between individual variability in drug disposition to target tissues. To test this hypothesis we have synthesized an 11C PET radiotracer of the ARB telmisartan, retaining the original molecular structure. As a first step, we will evaluate 11C-telmisartan receptor specific binding, receptor occupancy, and optimal PET scanning time. As such, in this clinical feasibility study, we will generate essential PET data to optimize the design of a future clinical study in patients with type 2 diabetes and microvascular complications.
- Main changes (audit trail)
- RECORD14-nov-2017 - 29-dec-2017

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