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

Primary Purpose

REM Sleep Behavior Disorder, Pre-motor Parkinson Disease, Symptomatic Parkinson Disease

Status
Enrolling by invitation
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Carvedilol
Sponsored by
Cedars-Sinai Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for REM Sleep Behavior Disorder

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Michele L Lima Gregorio

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

carvedilol therapy

Arm Description

Twice daily oral doses of adrenergic blocker 12.5 mg or 25mg, according to patient tolerability.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Diagnosis of PD or other synucleinopathies by the end of 3 years in the study population
Clinical evaluation
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
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
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.

Full Information

First Posted
December 26, 2019
Last Updated
October 16, 2023
Sponsor
Cedars-Sinai Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04218968
Brief Title
Cardiac Changes in Early Parkinson's Disease: A Follow up Study
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
December 30, 2019 (Actual)
Primary Completion Date
December 30, 2025 (Anticipated)
Study Completion Date
December 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Cedars-Sinai Medical Center

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
REM Sleep Behavior Disorder, Pre-motor Parkinson Disease, Symptomatic Parkinson Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
carvedilol therapy
Arm Type
Experimental
Arm Description
Twice daily oral doses of adrenergic blocker 12.5 mg or 25mg, according to patient tolerability.
Intervention Type
Drug
Intervention Name(s)
Carvedilol
Intervention Description
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.
Primary Outcome Measure Information:
Title
Changes in 123I-Ioflupane uptake - DATscan
Description
Changes in 123I-Ioflupane uptake, as measured by specific binding ratio (SBR), between baseline, year one, year two and year three.
Time Frame
Every year for three years
Secondary Outcome Measure Information:
Title
Diagnosis of PD or other synucleinopathies by the end of 3 years in the study population
Description
Clinical evaluation
Time Frame
Every year for 3 years
Title
Changes in 123I-MIBG late H/M
Description
Changes in 123I-MIBG reuptake, as measured by late H/M ratio, between baseline and every six months for three years
Time Frame
Every 6 months for 3 years
Title
Changes in 123I-MIBG WR rate
Description
Changes in 123I-MIBG WR reuptake, as measured by WR rate, between baseline and every six months for three years
Time Frame
Every 6 months for 3 years
Title
Sensitivity and specificity of DAT Scan compared to MIBG in predicting RBD conversion to PD/other synucleinopathies
Description
Changes in 123I-Ioflupane uptake, as measured by specific binding ratio (SBR), between baseline, year one, year two and year three.
Time Frame
Every year for3 years
Other Pre-specified Outcome Measures:
Title
MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
Description
MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III changes from OFF medication between baseline and every 6 months for three years
Time Frame
Every 6 months for 3 years
Title
Non-Motor Symptoms Scale (NMSS) changes
Description
Non-Motor Symptoms Scale (NMSS) changes between baseline and every 6 months for three years
Time Frame
Every 6 months for 3 years
Title
Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT)
Description
Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT) changes between baseline and every 6 months for three years
Time Frame
Every 6 months for 3 years
Title
REM sleep Behavior Disorder Screening questionnaire (RBDSQ)
Description
REM sleep Behavior Disorder Screening questionnaire (RBDSQ) changes between baseline and every 6 months for three years
Time Frame
Every 6 months for 3 years
Title
University of Pennsylvania Smell Identification Test (UPSIT)
Description
University of Pennsylvania Smell Identification Test (UPSIT) changes between baseline and every 6 months for three years
Time Frame
Every 6 months for 3 years
Title
Functional constipation score changes
Description
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
Time Frame
Every 6 months for 3 years
Title
Color vision changes
Description
Color vision changes, as assessed using HRR Pseudoisochromatic Plates, between baseline and every 6 months for three years
Time Frame
Every 6 months for 3 years
Title
Central and peripheral insulin resistance changes
Description
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
Time Frame
Every 6 months for 3 years
Title
Differences in integrity of pigmented neurons in the locus coeruleus and substantia nigra between baseline, year one, year two and year three
Description
This outcome will be measured by the content of neuromelanin, a product of cathecolamine metabolism in LC and SN.
Time Frame
3 years
Title
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)
Description
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
Time Frame
3 years
Title
Heart Rate Variability (HRV) changes between baseline and every 6 months for three years
Description
Beat-to-beat intervals will be registered to assess sympatho-vagal balance every 6 months for 3 years
Time Frame
Every 6 months for 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michele L Lima Gregorio, MD, FAAN
Organizational Affiliation
Cedars-Sinai Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Michele L Lima Gregorio
City
Los Angeles
State/Province
California
ZIP/Postal Code
90046
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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