<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/NCT03762746</url>
  </required_header>
  <id_info>
    <org_study_id>17-03-0206</org_study_id>
    <nct_id>NCT03762746</nct_id>
  </id_info>
  <brief_title>Transcranial Magnetic Stimulation (TMS) for Patients With Treatment Resistant Auditory Verbal Hallucination</brief_title>
  <acronym>TMS</acronym>
  <official_title>TMS for Treatment Resistant Auditory Verbal Hallucination in Schizophrenia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dr Cipto Mangunkusumo General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Dr Cipto Mangunkusumo General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) in&#xD;
      schizophrenia with treatment resistant auditory verbal hallucination&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Brief summary:&#xD;
&#xD;
      This study will evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) in&#xD;
      schizophrenia with treatment resistant auditory hallucination&#xD;
&#xD;
      Detailed description:&#xD;
&#xD;
      Auditory verbal hallucinations in schizophrenia disorders have been proposed to be associated&#xD;
      with a source- monitoring deficit. The improvement of the monitoring deficit will have major&#xD;
      impact on the improvement of hallucinatory symptoms and the social function. Brain network&#xD;
      considered to play a major role in source monitoring is the default mode (DM) network. An&#xD;
      increasing activity during the brain's resting phase and decreasing activity during&#xD;
      stimulus-induced brain activity, increased rest activity in the primary auditory cortex which&#xD;
      contributes to conditions, internal speech perceived as a tangible external sound, triggering&#xD;
      the occurrence of verbal auditory hallucinations in schizophrenic disorders.&#xD;
&#xD;
      This study will determine if&#xD;
&#xD;
      1-Hz low-frequency, transcranial repetitive magnetic stimulus could be used to inhibit&#xD;
      hyperconnectivity between these DM networks and other brain regions, allowing the&#xD;
      source-monitoring capability to function properly. This study will measure the oscillatory&#xD;
      strength and functional connectivity in the DM network via EEG resting-state activity in&#xD;
      schizophrenic with auditory hallucinations before and after rTMS administration. With a&#xD;
      seed-based analysis, using the region of interest (ROIs) in the posterior cortex area of the&#xD;
      cortex (PPC), precuneus area (PCu), the inferior parietal area (IPC), the medial temporal&#xD;
      (MT) area, the medial frontal area (MFC) and the singulatum cortex anterior (ACC) in&#xD;
      bilateral hemispheres to create an EEG-based brain activity mapping, measuring cortical&#xD;
      spectral power and functional connectivity in the ROIs.&#xD;
&#xD;
      Before starting rTMS, participants will undergo : (1) general and psychiatric assessment, (2)&#xD;
      neuropsychological test to evaluate hallucination and source-monitoring ability, (3) an EEG&#xD;
      recording (which takes about 1 hour). After these assessment are completed, participants will&#xD;
      be randomly assigned (by computer program) to receive either 1 Hz frequency rTMS or placebo&#xD;
      stimulation for 20 minutes per day over a 10-day period. During this time, the participants&#xD;
      will not know whether they received real or placebo TMS. For 10-days, stimulation will be&#xD;
      administered to an area of the left temporal lobe of the brain (temporo-parietal junction).&#xD;
&#xD;
      After trial is completed, participants will be told if they received real or placebo. If the&#xD;
      participants have receive only place stimulation, they will then be offered a trial of real&#xD;
      rTMS.&#xD;
&#xD;
      TMS is not causing pain, but it can be uncomfortable due to a tingling or knocking sensation,&#xD;
      contraction of scalp and facial muscles. There is also a small risk of seizure associated&#xD;
      with TMS, but because of the lower frequency of stimulation used in this study (1 stimulation&#xD;
      per second), this risk is significant only for participants who have a prior history of&#xD;
      seizures, epilepsy, or other neurological problem. Investigators are also concerned that TMS&#xD;
      may cause hearing problems. Therefore, investigators will carefully monitor participants for&#xD;
      early signs of such problem, using hearing-safety aid to every stimulation session. If&#xD;
      investigators suspect that a participant is experiencing problems with hearing, the trial is&#xD;
      stopped.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 1, 2018</start_date>
  <completion_date type="Anticipated">February 1, 2019</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2018</primary_completion_date>
  <phase>Phase 3</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>
    <intervention_model_description>Forty schizophrenic or schizoaffective patients with predominant audiotoric hallucinatory symptoms will be given rTMS 1 Hz intervention, 1000-pulse train, 20 min, 90% strength, 1000 pulse in left temporo-parietal cortex for 10 consecutive days (except holidays). Assessment of DN network connectivity in the brain using the results of brain wave decomposition analysis with EEGLAB. For measurement of auditor hall of hallucinations used Indonesian-Psychosis Symptom Rating Scale (INA-PSYRATS) instrument. Source monitoring capability using the INA-Source Monitoring instrument.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
    <masking_description>We apply blinding status of trial participants, care providers, and outcome assessors. We are using TMS sham-coil with similarities in appearance, sound, heavy; also we have the timing of final unblinding of all trial participants</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Hallucinations change</measure>
    <time_frame>2 weeks</time_frame>
    <description>Hallucinations score by Indonesia Version-Psychotic Symptom Rating Scale or PSYRATS. This auditory hallucination scale included 11 items and rated from zero to four. Symptoms over the last week will rated. The dimensions of auditory hallucinations are: frequency, duration, location, loudness, beliefs about origin, negative content, intensity of negative content, amount of distress, intensity of distress, disruption of life and control. Investigators will measure hallucination score before and after 10 session TMS. Total score consist of averaged score of dimensions. A higher score represent a worse outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Source-monitoring ability</measure>
    <time_frame>2 weeks</time_frame>
    <description>Source-monitoring score by source monitoring task performance. Participants will ask to distinguish word between 10 silent reading and 10 covert reading and 10 new non-presented word, before TMS and after 10 session TMS. Words are current Indonesian word extract from a verbal fluency task. During the test, word will be presented during 3 seconds on a computer screen.&#xD;
To evaluate the source monitoring performance, investigators will consider source attribution, corresponding to number incorrect attribution for source. Score range is between 0-20 A higher total score represents a worse outcome.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>electrophysiological changes</measure>
    <time_frame>2 weeks</time_frame>
    <description>This study will investigate all frequency bands (delta, theta, alpha, beta, gamma) coherence in each region of interest of default-mode network. To examine whether functional connectivity between DMN structures differs before and after TMS, the average EEG time series for all nodes in each seed ROI will normalize using transformation and correlations will perform with all other seeds in the DMN network in a 9×9 correlation matrix. The resulting correlation coefficients for each participant will then compare using a two-sided samples t-test to evaluate between-group differences in ROI-ROI connectivity for each seed. A score will represent a functional connectivity between ROIs</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Hallucinations, Verbal Auditory</condition>
  <arm_group>
    <arm_group_label>Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intervention with transcranial magnetic stimulation (TMS) low frequency 1 Hz , 1000-pulse train, 20 minutes, 90% motor threshold in left temporo-parietal cortex for 10 consecutive days for 20 schizophrenia patients with auditory hallucination</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Control group is received treatment as usual</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Transcranial Magnetic Stimulation</intervention_name>
    <description>A custom TMS stimulator (MagStim) is used to generate repetitive biphasic magnetic pulses. Magnetic pulses are delivered with a figure-8-coil (Magnetic Coil Transducer). During the experiment, rTMS pulse intensity is adjusted to 90% of the motor threshold. Patients will be randomly assigned to receive a 1 Hz. The target area is stimulated for 10 consecutive days. Stimulation at 1 Hz was applied once a day for 10-days</description>
    <arm_group_label>Active</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Control</intervention_name>
    <description>The control group is receiving treatment as usual. EEG recording and psychopathological ratings are performed one day before the start and on the last day of the study</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Met the criteria of all types of schizophrenia or schizoaffective based on structured&#xD;
             clinical interview instruments for the DSM-IV axis I disorders (SCID-I)&#xD;
&#xD;
          2. Patients had entered the stabilization phase with 2 to 3 months of antipsychotic&#xD;
             treatment and no drug changes within the last 2 (two) months&#xD;
&#xD;
          3. Elementary school graduated (minimum)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with a history of stroke, heart failure, head injury, infection or brain&#xD;
             tumor, epilepsy, alcohol and opiate abuse, amphetamines obtained from anamnesis,&#xD;
             physical examination and patient medical records&#xD;
&#xD;
          2. Patients with neurological focal deficits such as hemiparesis and cranial nerve&#xD;
             paresis&#xD;
&#xD;
          3. Patients with severe cognitive deficits (MMSE scores &lt;25 in the first and second&#xD;
             graders of Senior Secondary School and &lt;21 in Primary School Graduates)&#xD;
&#xD;
          4. Patients with severe hearing loss were assessed with a 5-word auditory test&#xD;
&#xD;
          5. Patients with mental retardation, assessed using the Wechsler Test of Adult Reading&#xD;
             (WTAR) test and data from medical records.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>59 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Khamelia Malik, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Psychiatry, RSCM</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Khamelia Malik, MD</last_name>
    <phone>+6181281296600</phone>
    <email>khameliapsi@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Nurmiati Amir, MD</last_name>
    <phone>+6281316111953</phone>
    <email>nurmiati.a@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Department of Psychiatry, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital Jakarta</name>
      <address>
        <city>Jakarta Pusat</city>
        <state>DKI Jakarta</state>
        <country>Indonesia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kristiana Siste, MD</last_name>
      <phone>+6287782516771</phone>
      <email>ksiste@yahoo.com</email>
    </contact>
    <investigator>
      <last_name>Khamelia Malik, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Nurmiati Amir, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Alfonsus Edward, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Indonesia</country>
  </location_countries>
  <reference>
    <citation>Kubera KM, Barth A, Hirjak D, Thomann PA, Wolf RC. Noninvasive brain stimulation for the treatment of auditory verbal hallucinations in schizophrenia: methods, effects and challenges. Front Syst Neurosci. 2015 Oct 12;9:131. doi: 10.3389/fnsys.2015.00131. eCollection 2015.</citation>
    <PMID>26528145</PMID>
  </reference>
  <reference>
    <citation>Ray P, Sinha VK, Tikka SK. Adjuvant low-frequency rTMS in treating auditory hallucinations in recent-onset schizophrenia: a randomized controlled study investigating the effect of high-frequency priming stimulation. Ann Gen Psychiatry. 2015 Feb 15;14:8. doi: 10.1186/s12991-015-0046-2. eCollection 2015.</citation>
    <PMID>25699086</PMID>
  </reference>
  <reference>
    <citation>Moseley P, Fernyhough C, Ellison A. Auditory verbal hallucinations as atypical inner speech monitoring, and the potential of neurostimulation as a treatment option. Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 2):2794-805. doi: 10.1016/j.neubiorev.2013.10.001. Epub 2013 Oct 12.</citation>
    <PMID>24125858</PMID>
  </reference>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>February 23, 2018</study_first_submitted>
  <study_first_submitted_qc>November 30, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 4, 2018</study_first_posted>
  <last_update_submitted>November 30, 2018</last_update_submitted>
  <last_update_submitted_qc>November 30, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 4, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dr Cipto Mangunkusumo General Hospital</investigator_affiliation>
    <investigator_full_name>Khamelia Malik</investigator_full_name>
    <investigator_title>Head Psychiatry Research and Development Unit</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hallucinations</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>research protocols, analysis</ipd_description>
  </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/NCT03762746
org study id: 17-03-0206
nct id: NCT03762746
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: Yes
is us export: Yes
This study will evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) in
      schizophrenia with treatment resistant auditory verbal hallucination
Brief summary:

      This study will evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) in
      schizophrenia with treatment resistant auditory hallucination

      Detailed description:

      Auditory verbal hallucinations in schizophrenia disorders have been proposed to be associated
      with a source- monitoring deficit. The improvement of the monitoring deficit will have major
      impact on the improvement of hallucinatory symptoms and the social function. Brain network
      considered to play a major role in source monitoring is the default mode (DM) network. An
      increasing activity during the brain's resting phase and decreasing activity during
      stimulus-induced brain activity, increased rest activity in the primary auditory cortex which
      contributes to conditions, internal speech perceived as a tangible external sound, triggering
      the occurrence of verbal auditory hallucinations in schizophrenic disorders.

      This study will determine if

      1-Hz low-frequency, transcranial repetitive magnetic stimulus could be used to inhibit
      hyperconnectivity between these DM networks and other brain regions, allowing the
      source-monitoring capability to function properly. This study will measure the oscillatory
      strength and functional connectivity in the DM network via EEG resting-state activity in
      schizophrenic with auditory hallucinations before and after rTMS administration. With a
      seed-based analysis, using the region of interest (ROIs) in the posterior cortex area of the
      cortex (PPC), precuneus area (PCu), the inferior parietal area (IPC), the medial temporal
      (MT) area, the medial frontal area (MFC) and the singulatum cortex anterior (ACC) in
      bilateral hemispheres to create an EEG-based brain activity mapping, measuring cortical
      spectral power and functional connectivity in the ROIs.

      Before starting rTMS, participants will undergo : (1) general and psychiatric assessment, (2)
      neuropsychological test to evaluate hallucination and source-monitoring ability, (3) an EEG
      recording (which takes about 1 hour). After these assessment are completed, participants will
      be randomly assigned (by computer program) to receive either 1 Hz frequency rTMS or placebo
      stimulation for 20 minutes per day over a 10-day period. During this time, the participants
      will not know whether they received real or placebo TMS. For 10-days, stimulation will be
      administered to an area of the left temporal lobe of the brain (temporo-parietal junction).

      After trial is completed, participants will be told if they received real or placebo. If the
      participants have receive only place stimulation, they will then be offered a trial of real
      rTMS.

      TMS is not causing pain, but it can be uncomfortable due to a tingling or knocking sensation,
      contraction of scalp and facial muscles. There is also a small risk of seizure associated
      with TMS, but because of the lower frequency of stimulation used in this study (1 stimulation
      per second), this risk is significant only for participants who have a prior history of
      seizures, epilepsy, or other neurological problem. Investigators are also concerned that TMS
      may cause hearing problems. Therefore, investigators will carefully monitor participants for
      early signs of such problem, using hearing-safety aid to every stimulation session. If
      investigators suspect that a participant is experiencing problems with hearing, the trial is
      stopped.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Forty schizophrenic or schizoaffective patients with predominant audiotoric hallucinatory symptoms will be given rTMS 1 Hz intervention, 1000-pulse train, 20 min, 90% strength, 1000 pulse in left temporo-parietal cortex for 10 consecutive days (except holidays). Assessment of DN network connectivity in the brain using the results of brain wave decomposition analysis with EEGLAB. For measurement of auditor hall of hallucinations used Indonesian-Psychosis Symptom Rating Scale (INA-PSYRATS) instrument. Source monitoring capability using the INA-Source Monitoring instrument.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Outcomes Assessor)
masking description: We apply blinding status of trial participants, care providers, and outcome assessors. We are using TMS sham-coil with similarities in appearance, sound, heavy; also we have the timing of final unblinding of all trial participants
measure: Hallucinations change
time frame: 2 weeks
description: Hallucinations score by Indonesia Version-Psychotic Symptom Rating Scale or PSYRATS. This auditory hallucination scale included 11 items and rated from zero to four. Symptoms over the last week will rated. The dimensions of auditory hallucinations are: frequency, duration, location, loudness, beliefs about origin, negative content, intensity of negative content, amount of distress, intensity of distress, disruption of life and control. Investigators will measure hallucination score before and after 10 session TMS. Total score consist of averaged score of dimensions. A higher score represent a worse outcome.
measure: Source-monitoring ability
time frame: 2 weeks
description: Source-monitoring score by source monitoring task performance. Participants will ask to distinguish word between 10 silent reading and 10 covert reading and 10 new non-presented word, before TMS and after 10 session TMS. Words are current Indonesian word extract from a verbal fluency task. During the test, word will be presented during 3 seconds on a computer screen.
To evaluate the source monitoring performance, investigators will consider source attribution, corresponding to number incorrect attribution for source. Score range is between 0-20 A higher total score represents a worse outcome.
measure: electrophysiological changes
time frame: 2 weeks
description: This study will investigate all frequency bands (delta, theta, alpha, beta, gamma) coherence in each region of interest of default-mode network. To examine whether functional connectivity between DMN structures differs before and after TMS, the average EEG time series for all nodes in each seed ROI will normalize using transformation and correlations will perform with all other seeds in the DMN network in a 9×9 correlation matrix. The resulting correlation coefficients for each participant will then compare using a two-sided samples t-test to evaluate between-group differences in ROI-ROI connectivity for each seed. A score will represent a functional connectivity between ROIs
arm group label: Active
arm group type: Active Comparator
description: Intervention with transcranial magnetic stimulation (TMS) low frequency 1 Hz , 1000-pulse train, 20 minutes, 90% motor threshold in left temporo-parietal cortex for 10 consecutive days for 20 schizophrenia patients with auditory hallucination
arm group label: Control
arm group type: Sham Comparator
description: Control group is received treatment as usual
intervention type: Device
intervention name: Transcranial Magnetic Stimulation
description: A custom TMS stimulator (MagStim) is used to generate repetitive biphasic magnetic pulses. Magnetic pulses are delivered with a figure-8-coil (Magnetic Coil Transducer). During the experiment, rTMS pulse intensity is adjusted to 90% of the motor threshold. Patients will be randomly assigned to receive a 1 Hz. The target area is stimulated for 10 consecutive days. Stimulation at 1 Hz was applied once a day for 10-days
arm group label: Active
intervention type: Drug
intervention name: Control
description: The control group is receiving treatment as usual. EEG recording and psychopathological ratings are performed one day before the start and on the last day of the study
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: 59 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Khamelia Malik, MD
role: Principal Investigator
affiliation: Department of Psychiatry, RSCM
last name: Khamelia Malik, MD
phone: +6181281296600
email: khameliapsi@gmail.com
last name: Nurmiati Amir, MD
phone: +6281316111953
email: nurmiati.a@gmail.com
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
country: Indonesia
citation: Kubera KM, Barth A, Hirjak D, Thomann PA, Wolf RC. Noninvasive brain stimulation for the treatment of auditory verbal hallucinations in schizophrenia: methods, effects and challenges. Front Syst Neurosci. 2015 Oct 12;9:131. doi: 10.3389/fnsys.2015.00131. eCollection 2015.
PMID: 26528145
citation: Ray P, Sinha VK, Tikka SK. Adjuvant low-frequency rTMS in treating auditory hallucinations in recent-onset schizophrenia: a randomized controlled study investigating the effect of high-frequency priming stimulation. Ann Gen Psychiatry. 2015 Feb 15;14:8. doi: 10.1186/s12991-015-0046-2. eCollection 2015.
PMID: 25699086
citation: Moseley P, Fernyhough C, Ellison A. Auditory verbal hallucinations as atypical inner speech monitoring, and the potential of neurostimulation as a treatment option. Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 2):2794-805. doi: 10.1016/j.neubiorev.2013.10.001. Epub 2013 Oct 12.
PMID: 24125858
responsible party type: Principal Investigator
investigator affiliation: Dr Cipto Mangunkusumo General Hospital
investigator full name: Khamelia Malik
investigator title: Head Psychiatry Research and Development Unit
mesh term: Hallucinations
sharing ipd: Undecided
ipd description: research protocols, analysis