<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/NCT02200887</url>
  </required_header>
  <id_info>
    <org_study_id>EOC-NSI.12.01</org_study_id>
    <nct_id>NCT02200887</nct_id>
  </id_info>
  <brief_title>Sleep Homeostasis in Parkinson's Disease</brief_title>
  <official_title>Role of Sleep Homeostasis in the Development of the L-Dopa Induced Dyskinesias in Patients With Parkinson's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Salvatore Galati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ospedale Civico, Lugano</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Parkinson's disease is characterized in the advanced phases by an altered response to&#xD;
      dopaminergic therapy for the occurrence of abnormal movements called dyskinesias, that&#xD;
      worsens the quality of life of the patient and exposes him to comorbidities. Several data&#xD;
      show a reduction in the amount of slow wave sleep that correlates inversely with disease&#xD;
      duration. Since this stage of sleep is linked to mechanisms of deletion of superfluous&#xD;
      information the investigators hypothesize that the onset of dyskinesias is related to such&#xD;
      alteration of sleep.&#xD;
&#xD;
      -This study is aimed to investigate, by means of high-density electroencephalography&#xD;
      (hd-EEG), the sleep and in particular the slow wave in order to clarify the relations with&#xD;
      the development of dyskinesias.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Wakefulness in PD is frequently interrupted by sleep episodes, even rapid eye movement sleep&#xD;
      (REM), whilst nocturnal sleep is disturbed by abnormal motor activity interference, such as&#xD;
      REM sleep behaviour disorder (RBD) or periodic limb movements (PLMS). Several lines of&#xD;
      evidence have suggested a close relation between sleep-wake changes and dopaminergic&#xD;
      degeneration in PD(1-7) while sleep disorders commonly precede the clinical motor onset by&#xD;
      many years (8,9). On the other hand, morning motor performance improvement is frequently&#xD;
      mentioned by patients, mainly in those with long disease duration and motor fluctuation&#xD;
      (10,11). Of note, the same state of vigilance can profoundly influence some clinical PD&#xD;
      features (for instance rigidity) as well as basal ganglia neuronal activity(12).&#xD;
&#xD;
      Few reports have shown changes in sleep architecture: a reduction of the amount of SWS in&#xD;
      parallel with disease duration (13-15) has been observed, but no study, so far, has addressed&#xD;
      how sleep may impact on LID. Once these abnormal movements develop, they are difficult to&#xD;
      treat and negatively affect the quality of life and the treatment costs of PD patients&#xD;
      (16,17). Although levodopa represents, so far, the more effective treatment for PD patients&#xD;
      (18,19) to ameliorate the cardinal signs such as bradykinesia/akinesia and rigidity (20), as&#xD;
      the disease progresses, these benefits are in some measure abolished by the emergence of&#xD;
      dyskinesia (21). During the early stages PD patients experience a rather satisfying quality&#xD;
      of life that is impeded in the advanced stages by the emerging of these involuntary movements&#xD;
      frequently at the peak of the levodopa effect (16,22,23). In other words, when the patients&#xD;
      experience these motor complications (shortening motor response and development of&#xD;
      dyskinesia) the delivery of levodopa without inducing dyskinesia becomes increasingly&#xD;
      difficult (21,24-27).&#xD;
&#xD;
      Several efforts have been made in order to find &quot;pure&quot; anti-dyskinetic drugs that are able to&#xD;
      uncouple the anti-akinetic effect from the dyskinetic response. Serotoninergic receptor&#xD;
      agonists were claimed to be drugs against dyskinesia (28), however, it was observed that they&#xD;
      may also impair levodopa efficacy (29-31). As of today, no clinical effective therapies are&#xD;
      able to alleviate dyskinesia without worsening parkinsonism.&#xD;
&#xD;
      Great efforts have been made to clarify LID pathogenesis, emphasizing the role of pulsative&#xD;
      stimulation of striatal receptors by dopaminergic treatment (25) and more recently, on&#xD;
      molecular changes of postsynaptic (32,33) or presynaptic mechanisms (34). Although no&#xD;
      conclusive results on LID pathogenesis have been achieved, indeed disease duration (i.e. the&#xD;
      degree of dopaminergic degeneration) rather than long-term use of levodopa, seems to play a&#xD;
      crucial role (22,23). This notion can be inferred from clinical practice, but is also evident&#xD;
      in MPTP-induced parkinsonism in humans in which the extended dopaminergic lesion caused&#xD;
      within a few days the development of dyskinesias undistinguishable from those in the&#xD;
      idiopathic form (35).&#xD;
&#xD;
      General Aim:&#xD;
&#xD;
      The study is aimed 1) to define abnormal cortical synaptic homeostasis, measured by means of&#xD;
      SWS and waking EEG evoked responses, as key components for the development of LID; 2) to&#xD;
      analyse the impact of anti-dyskinetic effect of rTMS on the SWA in additional ten PD patient&#xD;
      with LID.&#xD;
&#xD;
      Specific aims:&#xD;
&#xD;
        1. To compare, in the four groups of subjects (control, de novo, advanced without&#xD;
           dyskinesia, and advanced with dyskinesia), changes of the EEG features of NREM sleep:&#xD;
           slow wave/slow oscillation and sleep spindles. A significant reduction of the&#xD;
           physiological reduction of SWA in dyskinetic patients in comparison with the other&#xD;
           groups is expected.&#xD;
&#xD;
        2. To identify the homeostatic reduction of cortical synaptic strength (downscaling) in the&#xD;
           four categories of subjects by comparing late sleep (i.e. towards morning) SWA with&#xD;
           early sleep (i.e. at the beginning of the night) SWA as well as by comparing the&#xD;
           overnight changes in the amplitude of EEG somatosensory, auditory and visual evoked&#xD;
           responses recorded before and after sleep. The study is aimed to demonstrate the&#xD;
           reduction/absence of a physiological downscaling in dyskinetic patients versus the other&#xD;
           groups.&#xD;
&#xD;
        3. To analyse the effect of rTMS on SWA of PD patients with LID in order to demonstrate a&#xD;
           recovery of physiological downscaling of SWA in these patients parallel to the reduction&#xD;
           of dyskinesia.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2013</start_date>
  <completion_date type="Actual">June 2015</completion_date>
  <primary_completion_date type="Actual">June 2015</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Slow wave sleep</measure>
    <time_frame>1 night</time_frame>
    <description>Percentage of total sleep classified as slow wave sleep</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Amplitude of slow waves during sleep</measure>
    <time_frame>1 Night</time_frame>
    <description>Reduction of homeostatic synaptic plasticity during the time of sleep</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Actual">48</enrollment>
  <condition>Parkinson Disease</condition>
  <arm_group>
    <arm_group_label>Advanced Parkinsons Disease</arm_group_label>
    <description>Polysomnogram</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Parkinsons Disease with Dyskinesia</arm_group_label>
    <description>Polysomnogram</description>
  </arm_group>
  <arm_group>
    <arm_group_label>De novo Parkinsons Disease</arm_group_label>
    <description>Polysomnogram</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Volunteers</arm_group_label>
    <description>Polysomnogram</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Healthy volunteers and patients with parkinson disease&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  clinical characteristics of the patients must be according the UK (United Kingdom)&#xD;
             Brain Bank&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  anamnestic obstructive sleep apneas syndrome&#xD;
&#xD;
          -  known cognitive deterioration or with MMSE (Mini-Mental State Examination) ≤24/30&#xD;
&#xD;
          -  depression ≥ 20 of the BDI scale (Beck Depression Inventory)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Salvatore Galati, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ospedale Regionale di Lugano</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ospedale Regionale di Lugano</name>
      <address>
        <city>Lugano</city>
        <state>Ticino</state>
        <zip>6903</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
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  <verification_date>April 2018</verification_date>
  <study_first_submitted>July 24, 2014</study_first_submitted>
  <study_first_submitted_qc>July 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 25, 2014</study_first_posted>
  <last_update_submitted>April 5, 2018</last_update_submitted>
  <last_update_submitted_qc>April 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 9, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Ospedale Civico, Lugano</investigator_affiliation>
    <investigator_full_name>Salvatore Galati</investigator_full_name>
    <investigator_title>MD, head of service</investigator_title>
  </responsible_party>
  <keyword>Dyskinesia</keyword>
  <keyword>Slow Wave Sleep</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Parkinson Disease</mesh_term>
  </condition_browse>
  <!-- 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/NCT02200887
org study id: EOC-NSI.12.01
nct id: NCT02200887
lead sponsor: 
has dmc: No
Parkinson's disease is characterized in the advanced phases by an altered response to
      dopaminergic therapy for the occurrence of abnormal movements called dyskinesias, that
      worsens the quality of life of the patient and exposes him to comorbidities. Several data
      show a reduction in the amount of slow wave sleep that correlates inversely with disease
      duration. Since this stage of sleep is linked to mechanisms of deletion of superfluous
      information the investigators hypothesize that the onset of dyskinesias is related to such
      alteration of sleep.

      -This study is aimed to investigate, by means of high-density electroencephalography
      (hd-EEG), the sleep and in particular the slow wave in order to clarify the relations with
      the development of dyskinesias.
Wakefulness in PD is frequently interrupted by sleep episodes, even rapid eye movement sleep
      (REM), whilst nocturnal sleep is disturbed by abnormal motor activity interference, such as
      REM sleep behaviour disorder (RBD) or periodic limb movements (PLMS). Several lines of
      evidence have suggested a close relation between sleep-wake changes and dopaminergic
      degeneration in PD(1-7) while sleep disorders commonly precede the clinical motor onset by
      many years (8,9). On the other hand, morning motor performance improvement is frequently
      mentioned by patients, mainly in those with long disease duration and motor fluctuation
      (10,11). Of note, the same state of vigilance can profoundly influence some clinical PD
      features (for instance rigidity) as well as basal ganglia neuronal activity(12).

      Few reports have shown changes in sleep architecture: a reduction of the amount of SWS in
      parallel with disease duration (13-15) has been observed, but no study, so far, has addressed
      how sleep may impact on LID. Once these abnormal movements develop, they are difficult to
      treat and negatively affect the quality of life and the treatment costs of PD patients
      (16,17). Although levodopa represents, so far, the more effective treatment for PD patients
      (18,19) to ameliorate the cardinal signs such as bradykinesia/akinesia and rigidity (20), as
      the disease progresses, these benefits are in some measure abolished by the emergence of
      dyskinesia (21). During the early stages PD patients experience a rather satisfying quality
      of life that is impeded in the advanced stages by the emerging of these involuntary movements
      frequently at the peak of the levodopa effect (16,22,23). In other words, when the patients
      experience these motor complications (shortening motor response and development of
      dyskinesia) the delivery of levodopa without inducing dyskinesia becomes increasingly
      difficult (21,24-27).

      Several efforts have been made in order to find "pure" anti-dyskinetic drugs that are able to
      uncouple the anti-akinetic effect from the dyskinetic response. Serotoninergic receptor
      agonists were claimed to be drugs against dyskinesia (28), however, it was observed that they
      may also impair levodopa efficacy (29-31). As of today, no clinical effective therapies are
      able to alleviate dyskinesia without worsening parkinsonism.

      Great efforts have been made to clarify LID pathogenesis, emphasizing the role of pulsative
      stimulation of striatal receptors by dopaminergic treatment (25) and more recently, on
      molecular changes of postsynaptic (32,33) or presynaptic mechanisms (34). Although no
      conclusive results on LID pathogenesis have been achieved, indeed disease duration (i.e. the
      degree of dopaminergic degeneration) rather than long-term use of levodopa, seems to play a
      crucial role (22,23). This notion can be inferred from clinical practice, but is also evident
      in MPTP-induced parkinsonism in humans in which the extended dopaminergic lesion caused
      within a few days the development of dyskinesias undistinguishable from those in the
      idiopathic form (35).

      General Aim:

      The study is aimed 1) to define abnormal cortical synaptic homeostasis, measured by means of
      SWS and waking EEG evoked responses, as key components for the development of LID; 2) to
      analyse the impact of anti-dyskinetic effect of rTMS on the SWA in additional ten PD patient
      with LID.

      Specific aims:

        1. To compare, in the four groups of subjects (control, de novo, advanced without
           dyskinesia, and advanced with dyskinesia), changes of the EEG features of NREM sleep:
           slow wave/slow oscillation and sleep spindles. A significant reduction of the
           physiological reduction of SWA in dyskinetic patients in comparison with the other
           groups is expected.

        2. To identify the homeostatic reduction of cortical synaptic strength (downscaling) in the
           four categories of subjects by comparing late sleep (i.e. towards morning) SWA with
           early sleep (i.e. at the beginning of the night) SWA as well as by comparing the
           overnight changes in the amplitude of EEG somatosensory, auditory and visual evoked
           responses recorded before and after sleep. The study is aimed to demonstrate the
           reduction/absence of a physiological downscaling in dyskinetic patients versus the other
           groups.

        3. To analyse the effect of rTMS on SWA of PD patients with LID in order to demonstrate a
           recovery of physiological downscaling of SWA in these patients parallel to the reduction
           of dyskinesia.
observational model: Case-Control
time perspective: Cross-Sectional
measure: Slow wave sleep
time frame: 1 night
description: Percentage of total sleep classified as slow wave sleep
measure: Amplitude of slow waves during sleep
time frame: 1 Night
description: Reduction of homeostatic synaptic plasticity during the time of sleep
arm group label: Advanced Parkinsons Disease
description: Polysomnogram
arm group label: Parkinsons Disease with Dyskinesia
description: Polysomnogram
arm group label: De novo Parkinsons Disease
description: Polysomnogram
arm group label: Healthy Volunteers
description: Polysomnogram
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 45 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Salvatore Galati, MD
role: Principal Investigator
affiliation: Ospedale Regionale di Lugano
facility: 
country: Switzerland
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responsible party type: Sponsor-Investigator
investigator affiliation: Ospedale Civico, Lugano
investigator full name: Salvatore Galati
investigator title: MD, head of service
mesh term: Parkinson Disease