Terazosin and Parkinson's Disease Extension Study

REM Sleep Behavior Disorder Clinical Trial

Official title:

The Effect of alpha1- Adrenergic Receptor Antagonist Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease: A Follow up Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05109364
• Other study ID #: STUDY00001770
• Status: Recruiting
• Phase: Phase 2
• Start date: September 23, 2022
• Est. completion date: November 1, 2025

Study information

• Verified date: October 2023
• Source: Cedars-Sinai Medical Center
• Contact: Michele Gregorio, PhD
• Phone: 424-315-0021
• Email: michele.gregorio[@]cshs.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate the long-term effects of treatment with the selective post-synaptic a1-adrenergic blocker terazosin on serial in a population of subjects with defined pre-motor Parkinson's disease (PD) risks and abnormal imaging exams. Imaging changes will be correlated to the presence and severity of motor and non-motor symptoms of PD, measured by validated clinical scales and cardiac autonomic function tests.

Description:

The purpose of this study is to investigate the long-term effects of treatment with the selective post-synaptic a1-adrenergic blocker terazosin on serial 123 Ioflupane Dopamine Transporter single-photon emission-computed tomography (123I-FP DAT-SPECT) in a population of subjects with defined pre-motor PD risks (i.e., RBD and at least one among hyposmia, constipation, depression and color vision abnormality) and abnormal Iodine-123 meta-iodobenzylguanidine (123I-MIBG) uptake. Imaging changes will be correlated to the presence and severity of motor and non-motor symptoms of PD, measured by validated clinical scales and cardiac autonomic function tests. The rate of RBD clinical conversion to PD will be estimated and compared to available data in the literature.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: November 1, 2025
• Est. primary completion date: November 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

Inclusion Criteria:

• Enrolled in the study "The Effect of alpha1- adrenergic receptor antagonist Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease" (STUDY #000540)
• Capacity to give informed consent

Exclusion Criteria:

• Secondary Parkinsonism, including tardive
• Concurrent dementia defined by a score lower than 22 on The Montreal Cognitive Assessment (MoCA)
• Concurrent severe depression defined by a Beck Depression Inventory-Fast Screen (BDI fast screen) score greater than 13
• Comorbidities related to sympathetic nervous system (SNS) hyperactivity
• Heart failure (LVEF <45%)
• Recent myocardial revascularization (<12 weeks)
• Hypertension (systolic blood pressure SBP>150mmHg (millimeters of mercury) or diastolic blood pressure DBP>100mmHg)
• Chronic Atrial fibrillation
• Concurrent Use of Beta-adrenergic antagonist
• Diabetes mellitus
• Chronic Obstructive Pulmonary Disease (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 terazosin
• Recent myocardial infarction (<48 h)
• Ongoing angina pectoris
• Cardiogenic shock or prolonged hypotension
• Breast-feeding
• Current use of phosphodiesterase type 5 inhibitors: sildenafil (ViagraTM), tadalafil (CialisTM), or vardenafil (LevitraTM)
• History of priapism (persistent and painful erection)
• Neurogenic orthostatic hypotension defined as symptomatic decrease in BP > 20mmHg systolic or > 10mmHg diastolic and HR increase < 20bpm on supine to sitting or standing.
• Blood pressure less than 110 mm Hg systolic at screening or baseline visit
• Use of investigational drugs within 30 days before screening
• For female participant, pregnancy, or plans for child-bearing during study period
• Allergy/hypersensitivity to iodine or study medication

Related Conditions & MeSH terms

• Mental Disorders
• Parkinson Disease
• Parkinson Disease, Secondary
• Pre-motor Parkinson's Disease
• REM Sleep Behavior Disorder
• Symptomatic Parkinson Disease

Intervention

Drug:
• Terazosin therapy
Primary procedures in this study are MIBG scan, DAT scan, NM-MRI, and terazosin 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 a1- Adrenergic Receptor Antagonist Terazosin, resulting in a decreased clinical conversion rate to parkinsonism.

Locations

Country	Name	City	State
United States	Cedars Sinai Medical Center	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Cedars-Sinai Medical Center

Country where clinical trial is conducted

United States, 

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* Note: There are 78 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III changes from without (OFF) medication between baseline and every 6 months for three years	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 without (OFF) medication in those subjects that might be receiving dopaminergic drugs	Every 6 months for 3 years
Other	Non-Motor Symptoms Scale (NMSS) changes between baseline and every 6 months for three years	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).	Every 6 months for 3 years
Other	Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT) changes between baseline and every 6 months for three years	The SCOPA-AUT was developed to evaluate autonomic symptoms in patients with Parkinson's disease. The scale is self-completed by patients and consists of 25 items assessing the following domains: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women).	Every 6 months for 3 years
Other	Rapid Eyes Movement (REM) sleep Behavior Disorder Screening questionnaire (RBDSQ) changes between baseline and every 6 months for three years	The RBDSQ is a 10-item, patient self-rating instrument assessing the subject's sleep behavior with short questions that have to be answered by either "yes" or "no" that address frequency and content of dreams, their relationship to nocturnal movements/behavior, injuries of the bed partner, nocturnal vocalization, etc. The maximum total score of the RBDSQ is 13 points.	Every 6 months for 3 years
Other	Smell changes as measured by University of Pennsylvania Smell Identification Test (UPSIT)	University of Pennsylvania Smell Identification Test (UPSIT) changes.	Every 6 months for 3 years
Other	Functional constipation score changes between baseline and every 6 months for three years	Functional constipation will be assessed at screening and at 26 weeks after study medication titration using a questionnaire based on modified The Rome III Criteria for Functional Digestive Disorders (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.	Every 6 months for 3 years
Other	Color vision changes, as assessed using Hardy, Rand and Rittler (HRR) pseudoisochromatic Plates, between baseline and every 6 months for three years	Color vision changes will be assessed using HRR pseudoisochromatic Plates.	Every 6 months for 3 years
Other	Central insulin resistance changes between baseline and every 6 months for three years	Measures of insulin sensitivity in neuronal-origin enriched plasma extracellular vesicles EVs (central IR) will be used to test the association of changes in such sensitivity to changes in MIBG uptake and clinical scores. For that purpose, plasma samples will be collected and stored and -80oC (celsius degrees) to allow for isolation of neuronal origin EVs at the completion of the study.	Every 6 months for 3 years
Other	Differences in integrity of pigmented neurons in the locus coeruleus and substantia nigra between baseline, year one, year two and year three	This outcome will be measured by the content of neuromelanin, a product of catecholamine metabolism in locus coeruleus (LC) and substantia nigra (SN).	3 years
Other	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)	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	3 years
Other	Heart Rate Variability (HRV) changes between baseline and every 6 months for three years	Beat-to-beat intervals will be registered to assess sympatho-vagal balance. This measurement will be used for HRV analysis.	Every 6 months for 3 years
Other	Peripheral insulin resistance (IR) changes between baseline and every 6 months for three years.	Peripheral IR will be defined by the homeostasis model assessment of IR (HOMA-IR) defined as fasting glucose (mmol/L) x fasting insulin (mU/mL)/22.5. A cutoff HOMA index of 2.0, equivalent to <50% sensitivity, will be used to define IR. Subjects will be considered to have IR if they either have a HOMA=2.0 and/or HbA1c=5.7	Every 6 months for 3 years
Primary	Changes in 123I-MIBG reuptake - early Heart to Mediastinal ratio (H/M)	123I-MIBG early reuptake will be measured by Heart to Mediastinal ratio (H/M) which will be calculated from the early images after drawing regions of interest (7×7 pixels) over the upper mediastinum and circular ROI around the entire heart. MIBG abnormality cutoff will be set for values of late H/M <2.2.	Every 6 months for 3 years
Primary	Changes in 123I-MIBG reuptake - late Heart to Mediastinal ratio (H/M)	123I-MIBG late reuptake will be measured by Heart to Mediastinal ratio (H/M) which will be calculated from the late images after drawing regions of interest (7×7 pixels) over the upper mediastinum and circular ROI around the entire heart. MIBG abnormality cutoff will be set for values of late H/M <2.2.	Every 6 months for 3 years
Primary	Changes in 123I-MIBG - Washout ratio (WR)	123I-MIBG Washout ratio (WR) 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 cutoff will be set for values of WR >30%.	Every 6 months for 3 years
Secondary	Diagnosis of PD or other synucleinopathies by the end of 3 years in the study population	Diagnosis of PD will be defined or ruled out according to the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) criteria	3 years
Secondary	Changes in 123I-Ioflupane uptake	Measured by 123I-Ioflupane uptake, between baseline, year one, year two and year three.	Every year for three years
Secondary	Sensitivity and specificity of DAT Scan compared to MIBG in predicting RBD conversion to PD/other synucleinopathies	Integrity of pigmented neurons of substantia nigra.	3 years
Secondary	Heart Rate Variability Analysis (HRV) compared to MIBG results in predicting RBD conversion to PD/other synucleinopathies	Beat-to-beat intervals will be registered to assess sympatho-vagal balance. This measurement will be used for HRV analysis.	Every 6 months for 3 years