Clinical trial NCT03757585
Conditions: Non-verbal Learning Disorder Autism Spectrum Disorder Autism
Keywords: autism learning disorder natural supplements NAC omega-3
Sponsor: Massachusetts General Hospital
Start date: 2019-05-20; Completion date: 2024-05-06
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study consists of a 6-week, open-label, randomized clinical trial study to compare efficacy and tolerability of the natural treatments omega-3 fatty acids, inositol, and N-acetylcysteine (NAC) in the treatment of mood dysregulation in children and adolescents with non-verbal learning disability (NVLD) or Autism Spectrum Disorder (ASD). Subjects will include youth ages 5-17 years with a non-verbal learning disability (NVLD) or autism spectrum disorder (ASD) and current symptoms of emotional dysregulation.

Detailed description:

Arms: arm 1: Subjects will be treated with 1020mg QAM + 1020mg QPM of omega-3 fatty acids and inositol based on weight (subjects under 25kg: 1000mg QD; Subjects weighing 25kg or more: 2000mg QD). arm 2: Subjects will be treated with N-acetylcysteine capsules (subjects ages 5-12: 1800mg QD; subjects ages 13-17: 2400 mg QD) or effervescent tablets (subjects ages 5-12: 1800mg QD; subjects ages 13-17: 2700 mg QD) based on age.
Interventions: intervention 1: Open-label Treatment with Omega-3 Fatty Acids + Inositol intervention 2: Open-label Treatment with N-acetylcysteine
Intervention descriptions: intervention 1: Open-label Treatment with Omega-3 Fatty Acids + Inositol intervention 2: Open-label Treatment with acetylcysteine

Protocol documents:
SAP_003.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning 
Disability (NVLD) and/or Autism Spectrum Disorders (ASD) 
 
NCT03757585 
 
 
April 23, 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Methods 
Participants were included in the analysis based on a modified intent to treat analysis plan with the criterion that 
participants had to be exposed to the study medications for ?2 weeks. Baseline clinical characteristics were 
examined using Pearson’s chi-squared test for dichotomous measures and truncated Poisson regression models for 
continuous measures (CBCL-AAA and CBCL-AT: lower level [ll] of truncation=150, upper level [ul] of 
truncation=270; SRS: ll=30, ul=90; BRIEF: ll=30, ul=100; YMRS: ul=60; CDI: ul=40). Primary efficacy 
measures of mania and depression, as well as secondary measures of autism symptoms and executive functioning, 
were analyzed using mixed-effects Poisson regression models with robust standard errors to account for the 
repeated measures on each participant. These models predict the outcome measure of interest from the study 
group, study week (continuous), and the study group-by-study week interaction, which is the primary effect of 
interest. Secondary efficacy measures of mania and depression assessed at endpoint were examined using logistic 
regression models predicting the outcome of interest from the study group. Adverse events (AEs) were analyzed 
using a Poisson regression model for AE counts and Fisher’s exact tests for AE prevalence. All analyses were 
two-tailed with an alpha level of 0.05 and conducted using Stata (Version 18.1) (StataCorp, 2023). 
We also examined the moderating effect of 1) the CBCL Autistic Traits (AT) profile defined by a 
combined T-score ?195 on the CBCL Withdrawn/Depressed, Social Problems, and Thought Problems scales, and 
2) the CBCL-Bipolar (BP) profile defined by a combined T-score ?210 on the CBCL Aggressive Behavior, 
Attention Problems, and Anxious/Depressed scales. To examine these moderating effects, we added a 3-way 
interaction term between study group, study visit, and CBCL profile group to each of the models for the primary 
and secondary outcomes of interest. The moderating effects of the CBCL-AT and CBCL-BP profiles were 
examined separately. 

Prot_001.pdf: 
PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
1 
 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Janet Wozniak, MD 
 
PROTOCOL TITLE 
An Open-Label Clinical Trial Conducted via Telepsychiatry of Complementary 
and Alternative Treatments (Omega-3 Fatty Acids and Inositol vs. N-
acetylcysteine) for the Management of Emotional Dysregulation in Youth 
with Non-verbal Learning Disability (NVLD) and/or Autism Spectrum 
Disorders (ASD) 
 
FUNDING 
Sponsored by Demarest Lloyd, Jr. Foundation 
 
VERSION DATE 
Version: AME 29 
Last Modified Date: 2/22/2023 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
The purpose of this study is to examine the relative effectiveness of omega-
3 fatty acids plus inositol versus N-acetylcysteine (NAC) in reducing 
symptoms of emotional dysregulation in children and adolescents (ages 5-
17) with non-verbal learning disability (NVLD) and/or autism spectrum 
disorders (ASD). We hypothesize that omega-3 fatty acids plus inositol 
combined intervention will result in improved outcomes relative to using NAC 
as monotherapy. 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Emotional dysregulation affects a sizeable minority of children with non-
verbal learning disability (NVLD) and related conditions such as autism 
spectrum disorders (ASD). The occurrence of a mood disorder in these 
children and adolescents further compromises their problematic course and 
outcome. Unfortunately, none of the current conventional treatments for 
mood disorders can claim a high level of efficacy combined with easy 
tolerability in all individuals. Increasingly, clinicians, researchers, and 
patients and their families are turning to natural products considered 


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complementary and alternative treatments. Yet, few studies exist to support 
the use of these dietary supplements in pediatric populations. 
 
Omega-3 fatty acids (including EPA and DHA) are important components of 
cell membranes and are important for cell-to-cell communication in the 
brain. However, abnormalities in fatty acid composition of phospholipids in 
cell membranes have been described in psychiatric disorders in general and 
in bipolar disorder in particular (Horrobin & Bennett, 1999; Horrobin, Glen, & 
Vaddadi, 1994; Peet, Murphy, Shay, & Horrobin, 1998; Stoll et al., 1999). 
With reduced omega-3 fatty acids, the fatty acid composition of the cell 
membrane phospholipids would be altered, possibly leading to altered 
neurotransmitter binding and psychopathology. Thus, supplementing 
omega-3 fatty acids is suggested to have a potentially therapeutic role in the 
management of mood disorders. 
 
Inositol is a precursor for, as well as a product of, the phosphatidylinositol 
(PI) cycle and is therefore common and widely found, located primarily 
within cell membranes (Baraban, Worley, & Snyder, 1989). Although the 
mechanism of action of inositol remains unclear, we can indirectly presume 
from the available evidence that subjects with mood disorders experience a 
decrease in brain myo-inositol, which adversely affects the functioning of the 
PI second messenger system, which in turn results in mood changes. Dietary 
supplement with inositol, therefore, could improve the functioning of the PI 
system and treat depressive symptoms. 
 
N-acetylcysteine (NAC) is an acetylated amino acid and a precursor of 
glutathione that acts as an antioxidant in the brain to reduce oxidative 
stress, which has been implicated in bipolar disorder and major depression 
(Magalhaes et al., 2011). The main interest in psychiatry involves NAC as a 
precursor to glutathione, which acts as a potent antioxidant diminishing free 
radicals that can lead to cell damage and death. Glutathione is a major 
endogenous antioxidant in the brain. Glutathione is a molecule comprising 
three peptides: glutamate, cysteine, and glycine. The addition of the 
cysteine is the rate-limiting step, and NAC provides this key substrate for 
the creation of glutathione. 
 
Recent work by our group has shown improvements in emotional 
dysregulation in youth using omega-3 fatty acids (Wilens et al., 2017; 
Wozniak et al., 2007) and an even more robust outcome when combining 
omega-3 fatty acids with inositol (Wozniak et al., 2015; Wozniak et al., 
2016). Work by our group also suggests that N-acetylcysteine (NAC) is 
helpful in the management of emotional dysregulation in youth. However, 
these studies are not directly comparable as they were conducted at 
different times with different study clinicians and age groups. 
 


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Additionally, a major limitation of the previous clinical trials by our group on 
the efficacy of natural supplements is the burden on families incurred by 
travel to appointments. In our previous clinical trials, recruitment, retention, 
and patient satisfaction were all negatively impacted by the need to come 
into the office for study visits. Telepsychiatry is an established and rapidly 
growing initiative in the Department of Psychiatry at MGH. Dr. Wozniak has 
lead the department in using virtual visits to connect with patients and 
provide clinical psychiatric care. She has personally championed the use of 
virtual visits with the autism spectrum population, for whom the adverse 
sensory experience of a hospital visit is especially burdensome. 
 
Since omega-3 fatty acids, inositol, and NAC are safe with nor serious 
associated adverse events, studies of these treatments are well suited to 
virtual visits. Our preliminary data with all three supplements demonstrated 
minimal adverse events and no medical safety events. Therefore, this study 
is proposed to examine the relative effectiveness of omega-3 fatty acids and 
inositol versus NAC using telemedicine to conduct study visits. This will allow 
for a comparison of these natural supplements for the treatment of 
emotional dysregulation while providing subjects and their families with a 
more convenient and pleasant experience, which will most likely positively 
impact both recruitment and subject satisfaction and retention. 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
 
This will be a 6-week, open-label, randomized clinical trial study to compare 
efficacy and tolerability of the natural treatments omega-3 fatty acids, 
inositol, and NAC in the treatment of mood dysregulation in children and 
adolescents with NVLD/ASD. Subjects will include youth ages 5-17 years 
with a non-verbal learning disability (NVLD) or autism spectrum disorder 
(ASD) and current symptoms of emotional dysregulation. We will enroll 60 
subjects to allow for the randomization of 30 subject into each treatment 
arm. 
 
The full inclusion and exclusion criteria are included below: 
 
A. Inclusion Criteria: 
1. Male or female subjects, 5-17 years of age. 
2. A previous established diagnosis of non-verbal learning disability 
(NVLD) or DSM-V Autism Spectrum Disorder and/ or combined T-
scores on the Child Behavior Checklist  > 195 on the Withdrawn + 
Social Problems + Thought Problems subscales. 


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3. Current symptoms of emotional dysregulation as indicated by 
combined T-scores on the Child Behavior Checklist > 180 on the 
Anxiety/Depression + Aggression + Attention subscales. 
4. Subjects and their caregivers must be English-speaking and have a 
level of understanding sufficient to communicate intelligently with the 
investigator and study coordinator, and to cooperate with all tests and 
examinations required by the protocol. 
5. Subjects and their caregivers must be willing and able to comply with 
all study procedures. 
6. Each subject and his/her authorized legal representative must 
understand the nature of the study. The subject’s authorized legal 
representative must sign an informed consent document and the 
subject must sign an informed assent document. 
7. Subject must be able to swallow pills. 
8. Subject must have access to a computer with a camera, speaker, 
microphone, and internet connection. 
9. Subjects must be willing to refrain from treatment changes during the 
study protocol. 
 
B. Exclusion Criteria: 
1. Investigator and his/her immediate family; defined as the 
investigator’s spouse, parent, child, grandparent, or grandchild. 
2. Serious or unstable illness including hepatic, renal, gastroenterological, 
respiratory, cardiovascular (including ischemic heart disease), 
endocrinologic, neurologic, immunologic, or hematologic disease. 
3. History of bleeding diathesis, including those with von Willebrand 
disease. 
4. Uncorrected hypothyroidism or hyperthyroidism. 
5. History of sensitivity to omega-3 fatty acids, inositol or NAC. A non-
responder or history of intolerance to omega-3 fatty acid, inositol or 
NAC after 2 months of treatment at adequate doses as determined by 
the clinician. 
6. Severe allergies or multiple adverse drug reactions. 
7. Unstable or untreated seizure disorder. 
8. DSM-IV substance use, abuse or dependence. 
9. Judged clinically to be at serious suicidal risk for C-SSRS score ≥ 4. 
10. Current diagnosis of schizophrenia. 
11. Current diagnosis or symptoms of psychosis. 
12. IQ < 70. 
13. Pregnant or nursing. 
14. Weighs less than 12.5kg. 
 
The main outcome measures will be improvement in manic symptoms as 
measured by the Parent-Young Mania Rating Scale (P-YMRS) and 
improvement in depressive symptoms as measured by the parent-completed 
Children’s Depression Inventory (CDI) scale. 


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Only subjects who are not responding to their current treatment regimen will 
be recommended to taper from their medications. No subject on a useful 
treatment will be recommended for taper from medication for entry into this 
study. Subjects and their current treating prescriber may opt to continue 
with current treatment even if taper is recommended. Typically, a 7-day 
washout period is recommended for antidepressant medications and 
atomoxetine (with the exception of Prozac requiring 14 days). Mood 
stabilizers/atypical antipsychotics are generally washed out over the course 
of 7 days, while stimulants are discontinued in 3 days. Discontinuation of 
medications will be done in consultation in the prescribing clinician. 
 
We plan to treat subjects with the following doses: 
 
Omega-3 Fatty Acids 
All subjects: 1020mg QAM + 1020mg QPM 
+ 
Inositol 
Subjects under 25kg: 1000mg daily  
Subjects weighing 25kg or more: 2000mg daily  
 
OR  
 
NAC: 
Effervescent Tablets 
Subjects ages 5-12: 1800mg daily 
Subjects ages 13-17: 2700 mg daily 
Capsules 
Subjects ages 5-12: 1800mg daily 
Subjects ages 13-17: 2400mg daily 
 
At each visit, measures of safety and effectiveness will be obtained using 
rating scales.  
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
 
Interested parents/guardians will first complete a phone screen with the 
study coordinator or a research assistant. If the child meets eligibility criteria 
based on the phone screen, the parent/guardian will be asked to complete 
the Child Behavior Checklist (CBCL) via RedCap, a secure online data 
capture system. The parent/guardian will be provided with an online consent 
statement and asked to indicate their agreements to participate in the online 
questionnaire portion of the study before they are brought the CBCL. 
 


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If a parent/guardian has completed pre-screening procedures for another 
research study or the clinic in our department within the past 3 months, 
they will not be asked to complete that procedure again, and the data 
collected previously will be used for pre-screening for this protocol. 
 
Subjects deemed to be eligible following the phone screen and completion of 
the CBCL will either be scheduled for an in-person visit at our office or, 
during the COVID-19 pandemic, to speak with a study clinician via phone to 
obtain informed consent prior to completing further screening and baseline 
study procedures via virtual visit. Informed consent will be obtained from all 
subjects and their legal guardian at the initial in-person visit or, during the 
COVID-19 pandemic, during a phone call with a study clinician. The subject’s 
legal guardian will then answer questionnaires regarding current medications 
and demographic details. They will also complete the BRIEF, SRS, P-YMRS, 
and CDI questionnaires. A study clinician will complete the Columbia Suicide 
Severity Rating Scale (C-SSRS) to assess past and current suicidality and 
self-harmful behaviors; conduct an observational mental status exam; 
record baseline severity scores of Clinical Global Impression (CGI) for mania, 
depression, and overall bipolar disorder; and will review current medications 
and recommend any medication taper. A trained member of study staff will 
obtain and record height and weight for all subjects. A urine pregnancy test 
will be conducted for all female subjects who have reached menstruation. If 
the test is positive, the subject will not be able to participate in the study 
and she will be informed of the results, along with her parent/guardian if she 
agrees. Even if she does not agree, the study doctor may still decide, based 
on the subject’s age, maturity, or medical condition, to inform the 
parent/guardian.  
 
In the case that it is deemed necessary at the in-person screening/baseline 
visit (i.e. if a subject has plans to make changes to concomitant medications 
or cannot begin active participation in the study at the time for some other 
reason), the subject will be allowed to enroll in the study and complete study 
tasks that require the subject to be in the office at that time and to complete 
all other tasks that can be completed remotely at a later date, without 
returning to the office. 
 
During the COVID-19 pandemic, the screening/baseline visit will be 
conducted remotely. Revised timeline: parental consent and child assent  
dispensation of study medication  week 99/0 tele-visit. After consent has 
been obtained, the study medication will be mailed to the subject. Once the 
subject has received the study medication by mail, the subject and their 
parent(s)/guardian will complete a tele-visit with a study clinician in order to 
complete all study procedures requiring a clinician. All typically completed 
clinician assessments/rating scales can safely and effectively be completed 
remotely during the tele-visit with the study clinician and the subject and 
their parent(s)/guardian. The study coordinator will also complete a phone 


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call with the subject and their parent(s)/guardian on the same day as the 
tele-visit with the study clinician in order to complete the following 
procedures. Parents/guardians will be asked to self-report height and 
weight. It will be noted that these measurements were provided by a 
parent/guardian report rather than study staff measurement. For any female 
subjects who have begun menstruation, a pregnancy test will be ordered 
using study funds and sent directly to the subject’s home address. The test 
will be ordered in advance to ensure delivery before the week 99/0 tele-visit. 
The study coordinator will review the procedure for completing the urine 
pregnancy test while on the phone and have the subject complete the test 
while remaining on the line. The subject/subject’s parent or guardian will 
verbally report the result to the study coordinator, and will also send visual 
confirmation (i.e. a photo of the test with results send via secure email) 
prior to beginning the study treatment. Finally, the study coordinator will 
send an email link to the parent(s)/guardians to complete a battery of 
assessments/rating scales via REDCap. All typically completed parent 
assessments/rating scales can safely and effectively be completed remotely. 
These assessments/rating scales are already approved to be completed via 
email link to REDCap for the week 1-6 tele-visits. 
 
At each following weekly tele-visit, parents will indicate adherence to the 
study treatment, list any new concomitant medications, and complete 
questionnaires regarding symptoms of emotional dysregulation, mania, and 
depression. A study clinician will also complete the C-SSRS to monitor 
suicidality and self-harmful behaviors, record CGI (Severity and 
Improvement) scales for mania, depression, and overall bipolar disorder, 
record any side effects or adverse events, and review and confirm parent-
reported information. 
 
At endpoint, parents will report current weight and complete the BRIEF and 
SRS questionnaires in addition to the weekly questionnaires. 
 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
 
Families with children and adolescents with NVLD/ASD and emotional 
dysregulation can speak with their primary care doctor to obtain a 
prescription for medication to treat mood disorders or receive a referral to a 
specialist. Available medications for treating severe mood problems in 
children include atypical antipsychotic medications and mood stabilizers and 
in some cases antidepressants. The study doctor can discuss the risks and 
benefits of other treatments with potential participants and their 
parent/guardian prior to enrollment. 
 


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Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
 
All efforts are made to minimize risks to subjects. The protocol is designed 
to ensure that safety measurements are completed prior to study drug 
treatment and that the subject’s response to study drug is closely 
monitored. Previous studies by our research group confirm that these study 
treatments are safe for use in children at these doses. All procedures used in 
this study are consistent with sound research design and do not 
unnecessarily expose subjects to risk. Clear drop criteria will be employed, 
as described below. 
 
We will be using secure Partners workstations to access Vidyo, a 
videoconferencing platform, in combination with Skills Based Routing (SBR), 
a patient management software, to conduct the weekly study visits. Both 
Vidyo and SBR are secure mediums. Partners Information Systems and MGH 
Health Information Services have already approved this technology for use. 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
 
Each week, a study clinician will record any adverse events.  
 
Poor response to treatment, leading to drop from the study, will be 
measures by a CGI-bipolar score that is 2 points higher (more severe) than 
baseline for more than 2 consecutive weeks or a P-YMRS score that is 30% 
higher than baseline for more than 2 consecutive weeks only if the P-YMRS 
is in a clinically significant range of >15. If a subject should score a 4 or 
higher on the C-SSRS, he or she will be dropped from the study. The study 
clinician will assess the level of risk and take appropriate actions, including 
an immediate referral to emergency services. 
 
In addition, drop from the study will occur at clinician discretion for 
worsening of clinical course, non-compliance with treatment, or inability to 
tolerate study treatment. 
 
Subjects who fail to keep study appointments or are non-complaint (less 
than 70% compliance for 2 weeks or longer) may be dropped from the 
study. If a subject becomes pregnant or is found to be abusing substances 
during the study, he or she will be dropped from the study. These study 
subjects will be given a referral for local treatment. 
 


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FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
 
Potential side effects are few and will be monitored for throughout the 
research study. Consent forms will clearly list potential treatment side 
effects. Since they are natural products, it appears that omega-3 fatty acids, 
inositol, and NAC have a low potential for unwanted side effects or negative 
effects on the child’s growth and development. It should also be noted that 
no important toxic effects have been reported in previous use in humans and 
animals. 
 
The treatment omega-3 fatty acids has been used and studied in pediatric 
populations with few side effects. The most common side effects reported 
with use of omega-3 fatty acids are upset stomach and complaints of a fishy 
taste. Other side effects include nausea, skin rashes, decreased platelet 
aggregation, bleeding tendencies, and increased restlessness. 
Inositol is a safe, natural diet supplement with emerging evidence of utility 
in psychiatric populations. The most common side effects include mild 
clinically insignificant increases in glucose, flatus, nausea, sleepiness and 
insomnia, dizziness, headache, and diarrhea. 
 
The most common side effects reported with use of NAC are gastrointestinal. 
Other less common side effects that have been reported include fatigue, 
nervousness, vivid dreams, heartburn, pruritus (without rash), and 
headaches (Berk et al., 2008; Ghanizadeh & Moghimi-Sarani, 2013; Gray et 
al., 2012; Hardan et al., 2012; Mardikian, LaRowe, Hedden, Kalivas, & 
Malcolm, 2007). Serious side effects are uncommon. 
 
Answering detailed questionnaires may create a mild degree of 
inconvenience or emotional upset for the subjects. The PI will be available to 
respond to any concerns or to answer other questions about the study 
(available by pager 24 hours per day). All of the information about 
participants will be treated confidentially. Subjects may refuse to answer any 
of these questions. 
 
Having treated hundreds of bipolar patients, we are aware that this is a 
group of very highly disturbed children at risk for psychosis, suicide and 
disruption in the family. Although it is unlikely that these risks will be 
exacerbated by the protocol, we will be vigilant regarding the potential for 
patient decompensation or dangerousness to self or others. In the execution 
of research protocols, our primary concern is always the safety of the 
research participant. Given the especially unstable nature of bipolar 
patients, we will be available to the study staff and to handle clinical 


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emergencies with patients and their families. The PI has a beeper and is 
available for emergencies 24 hours per day. The Massachusetts General 
Hospital has an active and well-staffed psychiatric emergency service that 
will be available to subjects if needed. This study has clearly defined exit 
criteria to ensure the safety of participants. Dr. Wozniak has treated 
hundreds of bipolar patients via tele-psychiatry and is aware of how to assist 
in the event of a crisis with call to 911 and local police. 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 
There may be no direct benefit to the subjects participating in this trial. 
Potential benefits to the subjects include rapid access to treatment, free 
psychiatric assessment, and a free trial of potentially useful treatments with 
low associated risks, and the opportunity to contribute to medical science 
and thus help others with the same disorder(s). 
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
 
We do not include pregnant or nursing women due to the unknown effects of 
study treatments on fetuses and infants. We do not involve prisoners or 
institutionalized individuals in our studies. Those who are economically or 
educationally disadvantaged, hospital employees, or patients from medical 
practices of the investigators are eligible to participate in our studies 
provided that they meet inclusion and exclusion criteria. Females and 
minorities are also welcome to participate as study subjects, provided that 
they meet inclusion and exclusion criteria. 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
 
Subjects who do not understand English cannot participate in our studies, for 
the study requires that subjects and their parents be able to verbally 


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communicate with the clinicians during the weekly completing of rating 
scales. The assessment instruments are not available and have not been 
adequately standardized in other languages. If available, adding the 
complexity of a translator has the potential to make the subject experience 
exhausting. 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          https://partnershealthcare-public.sharepoint.com/ClinicalResearch/Non-
English_Speaking_Subjects.1.10.pdf
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
 
We will use advertisements on the Internet, including advertisements posted 
on the Partners Clinical trials website, and flyers to recruit participants. 
Individuals who respond to advertising will go through a phone screen with 
the study coordinator or research assistant via phone and will then be 
screened by a study clinician. 
 
Participants may also be recruited from the referral pool of existing and new 
patients in the Pediatric Psychopharmacology Program and the MGH Child 
Psychiatry Outpatient Clinic, from the pool of children screened for 
participation in Protocol #2019-P-000846 (“An Open-Label Clinical Trial 
Conducted via Telepsychiatry of Complementary and Alternative Treatments 
(Omega-3 Fatty Acids and Inositol vs. N-acetylcysteine) for the Management 
of Emotional Dysregulation in Youth”), or via advertising in the local media. 
Clinicians may introduce the study to appropriate patients and their 
parent/guardian and provide those who may be interested in participating 
with the study coordinator’s contact information. The patient and their 
parent/guardian may then contact the study coordinator for more 
information about the study and to be screened for eligibility over the phone. 
Prospective subjects and their parents/ guardians will not be contacted by 
research staff unless they have given explicit permission to be contacted for 
research.   
 
All subjects that enter the study will undergo standard screening and 
diagnostic procedures. 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 


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parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
 
Subjects will be provided with omega-3 fatty acids, inositol, or NAC as 
appropriate at no cost. Subjects can be reimbursed for parking at MGH 
for the initial in-person visit. 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Recruitment_Of_Research_Subjects.pdf
 
          Guidelines for Advertisements for Recruiting Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Guidelines_For_Advertisements.1.11.pdf
 
          Remuneration for Research Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Remuneration_for_Research_Subjects.pdf
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
 
Informed consent and assent will be obtained prior to performing any 
protocol procedures and prior to administration of study treatment. The 
informed consent and assent documents will be used to explain in simple 
terms the risks and benefits of study participation to the subject and his/her 
parents/guardians. The nature of the study will be fully explained to the 
subject and his/her parents/guardians by a board-certified physician who is 
either the primary investigator or co-investigator. The subject and his/her 
parents/guardians will be encouraged to ask questions pertaining to their 
participation in the study, and they may take as much time as they feel 
necessary to consider their participation, as well as consult with their family 
members or physician. Participation in this study is voluntary and the 
subjects may withdraw from the study at any time. 
 
Assent for adolescents ages 14-17 will be documented on a separate line of 
the parent/guardian consent form. Assent for children ages 7-13 will be 
documented on a separate assent form that describes the study in age-
appropriate language. Subjects who turn 18-years-old during the trial must 


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re-sign on a designated line on the parent/guardian consent form when they 
reach the age of maturity. 
 
Should a subject be enrolled from a clinician’s own patients, the subject will 
be offered the opportunity to take as much time as they feel necessary to 
review to consent form at their convenience and consider their participation 
in the study. Study staff will be available to contact if potential subjects have 
any further questions about the study and consent. All subjects recruited 
from among the investigator’s own patients will be offered the opportunity to 
discuss participation with a physician colleague before deciding whether or 
not to participate. In this case, the investigator will also reinforce that 
participation in voluntary and the decision not to participate will not affect 
their care, now or in the future.  
 
During the COVID-19 pandemic, informed consent will be obtained remotely. 
This may be done in 2 ways: 
1. Using Adobe eSignature: Study staff will send the consent form and 
assent form (when applicable) to subjects in PDF form ready for Adobe 
eSignature via email with a brief statement (email template submitted) 
explaining why they are receiving this form and further instructions. 
Study staff will schedule a time for the subject and their 
parent(s)/guardian to meet with a study clinician via phone to complete 
consent. The study clinician will have a conversation by phone with the 
subject and their parent(s)/guardian to obtain consent in the usual 
fashion: review the consent form, review inclusion and exclusion criteria, 
review risks and benefits of the study, review alternatives to 
participation, and answer any questions subjects and their 
parent(s)/guardian may have. If the subject and their parent(s)/guardian 
decide to participate, they will sign the consent form and assent form 
(when applicable) using Adobe eSignature. The study clinician will also 
sign the consent form using Adobe eSignature prior to beginning any 
study procedures. Subjects will be sent a copy of the signed form by 
email for their records. 
2. Mailing a physical copy of forms: Study staff will send the consent form 
and assent form (when applicable) to subjects via mail or secure email 
along with a brief letter explaining why they are receiving this form and 
the phone number to call once they receive it. Study staff will schedule a 
time for the subject and their parent(s)/guardian to meet with a study 
clinician via phone to complete consent once they receive the forms via 
mail or email. The study clinician will have a conversation by phone with 
the subject and their parent(s)/guardian to obtain consent in the usual 
fashion: review the consent form, review inclusion and exclusion criteria, 
review risks and benefits of the study, review alternatives to 
participation, and answer any questions subjects and their 
parent(s)/guardian may have. If the subject and their parent(s)/guardian 
decide to participate, they will sign the consent form and assent form 


Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
14 
(when applicable) and mail it to the study clinician, who will also sign the 
consent form prior to beginning any study procedures. Subjects will be 
sent a copy of the signed form by secure email for their records. 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb 
 
For guidance, refer to the following Partners policy: 
     Informed Consent of Research Subjects:
     https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Informed_Consent_of_Research_Subjects.pdf
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
 
Study monitoring will include periodic inspection of all documents at regular 
intervals by the Principal Investigator and members of study staff. Such 
documents will include diagnostic testing, evaluations, progress notes, 
copies of medication test results, and written informed consent forms. The PI 
is responsible for monitoring safety and data. 
 
A subject may discontinue from this trial at any time, whether it is due to 
adverse effects or disinterest. All procedures have been designed to 
minimize subject discomfort and no subject will be asked to engage in 
research procedures not outlined in the consent form. 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 


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the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
 
The Principal Investigator and the project medical staff will be available 24 
hours per day via pager to respond to all reports of adverse events, 
including those that emerge outside of regularly scheduled visits.  
 
Unanticipated problems involving risks to subjects or others including 
adverse events will be reported to the PHRC in accordance with PHRC 
unanticipated problems including adverse events reporting guidelines. 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
 
The Principal Investigator will meet weekly with study staff to address 
procedural issues and the coordinator will audit each subject’s binder within 
a month of his/her completion of the study. Co-investigators are actively 
involved in the monitoring and quality assurance of these trials. These 
periodic quality assurance audits will ensure accuracy and completeness of 
all medical records, IRB files and correspondence, and the informed consent 
documentation. 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
            https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/DSMP_in_Human_Subjects_Research.pdf  
          
          Reporting Unanticipated Problems (including Adverse Events)
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Reporting_Unanticipated_Problems_including_Adverse_Events.pdf
 
 
 


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PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
 
Subject information collected during the study will be kept confidential by 
the study doctor and staff and will not be made publicly available unless 
disclosure is required by law. Subjects will be assigned code-names and ID 
numbers. Only study staff and co-investigators will have access to the 
information linking subjects to their ID numbers. Information will be held 
and processed on a computer. Access to these computerized records will be 
password protected and restricted to study staff. 
 
Data will be collected using RedCap, an electronic data capture system that 
streamlines data collection and management and ensures data integrity. 
RedCap software allows researchers to design and implement study surveys 
for collection, storage, retrieving, and manipulating data electronically. 
Subjects and their guardians will enter survey responses into electronic 
assessment forms, using personal computers. Study staff will use terminals 
at the research site or encrypted computers. The responses will then be 
transmitted securely via an encrypted connection and stored in a secures 
database. Electronic data capture obviated the need for subsequent data 
entry by staff, thus minimizing human error. Data will be collected on paper 
versions of scales or assessments and entered manually if the electronic 
data capture system, RedCap, is not functioning properly. 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
 
N/A 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 


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Version Date:  October 15, 2014 
 
  
17 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
 
N/A 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
 
N/A