Cardiac Changes in Early Parkinson's Disease: A Follow up Study

The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease: A Follow up Study

The purpose of this study is to investigate the long-term effects of treatment with the adrenergic blocker carvedilol on serial DaTscan, a dopamine transporter (DAT) single photon emission computerized tomography (SPECT) imaging technique in a population of subjects with defined pre-motor Parkinson's disease risks (i.e., REM sleep Behavior Disorder (RBD) and at least one among hyposmia, constipation, depression and color vision abnormality) and abnormal 123I-Metaiodobenzylguanidine (MIBG) scintigraphy.

Study Overview

• Status: Enrolling by invitation
• Conditions: REM Sleep Behavior Disorder; Symptomatic Parkinson Disease; Pre-motor Parkinson Disease
• Intervention / Treatment: Drug: Carvedilol

Detailed Description

Primary procedures in this study are MIBG scan, DAT scan, Neuromelanin Magnetic Resonance Imaging (NM-MRI), and carvedilol treatment. Subjects will return for research visits and imaging tests every six months for three years. We hypothesize that the rate of decline in DAT scan123I-Ioflupane uptake will be slower in subjects who have received the adrenergic blocker carvedilol, resulting in a decreased clinical phenoconversion rate to parkinsonism. If this is true, it might create a considerable window of opportunity for treatment with adrenergic blockers - or similar compounds able to reduce Sympathetic Nervous System (SNS) hyperactivity - which may result in long-term benefits such as delaying the neurodegenerative process and the onset of neurological symptoms.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90046
      • Michele L Lima Gregorio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Enrolled in the study "The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease" (Pro#00053136)
• Capacity to give informed consent

Exclusion Criteria:

• Secondary Parkinsonism, including tardive
• Concurrent dementia defined by a score lower than 22 on the MoCA
• Concurrent severe depression defined by a BDI fast screen score greater than 13

• Comorbidities related to SNS hyperactivity

  • Heart failure (LVEF <45%)
  • Recent myocardial revascularization (<12 weeks)
  • Hypertension (SBP>150mmHg or DBP>100mmHg)
  • Chronic Atrial fibrillation
  • Concurrent Use of Beta-adrenergic antagonist
  • Diabetes mellitus
  • COPD
  • Untreated Sever Sleep Apnea; Apnea-Hypopnea Index (AHI) > 30/h.
  • Severely reduced kidney function (Glomerular Filtration Rate<30ml/min)

• Contraindications to the use of carvedilol

  • Asthma or bronchospasm
  • Recent myocardial infarction (<48 h)
  • Ongoing unstable angina
  • Cardiogenic shock or prolonged hypotension
  • Second or Third-Degree AV block
  • Significant valvular aortic stenosis
  • Obstructive cardiomyopathy, or constrictive pericarditis
  • Resting Heart Rate (RHR)< 45 Or Bradycardia (HR<60) with at least one of the following symptoms; Lightheadedness, dizziness, weakness, Altered mental status, Shortness of breath, Pre-Syncope, Syncope, Sick Sinus Syndrome, Stroke within the past 1 month, Severe Hepatic Dysfunction
• Allergy/hypersensitivity to iodine or study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: carvedilol therapy; Twice daily oral doses of adrenergic blocker 12.5 mg or 25mg, according to patient tolerability.

Drug: Carvedilol; Primary procedures in this study are MIBG scan, DAT scan, NM-MRI, and carvedilol titration. Subjects will return for research visits and imaging every six months for three years. The investigators hypothesize that the rate of decline in DAT scan123I-Ioflupane uptake will be slower in subjects who have received the adrenergic blocker carvedilol, resulting in a decreased clinical phenoconversion rate to parkinsonism.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in 123I-Ioflupane uptake - DATscan	Changes in 123I-Ioflupane uptake, as measured by specific binding ratio (SBR), between baseline, year one, year two and year three.	Every year for three years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnosis of PD or other synucleinopathies by the end of 3 years in the study population	Clinical evaluation	Every year for 3 years
Changes in 123I-MIBG late H/M	Changes in 123I-MIBG reuptake, as measured by late H/M ratio, between baseline and every six months for three years	Every 6 months for 3 years
Changes in 123I-MIBG WR rate	Changes in 123I-MIBG WR reuptake, as measured by WR rate, between baseline and every six months for three years	Every 6 months for 3 years
Sensitivity and specificity of DAT Scan compared to MIBG in predicting RBD conversion to PD/other synucleinopathies	Changes in 123I-Ioflupane uptake, as measured by specific binding ratio (SBR), between baseline, year one, year two and year three.	Every year for3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in integrity of pigmented neurons in the locus coeruleus and substantia nigra between baseline, year one, year two and year three	This outcome will be measured by the content of neuromelanin, a product of cathecolamine metabolism in LC and SN.	3 years
Correlation between changes in integrity of pigmented neurons of substantia nigra as measured by neuromelanin-sensitive magnetic resonance imaging (MRI) and 123I-Ioflupane uptake as measured by Dopamine Transporter Imaging (DAT scan)	These measurements will be aggregated to calculate the correlation between changes in neuromelanin content as measured by NM-MRI and dopamine content as measured by DAT scan	3 years
MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III	MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III changes from OFF medication between baseline and every 6 months for three years	Every 6 months for 3 years
Non-Motor Symptoms Scale (NMSS) changes	Non-Motor Symptoms Scale (NMSS) changes between baseline and every 6 months for three years	Every 6 months for 3 years
Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT)	Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT) changes between baseline and every 6 months for three years	Every 6 months for 3 years
REM sleep Behavior Disorder Screening questionnaire (RBDSQ)	REM sleep Behavior Disorder Screening questionnaire (RBDSQ) changes between baseline and every 6 months for three years	Every 6 months for 3 years
University of Pennsylvania Smell Identification Test (UPSIT)	University of Pennsylvania Smell Identification Test (UPSIT) changes between baseline and every 6 months for three years	Every 6 months for 3 years
Color vision changes	Color vision changes, as assessed using HRR Pseudoisochromatic Plates, between baseline and every 6 months for three years	Every 6 months for 3 years
Central and peripheral insulin resistance changes	Peripheral Insulin Resistance (IR) will be defined by testing for fasting plasma insulin (FPI), fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). HOMA index will be calculated by the formula: HOMA-IR = (FPI x FPG)/405 . A cutoff HOMA index of 2.0, equivalent to <50% sensitivity, will be used to define IR. Subjects were considered to have IR if they either had a HOMA≥2.0 and/or HbA1c≥5.7 . In addition, measures of insulin sensitivity in neuronal-origin enriched plasma EVs (central IR) will be used to test the association of changes in such sensitivity to changes in MIBG uptake and clinical scores from baseline and every 6 months. For that purpose, plasma samples will be collected and stored and -80oC to allow for isolation of neuronal origin EVs at the completion of the study	Every 6 months for 3 years
Heart Rate Variability (HRV) changes between baseline and every 6 months for three years	Beat-to-beat intervals will be registered to assess sympatho-vagal balance every 6 months for 3 years	Every 6 months for 3 years
Functional constipation score changes	Functional constipation score changes between baseline and every 6 months for three years. The total score has a range of 0 to 12, with scores > 4 identifying functional constipation	Every 6 months for 3 years

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Investigators: Principal Investigator: Michele L Lima Gregorio, MD, FAAN, Cedars-Sinai Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2019
• Primary Completion (Estimated): December 30, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: December 26, 2019
• First Submitted That Met QC Criteria: January 2, 2020
• First Posted (Actual): January 6, 2020

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sleep Wake Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parasomnias; REM Sleep Parasomnias; Parkinson Disease; Mental Disorders; REM Sleep Behavior Disorder; Parkinson Disease, Secondary; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Protective Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol
• Other Study ID Numbers: Study00000349

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No