68Ga-NODAGA-exendin-4 PET/CT in patients with AHH - a prospective comparative evaluation of preoperative imaging

We hypothesize that we can improve the sensitivity and specificity of
pre-operative imaging for the localization of insulin producing pancreatic
neuroendocrine tumours (IPPNET) in patients with adult endogenous
hyperinsulinemic hypoglycemia (AHH) by using a novel imaging compound which
targets the glucagon-like peptide-1 receptor (GLP-1R); 68Ga-NODAGA-exendin-4

The primary objective is to compare GLP-1R-imaging to standard imaging
techniques now used in pre-operative imaging of patients with AHH. All patients
will undergo the standard imaging procedures of the specific centre and in
addition we will perform a 68Ga-NODAGA-exendin 4 PET/CT. The results of the
GLP-1R-imaging, in respect to sensitivity, specificity and diagnostic odds
ratio for location and size of the IPPNET will be compared to the standard
imaging modalities.
GLP-1- and sst-2-receptor expression and autoradiography of surgical specimens
will be compared to results of quantitative imaging in order to determine the
interdependency of radiotracer uptake, beta cell mass and receptor expression.

Multicenter prospective imaging (phase II) study in which we will compare
GLP-1R-imaging with the standard imaging protocols for pre-operative imaging in
patients with AHH.

All individuals will undergo physical examination and blood sampling for
standard laboratory parameters. In addition, all patients will undergo the
current standard preoperative care (68Ga-DOTATOC PET/CT or 68Ga-DOTATATE PET/CT
combined with conventional imaging (endoscopic ultrasound (EUS) and triple
phase CT or MRI) and in some centers 18F-DOPA PET and/or 11C-5-HTP PET. At the
next visit 4-7 µg 68Ga-NODAGA-Exendin-4 will be administered intravenously and
scanning will be performed 1 hour after injection of the tracer. Blood pressure
and blood glucose levels will be measured just before and 15, 30, 60 and 120
minutes after injection of the radiopharmaceutical. Injection of the
radiolabeled tracer may result in nausea and headache as has been reported for
(very high doses (10-100µg) of) Byetta® in therapy studies. In addition, a
decrease of blood glucose levels (0.8 - 2.1 mmol/l have been described after
injection of 8 - 14 µg 111In-DTPA-exendin-4 in patients with AHH (Christ E. et
al. Lancet Diabetes Endocrinol 2013;1:115-22). Importantly, regular monitoring
of glucose concentrations injection led to no serious episodes of
hypoglycaemia. Therefore, no side-effects are anticipated with injection of 4-7
µg of radiolabeled exendin, although patients will be closely monitored.
Furthermore, glucose infusion (10%) will be administered of needed.
The expected radiation exposure will not exceed 5,5 mSv for
68Ga-NODAGA-exendin-4 PET/CT. In relation to the expected benefit in diagnostic
imaging by improving preoperative non-invasive localization of foci in AHH with
higher sensitivity and specificity and the resulting impact on AHH treatment,
this additional radiation exposure is acceptable. Especially in view of the
expected replacement of several other imaging procedures by GLP-1R scanning in
the future, the radiation burden for future AHH patients will significantly be
reduced.