Clinical trial NCT02669563: An Exploratory Study of 18F-Labeled Hydroxyphenethylguanidines in Heart Failure Patients
Official title: An Exploratory Study of 18F-Labeled Hydroxyphenethylguanidines in Heart Failure Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Cardiomyopathy
Lead sponsor: University of Michigan
Sponsor class: OTHER
First posted: 2016-02-01
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: The main goal of this study is to test two new radioactive drugs, 4-\[18F\]fluoro-meta-hydroxyphenethylguanidine (\[18F\]4F-MHPG) and 3-\[18F\]fluoro-para-hydroxyphenethylguanidine (\[18F\]3F-PHPG) in human subjects with congestive heart failure.

Evaluations of these imaging agents will include their uptake in heart, lungs and liver, their metabolic breakdown in blood, and their kinetics in the heart. Based on these studies, the better of the two drugs will be chosen for further studies in patients with heart disease. After the better compound is chosen, additional measures of its imaging properties, metabolism and pharmacokinetics will be done in subjects with heart failure.

Detailed description: The human heart contains many nerve fibers that are involved in controlling the heart's pumping function. Several heart diseases have been shown to damage the nerves in the heart. Studies have shown that damage to the heart nerves may be a cause of death in patients with diseases like heart failure or diabetes.

Two new radioactive drugs been developed at the University of Michigan for taking pictures of the nerve fibers in the heart using a medical imaging method called positron emission tomography (PET).

These two drugs are 4-\[18F\]fluoro-meta-hydroxyphenethylguanidine (\[18F\]4F-MHPG) and 3-\[18F\]fluoro-para-hydroxyphenethylguanidine (\[18F\]3F-PHPG). Initial PET imaging studies in normal human subjects (see NCT 02385877) have shown that \[18F\]4F-MHPG and \[18F\]3F-PHPG are each able to provide a detailed regional map of the distribution of nerve fibers in the heart.

In Stage 1 of this study, enrolled subjects with heart failure will undergo PET studies with \[18F\]4F-MHPG and \[18F\]3F-PHPG to allow direct comparison of the imaging properties, metabolism and pharmacokinetics of the two radioactive drugs in the same subjects.

A third PET scan with \[13N\]ammonia will be done to assess resting blood flow in different areas of the heart. The results of these studies will be used to select the better of the two tracers for further study in patients with heart disease.

In Stage 2 of the study, enrolled subjects with heart failure will undergo additional PET evaluations of the imaging properties and kinetics of the cardiac nerve tracer selected in Stage 1 (either \[18F\]4F-MHPG or \[18F\]3F-PHPG).

Again, a PET scan with \[13N\]ammonia will also be performed to measure regional resting blood flow. A third PET scan with \[11C\]meta-hydroxyephedrine (\[11C\]HED), an established cardiac nerve tracer, will also be done to address research questions related to the mechanisms involved in the retention of \[18F\]4F-MHPG and \[18F\]3F-PHPG inside the nerve of the heart.

For all study stages, subjects will be assessed during the scan for heart rate, blood pressure and oxygen saturation. Patients will be followed at 30 min, 24 hours and 30 hours regarding any adverse events or serious adverse events they might have experienced. These will be reported as required.

Eligibility criteria: Inclusion Criteria:

* Age 18-80y
* Cardiomyopathy (ischemic and non-ischemic)
* Left ventricular ejection fraction (LVEF) \< 35%
* Clinically appropriate referral for surgical implantation of an implantable cardiodefibrillator (ICD) for primary prevention of sudden cardiac death
* Not claustrophobic
* Ability to lie flat for 90 min
* Give informed consent

Exclusion Criteria:

* Revascularization such as the placement of a stent or balloon angioplast in the preceding 40 days
* Renal dysfunction with eGFR \< 50 mL/min/1.73 m2
* Currently taking medications or drugs that may alter PET scans of cardiac sympathetic nerve terminals with these tracers, including any of the following:

  * Tricyclic antidepressants, which inhibit the norepinephrine transporter, such as amitriptyline, desipramine, imipramine, etc.
  * Cold medications (e.g., Sudafed®, as they may contain sympathomimetic amines, such as phenylephrine, phenylpropanolamine, pseudoephedrine, etc.)
  * Nasal decongestants (some use phenylephrine as the active agent)
  * Cocaine (which inhibits the norepinephrine transporter)
  * Tetrabenazine (Xenazine, which inhibits VMAT2 transporters on vesicles inside neurons)
  * Monoamine oxidase inhibitors (MAOI)
  * Some antihypertensive drugs (reserpine, labetalol, α-methyldopa, and clonidine)
* Pregnancy or lactation
* Claustrophobia
* Inability to lie flat for 90 min

Primary outcomes:
measure: Composite measures based on radiotracer tissue uptake ratios (heart-to-lung ratio, heart-to-liver ratio, heart-to-blood ratio) and rates of metabolism in plasma (half-time, minutes) of [18F]4F-MHPG and [18F]3F-PHPG in patients with heart failure.
timeFrame: 12 months
Secondary outcomes:
measure: Quantitative measures of regional cardiac sympathetic nerve density in patients with heart failure using tracer kinetic analyses.
timeFrame: 36 months
measure: Number of study participants with adverse events as a measure of safety and tolerability following intravenous administration of [18F]4F-MHPG or [18F]3F-PHPG.
timeFrame: Up to 30 days after [18F]4F-MHPG or [18F]3F-PHPG injection.
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
Study officials:
affiliation: University of Michigan
name: David M Raffel, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Raffel DM, Crawford TC, Jung YW, Koeppe RA, Gu G, Rothley J, Frey KA. Quantifying cardiac sympathetic denervation: first studies of 18F-fluorohydroxyphenethylguanidines in cardiomyopathy patients. Eur J Nucl Med Mol Imaging. 2022 Jan;49(2):619-631. doi: 10.1007/s00259-021-05517-7. Epub 2021 Aug 13.