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Terazosin and Parkinson's Disease Extension Study

Primary Purpose

Symptomatic Parkinson Disease, REM Sleep Behavior Disorder, Pre-motor Parkinson's Disease

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Terazosin therapy

About this trial

This is an interventional treatment trial for Symptomatic Parkinson Disease focused on measuring Parkinson's disease, REM sleep behavior disorder (RBD), Autonomic dysfunction, Neurodegeneration, Terazosin

Eligibility Criteria

50 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Cedars Sinai Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

terazosin therapy extension

Arm Description

Primary procedures in this study are MIBG scan, DAT scan, NM-MRI, and terazosin medication. 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 alpha1- adrenergic receptor antagonist terazosin, resulting in a decreased clinical conversion rate to parkinsonism.

Outcomes

Primary Outcome Measures

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.

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.

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%.

Secondary Outcome Measures

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

Changes in 123I-Ioflupane uptake

Measured by 123I-Ioflupane uptake, between baseline, year one, year two and year three.

Sensitivity and specificity of DAT Scan compared to MIBG in predicting RBD conversion to PD/other synucleinopathies

Integrity of pigmented neurons of substantia nigra.

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.

Full Information

NCT ID

NCT05109364

First Posted

October 13, 2021

Last Updated

October 4, 2023

Sponsor

Cedars-Sinai Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT05109364

Brief Title

Terazosin and Parkinson's Disease Extension Study

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 23, 2022 (Actual)

Primary Completion Date

November 1, 2025 (Anticipated)

Study Completion Date

November 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Cedars-Sinai Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Symptomatic Parkinson Disease, REM Sleep Behavior Disorder, Pre-motor Parkinson's Disease

Keywords

Parkinson's disease, REM sleep behavior disorder (RBD), Autonomic dysfunction, Neurodegeneration, Terazosin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

terazosin therapy extension

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Terazosin therapy

Intervention Description

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.

Primary Outcome Measure Information:

Title

Changes in 123I-MIBG reuptake - early Heart to Mediastinal ratio (H/M)

Description

Time Frame

Every 6 months for 3 years

Title

Changes in 123I-MIBG reuptake - late Heart to Mediastinal ratio (H/M)

Description

Time Frame

Every 6 months for 3 years

Title

Changes in 123I-MIBG - Washout ratio (WR)

Description

Time Frame

Every 6 months for 3 years

Secondary Outcome Measure Information:

Title

Diagnosis of PD or other synucleinopathies by the end of 3 years in the study population

Description

Diagnosis of PD will be defined or ruled out according to the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) criteria

Time Frame

3 years

Title

Changes in 123I-Ioflupane uptake

Description

Measured by 123I-Ioflupane uptake, between baseline, year one, year two and year three.

Time Frame

Every year for three years

Title

Sensitivity and specificity of DAT Scan compared to MIBG in predicting RBD conversion to PD/other synucleinopathies

Description

Integrity of pigmented neurons of substantia nigra.

Time Frame

3 years

Title

Heart Rate Variability Analysis (HRV) compared to MIBG results in predicting RBD conversion to PD/other synucleinopathies

Description

Beat-to-beat intervals will be registered to assess sympatho-vagal balance. This measurement will be used for HRV analysis.

Time Frame

Every 6 months for 3 years

Other Pre-specified Outcome Measures:

Title

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

Description

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

Time Frame

Every 6 months for 3 years

Title

Non-Motor Symptoms Scale (NMSS) changes between baseline and every 6 months for three years

Description

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).

Time Frame

Every 6 months for 3 years

Title

Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT) changes between baseline and every 6 months for three years

Description

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).

Time Frame

Every 6 months for 3 years

Title

Rapid Eyes Movement (REM) sleep Behavior Disorder Screening questionnaire (RBDSQ) changes between baseline and every 6 months for three years

Description

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.

Time Frame

Every 6 months for 3 years

Title

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

Description

University of Pennsylvania Smell Identification Test (UPSIT) changes.

Time Frame

Every 6 months for 3 years

Title

Functional constipation score changes between baseline and every 6 months for three years

Description

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.

Time Frame

Every 6 months for 3 years

Title

Color vision changes, as assessed using Hardy, Rand and Rittler (HRR) pseudoisochromatic Plates, between baseline and every 6 months for three years

Description

Color vision changes will be assessed using HRR pseudoisochromatic Plates.

Time Frame

Every 6 months for 3 years

Title

Central insulin resistance changes between baseline and every 6 months for three years

Description

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.

Time Frame

Every 6 months for 3 years

Title

Differences in integrity of pigmented neurons in the locus coeruleus and substantia nigra between baseline, year one, year two and year three

Description

This outcome will be measured by the content of neuromelanin, a product of catecholamine metabolism in locus coeruleus (LC) and substantia nigra (SN).

Time Frame

3 years

Title

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)

Description

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

Time Frame

3 years

Title

Heart Rate Variability (HRV) changes between baseline and every 6 months for three years

Description

Beat-to-beat intervals will be registered to assess sympatho-vagal balance. This measurement will be used for HRV analysis.

Time Frame

Every 6 months for 3 years

Title

Peripheral insulin resistance (IR) changes between baseline and every 6 months for three years.

Description

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

Time Frame

Every 6 months for 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Michele Gregorio, PhD

Phone

424-315-0021

Ext

50021

michele.gregorio@cshs.org

First Name & Middle Initial & Last Name or Official Title & Degree

MaryClare Kelly, MS

Phone

3104238497

Ext

1704

maryclare.kelly@cshs.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michele Tagliati, MD, FAAN

Organizational Affiliation

Cedars-Sinai Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cedars Sinai Medical Center

City

Los Angeles

State/Province

California

ZIP/Postal Code

90048

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michele L Gregorio, PhD

Phone

424-315-0021

Ext

50021

michele.gregorio@cshs.org

First Name & Middle Initial & Last Name & Degree

MaryClare Kelly, MS

Phone

310-423-8497

Ext

38497

maryclare.kelly@cshs.org

First Name & Middle Initial & Last Name & Degree

Michele Tagliati

12. IPD Sharing Statement

Plan to Share IPD

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