An Exploratory Study of 18F-Labeled Hydroxyphenethylguanidines in Heart Failure Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Exploratory Study of 18F-Labeled Hydroxyphenethylguanidines in Heart Failure Patients

Conditions
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Cardiomyopathy

Intervention / Treatment
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* Drug: [18F]4F-MHPG
* Drug: [18F]3F-PHPG
* Drug: [13N]ammonia
* Drug: [11C]HED


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1<br>Subjects (n = 4 to 10) will be injected once with 20 mCi of [13N]ammonia and receive a 20 minute PET scan. They will then be injected once with 6.5 mCi of one of the two new drugs under study, [18F]4F-MHPG or [18F]3F-PHPG, and receive a 60 minute PET scan. On a second visit to the clinic, subjects will be injected once with 6.5 mCi of [18F]3F-PHPG or [18F]4F-MHPG (whichever was not used for the first visit) and receive a 60 minute PET scan. | Drug: [18F]4F-MHPG<br>* IV injection of [18F]4F-MHPG<br>* Other names: 4-[18F]fluoro-meta-hydroxyphenethylguanidine;Drug: [18F]3F-PHPG<br>* IV injection of [18F]3F-PHPG<br>* Other names: 3-[18F]fluoro-para-hydroxyphenethylguanidine;Drug: [13N]ammonia<br>* IV injection of [13N]ammonia<br>* Other names: [13N]NH3;|
| Experimental: Stage 2<br>Subjects (n = 20 to 26) will be injected with 20 mCi of [13N]ammonia and receive a 20 minute PET scan. They will then be injected once with 6.5 mCi of [18F]4F-MHPG or [18F]3F-PHPG (whichever was chosen based on Stage 1 of the study) and receive a 60 minute PET scan. On a second visit to the clinic, subjects will be injected once with 20 mCi of [11C]HED and receive a 40 minute scan. | Drug: [18F]4F-MHPG<br>* IV injection of [18F]4F-MHPG<br>* Other names: 4-[18F]fluoro-meta-hydroxyphenethylguanidine;Drug: [18F]3F-PHPG<br>* IV injection of [18F]3F-PHPG<br>* Other names: 3-[18F]fluoro-para-hydroxyphenethylguanidine;Drug: [13N]ammonia<br>* IV injection of [13N]ammonia<br>* Other names: [13N]NH3;Drug: [11C]HED<br>* IV injection of [11C]HED<br>* Other names: [11C]meta-hydroxyephedrine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | These data on the relative imaging properties and metabolism of [18F]4F-MHPG and [18F]3F-PHPG in heart failure patients will be used to select the lead radiotracer for further clinical development. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative measures of regional cardiac sympathetic nerve density in patients with heart failure using tracer kinetic analyses. | Robust metrics of regional sympathetic nerve density in the heart obtained using tracer kinetic analysis techniques, including compartmental modeling and Patlak graphical analysis, will contribute to selection of a lead radiotracer. | 36 months | 
| 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. | Assessments of the safety of [18F]4F-MHPG and [18F]3F-PHPG as PET radiopharmaceuticals for routine studies in patients. | Up to 30 days after [18F]4F-MHPG or [18F]3F-PHPG injection. |