<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03775096</url>
  </required_header>
  <id_info>
    <org_study_id>U1111-1223-7784</org_study_id>
    <nct_id>NCT03775096</nct_id>
  </id_info>
  <brief_title>Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease (Protocol 53136)</brief_title>
  <official_title>The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Michele Tagliati, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cedars-Sinai Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      REM Behavior Sleep Disorder (RBD) is a sleep disorder causing people to 'act out' their&#xD;
      dreams. A high percentage of individuals with idiopathic RBD (iRBD) are known to develop&#xD;
      conditions affecting the neurons in the brain such as Parkinson's disease (PD). Based on the&#xD;
      increased risk to develop PD, individuals with iRBD are currently considered ideal candidates&#xD;
      for therapies that can possibly protects brain cells, due to the critical window of&#xD;
      opportunity to intervene early before brain cell loss progresses significantly.&#xD;
&#xD;
      Early changes of PD are associated with a number of symptoms including loss of smell,&#xD;
      constipation, anxiety and depression. In addition, early heart and brain abnormalities can be&#xD;
      visualized using specialized imaging techniques called 123I-MIBG myocardial scintigraphy&#xD;
      (MIBG) and dopamine transporter (DAT) single photon emission computerized tomography (SPECT)&#xD;
      respectively. The combined presence of certain symptoms and the use of these imaging&#xD;
      techniques are considered early markers of PD in individuals with iRBD.&#xD;
&#xD;
      In other conditions, like heart failure, MIBG abnormalities are reversed by drugs able to&#xD;
      block excessive adrenergic stimulation, known as beta-blockers. In this study the&#xD;
      investigators want to learn about the effect of treatment with the beta-blocker carvedilol on&#xD;
      MIBG abnormalities found in iRBD patients at risk to develop PD. The investigators believe&#xD;
      that reversing the MIBG abnormality might prelude to a slowing of the neurodegenerative&#xD;
      process. This drug is approved by the U.S. Food and Drug Administration (FDA) for congestive&#xD;
      heart failure, hypertension and left ventricular dysfunction after myocardial infarction.&#xD;
      However, carvedilol is not approved by the FDA in patients with iRBD at risk for PD. The&#xD;
      available doses for this drug oral formulations are 3.125mg, 6.25mg, 12.5mg and 25mg.&#xD;
&#xD;
      Changes visualized with the MIBG imaging technique will be correlated to the presence and&#xD;
      severity of neurological (i.e. tremors, stiffness, slow movements, walking difficulties) and&#xD;
      other symptoms associated with PD (i.e. abnormal smell, constipation, depression, color&#xD;
      vision abnormalities), as measured by specific clinical scales and exams.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder of unknown&#xD;
      etiology, characterized by bradykinesia (slowness of movements) associated with tremor at&#xD;
      rest and/or muscle rigidity. PD is typically associated with a significant loss of&#xD;
      dopaminergic neurons in the substantia nigra pars compacta(SNpc).The resulting nigro-striatal&#xD;
      degeneration can be detected and quantified using a dopamine transporter (DAT) single photon&#xD;
      emission computerized tomography (SPECT) imaging technique. This type of imaging, recently&#xD;
      approved for clinical use in the United States, uses a labeled ligand (123I-Ioflupane) with&#xD;
      high affinity to the DAT in the striatum. The amount of transporter, which plays a crucial&#xD;
      role in the health of the presynaptic dopaminergic neurons, is then visualized by SPECT.&#xD;
      123I-Ioflupane uptake is reduced 50-70% in patients with early PD.&#xD;
&#xD;
      In addition to cardinal motor symptoms, PD is characterized by a large number of &quot;non-motor&quot;&#xD;
      symptoms (NMS), which add to the overall morbidity burden. Importantly, non--motor features&#xD;
      may precede the diagnosis of PD, sometimes by several years. They include autonomic&#xD;
      (gastrointestinal dysfunction, cardiovascular dysfunction with orthostatic hypotension (OH),&#xD;
      urinary and sexual dysfunction, and hyperhidrosis), sleep (impaired sleep initiation and&#xD;
      maintenance, rapid eye movement behavior disorder (RBD), sleep apnea and excessive daytime&#xD;
      sleepiness), sensory (pain, hyposmia, and visual dysfunction), and neuropsychiatric&#xD;
      disturbances (anhedonia, apathy, anxiety, depression, panic attacks, dementia, and&#xD;
      psychosis).&#xD;
&#xD;
      Among NMS, cardiac dysautonomia is a common feature of PD, manifesting in 30% of patients as&#xD;
      orthostatic hypotension, a symptom that is correlated to disease duration and severity.&#xD;
      Cardiac sympathetic innervation (CSI) is also affected in PD and other synucleinopathies.&#xD;
      Lewy Body (LB) pathology, widely considered a marker of PD when detected in the SNpc, is also&#xD;
      found in the sinoatrial nodal ganglion and myocardium of PD patients at autopsy. Despite the&#xD;
      high prevalence of both conditions, the relationship between CSI impairment and cardiac&#xD;
      dysautonomia is still poorly understood.&#xD;
&#xD;
      Iodine-123 meta-iodobenzylguanidine (123I-MIBG) is an inactive physiological analogue that&#xD;
      mimics the kinetics of norepinephrine (NE) and competes with NE for active cardiac uptake&#xD;
      into the postganglionic sympathetic nerve terminal, where it is stored into granules by NE&#xD;
      transport proteins. 123I-MIBG myocardial scintigraphy, an accepted measure of CSI, is&#xD;
      abnormal in PD patients, with a characteristic reduction of Heart/Mediastinum (H/M) ratio&#xD;
      (early and late uptake) and an increased Washout Rate (WR). 123I-MIBG uptake impairment is&#xD;
      specific to PD and other synucleinopathies and can be used to differentiate PD and dementia&#xD;
      with Lewy bodies (DLB) from other disorders with similar neurological phenomenology such as&#xD;
      multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal&#xD;
      degeneration (CBD).&#xD;
&#xD;
      123I-MIBG uptake deficit in PD is attributed to cardiac sympathetic denervation, based on&#xD;
      neuropathological studies using tyrosine hydroxylase (TH) immunostaining in epicardial&#xD;
      nerves. There is evidence of alpha-synuclein aggregation in the epicardial nerve fascicles -&#xD;
      the distal axons of the cardiac sympathetic nerve - in subjects with incidental Lewy Body&#xD;
      Disease (ILBD) at stage 2 or 3 of Braak staging with preserved TH immunoreactive axons,&#xD;
      suggesting a preliminary stage in the development of cardiac sympathetic denervation.&#xD;
      However, while 123I-MIBG myocardial scintigraphy abnormalities have been correlated with&#xD;
      pre-motor symptoms like RBD, hyposmia and constipation, there is no pathological evidence of&#xD;
      cardiac sympathetic denervation in subjects with signs of 123I-MIBG myocardial scintigraphy&#xD;
      abnormality and recognized pre-motor symptoms of PD. Finally, despite the specific&#xD;
      association with PD diagnosis, the relationship between CSI impairment and nigrostriatal&#xD;
      degeneration is poorly understood. Two studies found a strong correlation between&#xD;
      nigrostriatal dopaminergic degeneration, as measured by 123I Ioflupane SPECT, and CSI&#xD;
      impairment at different stages of disease. 123I-MIBG uptake deficits have been correlated&#xD;
      with the progression of the disease.&#xD;
&#xD;
      Interestingly, CSI - and therefore 123I-MIBG cardiac uptake - is impaired in other chronic&#xD;
      conditions such as Heart Failure (HF), Hypertension, Diabetes Mellitus, Chronic Obstructive&#xD;
      Pulmonary Disease and Sleep Apnea, with an identical pattern of abnormality as the one&#xD;
      detected in PD patients. As opposed to cardiac sympathetic denervation, 123I-MIBG cardiac&#xD;
      uptake impairment in these chronic conditions - and in particular HF - is explained with the&#xD;
      hyperactivity of the sympathetic nervous system (SNS) acting as compensatory mechanism&#xD;
      related to specific organ failure (i.e. post-ischemic/idiopathic heart failure). In fact,&#xD;
      123I-MIBG cardiac uptake is of prognostic value and can be used to stratify HF patients at&#xD;
      risk for ventricular arrhythmias and sudden death. By reducing SNS hyperactivity, chronic&#xD;
      treatment with beta-blockers improves 123I-MIBG cardiac uptake and reduces mortality in&#xD;
      patients with HF.&#xD;
&#xD;
      Many recognizable triggers for PD appear to be associated with increased sympathetic tone,&#xD;
      including most notably brain traumatic injuries, but also microbiota perturbations, air&#xD;
      pollution, heavy metals like iron and manganese, and finally aging itself. In addition, there&#xD;
      is reason to believe that SNS overactivity might trigger the principal pre-motor symptoms of&#xD;
      PD, including hyposmia, constipation and RBD. Finally, SNS overactivity typically drives&#xD;
      reduced low-frequency heart rate variability (HRV), another clinical sign associated with&#xD;
      pre-motor - particularly RBD - and early PD. Interestingly, low delayed uptake and high&#xD;
      washout rate, the 123I-MIBG scintigraphy indices of increased adrenergic drive, are typically&#xD;
      described in PD patients.&#xD;
&#xD;
      Based on these considerations, the investigators hypothesize that 123I-MIBG cardiac&#xD;
      impairment in neurodegenerative disease shares the same pathophysiology of other chronic&#xD;
      conditions like HF, at least in the very early, pre-motor stages of development. Therefore,&#xD;
      treatment of SNS hyperactivity with adrenergic blockers will improve cardiac sympathetic&#xD;
      denervation in PD patients, providing evidence that this process is reversible. If this is&#xD;
      true, the early detection of 123I-MIBG cardiac impairment in PD, particularly in the&#xD;
      pre-motor phase, might create a considerable window of opportunity for treatment with&#xD;
      adrenergic blockers - or similar compounds able to reduce SNS hyperactivity - which may&#xD;
      result in long-term benefit such as delaying the neurodegenerative process and the onset of&#xD;
      neurological symptoms. This may be documented and monitored using nigrostriatal dopaminergic&#xD;
      scintigraphy (DAT scan), a strategy that would implement a dual imaging algorithm to provide&#xD;
      early and viable biomarkers of the neurodegenerative process.&#xD;
&#xD;
      Among adrenergic blockers, carvedilol is particularly well-suited to block impaired&#xD;
      sympathetic over-activation in virtue of several effects on the adrenoceptors, including β-1&#xD;
      and β-2 adrenergic blockade and α-1 adrenergic blockade, in addition to antioxidant activity,&#xD;
      L-type calcium channel blockade, and inhibition of stress-activated protein kinase.&#xD;
      Absorption of current oral formulations of carvedilol is typically rapid and complete, with&#xD;
      an average elimination half -life of about 8 hours. The high lipophilic structure of&#xD;
      carvedilol makes it one of the beta-blockers most readily crossing the blood brain barrier.&#xD;
      Carvedilol is associated with greater reduction of sympathetic activity, as measured by&#xD;
      123I-MIBG myocardial uptake, than metoprolol and other selective beta-blockers. In addition,&#xD;
      due to its α-1 adrenergic blockade properties, carvedilol may exert beneficial effects on&#xD;
      olfactory dysfunction and insulin resistance, two abnormalities frequently associated with&#xD;
      the neurodegenerative process in PD. Adrenergic blockers have been associated with sleep&#xD;
      disturbances including RBD, although the latter is based on isolated anecdotal reports. The&#xD;
      negative effect of beta-blockers on sleep quality and duration appears to be related with the&#xD;
      suppression of night time levels of melatonin. Interestingly however, carvedilol is not&#xD;
      associated with melatonin suppression.&#xD;
&#xD;
      The purpose of this pilot study is to investigate the effect of treatment with the adrenergic&#xD;
      blocker carvedilol on 123I-MIBG myocardial uptake in a population of subjects with defined&#xD;
      pre-motor PD risks (i.e. hyposmia and RBD) and abnormal baseline 123I-MIBG uptake, with or&#xD;
      without 123I-Ioflupane uptake abnormality or PD motor symptoms. Scintigraphic changes will be&#xD;
      correlated to motor and non-motor severity of PD, measured by validated clinical scales and&#xD;
      cardiac autonomic function tests.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 4, 2019</start_date>
  <completion_date type="Anticipated">May 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">May 1, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>123I-MIBG reuptake changes</measure>
    <time_frame>30 weeks</time_frame>
    <description>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 &lt;2.2 and WR &gt;30%.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse Events frequency</measure>
    <time_frame>30 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart rate variability changes</measure>
    <time_frame>30 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>MDS-UPDRS part III changes</measure>
    <time_frame>30 weeks</time_frame>
    <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 OFF medication in those subjects that might be receiving dopaminergic drugs</description>
  </other_outcome>
  <other_outcome>
    <measure>Sleep changes as measured by REM Behavior Disorder questionnaire</measure>
    <time_frame>30 weeks</time_frame>
    <description>RBD questionnaire (RBDSQ) changes from Screening at 26 weeks after study drug titration</description>
  </other_outcome>
  <other_outcome>
    <measure>Smell changes as measured by University of Pennsylvania Smell Identification Test (UPSIT)</measure>
    <time_frame>30 weeks</time_frame>
    <description>University of Pennsylvania Smell Identification Test (UPSIT) changes from screening at 26 weeks after study medication titration</description>
  </other_outcome>
  <other_outcome>
    <measure>Constipation score changes using a questionnaire based on modified ROME III diagnostic criteria</measure>
    <time_frame>30 weeks</time_frame>
    <description>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 &gt; 4 identifying functional constipation.</description>
  </other_outcome>
  <other_outcome>
    <measure>Color vision changes as measured by HRR Pseudochromatic Plates</measure>
    <time_frame>30 weeks</time_frame>
    <description>Color vision changes will be assessed using HRR Pseudochromatic Plates from screening at 26 weeks after study medication titration</description>
  </other_outcome>
  <other_outcome>
    <measure>DAT scan Changes</measure>
    <time_frame>30 weeks</time_frame>
    <description>DaT/SPECT uptake at baseline will be quantified at baseline and 26 weeks after study medication titration</description>
  </other_outcome>
  <other_outcome>
    <measure>Non-Motor Symptoms Scale (NMSS) changes</measure>
    <time_frame>30 weeks</time_frame>
    <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 (&lt;1/wk); 2 = Often (1/wk); 3 = Frequent (several times per week); 4 = Very Frequent (daily or all the time).</description>
  </other_outcome>
  <other_outcome>
    <measure>Scopa-AUT changes</measure>
    <time_frame>30 weeks</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Peripheral insulin resistance changes</measure>
    <time_frame>30 weeks</time_frame>
    <description>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 &lt;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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Central insulin resistance changes</measure>
    <time_frame>30 weeks</time_frame>
    <description>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.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>REM Sleep Behavior Disorder</condition>
  <condition>Pre-motor Parkinson Disease</condition>
  <condition>Symptomatic Parkinson Disease</condition>
  <arm_group>
    <arm_group_label>carvedilol therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carvedilol</intervention_name>
    <description>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.</description>
    <arm_group_label>carvedilol therapy</arm_group_label>
    <other_name>Coreg</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Male or female of age between 25 and 85 years at time of enrollment.&#xD;
&#xD;
        Diagnosis of idiopathic REM sleep behavior disorder (iRBD) or Diagnosis of hyposmia.&#xD;
        Diagnosis of RBD will be, established either as 'definite RBD' according to the criteria&#xD;
        proposed by the International Classification of Sleep Disorders (ICSD)-2 [AASM, 2005] or&#xD;
        'probable RBD' following a score of 6 or higher in the RBD questionnaire (RBDSQ) with a&#xD;
        score of at least 1 in subitems 6.1 to 6.4 of question 6.&#xD;
&#xD;
        At least one of the following:&#xD;
&#xD;
          1. Diagnosis of hyposmia. Diagnosis of hyposmia will be established as a University of&#xD;
             Pennsylvania Smell Identification Test (UPSIT) score &lt; 20th percentile for the&#xD;
             individual's age group and sex.&#xD;
&#xD;
          2. Functional constipation, assessed by a scores &gt; 4 on a questionnaire based on modified&#xD;
             ROME III diagnostic criteria.&#xD;
&#xD;
          3. Color vision abnormality, as assessed using HRR Pseudoisochromatic Plates, in the&#xD;
             absence of congenital dyschromatopsia.&#xD;
&#xD;
          4. Symptoms of depression, as assessed by a Beck Depression Inventory (BDI) fast screen&#xD;
             score &gt;3 or concurrent use of antidepressant medications&#xD;
&#xD;
               -  Abnormal 123I-MIBG myocardial scintigraphy, as defined by a Late H/M ratio &lt; 2.2&#xD;
                  and/or a WR &gt;30%, with normal cardiac ejection fraction (LVEF &gt;55%).&#xD;
&#xD;
               -  Capacity to give informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Secondary Parkinsonism, including tardive&#xD;
&#xD;
        Concurrent dementia defined by a score lower than 22 on the MoCA&#xD;
&#xD;
        Concurrent severe depression defined by a BDI fast screen score greater than 13&#xD;
&#xD;
        Comorbidities related to SNS hyperactivity&#xD;
&#xD;
        Heart failure (LVEF &lt;45%)&#xD;
&#xD;
        Recent myocardial revascularization (&lt;12 weeks)&#xD;
&#xD;
        Chronic Hypertension (SBP&gt;140mmHg-DBP&gt;90mmHg)&#xD;
&#xD;
        Atrial fibrillation&#xD;
&#xD;
        Diabetes mellitus&#xD;
&#xD;
        COPD&#xD;
&#xD;
        Sleep Apnea&#xD;
&#xD;
        Severely reduced kidney function (Glomerular Filtration Rate&lt;30ml/min)&#xD;
&#xD;
        Contraindications to the use of carvedilol&#xD;
&#xD;
        Asthma or bronchospasm&#xD;
&#xD;
        Recent myocardial infarction (&lt;48 h)&#xD;
&#xD;
        Ongoing unstable angina&#xD;
&#xD;
        Cardiogenic shock or prolonged hypotension&#xD;
&#xD;
        Second or Third-Degree AV block&#xD;
&#xD;
        Significant valvular aortic stenosis&#xD;
&#xD;
        Obstructive cardiomyopathy, or constrictive pericarditis&#xD;
&#xD;
        Symptomatic Bradycardia (HR&lt;60) or Sick Sinus Syndrome&#xD;
&#xD;
        Stroke within the past 1 month&#xD;
&#xD;
        Severe Hepatic Dysfunction&#xD;
&#xD;
        Allergy/hypersensitivity to iodine or study medication&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michele Tagliati, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Michele L Gregorio, PhD</last_name>
    <phone>4243150016</phone>
    <email>michele.gregorio@cshs.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Gloria Obialisi, MS</last_name>
    <phone>3104231704</phone>
    <email>gloria.obialisi@cshs.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Cedars Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Helia Maghzi, MD</last_name>
      <phone>310-423-6646</phone>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H. Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol. 2005 Jan;15(1):29-34. doi: 10.1111/j.1750-3639.2005.tb00097.x.</citation>
    <PMID>15779234</PMID>
  </reference>
  <reference>
    <citation>Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci. 2010 Jan;1184:15-54. doi: 10.1111/j.1749-6632.2009.05115.x.</citation>
    <PMID>20146689</PMID>
  </reference>
  <reference>
    <citation>Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. doi: 10.1016/s0197-4580(02)00065-9.</citation>
    <PMID>12498954</PMID>
  </reference>
  <reference>
    <citation>Bugalho P, Mendonca M, Lampreia T, Miguel R, Barbosa R, Salavisa M. Heart rate variability in Parkinson disease and idiopathic REM sleep behavior disorder. Clin Auton Res. 2018 Dec;28(6):557-564. doi: 10.1007/s10286-018-0557-4. Epub 2018 Aug 20.</citation>
    <PMID>30128681</PMID>
  </reference>
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  <verification_date>August 2022</verification_date>
  <study_first_submitted>December 9, 2018</study_first_submitted>
  <study_first_submitted_qc>December 11, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 13, 2018</study_first_posted>
  <last_update_submitted>August 23, 2022</last_update_submitted>
  <last_update_submitted_qc>August 23, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Cedars-Sinai Medical Center</investigator_affiliation>
    <investigator_full_name>Michele Tagliati, MD</investigator_full_name>
    <investigator_title>Professor and Vice Chairman, Director of Movement Disorders</investigator_title>
  </responsible_party>
  <keyword>Early Parkinson Disease</keyword>
  <keyword>REM Sleep Behaviour Disorder (RBD)</keyword>
  <keyword>carvedilol</keyword>
  <keyword>Autonomic dysfunction</keyword>
  <keyword>Neurodegeneration</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Parkinson Disease</mesh_term>
    <mesh_term>REM Sleep Behavior Disorder</mesh_term>
    <mesh_term>Parkinson Disease, Secondary</mesh_term>
    <mesh_term>Mental Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carvedilol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03775096
org study id: U1111-1223-7784
nct id: NCT03775096
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
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.
Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder of unknown
      etiology, characterized by bradykinesia (slowness of movements) associated with tremor at
      rest and/or muscle rigidity. PD is typically associated with a significant loss of
      dopaminergic neurons in the substantia nigra pars compacta(SNpc).The resulting nigro-striatal
      degeneration can be detected and quantified using a dopamine transporter (DAT) single photon
      emission computerized tomography (SPECT) imaging technique. This type of imaging, recently
      approved for clinical use in the United States, uses a labeled ligand (123I-Ioflupane) with
      high affinity to the DAT in the striatum. The amount of transporter, which plays a crucial
      role in the health of the presynaptic dopaminergic neurons, is then visualized by SPECT.
      123I-Ioflupane uptake is reduced 50-70% in patients with early PD.

      In addition to cardinal motor symptoms, PD is characterized by a large number of "non-motor"
      symptoms (NMS), which add to the overall morbidity burden. Importantly, non--motor features
      may precede the diagnosis of PD, sometimes by several years. They include autonomic
      (gastrointestinal dysfunction, cardiovascular dysfunction with orthostatic hypotension (OH),
      urinary and sexual dysfunction, and hyperhidrosis), sleep (impaired sleep initiation and
      maintenance, rapid eye movement behavior disorder (RBD), sleep apnea and excessive daytime
      sleepiness), sensory (pain, hyposmia, and visual dysfunction), and neuropsychiatric
      disturbances (anhedonia, apathy, anxiety, depression, panic attacks, dementia, and
      psychosis).

      Among NMS, cardiac dysautonomia is a common feature of PD, manifesting in 30% of patients as
      orthostatic hypotension, a symptom that is correlated to disease duration and severity.
      Cardiac sympathetic innervation (CSI) is also affected in PD and other synucleinopathies.
      Lewy Body (LB) pathology, widely considered a marker of PD when detected in the SNpc, is also
      found in the sinoatrial nodal ganglion and myocardium of PD patients at autopsy. Despite the
      high prevalence of both conditions, the relationship between CSI impairment and cardiac
      dysautonomia is still poorly understood.

      Iodine-123 meta-iodobenzylguanidine (123I-MIBG) is an inactive physiological analogue that
      mimics the kinetics of norepinephrine (NE) and competes with NE for active cardiac uptake
      into the postganglionic sympathetic nerve terminal, where it is stored into granules by NE
      transport proteins. 123I-MIBG myocardial scintigraphy, an accepted measure of CSI, is
      abnormal in PD patients, with a characteristic reduction of Heart/Mediastinum (H/M) ratio
      (early and late uptake) and an increased Washout Rate (WR). 123I-MIBG uptake impairment is
      specific to PD and other synucleinopathies and can be used to differentiate PD and dementia
      with Lewy bodies (DLB) from other disorders with similar neurological phenomenology such as
      multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal
      degeneration (CBD).

      123I-MIBG uptake deficit in PD is attributed to cardiac sympathetic denervation, based on
      neuropathological studies using tyrosine hydroxylase (TH) immunostaining in epicardial
      nerves. There is evidence of alpha-synuclein aggregation in the epicardial nerve fascicles -
      the distal axons of the cardiac sympathetic nerve - in subjects with incidental Lewy Body
      Disease (ILBD) at stage 2 or 3 of Braak staging with preserved TH immunoreactive axons,
      suggesting a preliminary stage in the development of cardiac sympathetic denervation.
      However, while 123I-MIBG myocardial scintigraphy abnormalities have been correlated with
      pre-motor symptoms like RBD, hyposmia and constipation, there is no pathological evidence of
      cardiac sympathetic denervation in subjects with signs of 123I-MIBG myocardial scintigraphy
      abnormality and recognized pre-motor symptoms of PD. Finally, despite the specific
      association with PD diagnosis, the relationship between CSI impairment and nigrostriatal
      degeneration is poorly understood. Two studies found a strong correlation between
      nigrostriatal dopaminergic degeneration, as measured by 123I Ioflupane SPECT, and CSI
      impairment at different stages of disease. 123I-MIBG uptake deficits have been correlated
      with the progression of the disease.

      Interestingly, CSI - and therefore 123I-MIBG cardiac uptake - is impaired in other chronic
      conditions such as Heart Failure (HF), Hypertension, Diabetes Mellitus, Chronic Obstructive
      Pulmonary Disease and Sleep Apnea, with an identical pattern of abnormality as the one
      detected in PD patients. As opposed to cardiac sympathetic denervation, 123I-MIBG cardiac
      uptake impairment in these chronic conditions - and in particular HF - is explained with the
      hyperactivity of the sympathetic nervous system (SNS) acting as compensatory mechanism
      related to specific organ failure (i.e. post-ischemic/idiopathic heart failure). In fact,
      123I-MIBG cardiac uptake is of prognostic value and can be used to stratify HF patients at
      risk for ventricular arrhythmias and sudden death. By reducing SNS hyperactivity, chronic
      treatment with beta-blockers improves 123I-MIBG cardiac uptake and reduces mortality in
      patients with HF.

      Many recognizable triggers for PD appear to be associated with increased sympathetic tone,
      including most notably brain traumatic injuries, but also microbiota perturbations, air
      pollution, heavy metals like iron and manganese, and finally aging itself. In addition, there
      is reason to believe that SNS overactivity might trigger the principal pre-motor symptoms of
      PD, including hyposmia, constipation and RBD. Finally, SNS overactivity typically drives
      reduced low-frequency heart rate variability (HRV), another clinical sign associated with
      pre-motor - particularly RBD - and early PD. Interestingly, low delayed uptake and high
      washout rate, the 123I-MIBG scintigraphy indices of increased adrenergic drive, are typically
      described in PD patients.

      Based on these considerations, the investigators hypothesize that 123I-MIBG cardiac
      impairment in neurodegenerative disease shares the same pathophysiology of other chronic
      conditions like HF, at least in the very early, pre-motor stages of development. Therefore,
      treatment of SNS hyperactivity with adrenergic blockers will improve cardiac sympathetic
      denervation in PD patients, providing evidence that this process is reversible. If this is
      true, the early detection of 123I-MIBG cardiac impairment in PD, particularly in the
      pre-motor phase, might create a considerable window of opportunity for treatment with
      adrenergic blockers - or similar compounds able to reduce SNS hyperactivity - which may
      result in long-term benefit such as delaying the neurodegenerative process and the onset of
      neurological symptoms. This may be documented and monitored using nigrostriatal dopaminergic
      scintigraphy (DAT scan), a strategy that would implement a dual imaging algorithm to provide
      early and viable biomarkers of the neurodegenerative process.

      Among adrenergic blockers, carvedilol is particularly well-suited to block impaired
      sympathetic over-activation in virtue of several effects on the adrenoceptors, including β-1
      and β-2 adrenergic blockade and α-1 adrenergic blockade, in addition to antioxidant activity,
      L-type calcium channel blockade, and inhibition of stress-activated protein kinase.
      Absorption of current oral formulations of carvedilol is typically rapid and complete, with
      an average elimination half -life of about 8 hours. The high lipophilic structure of
      carvedilol makes it one of the beta-blockers most readily crossing the blood brain barrier.
      Carvedilol is associated with greater reduction of sympathetic activity, as measured by
      123I-MIBG myocardial uptake, than metoprolol and other selective beta-blockers. In addition,
      due to its α-1 adrenergic blockade properties, carvedilol may exert beneficial effects on
      olfactory dysfunction and insulin resistance, two abnormalities frequently associated with
      the neurodegenerative process in PD. Adrenergic blockers have been associated with sleep
      disturbances including RBD, although the latter is based on isolated anecdotal reports. The
      negative effect of beta-blockers on sleep quality and duration appears to be related with the
      suppression of night time levels of melatonin. Interestingly however, carvedilol is not
      associated with melatonin suppression.

      The purpose of this pilot study is to investigate the effect of treatment with the adrenergic
      blocker carvedilol 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.
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.
primary purpose: Treatment
masking: None (Open Label)
measure: 123I-MIBG reuptake changes
time frame: 30 weeks
description: 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%.
measure: Adverse Events frequency
time frame: 30 weeks
description: 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.
measure: Heart rate variability changes
time frame: 30 weeks
description: 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.
measure: MDS-UPDRS part III changes
time frame: 30 weeks
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 OFF medication in those subjects that might be receiving dopaminergic drugs
measure: Sleep changes as measured by REM Behavior Disorder questionnaire
time frame: 30 weeks
description: RBD questionnaire (RBDSQ) changes from Screening at 26 weeks after study drug titration
measure: Smell changes as measured by University of Pennsylvania Smell Identification Test (UPSIT)
time frame: 30 weeks
description: University of Pennsylvania Smell Identification Test (UPSIT) changes from screening at 26 weeks after study medication titration
measure: Constipation score changes using a questionnaire based on modified ROME III diagnostic criteria
time frame: 30 weeks
description: 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.
measure: Color vision changes as measured by HRR Pseudochromatic Plates
time frame: 30 weeks
description: Color vision changes will be assessed using HRR Pseudochromatic Plates from screening at 26 weeks after study medication titration
measure: DAT scan Changes
time frame: 30 weeks
description: DaT/SPECT uptake at baseline will be quantified at baseline and 26 weeks after study medication titration
measure: Non-Motor Symptoms Scale (NMSS) changes
time frame: 30 weeks
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).
measure: Scopa-AUT changes
time frame: 30 weeks
description: 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.
measure: Peripheral insulin resistance changes
time frame: 30 weeks
description: 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.
measure: Central insulin resistance changes
time frame: 30 weeks
description: 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.
arm group label: carvedilol therapy
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Carvedilol
description: 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.
arm group label: carvedilol therapy
other name: Coreg
criteria: 
gender: All
minimum age: 25 Years
maximum age: 85 Years
healthy volunteers: No
last name: Michele Tagliati, MD
role: Principal Investigator
affiliation: Cedars-Sinai Medical Center
last name: Michele L Gregorio, PhD
phone: 4243150016
email: michele.gregorio@cshs.org
last name: Gloria Obialisi, MS
phone: 3104231704
email: gloria.obialisi@cshs.org
facility: 
status: Recruiting
contact: 
country: United States
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responsible party type: Sponsor-Investigator
investigator affiliation: Cedars-Sinai Medical Center
investigator full name: Michele Tagliati, MD
investigator title: Professor and Vice Chairman, Director of Movement Disorders
mesh term: Parkinson Disease
mesh term: REM Sleep Behavior Disorder
mesh term: Parkinson Disease, Secondary
mesh term: Mental Disorders
mesh term: Carvedilol
sharing ipd: No