Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03907644 |
| Other study ID # |
2019-001-00 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 15, 2019 |
| Est. completion date |
June 15, 2023 |
Study information
| Verified date |
July 2023 |
| Source |
Laureate Institute for Brain Research, Inc. |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Opioid use disorder (OUD) is among the costliest and deadliest substance use disorders (SUDs)
in the US and world-wide. Opioids were involved in 42,249 deaths in the US in 2016, which
were more than deaths due to road accidents and gun violence combined. Opioid overdose deaths
were five times higher in 2016 than 1999. Meanwhile, the treatment options for OUD are
limited and long-term efficacy is poor. There is a hope that recent advances in understanding
of the cognitive neuroscience underlying addictive behavior, like drug craving and its
regulatory processes, can bring new opportunities for more effective and personalized
treatment options for OUD. Drug craving is the signature aspect of OUD as well as other SUDs
which has been associated with continued drug use and relapse. In previous studies, the
investigators have shown significant response to drug related cues in both frontoparietal and
limbic areas including amygdala and ventral striatum. In a recent pilot study, the
investigators showed significant lower connectivity between amygdala and frontoparietal
areas, including dorsolateral prefrontal cortex (DLPFC) and inferior parietal cortex (IPC),
major nodes of the executive control network (ECN), in patients with OUD compared with
healthy controls. The central role of the ECN is to perform top down regulation of
subcortical limbic areas during self-control, emotion-regulation, and response- inhibition
tasks. These processes are well known to be affected in different psychopathologies including
SUDs. There is a growing body of evidence that external frontoparietal synchronization (FPS)
with transcranial alternating current stimulation (tACS) can potentially modulate
connectivity within ECN and between ECN and limbic areas. This may improve some aspects of
executive function and top down regulation. tACS is a low-cost and scalable non-invasive
brain stimulation technology without any serious side effects. The procedure involves the
transcranial delivery of low levels of alternating current (0.1-2 mAmp) in different
frequencies through the skull into the brain with both online and long-term offline effects.
This trial is the first combined tACS/fMRI study to examine the acute offline effects of FPS
on neural substrates underlying drug induced craving. We hypothesize that FPS amplifies the
ECN top-down modulatory role via its connectivity to other cortical-subcortical areas. In
this experimental design, the investigators will recruit 60 people with OUD during the early
abstinence phase in a residential setting divided into two parallel arms with active and sham
FPS tACS. Each subject will undergo resting state and task based (drug cue exposure paradigm)
functional MRI pre and post FPS. The investigators will also conduct individual difference
analyses to explore the potential predictors for FPS response, including pre-FPS top-down
connectivity measures of ECN and other subjective, clinical, behavioral, structural, and
functional variables. The results of this study will provide mechanistic neuroscience-based
evidence for the efficacy of FPS and will advance the field towards precision addiction
medicine.
Description:
A. Background:
Opioid use disorder (OUD) is among the costliest and deadliest substance use disorders (SUDs)
in the US and world-wide. Opioids (including prescription opioids, heroin, and fentanyl) were
involved in more than 42,000 deaths in 2016 in US, more than any year on record and
accounting for more deaths than due to road accidents and gun violence combined1. Over 4.3
million Americans engaged in non-medical use of prescription opioids each month and 4.8
million people have used heroin at some point in their lives. From each year since 2002, past
month heroin use, past year heroin use, and heroin use disorder have increased among 18-25
years old. Among new heroin users, approximately three out of four reported using
prescription opioids prior to using heroin. Available treatment options for OUD are limited
and long-term efficacy to return to a normal life is very low. During the last two decades,
advancements in human neuroscience research have provided new hope for targeting
neurocognitive processes underlying drug addictions, including OUD, to introduce new
therapeutic interventions. In reality, however, neuroscience has played a very minimal role,
if any, in changing clinical practices for OUD, until now.
Although DSM V has added "drug craving" as a criterion for SUDs, it has been well-known as a
core process in drug dependence and addiction for many years. Exposure to drug-related cues
to induce drug craving, which is called "Cue Induced Craving" or "CIC", is one of the main
paradigms used to study the drug craving phenomenon2. There are many studies that have shown
CIC to be a valid core construct for continued drug use and relapse. Therefore, reduction of
CIC is now one of the main targets for enhancing substance use recovery2. Different brain
areas and networks are involved in CIC. In particular, top down modulation by frontoparietal
areas involved in the executive control network (ECN) including dorsolateral prefrontal
cortex (DLPFC), and inferior parietal cortex (IPC), over subcortical areas such as ventral
striatum (VSt) and amygdala, is thought to be the critical process underlying CIC. Failure of
top down modulation by ECN in relation to other large-scale networks is reported to be a
predictor of relapse among both cocaine and heroin users. Furthermore, improvement in ECN
top-down regulation has been reported in trials with medications that reduce drug craving3.
This is in line with current evidence from animal models for the central role of
frontoparietal network in top-down attention and executive control. It is frequently reported
that coherence in the theta band (4-8 Hz) within the frontoparietal network plays a central
role in executive functions including working memory and cognitive control. There is a
growing body of evidence that transcranial alternating current stimulation (tACS) can
increase this coherence, entrain ECN connectivity and improve its function. tACS is a
device-based technology employed to change cortical oscillations by applying a very weak (0.1
to 2mAmp) alternating current over the skull. In vivo studies show that tACS can modulate
ongoing neural rhythms by shifting spike timing and firing rates towards the stimulation
frequency (external synchronization)4. Meanwhile, it is strongly proposed that synchronized
oscillation plays the major role in communication and connection between nodes within a
network5. Based on this background, there is hope that multisite tACS (mtACS), with
synchronized current delivered to the sites (network nodes), can offer the potential to
enhance connectivity between nodes of these large-scale networks. FrontoParietal
Synchronization (FPS), defined as a double site, DLPFC and IPC, tACS both with in-phase
(synchronic) oscillatory electric current, more frequently in the theta or alpha bands, has
received particular attention among other mtACS methods. The goal of FPS is to improve ECN
connectivity and improve functions like working memory6-8 and attention control9. Most tACS
studies have explored the online effects of synchronization. However, recent evidence for the
long-lasting entraining effect of tACS after termination of stimulation (offline effect) has
increased the potential for meaningful clinical applications. Nevertheless, there are no
published fMRI studies to date (Dec 2018) that have aimed to delineate how FPS might modulate
top-down ECN regulatory control over the amygdala and ventral striatum. The overall aim of
the proposed research is thus to determine whether FPS can amplify top down modulation of ECN
over subcortical-limbic areas (VSt and Amygdala) during CIC among people with OUD.
Furthermore, the investigators will explore whether connectivity between these areas before
FPS along with other clinical and behavioral factors can predict inter- individual
differences in subjective response to FPS in CIC. This line of research will provide a
mechanistic background to use context-dependent tACS to enhance cognitive control in drug
craving to improve long term drug addiction treatment outcomes.
B. Significance:
This study combines an active intervention with behavioral and neuroimaging assessments in
people suffering from OUD, a target population in the US with extensive need for new
treatment options. tACS involves simple and low-cost technology without any significant side
effects that is largely scalable as a potential non-invasive therapeutic tool to help people
during addiction recovery. Results will help provide a mechanism for how transcranial
electrical current interventions can affect neurocognitive processes involved in drug
addiction with the long-term goal of improving treatment outcomes.
C. Innovation:
For the first time, the investigators will be able to delineate the mechanistic neural
substrates that are important for the efficacy of FPS for OUD using both task-based and
resting state functional neuroimaging methods. Moreover, using an individual differences
approach, the investigators will be able to identify prognostic biomarkers for the efficacy
of FPS among individuals with OUD, advancing the field towards precision addiction medicine.
D. Specific Aims:
1. To determine whether FPS changes ECN (DLPFC, and IPC) and limbic (VSt and Amygdala) task
(CIC) and resting state connectivity (neural response to FPS) in OUD
2. To determine whether FPS changes subjective self-report of craving (subjective response
to FPS)
3. To explore whether pre-FPS ECN-limbic connectivity predicts neural and/or subjective
response to FPS
4. To explore which of (a) subjective, (b) clinical, (c) behavioral, (d) structural, or (e)
neural circuits measures predict neural and/or subjective response to FPS
E. Research Design and Methods:
This is an experimental study of a single session FPS in medically healthy male individuals
with opioid use disorder (OUD). Subjects will be screened and enrolled from residential
abstinence-based treatment centers (like 12&12 Addiction Treatment Center) or inpatient
programs (like Laureate Psychiatric Clinic and Hospital). Effects of FPS on drug craving will
be assessed by both questionnaires and resting state and task-based fMRI.
Screening: The substance use core protocol (LIBR protocol #2018-012, PI: Martin Paulus),
which includes multi-level baseline assessment will be used to screen potential subjects at
addiction treatment programs in Tulsa (i.e., 12 & 12, LPCH and etc.). Participants who
complete that protocol and meet criteria for the current study will be invited to
participate. 12 & 12 is a leader in the substance abuse and addiction treatment and recovery
fields and the largest non-profit addiction treatment facility in a four-state area offering
residential and outpatient treatment services for both substance abuse and co-occurring
conditions (those with a mental health issue as well as an addiction diagnosis). It is
located less than 4 miles from Laureate Institute for Brain Research. Laureate Psychiatric
Clinic and Hospital (LPCH) is basically attached to LIBR and offer both inpatient and
outpatient treatment services for drug addiction. All potential subjects will be introduced
by the clinical team at the treatment programs and then be screened by the trained study
staff or the PI to determine whether they meet any exclusion criteria such as any major
medical or psychiatric illness that would preclude the use of tACS and or fMRI. Subjects will
be screened for psychiatric disorders by the trained staff with Mini International
Neuropsychiatric Interview.
Consent: The purpose, content, duration, and expected risks and benefits of the study will be
reviewed with each potential subject by the trained study staff. If they pass the screening
interview, written consent will also be obtained before subjects can participate in any
portion of the study. The actual consent form will either be given to the potential
participant by mail, email or in-person, depending on their preference. Subjects will be
encouraged to be open with the investigator and/or staff about any questions or concerns they
have either before, during, or after the study.
Enrollment: Sixty subjects with OUD will be recruited from residential or inpatient addiction
treatment programs in Tulsa in their first weeks of abstinence after being medically
stabilized. Participants will undergo screening and baseline assessments using self-report
and clinical assessments. Eligible participants will be allocated to either active or sham
stimulation arms in. Participants in the active arm will receive 20 minutes FPS on right ECN.
The right ECN is selected as its contribution is dominant among people with SUD 10. Moreover,
right FPS has been reported to have more pronounced effects on executive functions. Resting
state (rs) and task-based fMRI (pictorial opioid cue exposure, block-designed) and EEG
(electroencephalography) will be done immediately before and after active or sham FPS. Drug
craving will be assessed with a single item 0-100 VAS (visual analogue scale) question at
multiple time points before and after imaging and FPS. Subjective and neural response to drug
cue exposure in prefrontal cortical areas and subcortical-limbic areas (craving>neutral
activations) and their connectivity during resting state will be assessed before and after
FPS with contrasts made between active and sham stimulation with a random effects model.
F. Hypotheses and Statistical Methods The basic image processing will be done with the AFNI
software package. Subject-level analyses on rs- and task-based fMRI data will generate
functional connectivity z-scores and beta maps, respectively for group-level analyses.
For the primary outcome measure and first secondary outcome measure, subjective report and
neural response to drug cue exposure in prefrontal cortical areas and subcortical-limbic
areas (Fig 1) and their connectivity during resting state will be assessed before and after
FPS with contrasts made between active and sham stimulation with random effect. Beta maps
will be used to evaluate drug-cue reactivity at regions of interest (ROIs) by mixed-effects
models (AFNI 3dMEMA); multiple comparisons will be corrected by false-discovery rate (FDR) or
cluster level thresholds (AFNI 3dClustSim). The investigators hypothesize that FPS
significantly reduces subjective reports of craving, increase activations in the prefrontal
cortical areas and insula, decreases activations in the ventral striatum and amygdala and
increase top-down connectivity between cortical and subcortical areas within ROIs.
For the other secondary outcome measures, the investigators will use a linear regression
model to identify factors contributing to response to FPS in the active arm. The
investigators hypothesize that higher baseline top-down connectivity will have a significant
effect on the higher FPS effects in reducing activations in the subcortical areas. The
investigators also hypothesize that higher current intensity in the cortical areas would have
significant positive effects on the both subjective and neural responses to the FPS.
For the exploratory outcome measures, an exploratory regularized regression model (elastic
net) will be employed to define major prognostic factors for response to FPS in the active
arm of the study. This model will be validated with one-leave-out cross validation within
this dataset and will be validated with subsequent test datasets in the future studies.
The proposed sample size of 30 participants per arm will provide 80% power to detect an
effect size (Cohen's d) of 0.74 for changes in drug-cue reactivity between arms at a
two-sided 0.05 significance level in a two-sample t-test.
G. Gender/Minority/Pediatric Inclusion for Research The investigators will include male
participants age 18 and older. Women will not be included in this preliminary study to
control for the effects of hormonal changes on brain plasticity induced by FPS. Subjects will
be recruited without any predilection for any racial or ethnic groups.
H. Subject Risks
Assessments: Risks and general protections against risk: The main risk to the subjects is
that assessments with self-reports, interviews and cognitive tasks take time. The assessments
being used in this study are the same as those used in different studies at Laureate
Institute for Brain Research. Some people may find some of the questions to be too personal
but the subjects always have the option of not answering any questions.
FPS: Risks and general protections against risk: Subjects will be fully informed about the
foreseeable risks and discomforts associated with participation in this study.
1. Headaches/itching/paresthesia. Headaches, itching, and paresthesia are generally very
mild with FPS and are limited to the actual treatment duration. Since skin nerves
habituate to the electrical stimulation rather quickly, most subjects are not aware of
the stimulation after about the first 1-minute. This is what allows sham stimulation to
be effectively masked. More persistent headache can be treated with acetaminophen or
ibuprofen. The range of stimulation intensities for human studies of FPS is usually
1-2mAmps as the investigators do in this study.
2. Skin irritation. Skin redness is common with FPS studies because the electrical
stimulation increases local blood flow under the electrodes. This redness should
dissipate within 30-minutes or less. There should be no evidence of redness or skin
breakdown before the FPS application.
The consent forms describe these risks and discomforts clearly. Patients must know that they
have the option to withdraw from the study at any time. Withdrawal from this study can be
done without consequence. The investigators may also choose to terminate a participant from
this study, if they suffer a severe adverse event, do not follow study requirements, or feel
that continued participation would put the person at a greater risk than indicated.
Drug Cue Exposure: Risks and general protections against risk: Drug cue exposure is a
conventional method in experimental addiction studies. Functional neuroimaging with MRI
(fMRI) with drug cue exposure tasks is a routine method to activate and depict neurocircuits
involved in drug craving. There are over 300 published studies indexed at the National
Library of Medicine's website (www.pubmed.com) with drug cue exposure fMRI among drug users.
The only risk that is associated with these paradigms other than minimal risks associated
with fMRI in general is the increased level of drug craving among participants. In this
study, like other studies in the field, the investigators will assess the level of craving
after the cue exposure sessions inside or outside MRI scanner to ensure that subjects will
not leave the center with a significant level of craving. Different craving reduction
methods, such as relaxation, distraction or reappraisal will be instructed to the study staff
to help participants to calm down any potential craving. After assurance that the
participants are in stable condition, they will be escorted back to the treatment program or
other facilities with minimum risk for access to drugs.
I. Benefits versus Risk In accordance to the principle of beneficence, research should
maintain a favorable balance of benefit to risk. The proposed FPS parameters in OUD patients
in this protocol fall within a Class II classification of benefit-risk ratio. That is, FPS,
as used here, is of potential, but unproven benefit. Given the investigators experience, the
FDA approval of a tDCS (transcranial direct current stimulation) /tACS (transcranial
alternating current stimulation) device that is actively marketed to the public, and
experience of other tDCS/tACS laboratories, to date, the tDCS/tACS parameters used in this
protocol are safe and constitute a 'minimal risk' application.
J. Data and Safety Monitoring Plan The risk for adverse events is minimal. No medication,
therapeutic decision or investigational device is made based on the results of these studies.
Participants may experience some discomfort upon discussing their symptoms with staff and
receiving unanticipated information about diagnosis. Participants may find it difficult to
participate in detailed ratings. Any unanticipated adverse events will be reported
immediately to the IRB of record and Laureate Institute for Brain Research Human Protection
Administrator at (918) 502-5155 or via email at hpa@laureateinstitute.org.
Each subject is given a unique identifier with a code. Information for each participant is
entered into the Laureate Institute for Brain Research subject database and they are
automatically given a LIBR number. The code key that links the unique identifier to the
subjects' names is kept in a separate file. All data analysis is performed on de-identified
data. Other than the principal investigators, there is no need for personally identifying
information to be known to other investigators.
The electronic data will be kept in a firewalled and password protected database on a secure
server managed by LIBR. Vanderbilt University, with collaboration from a consortium of
institutional partners, has developed a software toolset and workflow methodology for
electronic collection and management of research and clinical trial data. REDCap (Research
Electronic Data Capture) data collection projects rely on a thorough study-specific data
dictionary defined in an iterative self-documenting process by all members of the research
team with planning assistance from the information technology staff. The iterative
development and testing process results in a well-planned data collection strategy for
individual studies. REDCap servers are housed in a local data center at Laureate Institute
for Brain Research and all web-based information transmission is encrypted. REDCap was
developed specifically around HIPAA-Security guidelines and is recommended to LIBR
researchers by both the investigators' Privacy Office and the Western Institutional Review
Board (WIRB). REDCap has been disseminated for use locally at other institutions and
currently supports 240+ academic/non-profit consortium partners on six continents and over
26,000 research end-users (www.project-redcap.org).
Subjects will not be identified in any reports or publications. If the PI leaves LIBR, and
agreement will be made between LIBR and the PI new institution to transfer the data so that
the study can continue.
Study information will be made available to the subjects when there has been sufficient data
analysis to make reasonable aggregate conclusions. The investigators can share general study
characteristics (how many people were recruited, age, primary disorder etc.) early in the
process but the investigators do not share study results with subjects until the quality of
the data is close to publication level.
K. CONFIDENTIALITY Records of the participant's participation in this study will be held
confidential except as disclosure is required by law or as described in the informed consent
document (under "Confidentiality"). The researchers will make every effort to minimize the
risk of breach of confidentiality and a Certificate of Confidentiality will be obtained from
NIH to further protect the subject. The study doctor, the sponsor or persons working on
behalf of the sponsor, and under certain circumstances, the United States Food and Drug
Administration (FDA) and WIRB will be able to inspect and copy confidential study-related
records that identify the subject by name. Therefore, absolute confidentiality cannot be
guaranteed. If the results of this study are published or presented at meetings, the subject
will not be identified. Paper copies of consents, screening forms, the Research Privacy Form,
and any other forms, testing results or papers containing Personally Identifiable Information
(PII) will be stored in a secured medical records room or electronically with access granted
only to authorized personnel.
The study PIs, the sponsor or persons working on behalf of the sponsor, and under certain
circumstances, the United States Food and Drug Administration (FDA) and the Institutional
Review Board (IRB) will be able to inspect and copy confidential study-related records which
identify the subject by name. Therefore, absolute confidentiality cannot be guaranteed. If
the results of this study are published or presented at meetings, the subject will not be
identified.
Electronic copies of consents, screening forms, and any other forms, testing results or
papers containing Personally Identifiable Information (PII) will be stored on a password
protected electronic database with access granted only to authorized personnel.
