<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/NCT03250741</url>
  </required_header>
  <id_info>
    <org_study_id>EudraCT 2015-002965-43</org_study_id>
    <nct_id>NCT03250741</nct_id>
  </id_info>
  <brief_title>Effects of Dopaminergic Therapy in Patients With Alzheimer's Disease</brief_title>
  <acronym>DOPAD</acronym>
  <official_title>Effects of Dopaminergic Therapy in Patients With Alzheimer's Disease: a Phase II 24-week, Randomized, Double-blind Placebo Controlled Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>I.R.C.C.S. Fondazione Santa Lucia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>I.R.C.C.S. Fondazione Santa Lucia</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is phase IIa 24-week, prospective, randomized, double-blind placebo controlled study.&#xD;
      The study is designed to evaluate the efficacy, safety, and tolerability of transdermal patch&#xD;
      of Rotigotine (RTG) versus placebo (PLC) as add-on therapy with AChEI in patients with mild&#xD;
      AD according to the consensus diagnostic criteria and MMSE score of ≥18 and ≤24 at screening.&#xD;
      Two groups of patients with mild AD will be involved (50 patients each). One group will be&#xD;
      assigned to treatment with RTG 4 mg and the other one to PLC as add on to AChEI therapy&#xD;
      (Rivastigmine). Clinical and neurophysiological measurements will be collected before and&#xD;
      after drug administration.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The current study has the ambition to provide first time evidence that dopaminergic&#xD;
      stimulation may have a clinical impact in patients with mild AD.&#xD;
&#xD;
      Cognitive Assessment: Before and after the 24 weeks of treatment the ADAS-Cog, ADCS-ADL and&#xD;
      the Frontal assessment battery (FAB) will be administered. FAB will be performed to measure&#xD;
      changes in frontal executive functions (Apollonio et al, 2005) .&#xD;
&#xD;
      Neurophysiological investigations will be performed to identify quantifiable biomarkers&#xD;
      underlying the effects induced by dopamine agonist on the neurodegenerative brain. The&#xD;
      application of recent neurophysiological tools, such as the combined use of transcranial&#xD;
      magnetic stimulation (TMS) during electroencephalography (EEG) will allow to measure how&#xD;
      dopamine agonists are able to modulate the cortical activity of the prefrontal cortex in AD&#xD;
      patients (Kähkönen et al., 2005; Julkunen et al., 2008), likely trough DA terminals&#xD;
      originating from the ventral tegmental nucleus, defining the neurophysiological biomarkers of&#xD;
      clinical improvement For EEG-TMS recordings, a TMS-compatible EEG equipment will be used for&#xD;
      recording EEG activity from the scalp (BrainAmp 32MRplus, BrainProducts). The EEG will be&#xD;
      continuously acquired from 64 scalp sites positioned according to the 10-20 International&#xD;
      System. To precisely position the coil over the cortical sites across different sessions, a&#xD;
      neuronavigation system (Softaxic, E.M.S.) will be used. Neurophysiological changes induced by&#xD;
      dopamine-agonist will be indexed by the following measures: corticospinal excitability,&#xD;
      cortical reactivity, connectivity and plasticity. Specifically, the cortical reactivity and&#xD;
      cortico-cortical connectivity will be evaluated respectively over the prefrontal cortex and&#xD;
      between connected areas. We will employ TMS-evoked cortical responses (i.e., TEPs) as a novel&#xD;
      probe of dopamine-agonist induced cortical excitability changes (Ilmoniemi et al., 1997;&#xD;
      Komssi and Kahkonen, 2006; Julkunen et al., 2008; Miniussi and Thut, 2009; Miniussi et al.,&#xD;
      2012; Premoli et al., 2014). To reach this aim, TEPs will serve as markers of left prefrontal&#xD;
      cortex (PFC) reactivity whereas the spreading of their cortical activation will serve as an&#xD;
      index of connectivity between targeted cortex and functionally connected areas underlying&#xD;
      frontal cognitive network.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 2016</start_date>
  <completion_date type="Actual">November 2018</completion_date>
  <primary_completion_date type="Actual">November 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Global cognition</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Frontal cognitive functions</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>Frontal assessment battery (FAB)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Activities of daily living</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>Alzheimer's disease Cooperative Study - Activities of Daily Living (ADCS-ADL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurophysiological markers of cortical activity</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>TEP amplitude over the PFC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychiatric evaluation</measure>
    <time_frame>change from baseline to Week 24</time_frame>
    <description>Neuropsychiatric Inventory (NPI)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">94</enrollment>
  <condition>Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>Rotigotine 4 mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Rotigotine transdermal patches 4 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo transdermal patches</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rotigotine transdermal patch</intervention_name>
    <description>Rotigotine transdermal patches 4mg/24hr</description>
    <arm_group_label>Rotigotine 4 mg</arm_group_label>
    <other_name>ROTIGOTINE</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo transdermal patches of the same size as for Rotigotine transdermal patches</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo transdermal patch</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The patient (or if applicable the legally acceptable representative if different from&#xD;
             the responsible caregiver) and the responsible caregiver have signed the Informed&#xD;
             Consent Form.&#xD;
&#xD;
          2. The patient has probable AD, diagnosed according to National Institute of Neurological&#xD;
             and Communicative Disorders and Stroke and the Alzheimer's Disease and Related&#xD;
             Disorders Association (NINCDS-ADRDA) criteria.&#xD;
&#xD;
          3. The patient is a man or woman, aged ≤ 85 years.&#xD;
&#xD;
          4. The patient has a Clinical Dementia Rating (CDR) total score of 0.5 or 1 (mild) and&#xD;
             MMSE score of 20-26 (inclusive) at Screening.&#xD;
&#xD;
          5. Has at least one identified adult caregiver who is able to provide meaningful&#xD;
             assessment of changes in subject behavior and function over time and provide&#xD;
             information on safety and tolerability, and is able to verify daily compliance with&#xD;
             study drug&#xD;
&#xD;
          6. The patient has been treated with acetylcholinesterase inhibitor (AChEI), i.e.,&#xD;
             donepezil, galantamine, or rivastigmine, at the time of Screening&#xD;
&#xD;
               -  For at least 3 months&#xD;
&#xD;
               -  The current dosage regimen and must have remained stable for ≥ 8 weeks&#xD;
&#xD;
               -  It must be planned that the dosage regimen will remain stable throughout&#xD;
                  participation in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Significant neurodegenerative disorder of the central nervous system other than&#xD;
             Alzheimer's disease, e.g., Lewy body dementia, Parkinson's disease, multiple&#xD;
             sclerosis, progressive supranuclear palsy, hydrocephalus, Huntington's disease, any&#xD;
             condition directly or indirectly caused by Transmissible Spongiform Encephalopathy&#xD;
             (TSE), Creutzfeldt-Jakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), or&#xD;
             new variant Creutzfeldt-Jakob Disease (nvCJD)&#xD;
&#xD;
          2. The patients has history of seizure (with the exception of febrile seizures in&#xD;
             childhood)&#xD;
&#xD;
          3. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision&#xD;
             (DSM IV-TR) criteria met for any of the following within specified period:&#xD;
&#xD;
               -  Major depressive disorder (current)&#xD;
&#xD;
               -  Schizophrenia (lifetime)&#xD;
&#xD;
               -  Other psychotic disorders, bipolar disorder, or substance (including alcohol)&#xD;
                  related disorders (within the past 5 years)&#xD;
&#xD;
          4. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other&#xD;
             non-removable items that are contraindications to MR imaging.&#xD;
&#xD;
          5. Evidence of clinically significant disease including but not limited to pulmonary,&#xD;
             gastrointestinal, renal, hepatic, endocrine, cardiovascular or metabolic disorder&#xD;
             (Patients with controlled diabetes, or hypertension, or complete/partial right bundle&#xD;
             branch block may be included in the study).&#xD;
&#xD;
          6. Treatment currently or within 6 months before Baseline with any of the following&#xD;
             medications:&#xD;
&#xD;
               -  Typical and atypical antipsychotics (i.e. Clozapine, Olanzapine)&#xD;
&#xD;
               -  Antiparkinson agents (e.g., levodopa, dopamine agonists, COMT inhibitors,&#xD;
                  amantadine, monoamine oxidase B inhibitors, anticholinergics etc)&#xD;
&#xD;
               -  Carbamazepine, Primidone, Pregabalin, Gabapentin&#xD;
&#xD;
               -  Memantine&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alessandro Martorana, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>University of Rome Tor Vergata</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Giacomo Koch, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Santa Lucia Foundation IRCCS</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Santa Lucia Foundation</name>
      <address>
        <city>Rome</city>
        <zip>00179</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Martorana A, Di Lorenzo F, Esposito Z, Lo Giudice T, Bernardi G, Caltagirone C, Koch G. Dopamine D(2)-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer's disease patients. Neuropharmacology. 2013 Jan;64:108-13. doi: 10.1016/j.neuropharm.2012.07.015. Epub 2012 Aug 1.</citation>
    <PMID>22863599</PMID>
  </reference>
  <results_reference>
    <citation>Martorana A, Koch G. &quot;Is dopamine involved in Alzheimer's disease?&quot;. Front Aging Neurosci. 2014 Sep 25;6:252. doi: 10.3389/fnagi.2014.00252. eCollection 2014.</citation>
    <PMID>25309431</PMID>
  </results_reference>
  <results_reference>
    <citation>Koch G, Di Lorenzo F, Bonni S, Giacobbe V, Bozzali M, Caltagirone C, Martorana A. Dopaminergic modulation of cortical plasticity in Alzheimer's disease patients. Neuropsychopharmacology. 2014 Oct;39(11):2654-61. doi: 10.1038/npp.2014.119. Epub 2014 May 26.</citation>
    <PMID>24859851</PMID>
  </results_reference>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>August 11, 2017</study_first_submitted>
  <study_first_submitted_qc>August 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 16, 2017</study_first_posted>
  <last_update_submitted>December 14, 2018</last_update_submitted>
  <last_update_submitted_qc>December 14, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 17, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>I.R.C.C.S. Fondazione Santa Lucia</investigator_affiliation>
    <investigator_full_name>Giacomo Koch</investigator_full_name>
    <investigator_title>PI</investigator_title>
  </responsible_party>
  <keyword>Rotigotine</keyword>
  <keyword>Dopamine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rotigotine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03250741
org study id: EudraCT 2015-002965-43
nct id: NCT03250741
lead sponsor: 
has dmc: No
is fda regulated drug: No
is us export: No
This is phase IIa 24-week, prospective, randomized, double-blind placebo controlled study.
      The study is designed to evaluate the efficacy, safety, and tolerability of transdermal patch
      of Rotigotine (RTG) versus placebo (PLC) as add-on therapy with AChEI in patients with mild
      AD according to the consensus diagnostic criteria and MMSE score of ≥18 and ≤24 at screening.
      Two groups of patients with mild AD will be involved (50 patients each). One group will be
      assigned to treatment with RTG 4 mg and the other one to PLC as add on to AChEI therapy
      (Rivastigmine). Clinical and neurophysiological measurements will be collected before and
      after drug administration.
The current study has the ambition to provide first time evidence that dopaminergic
      stimulation may have a clinical impact in patients with mild AD.

      Cognitive Assessment: Before and after the 24 weeks of treatment the ADAS-Cog, ADCS-ADL and
      the Frontal assessment battery (FAB) will be administered. FAB will be performed to measure
      changes in frontal executive functions (Apollonio et al, 2005) .

      Neurophysiological investigations will be performed to identify quantifiable biomarkers
      underlying the effects induced by dopamine agonist on the neurodegenerative brain. The
      application of recent neurophysiological tools, such as the combined use of transcranial
      magnetic stimulation (TMS) during electroencephalography (EEG) will allow to measure how
      dopamine agonists are able to modulate the cortical activity of the prefrontal cortex in AD
      patients (Kähkönen et al., 2005; Julkunen et al., 2008), likely trough DA terminals
      originating from the ventral tegmental nucleus, defining the neurophysiological biomarkers of
      clinical improvement For EEG-TMS recordings, a TMS-compatible EEG equipment will be used for
      recording EEG activity from the scalp (BrainAmp 32MRplus, BrainProducts). The EEG will be
      continuously acquired from 64 scalp sites positioned according to the 10-20 International
      System. To precisely position the coil over the cortical sites across different sessions, a
      neuronavigation system (Softaxic, E.M.S.) will be used. Neurophysiological changes induced by
      dopamine-agonist will be indexed by the following measures: corticospinal excitability,
      cortical reactivity, connectivity and plasticity. Specifically, the cortical reactivity and
      cortico-cortical connectivity will be evaluated respectively over the prefrontal cortex and
      between connected areas. We will employ TMS-evoked cortical responses (i.e., TEPs) as a novel
      probe of dopamine-agonist induced cortical excitability changes (Ilmoniemi et al., 1997;
      Komssi and Kahkonen, 2006; Julkunen et al., 2008; Miniussi and Thut, 2009; Miniussi et al.,
      2012; Premoli et al., 2014). To reach this aim, TEPs will serve as markers of left prefrontal
      cortex (PFC) reactivity whereas the spreading of their cortical activation will serve as an
      index of connectivity between targeted cortex and functionally connected areas underlying
      frontal cognitive network.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Global cognition
time frame: change from baseline to Week 24
description: Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)
measure: Frontal cognitive functions
time frame: change from baseline to Week 24
description: Frontal assessment battery (FAB)
measure: Activities of daily living
time frame: change from baseline to Week 24
description: Alzheimer's disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
measure: Neurophysiological markers of cortical activity
time frame: change from baseline to Week 24
description: TEP amplitude over the PFC
measure: Neuropsychiatric evaluation
time frame: change from baseline to Week 24
description: Neuropsychiatric Inventory (NPI)
arm group label: Rotigotine 4 mg
arm group type: Active Comparator
description: Rotigotine transdermal patches 4 mg
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo transdermal patches
intervention type: Drug
intervention name: Rotigotine transdermal patch
description: Rotigotine transdermal patches 4mg/24hr
arm group label: Rotigotine 4 mg
other name: ROTIGOTINE
intervention type: Other
intervention name: Placebo
description: Placebo transdermal patches of the same size as for Rotigotine transdermal patches
arm group label: Placebo
other name: Placebo transdermal patch
criteria: 
gender: All
minimum age: 50 Years
maximum age: 85 Years
healthy volunteers: No
last name: Alessandro Martorana, MD, PhD
role: Study Director
affiliation: University of Rome Tor Vergata
last name: Giacomo Koch, MD, PhD
role: Principal Investigator
affiliation: Santa Lucia Foundation IRCCS
facility: 
country: Italy
citation: Martorana A, Di Lorenzo F, Esposito Z, Lo Giudice T, Bernardi G, Caltagirone C, Koch G. Dopamine D(2)-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer's disease patients. Neuropharmacology. 2013 Jan;64:108-13. doi: 10.1016/j.neuropharm.2012.07.015. Epub 2012 Aug 1.
PMID: 22863599
citation: Martorana A, Koch G. "Is dopamine involved in Alzheimer's disease?". Front Aging Neurosci. 2014 Sep 25;6:252. doi: 10.3389/fnagi.2014.00252. eCollection 2014.
PMID: 25309431
citation: Koch G, Di Lorenzo F, Bonni S, Giacobbe V, Bozzali M, Caltagirone C, Martorana A. Dopaminergic modulation of cortical plasticity in Alzheimer's disease patients. Neuropsychopharmacology. 2014 Oct;39(11):2654-61. doi: 10.1038/npp.2014.119. Epub 2014 May 26.
PMID: 24859851
responsible party type: Principal Investigator
investigator affiliation: I.R.C.C.S. Fondazione Santa Lucia
investigator full name: Giacomo Koch
investigator title: PI
mesh term: Alzheimer Disease
mesh term: Rotigotine
sharing ipd: Undecided