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

• ClinicalTrials.gov Identifier: NCT04218968
• Recruitment Status: Enrolling by invitation
• First Posted: January 6, 2020
• Last Update Posted: August 26, 2022
• Sponsor: Cedars-Sinai Medical Center
• Information provided by (Responsible Party): Michele Tagliati, MD, Cedars-Sinai Medical Center

Tracking Information

• First Submitted Date: December 26, 2019
• First Posted Date: January 6, 2020
• Last Update Posted Date: August 26, 2022
• Actual Study Start Date: December 30, 2019
• Estimated Primary Completion Date: December 30, 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: January 2, 2020): 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 ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 2, 2020)

• Diagnosis of PD or other synucleinopathies by the end of 3 years in the study population [ Time Frame: 3 years ]
• 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 ]
• Changes in 123I-MIBG reuptake, as measured by WR reduction, between baseline and every six months for three years [ Time Frame: Every 6 months for 3 years ]
• Sensitivity and specificity of DAT Scan compared to MIBG in predicting RBD conversion to PD/other synucleinopathies [ Time Frame: 3 years ]

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: January 2, 2020)

• 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 ]
• Non-Motor Symptoms Scale (NMSS) changes between baseline and every 6 months for three years [ Time Frame: Every 6 months for 3 years ]
• 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 ]
• 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 ]
• 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 ]
• Functional constipation score changes between baseline and every 6 months for three years [ Time Frame: Every 6 months for 3 years ]
• 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 ]
• Central and peripheral insulin resistance changes between baseline and every 6 months for three years [ Time Frame: Every 6 months for 3 years ]
  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
• Differences in integrity of pigmented neurons in the locus coeruleus and substantia nigra between baseline, year one, year two and year three [ Time Frame: 3 years ]
  This outcome will be measured by the content of neuromelanin, a product of cathecolamine metabolism in LC and SN.
• 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) [ Time Frame: 3 years ]
  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
• Heart Rate Variability (HRV) changes between baseline and every 6 months for three years [ Time Frame: Every 6 months for 3 years ]

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• 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

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 123. I-Metaiodobenzylguanidine (MIBG) scintigraphy.

Primary procedures in this study are MIBG scan, DAT scan, Neuromelanin Magnetic Resonance Imaging (NM-MRI), and carvedilol titration. Subjects will return for research visits and imaging 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• REM Sleep Behavior Disorder
• Pre-motor Parkinson Disease
• 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.

Study Arms

Experimental: carvedilol therapy

Intervention: Drug: Carvedilol

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Enrolling by invitation
• Estimated Enrollment (submitted: January 2, 2020): 15
• Original Actual Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2025
• Estimated Primary Completion Date: December 30, 2025 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04218968
• Other Study ID Numbers: Study00000349
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Michele Tagliati, MD, Cedars-Sinai Medical Center
• Original Responsible Party: Michele Tagliati, MD, Cedars-Sinai Medical Center, Professor and Vice Chairman
• Current Study Sponsor: Cedars-Sinai Medical Center
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Cedars-Sinai Medical Center
• Verification Date: August 2022