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Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease (Protocol 53136)

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ClinicalTrials.gov Identifier: NCT03775096
Recruitment Status : Recruiting
First Posted : December 13, 2018
Last Update Posted : August 26, 2022
Information provided by (Responsible Party):
Michele Tagliati, MD, Cedars-Sinai Medical Center

Brief Summary:

REM Behavior Sleep Disorder (RBD) is a sleep disorder causing people to 'act out' their dreams. A high percentage of individuals with idiopathic RBD (iRBD) are known to develop conditions affecting the neurons in the brain such as Parkinson's disease (PD). Based on the increased risk to develop PD, individuals with iRBD are currently considered ideal candidates for therapies that can possibly protects brain cells, due to the critical window of opportunity to intervene early before brain cell loss progresses significantly.

Early changes of PD are associated with a number of symptoms including loss of smell, constipation, anxiety and depression. In addition, early heart and brain abnormalities can be visualized using specialized imaging techniques called 123I-MIBG myocardial scintigraphy (MIBG) and dopamine transporter (DAT) single photon emission computerized tomography (SPECT) respectively. The combined presence of certain symptoms and the use of these imaging techniques are considered early markers of PD in individuals with iRBD.

In other conditions, like heart failure, MIBG abnormalities are reversed by drugs able to block excessive adrenergic stimulation, known as beta-blockers. In this study the investigators want to learn about the effect of treatment with the beta-blocker carvedilol on MIBG abnormalities found in iRBD patients at risk to develop PD. The investigators believe that reversing the MIBG abnormality might prelude to a slowing of the neurodegenerative process. This drug is approved by the U.S. Food and Drug Administration (FDA) for congestive heart failure, hypertension and left ventricular dysfunction after myocardial infarction. However, carvedilol is not approved by the FDA in patients with iRBD at risk for PD. The available doses for this drug oral formulations are 3.125mg, 6.25mg, 12.5mg and 25mg.

Changes visualized with the MIBG imaging technique will be correlated to the presence and severity of neurological (i.e. tremors, stiffness, slow movements, walking difficulties) and other symptoms associated with PD (i.e. abnormal smell, constipation, depression, color vision abnormalities), as measured by specific clinical scales and exams.

Condition or disease Intervention/treatment Phase
REM Sleep Behavior Disorder Pre-motor Parkinson Disease Symptomatic Parkinson Disease Drug: Carvedilol Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Treatment: carvedilol titration; Experimental treatment with carvedilol will be offered at stabilized medical treatment. The dosage of carvedilol will be gradually increased from the initial recommended starting dose of 3.125mg twice daily and will be doubled every week according to patient tolerability, as measured by subjective complaints, arterial blood pressure and heart rate. The target dose will be 25mg twice daily (50 mg/day). Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease
Actual Study Start Date : April 4, 2019
Estimated Primary Completion Date : May 1, 2023
Estimated Study Completion Date : May 1, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Carvedilol

Arm Intervention/treatment
Experimental: carvedilol therapy
The dosage of carvedilol will be gradually increased from the initial recommended starting dose of 3.125 mg twice/daily, the target dose will be 25mg twice daily (50 mg/day) and participants will take 50 mg/day carvedilol for 6 months.Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose.
Drug: Carvedilol
At the end of Baseline visit, carvedilol 3.125 twice daily will be initiated and maintained for 1 week, increased to 6.25twice daily (dispensed at week 1visit), to 12.5mg twice daily (dispensed at week 2) and a max dose of 25mg twice daily (dispensed at week 4 visit), as tolerated. A subject that cannot tolerate at least a 25 mg daily dose will be excluded from the study. Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose. The project will include a washout period at study end.
Other Name: Coreg

Primary Outcome Measures :
  1. 123I-MIBG reuptake changes [ Time Frame: 30 weeks ]
    123I-MIBG reuptake will be measured by early and late Heart to Mediastinal ratio (H/M) and Washout ratio (WR) which will be calculated using the following formula: [(early heart counts/pixel - early mediastinum counts/pixel) - (late heart counts/pixel decay-corrected - late mediastinum counts/pixel decay-corrected)]/(early heart counts/pixel - early mediastinum counts/pixel). Care will be taken to exclude lung or liver from the myocardial and large vessels and lung from the mediastinum region of interest. MIBG abnormality cutoffs will be set for values of late H/M <2.2 and WR >30%.

Secondary Outcome Measures :
  1. Adverse Events frequency [ Time Frame: 30 weeks ]
    Safety will be monitored collecting the type and frequency of adverse events, including clinical symptoms, changes in vital signs, clinical laboratory measures and EKG abnormalities.

  2. Heart rate variability changes [ Time Frame: 30 weeks ]
    Twenty-four-hour Holter monitoring of all patients will be conducted at two points during the study: 1) After MIBG and prior to the administration of the study drug and 2) within one week of the end of the six-month treatment trial. Two-channel Holter recordings will obtained and analyzed on a commercially available scanner in the cardiac laboratory at Cedars Sinai Medical Center, according to published guidelines.

Other Outcome Measures:
  1. MDS-UPDRS part III changes [ Time Frame: 30 weeks ]
    The Movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS) Part III will be administered at baseline and 26 weeks after study medication titration. Each item of the MDS-UPDRS has a possible rating from 0 to 4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.Clinical scales will be performed OFF medication in those subjects that might be receiving dopaminergic drugs

  2. Sleep changes as measured by REM Behavior Disorder questionnaire [ Time Frame: 30 weeks ]
    RBD questionnaire (RBDSQ) changes from Screening at 26 weeks after study drug titration

  3. Smell changes as measured by University of Pennsylvania Smell Identification Test (UPSIT) [ Time Frame: 30 weeks ]
    University of Pennsylvania Smell Identification Test (UPSIT) changes from screening at 26 weeks after study medication titration

  4. Constipation score changes using a questionnaire based on modified ROME III diagnostic criteria [ Time Frame: 30 weeks ]
    Functional constipation will be assessed at screening and at 26 weeks after study medication titration using a questionnaire based on modified ROME III diagnostic criteria, which focuses on symptoms including straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction or blockage, manual maneuvers to facilitate evacuation, and two or fewer bowel movements per week. This questionnaire is based on a six item self-report measures with a three point summated rating scale. The total score has a range of 0 to 12, with scores > 4 identifying functional constipation.

  5. Color vision changes as measured by HRR Pseudochromatic Plates [ Time Frame: 30 weeks ]
    Color vision changes will be assessed using HRR Pseudochromatic Plates from screening at 26 weeks after study medication titration

  6. DAT scan Changes [ Time Frame: 30 weeks ]
    DaT/SPECT uptake at baseline will be quantified at baseline and 26 weeks after study medication titration

  7. Non-Motor Symptoms Scale (NMSS) changes [ Time Frame: 30 weeks ]
    The NMSS measures non-motor symptoms over the previous month. Each symptom is scored with respect to: Severity: 0 = None, 1 = Mild; 2 = Moderate; 3 = Severe and Frequency: 1 = Rarely (<1/wk); 2 = Often (1/wk); 3 = Frequent (several times per week); 4 = Very Frequent (daily or all the time).

  8. Scopa-AUT changes [ Time Frame: 30 weeks ]
    The SCOPA-AUT scale consists of 25 items assessing autonomic symptoms in the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction.

  9. Peripheral insulin resistance changes [ Time Frame: 30 weeks ]
    Peripheral IR will be defined by testing for fasting plasma insulin (FPI), fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) from baseline at 26 weeks after study medication titration. 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.

  10. Central insulin resistance changes [ Time Frame: 30 weeks ]
    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 to 26 weeks after carvedilol titration. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   25 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Male or female of age between 25 and 85 years at time of enrollment.

Diagnosis of idiopathic REM sleep behavior disorder (iRBD) or Diagnosis of hyposmia. Diagnosis of RBD will be, established either as 'definite RBD' according to the criteria proposed by the International Classification of Sleep Disorders (ICSD)-2 [AASM, 2005] or 'probable RBD' following a score of 6 or higher in the RBD questionnaire (RBDSQ) with a score of at least 1 in subitems 6.1 to 6.4 of question 6.

At least one of the following:

  1. Diagnosis of hyposmia. Diagnosis of hyposmia will be established as a University of Pennsylvania Smell Identification Test (UPSIT) score < 20th percentile for the individual's age group and sex.
  2. Functional constipation, assessed by a scores > 4 on a questionnaire based on modified ROME III diagnostic criteria.
  3. Color vision abnormality, as assessed using HRR Pseudoisochromatic Plates, in the absence of congenital dyschromatopsia.
  4. Symptoms of depression, as assessed by a Beck Depression Inventory (BDI) fast screen score >3 or concurrent use of antidepressant medications

    • Abnormal 123I-MIBG myocardial scintigraphy, as defined by a Late H/M ratio < 2.2 and/or a WR >30%, with normal cardiac ejection fraction (LVEF >55%).
    • 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)

Chronic Hypertension (SBP>140mmHg-DBP>90mmHg)

Atrial fibrillation

Diabetes mellitus


Sleep Apnea

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

Symptomatic Bradycardia (HR<60) or Sick Sinus Syndrome

Stroke within the past 1 month

Severe Hepatic Dysfunction

Allergy/hypersensitivity to iodine or study medication

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03775096

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Contact: Michele L Gregorio, PhD 4243150016 michele.gregorio@cshs.org
Contact: Gloria Obialisi, MS 3104231704 gloria.obialisi@cshs.org

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United States, California
Cedars Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Helia Maghzi, MD    310-423-6646      
Sponsors and Collaborators
Michele Tagliati, MD
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Principal Investigator: Michele Tagliati, MD Cedars-Sinai Medical Center

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Responsible Party: Michele Tagliati, MD, Professor and Vice Chairman, Director of Movement Disorders, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT03775096    
Other Study ID Numbers: U1111-1223-7784
First Posted: December 13, 2018    Key Record Dates
Last Update Posted: August 26, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.: Yes
Keywords provided by Michele Tagliati, MD, Cedars-Sinai Medical Center:
Early Parkinson Disease
REM Sleep Behaviour Disorder (RBD)
Autonomic dysfunction
Additional relevant MeSH terms:
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Parkinson Disease
REM Sleep Behavior Disorder
Parkinson Disease, Secondary
Mental Disorders
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
REM Sleep Parasomnias
Sleep Wake Disorders
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Protective Agents
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists