Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02715765 |
| Other study ID # |
PSYCH-2016-24233 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 2016 |
| Est. completion date |
July 2016 |
Study information
| Verified date |
September 2020 |
| Source |
University of Minnesota |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Schizophrenia is a serious mental health disorder that affects approximately 1% of the
population. Auditory hallucinations are present in as many as 50-75% of patients with this
diagnosis. The hallucinations experienced by patients vary greatly and can severely impact an
individual's ability to function on a daily basis. In approximately 25-30% of these patients,
medication is an ineffective mechanism for managing these symptoms. These hallucinations are
known as medication refractory auditory hallucination (MRAH). For those whose auditory
hallucinations do not respond to medication, non-surgical brain stimulation (NBS) has
recently shown promise as a therapeutic intervention. Two specific types of NBS, called
transcranial direct current stimulation (tDCS) and transcranial random noise stimulation
(tRNS), seem particularly well suited to treating MRAH. They have yet to be compared to each
other in large samples of patients with MRAH. The goal of the study is to investigate whether
tRNS and tDCS are effective in the treatment of MRAH and if one is better than the other when
compared directly.
Description:
Purpose and Background
Schizophrenia is a serious mental health disorder with a constellation of positive, negative,
and cognitive symptoms. Negative symptoms can include characteristics such as affective
flattening, avolition, and alogia. Positive symptoms can include delusions, hallucinations,
and disorganized speech or behavior. Auditory hallucinations (AH) are a hallmark of
schizophrenia. They are reported in as many as 50-75% of patients with this diagnosis. The
hallucinations experienced by patients vary greatly and can severely impact an individual's
ability to function on a daily basis. In approximately 25-30% of patients diagnosed with
schizophrenia, medication is an ineffective mechanism for managing these symptoms. These
hallucinations are known as medication refractory auditory hallucinations (MRAH). They are
defined as "the persistence of daily hallucinations without remission despite antipsychotic
medication at an adequate dosage for at least three months".
For those whose AH do not respond to medication, non-surgical brain stimulation (NBS) has
recently shown promise as a therapeutic intervention. Specifically, the use of conductive
electrical approaches termed transcranial electrical stimulation (tES). One method of tES
that has received renewed interest due to its high portability, safety, and modulatory
effects is transcranial direct current stimulation (tDCS). tDCS involves applying a weak
electrical current using saline soaked electrode sponges, causing either increases or
decreases in cortical excitability, respectively. Research has shown in both healthy subjects
and patients (e.g. Alzheimer's disease, Parkinson's disease, stroke, and depression) that
tDCS has the potential to modulate synaptic and neurotransmitter-dependent plasticity
underlying changes in behavior and learning. Brunelin et al utilized tDCS to successfully
reduce MRAH in a population diagnosed with schizophrenia. They were able to reduce AH by
approximately 30% in their sample after 5 days of twice-daily treatment and this effect was
maintained for approximately three months following treatment. This finding has yet to be
replicated in a similar study.
Along with tDCS, other new methods of NBS are being investigated across various disease
states. One such study looked at the impact of tES on tinnitus. They tested whether type of
tES made a difference in efficacy. They compared tDCS to tRNS. tRNS is very similar to tDCS
except that it superimposes a random "white noise" gaussian waveform (from 0.1 hz to 640 hz)
on top of the DC current. They found that tRNS induced a larger suppressive effect on
tinnitus loudness and tinnitus-related distress when compared to tDCS. While their findings
were in tinnitus, there are now multiple scholarly works describing a relationship of
tinnitus and AH, possibly as a continuum or dimension underlying a variety of normal and
disease states. This relationship suggests strategies found to be efficacious for tinnitus
may in fact also be efficacious for AH. Recently, there was a case series showing possible
efficacy in AH using tRNS.
The purpose of the study is to examine the efficacy of tES in the treatment of MRAH of
schizophrenia. The hypothesis is that tRNS will provide a larger reduction of AH in those
with schizophrenia as compared to tDCS and no treatment (i.e. sham). Confirmation of this
hypothesis would provide an exciting new option for treatment and may provide an even higher
level of efficacy than is seen in tDCS. Further, this study would also provide replication of
the work by Brunelin et al. and further support of tES as a compelling tool for the
management of severe MRAH.
Specific Aims
1. Determine efficacy of tES as a treatment for MRAH. Hypothesis 1a: tDCS is more effective
than sham in the treatment of MRAH shown by a reduction in both total and subscores of
the AHRS. Hypothesis 1b: tRNS is more effective than both sham and tDCS in the treatment
of MRAH as shown by a reduction in both total and subscores of the AHRS.
2. Demonstrate safety and tolerability of tES in the treatment of MRAH. Hypothesis 2a: tDCS
is safe and well tolerated in the treatment of MRAH as demonstrated by the TSEQ.
Hypothesis 2a: tRNS is safe and well tolerated in the treatment of MRAH as demonstrated
by TSEQ.
3. Exploratory: Detect tES sensitive subtypes of AH based on the MUPS.
Study Design
This study is double-blind, between group, and sham-controlled. Subjects will be randomized
to one of three arms (tRNS, tDCS, or sham) and will remain in that arm for the duration of
the study. All subjects will complete an enrollment visit, ten treatment visits (2 visits per
day), and 1, 3, and 6 month follow-up visits. Given that durability of effect has been
suggested in the literature to be less than 6 months, patients will not be followed beyond 6
months. The outcome of this study will be measured by standard auditory hallucination rating
scales including the Positive and Negative Symptoms Scale (PANSS), Auditory Hallucinations
Rating Scale (AHRS), and psychotic symptom rating scales (PSYRATS). Both the AHRS and PSYRATS
are included as outcome measures to ensure generalizability to existing studies on tES (which
use the AHRS) along with the broader body of AH research (which use the PSYRATS). The primary
efficacy parameter will be the PSYRATS as this has shown the most evidence for accurate
representation of AH.
Clinical Significance
- This study will replicate and expand on previous research regarding the use of tES as a
treatment for medication refractory auditory hallucinations
- Based on the findings, this study could have potential application as a non-invasive
clinical intervention for treating MRAH which affect 25% of medicated patients with
schizophrenia.
Subjects
This study will recruit individuals who are receiving outpatient services at the Minneapolis
VA Medical Center, the University of Minnesota Department of Psychiatry, or the University of
Minnesota Medical Center--Fairview. Patients will be referred by clinical staff from multiple
departments including Mental Health, Polytrauma, and Social Work. Referral will be based on a
clinical diagnosis of Schizophrenia or Schizoaffective disorder with medication refractory
auditory hallucinations as assessed by the patient's clinical provider. Subjects will also
have the ability to self-identify to flyers and local newspaper ads. Brunelin et al found a
large and significant effect size (d=1.58, p<0.001) which the investigators have used to
guide our power analysis. The investigators power analysis was performed for three arms using
an alpha of 0.025, a power of 0.8, and a desired effect size of 1.00. This analysis results
in a need for approximately 20 subjects per arm.
Pre-screening.
In order to reduce subject burden, the investigators will obtain a waiver of HIPAA
authorization and informed consent for recruitment and screening to allow potential subjects
to be pre-screened by chart review and in person or by telephone prior to scheduling
potential participants for initial visit. Potential participants will be provided with
information about the study and asked a series of questions to determine if they meet basic
inclusion/exclusion criteria, such as a history of MRAH. They will be told about the basic
aims of the study, and those interested in participating will be scheduled for an initial
visit at which time they will complete consent paperwork.
Initiation Visit
The initiation visit (visit 1) starts with completion of informed consent, HIPAA, and the
Modified Dysken Tool to assess capacity to consent. The participant must score 7 / 10 on the
Dysken Tool in order to participate in the study. Should the participant score less than 7,
s/he will be offered remedial teaching and re-assessment. Should the subject agree via
consent and demonstrate capacity to consent, s/he is enrolled into the study. A full baseline
evaluation is then performed. This includes assessment via MINI, MUPS, PANSS, AHRS, PSYRATS
and Edinburgh Handedness Inventory.
Treatment Visits
Visits 2 - 10 are exclusively treatment visits. At each visit the participant completes the
tES Side Effect Questionnaire (TSEQ) both pre and post treatment. Visits occur twice daily
for 5 days. Visits must be spaced at least 2 hours apart. Depending on the arm participants
have been randomized into, s/he will receive treatment with either tDCS, tRNS, or sham.
Treatment will be provided using the Starstim Neurostimulator (Neuroelectrics, Inc.) This
device has been approved for use in research in the United States without an investigational
device exemption due to meeting criteria for non-significant risk. The same energetic
parameters are used for both tDCS and tRNS (2mA for 20 min) as well as the same electrodes
(SPONSTIM-25 25cm2 electrodes). Both tDCS and tRNS are initiated in a ramp-like fashion over
10s from 0mA to 2mA. Once at 2mA, tDCS is held constant for the entire session whereas the
tRNS consists of an alternating current of 2mA with a 0mA offset applied at random
frequencies over a range of 0.1 to 100 Hz. The sham procedure involves only 40 sec
stimulation at 2mA and then drops to 0mA with 15msec pulses every 550msec. Should the
participant not be able to tolerate a current of 2mA due to pain or irritation, the current
will be decreased down to a minimum of 1.5mA. If 1.5 mA is still not tolerable, the
participant will be removed from the study. Electrode placement is based on the international
10-20 electrode placement system. The anode is placed at the midpoint between F3 and FP1, a
location corresponding approximately to the left dorsolateral prefrontal cortex, and the
cathode placed at the midpoint between T3 and P3, a location corresponding to left
temporo-parietal junction. Placement and parameters in tDCS are consistent with Brunelin et
al, 2012). Placement and parameters in tRNS are consistent with. Stimulation setup and
administration takes approximately 30 minutes.
Visit 11 is run the same as visits 2 - 10 but after completion of the final (10th)
stimulation session, the subject will again complete the PANSS, AHRS, and PSYRATS. This visit
typically takes 90 minutes.
Follow-Up Visits
Visits 12 - 14 are follow-up assessment only visits and occur at 1 month, 3 month, and 6
months post treatment. Participants will not receive stimulation but instead will be assessed
via PANSS, AHRS, and PSYRATS.
Missed Visits
In the event that a participant misses a session of treatment, the session will be
re-scheduled and treatment continued as soon as possible. The deviation from treatment will
be noted in the study record.
Informed Consent Process
Consenting will take place in a private office at the Minneapolis VA Health Care System,
University of Minnesota 717 Delaware office, the Ambulatory Research Center of the University
of Minnesota Department of Psychiatry, or the UMPhysicians MINCEP clinic, depending on
patient preference. Only the study staff obtaining consent, the subject, and any family
members invited by the subject will be present. The research coordinator or other trained
research staff will explain the study to the participants. After explaining the study, the
participants will be allowed as much time as needed to review the HIPAA and consenting
documents and ask any questions that might arise before making the decision to participate.
If necessary, participants can delay participation for up to a week. Subjects will be allowed
to review the consent form in private for as long as they need. Subjects will be allowed to
ask any and all questions prior to providing consent. Study personnel obtaining consent will
emphasize first and foremost that the study is voluntary and will not influence that
subject's clinical care through the VA Medical Center, University of Minnesota Medical
Center--Fairview, or the University of Minnesota Department of Psychiatry. To ensure
comprehension of the information provided in the informed consent forms, participants will be
asked to complete the Modified Dysken Tool and answer 7 out of 10 questions correctly.
Indications of Lack of Capacity to Consent
1. Potential participant has severe formal thought disorder that does not allow him or her
to ask understandable questions or to answer the questions on the Dysken Tool
2. Potential participant is unable to maintain attention to the description of the consent
form long enough to perceive the individual basic points in the consent form
3. Potential participant, either due to catatonia or otherwise, the potential participant
cannot ask questions or respond sufficiently to indicate agreement
4. Potential participant expresses delusions related to the research protocol that
significantly distort his or her basic understanding of the research.
No participant will be under legal commitment at the time of their consent or during their
participation in the study.
Data Analysis
Data will be analyzed for group by time effects of stimulation method as compared to sham.
Tolerability will also be assessed by looking at total side effect score compared to
stimulation type. The data will be further analyzed using a clustering technique to
understand the impact of symptom cluster and severity on overall treatment response.
Potential Risks and Benefits
This study involves the use of a tES device. With tES, both tDCS and tRNS are considered to
be safe brain stimulation techniques that rarely result in adverse events. There is currently
no evidence of serious side-effects. Criteria for discontinuation that may rarely occur are
sores at the tCS administration site, headaches that impair global functioning, and worsening
psychosis. Mild side-effects that typically resolve upon discontinuation tCS include light
itching under the electrode at the beginning of administration, headache, fatigue, and
nausea. The participant may choose to discontinue stimulation at any time during the session
if experiencing discomfort or side effects. No other risks are anticipated. Nonetheless, in
order to minimize risks, study staff will be using standards of administration that have been
shown to be safe in numerous other studies and across more than 2000 studies using tES; this
includes length of administration, magnitude of the current, size of electrode sponges used,
and method of applying stimulation. Any unanticipated problems or adverse events will be
reported according to MVAHCS standard operating procedure.
Study staff will use private (medical or educational) records during the recruitment process.
Therefore, the use of protected health information may be associated with negative feelings
about sharing medical/educational history. Participants may experience mild stress and/or
discomfort with completing surveys/interview. Participants could also experience temporary
feelings of stress or mental fatigue due to the behavioral assessment measures used in the
study.
In addition, breach of confidentiality is a potential risk due to the use of sensitive
private information. The results of this study may be published or presented but the
participant's identity and records will not be revealed unless required by Federal Law. A
Federal Law allows the U.S. Food and Drug Administration, Office for Human Research
Protections, Government Accountability Office and other Federal agencies, the Research and
Development Committee, representatives of USAMRMC, Henry M. Jackson Foundation, and/or the
Institutional Review Board (IRB)/Human Studies Subcommittee of the VA Medical Center or
University of Minnesota to review records. Because of the need for these inspections,
absolute confidentiality cannot be guaranteed. However, every effort would be made to
minimize these risks by providing the participant with a unique numerical identifier at the
beginning of the study in order to protect their actual identification and maintain complete
confidentiality.
It is possible that a participant may have a reduction of symptoms from the tES treatment but
there are no anticipated direct or societal benefits to participation in this research
project.
Research Monitor
A MVAHCS or University of Minnesota staff will act as an independent research monitor for
this study. Her/His duties may include discussing the research protocol and recruitment with
the investigator and staff, monitoring utilization of the tES device, follow-up with any
participants in which an adverse event was reported, and reporting findings to the IRB.
Discontinuation Criteria
Sores at the tES administration site Headaches that impair global functioning Worsening
psychosis
Privacy, Confidentiality, and Information Security
Self-report data will be collected on paper and scanned and stored in a password protected
database behind the MVAMC or University of Minnesota firewalls. All personal identifiers will
be stored on the consent form and in a master participant list within the database. All other
documents will contain the unique participant ID. All paper documents related to this study
will be stored in a locked file cabinet within locked research study offices. Access to
research data and documents will be restricted to research personnel listed on the study
protocol.
All data will be maintained at the MVAHCS and University of Minnesota indefinitely per
requisite data retention policies. No data will be destroyed. Information regarding research
results will not be shared with study participants.
