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

REM Sleep Behavior Disorder Clinical Trial

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04218968
• Other study ID #: Study00000349
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: December 30, 2019
• Est. completion date: December 30, 2025

Study information

• Verified date: October 2023
• Source: Cedars-Sinai Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 15
• Est. completion date: December 30, 2025
• Est. primary completion date: December 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Mental Disorders
• Parkinson Disease
• Parkinson Disease, Secondary
• Pre-motor Parkinson Disease
• REM Sleep Behavior Disorder
• Symptomatic Parkinson Disease

Intervention

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.

Locations

Country	Name	City	State
United States	Michele L Lima Gregorio	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Cedars-Sinai Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	Diagnosis of PD or other synucleinopathies by the end of 3 years in the study population	Clinical evaluation	Every year for 3 years
Secondary	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
Secondary	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
Secondary	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