Hallucinations, Verbal AuditoryPhase 3TMSNCT03762746
Transcranial Magnetic Stimulation (TMS) for Patients With Treatment Resistant Auditory Verbal Hallucination
A Phase 3 study testing Transcranial Magnetic Stimulation in people with Hallucinations, Verbal Auditory, run by Dr Cipto Mangunkusumo General Hospital at 1 site in Indonesia.
Trial summary
This study will evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) in schizophrenia with treatment resistant auditory verbal hallucination Read more about this study
- Who is it for?
- Ages 18 to 59 yearsHealthy volunteers can take part
- Conditions the study is for
- Hallucinations, Verbal Auditory
- What is being tested?
- Transcranial Magnetic Stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteIndonesia
- Study dates
- 1 Feb 2018to 1 Feb 2019
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 59 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Met the criteria of all types of schizophrenia or schizoaffective based on structured clinical interview instruments for the DSM-IV axis I disorders (SCID-I)
- Patients had entered the stabilization phase with 2 to 3 months of antipsychotic treatment and no drug changes within the last 2 (two) months
- Elementary school graduated (minimum)
Who cannot join
- Patients with a history of stroke, heart failure, head injury, infection or brain tumor, epilepsy, alcohol and opiate abuse, amphetamines obtained from anamnesis, physical examination and patient medical records
- Patients with neurological focal deficits such as hemiparesis and cranial nerve paresis
- Patients with severe cognitive deficits (MMSE scores <25 in the first and second graders of Senior Secondary School and <21 in Primary School Graduates)
- Patients with severe hearing loss were assessed with a 5-word auditory test
- Patients with mental retardation, assessed using the Wechsler Test of Adult Reading (WTAR) test and data from medical records.
Trial locations and contacts
1 site in 1 country.
Indonesia1 site, 1 recruiting
- Recruiting
Department of Psychiatry, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital Jakarta
Jakarta Pusat, DKI Jakarta
Kristiana Siste, MD, +6287782516771, ksiste@yahoo.com
Khamelia Malik, MD
About this study
Official title: TMS for Treatment Resistant Auditory Verbal Hallucination in Schizophrenia
This study will evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) in schizophrenia with treatment resistant auditory verbal hallucination
Read the detailed description
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.
- Conditions
- Hallucinations, Verbal Auditory
- Being tested
- Transcranial Magnetic Stimulation, Control
- Medical subject headings
- Hallucinations
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transcranial Magnetic StimulationDevice
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
ControlDrug
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
| Study group | Role | What they receive |
|---|---|---|
| Active | Active comparator | 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 Receives: Device: Transcranial Magnetic Stimulation |
| Control | Sham comparator | Control group is received treatment as usual Receives: Drug: Control |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hallucinations change
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.
Measured: 2 weeks
Source-monitoring ability
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.
Measured: 2 weeks
Secondary outcomes (1)
electrophysiological changes
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
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2018
- Study start1 Feb 2018
- Primary completion1 Dec 2018 (estimated)
- Study completion1 Feb 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Hallucinations, Verbal AuditoryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Dr Cipto Mangunkusumo General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Khamelia Malik, Dr Cipto Mangunkusumo General Hospital
- Investigators
- Khamelia Malik, MD, Principal investigator, Department of Psychiatry, RSCM
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03762746
- Sponsor's protocol ID
- 17-03-0206
- Acronym
- TMS
- Status last verified
- Nov 2018
- First submitted
- 23 Feb 2018
- Last updated
- 4 Dec 2018
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
- Individual data sharing
- Undecided: research protocols, analysis
Publications
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.
PubMed 26528145Ray 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.
PubMed 25699086Moseley 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.
PubMed 24125858
Study at a glance
From the registry record, last updated by the sponsor on 4 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- TMS for Treatment Resistant Auditory Verbal Hallucination in Schizophrenia
- ClinicalTrials.gov ID
- NCT03762746
- Acronym / sponsor ID
- TMS / 17-03-0206
- Conditions
- Hallucinations, Verbal Auditory
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Dr Cipto Mangunkusumo General HospitalUniversity, hospital or other
- Study start
- 1 Feb 2018 (actual)
- Primary completion
- 1 Dec 2018 (estimated)
- Study completion
- 1 Feb 2019 (estimated)
- First posted
- 4 Dec 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) in schizophrenia with treatment resistant auditory verbal hallucination
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Active | Active comparator | Device: Transcranial Magnetic StimulationIntervention 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 |
| Control | Sham comparator | Drug: ControlControl group is received treatment as usual |
Who may qualify
- Ages
- 18 to 59 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Met the criteria of all types of schizophrenia or schizoaffective based on structured clinical interview instruments for the DSM-IV axis I disorders (SCID-I)
- Patients had entered the stabilization phase with 2 to 3 months of antipsychotic treatment and no drug changes within the last 2 (two) months
- Elementary school graduated (minimum)
Key exclusion criteria (5 listed)
- Patients with a history of stroke, heart failure, head injury, infection or brain tumor, epilepsy, alcohol and opiate abuse, amphetamines obtained from anamnesis, physical examination and patient medical records
- Patients with neurological focal deficits such as hemiparesis and cranial nerve paresis
- Patients with severe cognitive deficits (MMSE scores <25 in the first and second graders of Senior Secondary School and <21 in Primary School Graduates)
- Patients with severe hearing loss were assessed with a 5-word auditory test
- Patients with mental retardation, assessed using the Wechsler Test of Adult Reading (WTAR) test and data from medical records.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transcranial Magnetic StimulationA 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 | Device | Active |
| ControlThe 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 | Drug | Control |
Primary outcome
Hallucinations change
Time frame: 2 weeks
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.
Source-monitoring ability
Time frame: 2 weeks
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.
1 secondary outcome
electrophysiological changes
Time frame: 2 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Dec 2018.
- Background: PubMed 26528145Kubera 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.
- Background: PubMed 25699086Ray 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.
- Background: PubMed 24125858Moseley 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.
- Individual participant dataSharing planned: Undecided. research protocols, analysis
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Khamelia Malik, MD principal investigator
Department of Psychiatry, RSCM
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Transcranial Magnetic Stimulation in people with Hallucinations, Verbal Auditory, run by Dr Cipto Mangunkusumo General Hospital at 1 site in Indonesia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 4 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Indonesia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Khamelia Malik, MD (+6181281296600, khameliapsi@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Hallucinations change (time frame: 2 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03762746, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Dec 2018; AzTrials last refreshed its copy on 7 Nov 2026.