An Extension Protocol for Patients Who Previously Completed the TMS Pilot Study

An Open-label Extension Trial of Individualized Repetitive Transcranial Magnetic Stimulation in Patients With Auditory Verbal Hallucinations Who Completed Protocol #8116

This is an open-label extension study to continue to evaluate the safety, tolerability and efficacy of the Repetitive Transcranial Magnetic Stimulation (rTMS) in subjects with schizophrenia or schizoaffective disorder who previously completed the treatment study of the protocol #8116 (NCT05319080). Protocol #8116 investigates the clinical efficacy of open-label individualized MRI-guided TMS applied to the left temporoparietal junction (TPJ) in schizophrenia patients. Participating patients who have completed the 4-week project #8116 can be screened for eligibility for this extension study in which they will continue treatment/assessment. They will be divided into three groups (non-responders, partial responders, or full responders) based on a reduction in the Auditory Hallucination Rating Scale (AHRS) scores from the study #8116.

Study Overview

• Status: Terminated
• Conditions: Schizophrenia and Related Disorders
• Intervention / Treatment: Device: Repetitive Transcranial Magnetic Stimulation (rTMS)

Detailed Description

The optimal neuroanatomical treatment targets remain unclear, though current neuroscience evidence suggests several brain areas such as the left temporo-parietal junction area (TPJ) or the right posterior superior temporal sulcus (rSTS) may be involved in the generation and development of AVH. During this extension study, non-responders to protocol #8116 will be administered 10 days (10 sessions) of MRI-guided 1 Hz rTMS delivered to the rSTS instead of the original target in TPJ. Partial responders will receive 10 additional low-frequency rTMS over the original left TPJ target. Like the protocol #8116, the investigators will use the MRI-guided targeting approach during rTMS treatment sessions to achieve greater precision as it can account for individual differences in anatomy. Complete responders will instead be followed for sustainability of response. Their clinical ratings will be repeated at one week, two week, four week and eight week follow-ups. Non-responders are defined as patients showing a reduction of AHRS less than 20% of the initial score. A partial response is defined as a reduction in a range of between 20% and 50% of the initial AHRS score. A complete response is defined as a reduction by at least 50% of the initial AHRS score.The combined outcome of protocol #8116 and the currently proposed protocol will help guide TMS targeting and the number of treatment sessions for a future larger randomized, double-blinded, shame-controlled clinical trial.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • New York State Psychiatric Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

For non responders and partial responders:

Inclusion Criteria:

• Completion of the study #8116 (NCT05319080)
• The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of schizophrenia or schizoaffective disorder
• A reduction of AHRS less than 50% of the initial score
• Capacity and willingness to provide informed consent
• If female and not infertile, must agree to use one of the following forms of contraception for the duration of study participation: systemic hormonal treatment, an intrauterine device (IUD) which was implanted at least 2 months prior to screening, or "double-barrier" contraception. Women of child bearing potential must have a negative pregnancy test at screening
• Right handed
• Normal hearing
• Taking an antipsychotic medication at a stable dose for at least 4 weeks. All oral and depot antipsychotics are allowable.

Exclusion Criteria:

• Substance use disorder (excluding nicotine) within last 90 days, or positive toxicology screen for any substance of abuse
• Pregnancy
• Severe adverse events of TMS
• History of seizure, epilepsy and neurologic conditions with structural cerebral damage, including stroke, multiple sclerosis, traumatic brain injury, Alzheimer's and other neurodegenerative diseases, meningoencephalitis or intracerebral abscess, parenchymal or leptomeningeal cancers, dementia, developmental disability, cerebrovascular disease, increased intracranial pressure, or central nervous system (CNS) tumors, brain surgery, head injury with loss of consciousness >1 hour or clear cognitive sequelae, intracranial metal implants, known structural brain lesion
• Subjects with devices that may be affected by TMS (pacemaker, cardioverter defibrillator, medication pump, intracardiac line, cochlear implant, implanted brain stimulator/neurostimulator)
• Subjects with suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in the 6 months prior to screening or subjects who represent a significant risk of suicide in the opinion of the investigator
• Frequent and persistent migraines
• Clinically significant skin disease
• Presence of unstable medical disorders, including those that are previously undiagnosed, untreated, inadequately treated, or active to an extent which might make participation hazardous. For example, hypertension, previous stroke, brain lesions, or heart disease
• History of prior clinically significant, adverse response to neurostimulation
• Current treatment with ototoxic medications (amino-glycosides, cisplatin)

For complete responders:

Inclusion Criteria:

• Completion of the study #8116 (NCT05319080)
• The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of schizophrenia or schizoaffective disorder
• A reduction by at least 50% of the initial AHRS score
• Taking an antipsychotic medication at a stable dose for at least 4 weeks. All oral and depot antipsychotics are allowable.

Exclusion Criteria:

• Substance use disorder (excluding nicotine) within last 90 days, or positive toxicology screen for any substance of abuse
• Subjects with suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in the 6 months prior to screening or subjects who represent a significant risk of suicide in the opinion of the investigator
• Presence or positive history of unstable significant medical or neurological illness

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Non-responders undergo rTMS of the right superior temporal sulcus (STS); Non-responders to protocol #8116 will receive a type of TMS called repetitive TMS (rTMS) wherein the magnetic pulses delivered will be close together in a rapid sequence. They will be administered 10 days (10 sessions) of MRI-guided 1 Hz rTMS delivered to the right superior temporal sulcus (STS). The rTMS parameters that will be used are a frequency of 1 Hz (1 pulse per second) at an intensity of 90% of the motor threshold (MT). Therefore, the investigators will deliver 1200 continuous pulses per session/day which adds up to 12,000 pulses in total for the whole treatment.	Device: Repetitive Transcranial Magnetic Stimulation (rTMS); During the rTMS session, an electromagnetic coil is placed on the scalp of the subject's head. The electromagnet painlessly delivers a magnetic pulse that stimulates nerve cells in the region of the brain involved in speech perception.
Experimental: Partial responders undergo rTMS of the left temporo-parietal junction (TPJ); Partial responders to protocol #8116 will receive a type of TMS called repetitive TMS (rTMS) wherein the magnetic pulses delivered will be close together in a rapid sequence. They will be administered 10 days (10 sessions) of MRI-guided 1 Hz rTMS delivered to the original left temporo-parietal junction (TPJ) target. The rTMS parameters that will be used are a frequency of 1 Hz (1 pulse per second) at an intensity of 90% of the motor threshold (MT). Therefore, the investigators will deliver 1200 continuous pulses per session/day which adds up to 12,000 pulses in total for the whole treatment.	Device: Repetitive Transcranial Magnetic Stimulation (rTMS); During the rTMS session, an electromagnetic coil is placed on the scalp of the subject's head. The electromagnet painlessly delivers a magnetic pulse that stimulates nerve cells in the region of the brain involved in speech perception.
No Intervention: Complete responders undergo four follow-up clinical assessments; Complete responders to protocol #8116 will be offered followup clinical assessments at 1, 2, 4, and 8 weeks to assess sustainability of their response.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of rTMS Sessions Completed	The total number of rTMS sessions completed for non responders and partial responders. A session is defined as 20 minutes of rTMS.	2 weeks.
Total Number of Follow-up Clinical Assessments Completed	The total number of follow-up clinical assessments completed for complete responders. A clinical assessment refers to answering questions about psychiatric symptoms to assess the sustainability of the patient's improvement from the previous study.	8 weeks
Total Number of Treatment Emergent Adverse Events	The total number of treatment emergent adverse events for non responders and partial responders. An emergent adverse event is defined as any rTMS risk induced incident in research such as headache and seizure.	2 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Clinical Global Impression Improvement (CGI-I) Scale	The CGI-I is a clinician-rated scale to quantify overall clinician impression of improvements in level of illness. The CGI-I is rated on a 7-point scale, to assess illness improvement. CGI-I scores range from 1 (very much improved) through to 7 (very much worse).	2 weeks
Change in Auditory Hallucination Rating Scale (AHRS)	The AHRS is an investigator-administered scale assessing multiple characteristics of auditory verbal hallucinations. The total score ranges from 2 to 41, with higher scores indicating more severe symptoms.	Up to 4/8 weeks.
Change in Psychotic Symptom Rating Scale (PSYRATS)	The PSYRATS consists of 17 items on delusions and auditory hallucinations, with each item being rated from 0 (absent) to 4 (severe). The total score ranges from 0 to 68, with higher scores indicating more severe symptoms.	Up to 4/8 weeks.
Change in Scale for the Assessment of Positive Symptoms (SAPS)	The SAPS includes 34 items that focus on the positive symptoms on schizophrenia. Each item is rated from o to 5 (range=0-170). Higher scores indicate more severe symptoms.	Up to 4/8 weeks.
Change in Positive and Negative Syndrome Scale (PANSS)	The PANSS rates the presence and severity of positive and negative symptoms, as well as general psychopathology associated with schizophrenia. Each item is rated from 1 to 7 (range=30-210). Higher scores indicate more severe symptoms.	Up to 4/8 weeks.
Change in Cardiff Anomalous Perceptions Scale (CAPS)	The CAPS is a 32 item scale for measuring perceptual anomalies, that includes subscales for measuring distress, intrusiveness and frequency. A higher score indicates a higher number of perceptual anomalies, scores range from 0 (low) to 32 (high).	Up to 4/8 weeks.
Change in Clinical Global Impression Severity (CGI-S) Scale	The CGI-S is a clinician-rated scale to quantify overall clinician impression of illness severity. The CGI-S is rated on a 7-point scale, to assess illness severity. CGI-S scores range from 1 (normal, not ill) through to 7 (among the most severely ill patients).	2 weeks

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Michael Avissar, MD, PhD, New York State Psychiatric Institute

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2022
• Primary Completion (Actual): January 24, 2023
• Study Completion (Actual): January 26, 2023

Study Registration Dates

• First Submitted: August 31, 2022
• First Submitted That Met QC Criteria: August 31, 2022
• First Posted (Actual): September 2, 2022

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Hallucinations; Auditory Verbal Hallucinations
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Schizophrenia Spectrum and Other Psychotic Disorders; Perceptual Disorders; Schizophrenia; Hallucinations
• Other Study ID Numbers: 8249 (CTEP); K23MH119318 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No