UTSW HP [13-C] Pyruvate Injection in HCM (HPHCM)

• ClinicalTrials.gov Identifier: NCT03057002
• Recruitment Status: Suspended
• First Posted: February 17, 2017
• Last Update Posted: March 5, 2021
• Sponsor: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Vlad Zaha, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

In this study the investigators propose to detect early mitochondrial metabolic changes in the heart in patients with a positive genotype and phenotype for Hypertrophic Cardiomyopathy (HCM) using a novel hyperpolarized [1-13C]pyruvate Magnetic Resonance Imaging (MRI) methodology.

Condition or disease	Intervention/treatment
Cardiomyopathy, Hypertrophic	Drug: Hyperpolarized 13C-Pyruvate

Detailed Description:

In this study the investigators propose to detect early mitochondrial metabolic changes in the heart in patients with a positive genotype and phenotype for HCM using a novel hyperpolarized [1-13C]pyruvate MRI methodology. Carbon-13 is a stable isotope (not radioactive) that makes up approximately 1.1% of all natural carbon. Carbon-13 has a non-zero spin quantum number that allows the investigation of carbon containing substances using magnetic resonance. However, compared with other analytical methods, carbon-13 magnetic resonance has been limited by an intrinsically low sensitivity [2}.

Recent experimental studies suggest that altered energy substrate metabolism may precede structural changes in myocardial hypertrophy. A better understanding of the myocardial metabolic changes in HCM is important, as the elucidation of such changes may precede the clinical development of myocardial fibrosis and malignant arrhythmias. Hyperpolarized [1-13C]pyruvate and its cellular metabolic flux can be assessed with a more than 10,000-fold higher sensitivity compared to traditional methods. The aim of this pilot study is to test the hypothesis that patients with HCM present focal alterations in myocardial hyperpolarized [1-13C]pyruvate flux.

To achieve this aim the investigators will assess myocardial metabolic changes in HCM subjects with a positive HCM genotype and phenotype (n=5) and in healthy control subjects (n=5) who are matched for age, sex, and Body Mass Index (BMI). Total target enrollment will be set at 15 subjects to allow for attrition and screen failures.

Cardiac function and structure will be evaluated with MRI (proton imaging) before and after contrast administration. Then myocardial metabolism will be assessed utilizing MRS (carbon spectroscopy) before and after intravenous injection with hyperpolarized [1-13C]pyruvate. The study agent, hyperpolarized [1-13C]pyruvate, will be administered under a Food and Drug Administration (FDA) Investigational New Drug (IND), currently in review process, PI Dr. Craig Malloy.

Human preliminary data are essential to secure larger scale funding required for clinical studies. The identification of mitochondrial metabolic changes preceding replacement fibrosis and malignant arrhythmias may generate a paradigm shift to early detection and more targeted treatment of HCM with potentially improved clinical outcomes. Cardiac focused applications at the Advanced Imaging Research Center, genetic disease diagnosis at the Eugene McDermott Center for Human Genetics and the development of a dedicated HCM Clinic at the UT Southwestern Medical Center offer today a unique opportunity to lead globally the translational scientific efforts in this field.

Study Design

• Study Type: Observational
• Estimated Enrollment: 10 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Detection of Regional Myocardial Metabolic Changes in Patients With Hypertrophic Cardiomyopathy Using Hyperpolarized Carbon 13 Magnetic Resonance Spectroscopic Imaging (MRSI)
• Actual Study Start Date: May 1, 2018
• Estimated Primary Completion Date: December 30, 2022
• Estimated Study Completion Date: December 30, 2022

Groups and Cohorts

Group/Cohort	Intervention/treatment
HCM Group; HCM patients will be observed for myocardial hyperpolarized 13C-pyruvate flux during magnetic resonance spectroscopic imaging.	Drug: Hyperpolarized 13C-Pyruvate; All subjects will be observed for myocardial hyperpolarized [1-13C]pyruvate flux during magnetic resonance spectroscopic imaging.; Other Name: HP [1-13C]pyruvate
Control Group; Healthy control subjects will be observed for myocardial hyperpolarized 13C-pyruvate flux during magnetic resonance spectroscopic imaging.	Drug: Hyperpolarized 13C-Pyruvate; All subjects will be observed for myocardial hyperpolarized [1-13C]pyruvate flux during magnetic resonance spectroscopic imaging.; Other Name: HP [1-13C]pyruvate

Outcome Measures

Primary Outcome Measures :

1. Hyperpolarized [1-13C]pyruvate flux [ Time Frame: Screening (Baseline) and 1 day of Study Visit ]
   Measurement of change in myocardial hyperpolarized [1-13C]pyruvate flux during Magnetic Resonance Spectroscopic Imaging.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

5 Hypertrophic cardiomyopathy (HCM) Patients and 5 Healthy Controls

Criteria

Inclusion Criteria for Control Subjects:

• Subjects who are 18 through 60 years of age.
• Subjects who have the ability to understand and the willingness to sign a written informed consent.
• While all races and ethnicities will be included, subjects must be able to read and speak the English language. Once the protocol is established, Spanish-speaking participants will be included.
• Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Inclusion Criteria for HCM subjects:

• Definitive diagnosis of HCM by genotype and imaging which demonstrates abnormal Left Ventricular (LV) wall thickness in the absence of other cause (Unexplained maximal wall thickness >15 mm in any myocardial segment [6-8]).
• Subjects who are 18 through 60 years of age.
• Subjects who have the ability to understand and the willingness to sign a written informed consent.
• While all races and ethnicities will be included, subjects must be able to read and speak the English language. Once the protocol is established, Spanish-speaking participants will be included.
• Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Exclusion criteria for Controls and HCM Subjects:

• Subjects who are receiving any other investigational agents.
• Intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled chronic diseases such as hypertension, lung disease, liver disease, kidney disease, diabetes, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Subjects who are taking thyroid hormone replacements, have a history of alcohol abuse or illicit drug use.
• Subjects who have contraindication to contrast enhanced MRI examination.

Contraindications to MRI examinations include:

• Medically unstable
• Heart failure
• Severe Left Ventricular Outflow Tract (LVOT) obstruction
• Unstable angina
• Child bearing
• Lactating
• Any contraindication per MRI Screening Form including
• Implants contraindicated at 3Tesla, pacemakers
• Implantable Cardioverter Defibrillator (ICD)
• Claustrophobia
• Since each subject is receiving a gadolinium based contrast agent intravenously:
• eGFR ≤ 30 mL/min/1.73m2
• Sickle cell disease
• Hemolytic anemia

Contacts and Locations

Locations

United States, Texas

UT Southwestern Medical Center - Advanced Imaging Research Center

Dallas, Texas, United States, 75390

Sponsors and Collaborators

University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Vlad G Zaha, MD, PhD; Advanced Imaging Research Center

More Information

• Responsible Party: Vlad Zaha, Assistant Professor, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03057002
• Other Study ID Numbers: STU 102016-046
• First Posted: February 17, 2017
• Last Update Posted: March 5, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy; Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Heart Valve Diseases