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

NCT03775096 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: U1111-1223-7784
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Early Parkinson Disease; REM Sleep Behaviour Disorder (RBD); carvedilol; Autonomic dysfunction; Neurodegeneration

Outcome Measures

Primary Outcomes (1)

• 123I-MIBG reuptake changes

  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%.

  At baseline and at 26 weeks of treatment.

Secondary Outcomes (2)

• Adverse Events frequency

  every 3 months up to 34 weeks

• Heart rate variability changes

  At baseline and at 26 weeks of treatment.

Other Outcomes (10)

• MDS-UPDRS part III changes

  At baseline and at 26 weeks of treatment.

• Sleep changes as measured by REM Behavior Disorder questionnaire

  At baseline and at 26 weeks of treatment.

• Smell changes as measured by University of Pennsylvania Smell Identification Test (UPSIT)

  At baseline and at 26 weeks of treatment.

Study Arms (1)

carvedilol therapy

EXPERIMENTAL

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

Interventions

Carvedilol DRUG

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.

Also known as: Coreg

carvedilol therapy

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female of age between 50 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:
• 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.
• Functional constipation, assessed by a scores \> 4 on a questionnaire based on modified ROME III diagnostic criteria.
• Color vision abnormality, as assessed using HRR Pseudoisochromatic Plates, in the absence of congenital dyschromatopsia.
• 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

You may not qualify if:

• 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
• COPD
• 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)

Sponsors & Collaborators

• Michele Tagliati, MD: lead

Study Sites (1)

Michele L Lima Gregorio

Los Angeles, California, 90046, United States

Location

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MeSH Terms

Conditions

REM Sleep Behavior Disorder; Parkinson Disease, Secondary; Parkinson Disease; Primary Dysautonomias; Nerve Degeneration

Interventions

Carvedilol

Condition Hierarchy (Ancestors)

REM Sleep Parasomnias; Parasomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Autonomic Nervous System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Study Officials

• Michele Tagliati, MD, FAAN

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor and Vice Chairman, Director of Movement Disorders

Model Details: 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.

Study Record Dates

• First Submitted: December 9, 2018
• First Posted: December 13, 2018
• Study Start: April 4, 2019
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: March 2, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)