Repetitive Transcranial Magnetic Stimulation for "Voices"

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00004980
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 50
• Location: 1
• Arms: 2
• Duration (Months): 66
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

OBJECTIVES:

1. Determine the effect of repetitive transcranial magnetic stimulation on treatment refractory auditory hallucinations of patients with schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Device: repetitive transcranial magnetic stimulation (rTMS); Device: sham stimulation	Phase 2

Detailed Description

PROTOCOL OUTLINE: This is a randomized, double blind study. Patients are randomized to one of two treatment arms.

Group I: Patients receive 9 sessions of active transcranial magnetic stimulation (rTMS) which consists of 8 minutes of rTMS during session 1, 12 minutes duration during session 2, and 16 minutes duration during sessions 3-9. The total duration of stimulation is 132 minutes. Each session was given on a separate day and in general each session occurred on consecutive days with the exception of weekends.

Group II: Patients receive 9 sessions of sham stimulation, which consists of 8 minutes of sham stimulation during session 1, 12 minutes duration sham stimulation during session 2, and 16 minutes duration sham stimulation during sessions 3-9. The total duration of sham stimulation is 132 minutes. Each session was given conducted on a separate day and in general each session occured on consecutive days with the exception of weekends.

This study provided pilot data supplying the basis for our current study - NCT00308997 -- see our website for details

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Repetitive Transcranial Magnetic Stimulation of Speech Processing Brain Areas in Schizophrenic Patients Who Hear "Voices"
• Study Start Date: Dec 1, 1999
• Actual Primary Completion Date: Jan 1, 2005
• Actual Study Completion Date: Jun 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: active rTMS 1-Hz rTMS delivered to left temporoparietal cortex at 90% motor threshold for 16 minutes per session given one session per day for nine consecutive days (with the exception of weekends)	Device: repetitive transcranial magnetic stimulation (rTMS); a total of 132 minutes of stimulation at one hertz, motor threshold set at 80%, delivered to TP3 scalp site; Other Names: MATSTIM SUPER RAPID
Placebo Comparator: sham stimulation Sham stimulation delivered 16 minutes per session given one session per day for nine consecutive days (with the exception of weekends)	Device: sham stimulation; 132 minutes of stimulation given at 80% motor threshold with coil tilted "single wing" 45 degrees away from scalp deliverd to TP3 site; Other Names: MAGSTIM SUPER RAPID

Outcome Measures

Primary Outcome Measures

1. Hallucination Change Score (HCS) After 9 Active/Sham rTMS Sessions [After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)]

   Change in hallucination severity relative to baseline with scores ranging 1 in unit intervals to 20 anchored as follows: 0=hallucinations stopped, 10=no change, 20=hallucinations twice as severe as baseline

Secondary Outcome Measures

1. Change From Baseline in Hallucination Frequency After 9 Active/Shame rTMS Sessions [After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)]

   Difference between baseline hallucination frequency and hallucintion frequency at last assessment. Assessed on the basis of a 0-9 scale, with higher scores being more severe.

2. Clinical Global Improvement (CGI) Scale After 9 Active/Shame rTMS Sessions [After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)]

   Scaled from 1-7 as follows: 1=dramatically improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worsened, 6=moderately worsened, 7=dramatically worsened

3. Responder Status [After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)]

   Responder defined as a participant who attains an endpoint hallucination change score (HCS) of 5 or lower after 9 active/shame rTMS sessions. Change in hallucination severity relative to baseline with scores ranging 1 in unit intervals to 20 anchored as follows: 0=hallucinations stopped, 10=no change, 20=hallucinations twice as severe as baseline

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

PROTOCOL ENTRY CRITERIA:

Inclusion criteria:

• Diagnosis of schizophrenia or schizoaffective disorder based on DSM-IV version of SCID

• Auditory hallucinations of spoken speech occurring at least 5 times per day where subject able to discern verbal content

• Right-handed

• At least 4 weeks on stable antipsychotic medication

Exclusion criteria:

• history of seizure (unless due to drug withdrawal or medication that is no longer prescribed)

• history of epilepsy in first degree relatives

• estimated IQ less than 80

• unable to provide informed consent

• significant unstable medical condition

• current treatment with clozapine or bupropion

• cochlear implants or other metal in the head (surgical, etc.)

• history of cardiac arrhythmia

• cardiac pacemaker

• active drug or alcohol abuse within prior 6 weeks

• pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University School of Medicine	New Haven	Connecticut	United States	06520-8099

Sponsors and Collaborators

• Yale University
• National Institute of Mental Health (NIMH)

Investigators

• Study Chair: Ralph Hoffman, Yale University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for the Yale School of Medicine Web site describing current, on-going rTMS trial for auditory hallucinations

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT00004980
• Other Study ID Numbers: R21MH063326; R21MH063326; YALESM-9281; 199/14809; A5-ETPD
• First Posted: Mar 13, 2000
• Last Update Posted: Aug 7, 2013
• Last Verified: Aug 1, 2013

• Keywords provided by Yale University: neurologic and psychiatric disorders; rare disease; schizophrenia
• Additional relevant MeSH terms: Schizophrenia

Study Results

Participant Flow

Arm/Group Title	Active Repetitive Transcanial Magnetic Stimulation	Placebo
Arm/Group Description	Participants received active repetitive transcranial magnetic stimulation (rTMS)	Participants received sham stimulation
Period Title: Overall Study
STARTED	27	23
COMPLETED	25	21
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Active Repetitive Transcanial Magnetic Stimulation	Placebo	Total
Arm/Group Description	Participants received active repetitive transcranial magnetic stimulation (rTMS)	Participants received sham stimulation	Total of all reporting groups
Overall Participants	27	23	50
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	35.1 (11.9)	35.5 (9.5)	35.3 (10.8)
Sex: Female, Male (Count of Participants)
Female	9 33.3%	8 34.8%	17 34%
Male	18 66.7%	15 65.2%	33 66%
Medication Resistance (Number) [Number]
Medication Resistant	21 77.8%	18 78.3%	39 78%
Not Medication Resistant	6 22.2%	5 21.7%	11 22%
Total Auditory Hallucination Rate Scale (AHRS) score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	25.1 (5.0)	26.1 (5.7)	25.6 (5.3)

Outcome Measures

1. Primary Outcome

Title	Hallucination Change Score (HCS) After 9 Active/Sham rTMS Sessions
Description	Change in hallucination severity relative to baseline with scores ranging 1 in unit intervals to 20 anchored as follows: 0=hallucinations stopped, 10=no change, 20=hallucinations twice as severe as baseline
Time Frame	After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)

Outcome Measure Data

Analysis Population Description

Last Observation Carried Forward (LOCF)

Arm/Group Title	Active Repetitive Transcanial Magnetic Stimulation	Placebo
Arm/Group Description	Participants received active repetitive transcranial magnetic stimulation (rTMS)	Participants received sham stimulation
Measure Participants	27	23
Mean (Standard Deviation) [Units on a scale]	5.85 (2.85)	8.61 (3.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Repetitive Transcanial Magnetic Stimulation, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.005
	Comments	a priori threshold for statistical significance was .05
	Method	t-test, 2 sided
	Comments	degree of freedom = 48
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.76
	Confidence Interval	() 95%; -4.65 to -.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .514
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Hallucination Frequency After 9 Active/Shame rTMS Sessions
Description	Difference between baseline hallucination frequency and hallucintion frequency at last assessment. Assessed on the basis of a 0-9 scale, with higher scores being more severe.
Time Frame	After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)

Outcome Measure Data

Analysis Population Description

LOCF

Arm/Group Title	Active Repetitive Transcanial Magnetic Stimulation	Placebo
Arm/Group Description	Participants received active repetitive transcranial magnetic stimulation (rTMS)	Participants received sham stimulation
Measure Participants	27	23
Mean (Standard Deviation) [Score on a scale]	1.42 (1.49)	.15 (1.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Repetitive Transcanial Magnetic Stimulation, Placebo
	Comments	null hypothesis is that the groups are the same
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.002
	Comments	a priori threshold for statistical significance was .05
	Method	t-test, 2 sided
	Comments	degrees of freedom = 48
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.27
	Confidence Interval	() 95%; .507 to 2.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .327
	Estimation Comments

3. Secondary Outcome

Title	Clinical Global Improvement (CGI) Scale After 9 Active/Shame rTMS Sessions
Description	Scaled from 1-7 as follows: 1=dramatically improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worsened, 6=moderately worsened, 7=dramatically worsened
Time Frame	After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Repetitive Transcanial Magnetic Stimulation	Placebo
Arm/Group Description	Participants received active repetitive transcranial magnetic stimulation (rTMS)	Participants received sham stimulation
Measure Participants	26	22
Mean (Standard Deviation) [Units on a scale]	2.84 (.845)	3.79 (.882)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Repetitive Transcanial Magnetic Stimulation, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.001
	Comments	A priori threshold for statistical significance was .05
	Method	t-test, 2 sided
	Comments	degrees of freedom = 46
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-.949
	Confidence Interval	() 95%; -1.45 to -.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .524
	Estimation Comments

4. Secondary Outcome

Title	Responder Status
Description	Responder defined as a participant who attains an endpoint hallucination change score (HCS) of 5 or lower after 9 active/shame rTMS sessions. Change in hallucination severity relative to baseline with scores ranging 1 in unit intervals to 20 anchored as follows: 0=hallucinations stopped, 10=no change, 20=hallucinations twice as severe as baseline
Time Frame	After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)

Outcome Measure Data

Analysis Population Description

LOCF

Arm/Group Title	Active Repetitive Transcanial Magnetic Stimulation	Placebo
Arm/Group Description	Participants received active repetitive transcranial magnetic stimulation (rTMS)	Participants received sham stimulation
Measure Participants	27	23
Number [Participants]	14 51.9%	4 17.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Repetitive Transcanial Magnetic Stimulation, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.01
	Comments	a priori threshold for statistical significance = .05
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	Adverse event reporting was collected for the duration of the study (41 months)
Adverse Event Reporting Description	Adverse events were systematically collected with focused questions each day during the trial
Arm/Group Title	Active Repetitive Transcanial Magnetic Stimulation		Placebo
Arm/Group Description	Participants received active repetitive transcranial magnetic stimulation (rTMS)		Participants received sham stimulation
All Cause Mortality
	Active Repetitive Transcanial Magnetic Stimulation		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Active Repetitive Transcanial Magnetic Stimulation		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Active Repetitive Transcanial Magnetic Stimulation		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/27 (59.3%)		3/23 (13%)
Nervous system disorders
Headache	16/27 (59.3%)		3/23 (13%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.