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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04218968
Recruitment Status : Enrolling by invitation
First Posted : January 6, 2020
Last Update Posted : August 26, 2022
Sponsor:
Information provided by (Responsible Party):
Michele Tagliati, MD, Cedars-Sinai Medical Center

Tracking Information
First Submitted Date  ICMJE December 26, 2019
First Posted Date  ICMJE January 6, 2020
Last Update Posted Date August 26, 2022
Actual Study Start Date  ICMJE December 30, 2019
Estimated Primary Completion Date December 30, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE 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  ICMJE Cardiac Changes in Early Parkinson's Disease: A Follow up Study
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • REM Sleep Behavior Disorder
  • Pre-motor Parkinson Disease
  • Symptomatic Parkinson Disease
Intervention  ICMJE 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  ICMJE Experimental: carvedilol therapy
Intervention: Drug: Carvedilol
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: January 2, 2020)
15
Original Actual Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2025
Estimated Primary Completion Date December 30, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04218968
Other Study ID Numbers  ICMJE 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  ICMJE
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  ICMJE Cedars-Sinai Medical Center
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Cedars-Sinai Medical Center
Verification Date August 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP