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Terazosin Effect on Cardiac Changes in Early Parkinson's Disease

Primary Purpose

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

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Terazosin
Sponsored by
Cedars-Sinai Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for REM Sleep Behavior Disorder

Eligibility Criteria

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

Inclusion Criteria:

  • Male or female of age between 25 and 85 years at time of enrollment.
  • Diagnosis of idiopathic REM sleep behavior disorder (iRBD), 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) [Nomura et al, 2011], with a score of at least 1 in subitems 6.1 to 6.4 of question 6 [Halsband et al, 2018].

  • At least one of the following:

    1. Diagnosis of hyposmia, 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 IV 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 >20%, 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

  • Comorbidites related to SNS hyperactivity

    • Heart failure (LVEF< 45%)
    • Recent myocardial revascularization (< 12 weeks)
    • Hypertension (SBP >150 mmHg or DBP> 100mmHg)
    • Chronic Atrial fibrillation
    • Concurrent use of Alpha- adrenergic antagonist
    • Diabetes mellitus
    • COPD
    • Untreated Severe Sleep Apnea; Apnea-Hypopnea Index (AHI) > 30/h.

  • Contraindication to the use of Terazosin

    • Recent myocardial infarction (< 48 h)
    • Ongoing angina pectoris
    • Cardiogenic shock or prolonged
    • Breast feeding
    • Current use of Phosphodiesterase type 5 inhibitors: sildenafil (Viagra TM), tadalafil (Cialis TM), or vardenafil (Levitra TM)
    • History of Priapism
    • Neurogenic orthostatic hypotensiondefiened as symptomatic decrease in BP> 20 mmHg systolic or > 10mmHg diastolic and HR increase < 20bpm on supine to sitting or standing
    • Blood pressure less than 110 mmHG systolic at screening or baseline visit
    • Use of investigational drugs whitin 30 days before screening
    • For female participant, Pregnacy, or plans for child-bearing during study period
  • Allergy/hypersenstivity to iodine or study medication

Sites / Locations

  • Michele L Lima GregorioRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

terazosin therapy

Arm Description

Daily oral doses of adrenergic blocker 5 mg or 10 mg. The dosage will be gradually increased from the initial recommended starting dose of 1 mg daily at bedtime and titrated stepwise to 2mg, 5mg or 10 mg weekly, according to patient tolerability, as measured by subjective complaints, arterial blood pressure and heart rate. The target dose will be 5 mg or 10 mg daily based on subject's tolerability.

Outcomes

Primary Outcome Measures

Differences in 123I-MIBG reuptake, as measured by early and late Heart to mediastinum (H/M) ratio, and Washout Ration (WR), at 26 weeks of treatment with the adrenergic blocker terazosin
1) Differences in 123I-MIBG reuptake, as measured by early and late H/M ratio, and WR, at 26 weeks of treatment with the adrenergic blocker Terazosin.

Secondary Outcome Measures

Incidence of adverse events
Safety will be monitored collecting the type and frequency of adverse events, including clinical symptoms
Heart Rate variability changes from baseline at 26 weeks after study medication titration
Beat-to-beat intervals will be registered to assess sympatho-vagal balance.
Incidence of abnormal vital signs
Changes in vital signs (Blood pressure and Heart rate)

Full Information

First Posted
April 24, 2020
Last Updated
October 4, 2023
Sponsor
Cedars-Sinai Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04386317
Brief Title
Terazosin Effect on Cardiac Changes in Early Parkinson's Disease
Official Title
The Effect of a1- Adrenergic Receptor Antagonist Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 1, 2020 (Actual)
Primary Completion Date
December 30, 2025 (Anticipated)
Study Completion Date
December 30, 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
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Parkinson's disease (PD) is characterized by many non-motor symptoms that occur several years before the diagnosis, in particular idiopathic REM behavior disorder (iRBD), which is associated with autonomic impairment. The purpose of this study is to investigate the effect of treatment with the selective post-synaptic a1-adrenergic blocker terazosin on 123I-MIBG myocardial uptake in a population of subjects with defined pre-motor PD risks (i.e. hyposmia and RBD) and abnormal baseline 123I-MIBG uptake, with or without 123I-Ioflupane uptake abnormality or PD motor symptoms. Scintigraphic changes will be correlated to motor and non-motor severity of PD, measured by validated clinical scales and cardiac autonomic function tests.
Detailed Description
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 this study the investigators want to learn about the effect of treatment with the adrenergic blocker terazosin on MIBG abnormalities 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 Benign Prostatic Hyperplasia (BPH) and Hypertension. However, terazosin is not approved by the FDA in patients with iRBD at risk for PD. The available doses for this drug oral formulations are 1mg, 2 mg, 5mg and 10 mg. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
REM Sleep Behavior Disorder, Pre-motor Parkinson's Disease, Symptomatic Parkinson Disease

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
Arm Type
Experimental
Arm Description
Daily oral doses of adrenergic blocker 5 mg or 10 mg. The dosage will be gradually increased from the initial recommended starting dose of 1 mg daily at bedtime and titrated stepwise to 2mg, 5mg or 10 mg weekly, according to patient tolerability, as measured by subjective complaints, arterial blood pressure and heart rate. The target dose will be 5 mg or 10 mg daily based on subject's tolerability.
Intervention Type
Drug
Intervention Name(s)
Terazosin
Intervention Description
Fifteen patients with defined pre-motor PD risk and abnormal baseline 123I-MIBG uptake, with or without 123I-Ioflupane uptake abnormality or PD motor symptoms, will be recruited to receive daily oral doses of terazosin 5 mg or 10 mg. The dosage of terazosin will be gradually increased from the initial recommended starting dose of 1 mg daily at bedtime and titrated stepwise to 2mg, 5mg or 10 mg weekly, according to patient tolerability, as measured by subjective complaints, arterial blood pressure and heart rate. The target dose will be 5 mg or 10 mg daily based on subject's tolerability. Development of incompatibility will be addressed by individually adjusting the dose of terazosin.
Primary Outcome Measure Information:
Title
Differences in 123I-MIBG reuptake, as measured by early and late Heart to mediastinum (H/M) ratio, and Washout Ration (WR), at 26 weeks of treatment with the adrenergic blocker terazosin
Description
1) Differences in 123I-MIBG reuptake, as measured by early and late H/M ratio, and WR, at 26 weeks of treatment with the adrenergic blocker Terazosin.
Time Frame
At baseline and at 26 weeks after medication titration
Secondary Outcome Measure Information:
Title
Incidence of adverse events
Description
Safety will be monitored collecting the type and frequency of adverse events, including clinical symptoms
Time Frame
At baseline and at 26 weeks after medication titration
Title
Heart Rate variability changes from baseline at 26 weeks after study medication titration
Description
Beat-to-beat intervals will be registered to assess sympatho-vagal balance.
Time Frame
At baseline and at 26 weeks after medication titration
Title
Incidence of abnormal vital signs
Description
Changes in vital signs (Blood pressure and Heart rate)
Time Frame
At baseline and at 26 weeks after medication titration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female of age between 50 and 85 years at time of enrollment. Diagnosis of idiopathic REM sleep behavior disorder (iRBD), 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) [Nomura et al, 2011], with a score of at least 1 in subitems 6.1 to 6.4 of question 6 [Halsband et al, 2018]. At least one of the following: Diagnosis of hyposmia, 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 IV 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 >20%, 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 Comorbidites related to SNS hyperactivity Heart failure (LVEF< 45%) Recent myocardial revascularization (< 12 weeks) Hypertension (SBP >150 mmHg or DBP> 100mmHg) Chronic Atrial fibrillation Concurrent use of Alpha- adrenergic antagonist Diabetes mellitus COPD Untreated Severe Sleep Apnea; Apnea-Hypopnea Index (AHI) > 30/h. Contraindication to the use of Terazosin Recent myocardial infarction (< 48 h) Ongoing angina pectoris Cardiogenic shock or prolonged Breast feeding Current use of Phosphodiesterase type 5 inhibitors: sildenafil (Viagra TM), tadalafil (Cialis TM), or vardenafil (Levitra TM) History of Priapism Neurogenic orthostatic hypotensiondefiened as symptomatic decrease in BP> 20 mmHg systolic or > 10mmHg diastolic and HR increase < 20bpm on supine to sitting or standing Blood pressure less than 110 mmHG systolic at screening or baseline visit Use of investigational drugs whitin 30 days before screening For female participant, Pregnacy, or plans for child-bearing during study period Allergy/hypersenstivity to iodine or study medication
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michele L Gregorio, PhD
Phone
4243150016
Email
michele.gregorio@cshs.org
First Name & Middle Initial & Last Name or Official Title & Degree
MaryClare Kelly
Phone
3104238497
Email
maryclare.kelly@cshs.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michele L Tagliati, MD
Organizational Affiliation
Cedars-Sinai Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Michele L Lima Gregorio
City
Los Angeles
State/Province
California
ZIP/Postal Code
90046
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michele L Lima Gregorio, PhD
Phone
323-690-9902
Email
michele.gregorio@cshs.org
First Name & Middle Initial & Last Name & Degree
MaryClare Kelly
Phone
3104238497
Email
maryclare.kelly@cshs.org

12. IPD Sharing Statement

Plan to Share IPD
No

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Terazosin Effect on Cardiac Changes in Early Parkinson's Disease

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