Evaluating the Efficacy of Supplementation With Micronutrients for ADHD in Youth (MADDY) Study
Phase: PHASE1
Conditions: Attention Deficit Hyperactivity Disorder
Sponsor: Oregon Health and Science University

DOCUMENT DATE (IRB A P P ROVAL): 
 
NCT NUMBER: 
 
OFFICIAL S T UDY T IT LE:  
 
INVESTIGATOR NAME:  
 
ORGANIZATION: 
Oregon Health & Science University 
Template Version 20201222 
ClinicalTrials.gov Document Upload 
23-Feb-2021
Jeanette Johnstone, PhD
Micronutrients for ADHD in Youth: 
 The “MADDY” study  
NCT03252522

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Protocol for 
Micronutrients for ADHD in Youth: 
 The “MADDY” study  
at 
Oregon Health & Science University 
The Ohio State University/Nationwide Children’s Hospital  
University of Lethbridge 
 
 
 

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Aims and Objectives 
Aim 1: Replicate acceptability/tolerability of a multi-ingredient micronutrient product for children 
with ADHD [1].  
Hypothesis 1: Consumption of 9-12 capsules, in 3 divided doses daily, of a product containing a 
blend of vitamins, minerals, amino acids and antioxidants (see Appendix A for ingredients), will be 
achieved at >80% success, as measured by self-report adherence and pill counts and with no or 
transient side effects (e.g. nausea, loose stool); and no directly attributable serious adverse events 
(AEs) (see definition of AE in the section on page 21) recorded via the Pediatric Adverse Events 
Rating Scale (PAERS). 
Aim 2: Determine the prevalence, severity, and effect size for symptoms of irritability and negative 
mood, which are often associated with ADHD.  
Hypothesis 2: Treatment will improve mood, irritability and aggression by a medium effect (d>=.50) 
[2] as measured by the parent-rated Child & Adolescent Symptom Inventory – 5 (CASI-5), 
Categories B, C, CD, K, L, Rz, Q, and the child-rated Patient Reported Outcomes Measurement 
Information System (PROMIS) measures: Depression, Anger, Anxiety, and Peer Relations. 
Aim 3: Estimate true effect sizes on ADHD symptoms in this age group, to inform a larger trial.  
Hypothesis 3: The micronutrients will reduce participants’ ADHD symptoms of inattention and/or 
hyperactivity/impulsivity, as measured by the parent-rated CASI-5, Question Category A, and the 
Clinician-rated Clinical Global Impression (CGI) by a medium effect (d>=.50) compared to the 
placebo [1].  
Aim 4: Collect and store biological samples of blood, hair, saliva, urine, and feces at three time 
points. The blood samples are being collected per a request from the FDA for safety screening. We 
will collect additional blood to look at nutrient level changes and metabolomics, both targeted and 
untargeted, blood. Collection of other biological samples will enable future examination of nutrient 
mechanisms including markers of methylation, inflammation, metabolism, and microbiome 
biodiversity, as funds are available.  
Hypothesis 4: Ingestion of micronutrients will alter one, two or three of the areas under examination. 
The rationale for the collection of these samples is to begin to identify nutrient biomarkers that 
indicate mechanisms of the treatment within participants and between participants that may account 
for clinical symptom change, an important step forward in ADHD treatment [3]. Blood levels from a 
complete blood count, as well as thyroid and iron tests, will show no safety concerns following 
ingestion of micronutrient treatment. Levels of certain supplemented nutrients (vit D, B12, folate) 
will increase in those who take the active product [4]. Hair is being collected to examine mineral 
distribution and changes over time as well as to record baseline levels of lead and mercury. Salivary 
DNA may show peripheral epigenetic marks that are relevant to ADHD symptom expression [5]. For 
urine, metabolomics may detect amino acid metabolism , such as tryptophan, which has been found 
to be related to autism in children [6],  which may contribute to increased oxidative stress, and 
altered gut microbiomes byproducts, which have been found in children with  Autism Spectrum 
Disorders (ASD)[7], but not yet studied in ADHD. In the case of feces, as gut bacteria synthesize 
water-soluble vitamins [39], it is possible to examine the impact of micronutrient supplementation on 
gut bacteria and biodiversity, which has not been described yet in this population. Lower 
bifidobacterium species have been found to be associated with rates of ADHD and  ASD [40] and 
indigenous gut microbiota bacteria have been found to regulate serotonin [8] which may impact 
mood symptoms related to ADHD. 

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Background 
Overview of ADHD 
Attention-Deficit/Hyperactivity Disorder (ADHD) is a chronic developmental disorder affecting about 
5% of children[9]. Existing treatments, both behavioral and pharmacological, suppress symptoms in 
many cases[10]. However, behavioral interventions are unavailable for many families and 
pharmacological interventions continue to raise significant public concerns over side effects, stigma, 
and the long-term health effects[11]. These concerns lead scientists to call for further development of 
alternative interventions [12]. As well, there is a strong public desire for a scientific investigation of 
the efficacy of non-pharmacological treatments for ADHD; for example, up to 70% of US families use 
some form of complementary alternative medicine[13]. Since the 1960s, there has been ongoing 
documentation of the long-term outcome of having ADHD symptoms as a child, including increased 
risk for incarceration, substance abuse, disability, poor educational achievements and ongoing 
psychiatric problems [14-16], despite receiving conventional treatments. To address this public health 
need, the present study examines a novel nutritional intervention.  
 
Recent research highlights the importance of considering nutritional factors in the expression of 
ADHD, based on investigations into the impact that processed foods play in symptom severity[17], the 
roles of food dyes[18] and essential fatty acids[19],  and long-term studies showing that early 
malnutrition is an important risk factor for ADHD[20]. One treatment that logically stems from these 
studies is providing individuals with ADHD with the nutrients required for optimal brain functioning. 
One method to achieve this would be through supplementation with micronutrients (vitamins and 
minerals), based on the assumption that micronutrients serve as cofactors for synthesizing essential 
neurotransmitters. Such an approach may seem to challenge conventional understanding that only one 
variable at a time should be manipulated. However, a single ingredient strategy is already known to be 
of limited utility and also is at odds with human physiology as optimal functioning requires presence 
of all nutrients in balance rather than one nutrient provided in high doses[21]. Indeed, single nutrient 
studies have yielded only modest findings[22] whereas research with multi-ingredient nutrient 
interventions are proving more promising[23-27]. Pilot research has demonstrated on-off-on-off 
control of symptoms in ADHD children using micronutrients and a just-published RCT in children in 
New Zealand has shown clinical symptom improvement, particularly in children with comorbid 
irritability, aggression and anger [4]. These results all point to the need for a controlled trial with 
children, run in the US, as well as trials that investigate mechanisms of action of the micronutrients to 
document the transformational potential of nutritional therapy for ADHD.  
Rationale and approach of RCT 
The randomized clinical trial (RCT) is viewed as the gold standard for testing treatment efficacy and 
is the appropriate next step to test the claim that micronutrients provided in combination, yield 
clinically meaningful effect on these debilitating psychiatric symptoms in children. This proposed 
research will use RCT methodology and compare micronutrients with placebo in 135 children with 
ADHD in 3:2 ratio. The study will extend beyond efficacy in terms of clinical outcome, by gathering 
data that can be used in follow up investigations of how micronutrients may work via changes in 
physiology. Many theories have been proposed as to how micronutrients exert an effect on psychiatric 
symptoms, including: 1) affecting dopamine function in the frontal-striatal pathway[28], 2) correcting 

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inborn errors of metabolism that slow metabolic reactions[29], increasing methylation, 3) correcting 
deficiencies present in western diets[30, 31], and/or 4) increasing the production of adenosine 
triphosphate (ATP), the energy source produced by  mitochondria[32]. Some of these ideas are testable. 
Although not without controversy, changes in methylation marks can be investigated through DNA 
sampling from saliva as well as via sampling of the microbiome (e.g. stool samples).   
The evidence to date  
Studies assessing micronutrients for the treatment of ADHD have reported positive benefits and large 
effect sizes; however, they have been either open-label[23, 24, 33], retrospective database 
analyses[25], case reports[26], or patient preference studies[27]. The field is generally plagued with 
poorly designed and uncontrolled studies, often leading to erroneous conclusions about the utility of 
micronutrients in treating serious psychiatric conditions. Despite the popularity with consumers of 
using nutritional methods for the treatment of psychiatric illnesses [13, 34-37] the research is 
surprisingly sparse. A recent review showed that there were only 27 published studies using nutritional 
approaches (most of them single nutrient studies) in the treatment of ADHD [22] compared with 
hundreds using conventional medications. An RCT of micronutrients in youth with ADHD found 
positive results with a high safety profile [4]. The role of micronutrients in the pathophysiology and 
management of other psychiatric disorders including bipolar disorder, anxiety states, and autism is 
receiving considerable international attention because of large and beneficial effects [24, 38-42], 
suggesting that this approach could prove meaningful.  
 
Concerns about long-term safety of supplementary nutrients have been raised; however, these studies 
typically use one nutrient at a time [43, 44]. It is not definitively known whether nutrients given in 
combination hold the same risk as when given alone, however, our data and that of prior studies have 
provided support for the safety and tolerability of the planned intervention at the dosages proposed 
here [40, 45, 46]. With the exception of niacin and magnesium, no one ingredient is given in a dose 
higher than the specified Lowest Observed Adverse Effect Level (LOAEL) for that nutrient based on 
the Dietary Reference Intake recommendations [47]. Details on risk management, data safety 
monitoring, and product safety are covered starting in the Risk Management section which begins on 
page 14. 
Study Design 
Design Overview 
The design is an 8-week randomized, double-blind, placebo-controlled trial, with an 8-week open-
label extension, of Daily Essential Nutrients (DEN; Hardy Nutritionals), and a 30-, 60-, and 365-day 
follow-up phone call or in person-visit. The follow-up calls will also assess for safety following 
study completion. Parent/guardian and child ratings, using standardized measures, will evaluate 
adherence, side effects and AEs (Aim 1); ADHD-associated mood and irritability (Aim 2); and 
ADHD symptoms (Aim 3), thus allowing evaluation for clinical significance. Other domains of 
psychopathology will be evaluated for purposes of sample characterization and secondary analyses. 
The design consists of three study periods, which are individualized for each participant as they 
enroll: 

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1. 
Screening and baseline. Participants will be screened by phone through a conversation with 
the parent/guardian for study eligibility. Those who are eligible and consent/assent to the study will 
receive a baseline assessment (see below for definition of eligibility and assessment). 
2. 
An 8-week period of fully randomized, placebo-controlled, treatment.  
3. 
An 8-week open-label extension period (OL). 
Study data collection will occur in-person at baseline and at weeks 4, 8, 12, and 16 and via phone 30- 
60- days after end-of-open label and 365- days after enrollment. Details of data collection are outlined 
in Tables 1 & 2 located on the last two pages of this proposal. 
Study Population  
Number of subjects 
Sample size power calculations are based on using power = 0.8, with a two-tailed α=0.05, and the a 
priori decision to detect a medium effect size (d>=.5) with a primary parent-rated measure that is a 
combination of CASI-5 subscale scores. Given the three sites and two treatments; a 3:2 
randomization ratio, active-to-placebo; and assuming two dropouts per arm, per site, based on a 
previous study (Rucklidge, 2017), (n = 12 total), sample needed to recruit = at least 135, with at least 
123 retained. To account for the 3 sites and the 3:2 randomization, a number divisible by 15 is 
needed, so, n = 45 participants per site.  
  
In terms of feasibility, we estimate being able to recruit the required number of participants over a 
period of 12-18 months, given proven success in recruitment for a vitamin D supplementation trial 
(Dr. Gracious) and established success recruiting participants in a longitudinal study on ADHD (Dr. 
Johnstone).  
 
Inclusion Criteria  
This study will include a vulnerable population: children. 
1) Age inclusive of and between 6 and 12 years at the time of enrollment; 2) Verbally willing to 
agree to swallowing a maximum of 9-12 capsules/day with food, attend all study appointments 
and complete questionnaires; and 3) Meet criteria for ADHD as assessed by the clinical cut-off 
(6+ questions scored as 2s or 3s, “often,” or “very often,” or sufficient “sometimes” responses to 
meet a score of 6) on the Category A: ADHD questions from on the Child & Adolescent 
Symptom Inventory-5 (CASI-5) with at least several symptoms present in more than 1 setting, 
based on the DSM-5 symptom criteria, including significant impairment in functioning socially 
and/or academically41; 4) Demonstrate at least one symptom of irritability or anger as assessed by 
a score of 2 or 3 from an “often,” or “very often” response on one question from Category B or 
Rz from the CASI-5; or two “sometimes” responses; 5) Be medication-free, or washout with 
medical supervision to be provided by the child’s pediatrician or primary care physician, reliant 
on the parent/guardian to work with that physician, for at least 2 weeks prior to in-person study 
assessment. 5) Willing to give blood sample at two time points: baseline, week 8; week 16 is 
optional. 
Participants identified as having trouble swallowing pills during the phone will be asked to complete 
the pill swallowing program developed by Kaplan et al[48] and successfully complete this prior to 
being invited to come in for a lab visit. The video can be viewed at: 

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http://research4kids.ucalgary.ca/pillswallowing. Children who continue to be unable to swallow the 
pills after completing the pill swallowing program will not be included in the study.  
 
Exclusion criteria  
1) Neurological disorder involving brain or other central function (e.g., history of or suspected 
intellectual disability, autism spectrum disorder, epilepsy, multiple sclerosis, narcolepsy) or other 
major psychiatric condition requiring hospitalization (e.g. significant mood disorder, active 
suicidal ideation, or psychosis), based on parent/guardian self-report of child’s condition and 
response to category M on the CASI-5 subscale; 2) Any serious medical condition, including 
inflammatory bowel disease, history of cancer, kidney or liver disease, hyperthyroidism, diabetes 
Type I or II; 3) Known allergy to any ingredients of the intervention; 4) Any known abnormality 
of mineral metabolism (e.g., Wilson’s disease, hemochromatosis); 5) Taking any other 
medication with primarily central nervous system activity, including stimulants, within the last 2 
weeks prior to in-person assessment; participants must be off these medications for a minimum 
of two weeks prior to the screening 6) Severe separation anxiety that would preclude separating 
from parent/guardian to answer study questionnaires; 7) Any disability that would interfere with 
participant answering questions verbally; 8) Non-English speaking; 9) Pregnancy or sexually 
active at baseline. Exclusion criteria 1-6 and 9, will be based on parent/guardian self-report of 
child’s condition. If the parent/guardian reports medical exclusion criteria, or concerns about 
eligibility, data provided by parent/guardian will be confirmed by review of medical records with 
release of information signed by parent/guardian. Potential participant may be reviewed in-person 
by study physician in the case of any concerns about participation. 
 
The data collected from potential participants who are not included in the study due to screening 
failure will be securely stored (as outlined below) until the end of the study for the purpose of 
including in the recruitment section of the CONSORT diagram. 
 
Setting and Recruitment methods 
Participants will be recruited, enrolled and will participate in study procedures at three locations: two in the 
US and one in Canada. In Oregon, participants will be recruited at Oregon Health & Science University 
(OHSU) through Child & Adolescent Psychiatry, the Child Development and Rehabilitation Center, the 
ADHD Research Lab Newsletter, and the National University of Natural Medicine (NUNM), OHSU social 
media, a study-specific Facebook profile that would initiate contact with local parenting groups on Facebook 
and request to post a study flier through that page’s administrator, and referrals from community 
pediatricians and mental health providers. Approved flyers may be placed on the windshield, under the 
windshield wiper on cars at local parks where sporting events are occurring. Peachjar, 
https://www.peachjar.com/, will be used to email flyers to parents at participating local elementary schools. 
Study procedures themselves, including enrollment, will only occur at OHSU, not at NUNM. In Ohio, 
participants will be recruited at Nationwide Children’s Hospital and The Ohio State University through the 
intake services where parent/guardians and youth are typically on wait lists for outpatient ADHD assessment 
for up to 6 months. In Canada, participants will be recruited from schools, community agencies, and clinics 
(e.g. pediatricians, psychologist, and counsellors) within the surrounding communities of the University of 
Lethbridge in Southern Alberta. Bearing in mind that the population base in Canada is smaller than in 
Oregon or Ohio, a detailed plan for recruitment has been created to address the process locally. Recruitment 
materials will include a flyer which will be displayed in clinics and onsite at each of the three locations, as 
well as posting of the YouTube video:  https://youtu.be/Gslb9cLkt-c, of a family whose son has experienced 

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success with using the intervention. He was non-randomized (given the active intervention) due to low 
behavioral functioning at baseline. 
 
At the two US sites, the child participant will be paid $10 per in-person assessment (n=5), in the 
form of a gift card, (see Table 1 for assessment schedule) for a total of $50. Gift card payment will be 
made for each instance the child completes the questionnaires and measures associated with that 
assessment time point.  If the child declines to answer any questions, questionnaires and measures 
despite reassurance or assistance including by parent and the study coordinator, or actively declines 
to participate at any visit, s/he will be discontinued from the study. Children will also be paid $10 for 
each blood sample provided, and $5 for each of the other biological samples they provide, for up to 
$105 for each of the 3 time points. Except for blood, children will not be withdrawn from the study 
for not providing a biological sample (hair, saliva, stool, urine), but the samples collection will be 
prioritized as part of the study. Parent/guardians will be paid $20 for traveling to the site for in-
person assessments, for a total of 5 visits during the main, 16 weeks of the study ($100), and 
additionally, $10 for questionnaires completed online and over the phone at 2-month follow up, or 
$20 for parents and $10 for the child, if 2-month follow up occurs in person. One year after 
enrollment in the study, participant families will be contacted regarding their willingness to provide 
follow-up data including questionnaires and, potentially, biological samples. Parents and children 
will be paid for that in-person visit, or phone visit, according to the previously described schedule: 
$10 for phone completion; $20 to parent for in-person completion; $10 to child for in-person 
completion; $5 for each biological sample provided, except blood, $10. 
 
At the Canadian site, payment to participants is not expected or customary. As such, parents will be 
given $25 gift vouchers for their participation in the qualitative part of the study (i.e. in-person 
interviews) and will be reimbursed for cost of travel, including parking and mileage per onsite visit. 
In Canada, blood and urine will not be collected due to storage limitations. Health Canada, the 
Canadian equivalent of the FDA, has not required collection of blood. 
 
Each site will submit an identical protocol to their internal IRB or ethics committee. All study 
protocols and materials (identical for each site, except where differentiation or specification is 
required by an individual IRB) will be approved by the IRB/ethics committee at that site. Details 
concerning coordination of activities are located in the Multi-Site Coordination section. 
 
Phone screen  
At initial phone contact, which will be initiated following contact from the potential participants, a 
study coordinator/research associate will conduct a phone screen with interested families by 
outlining the purpose of the study, confirming willingness to participate by asking eligibility 
questions from the inclusion and exclusion criteria below. Parent/guardians of females will be asked 
if they have begun menstruating. If yes, parent/guardian will be asked whether child is sexually 
active. If yes, or unsure, potential participant will need to take a urine test at baseline as a pregnancy 
screen. Any questions of the parent/guardian and potential participant will be answered as well. 
Parent will be asked for the email address of a teacher, coach, or other adult who knows the child, 
and CASI-5 questions will be sent to that person to answer on behalf of the child. The questionnaire 
will be sent to the teacher or named adult using the email provided, via the secure REDCap system. 

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Only children who are ADHD-medication-free for at least 2 weeks prior to in-person assessment will 
be scheduled for an in-person screening assessment and considered for participation. A phone screen 
process has been used with success in multiple previous studies by one of the co-investigators [49] If 
the child is eligible based on the screening, the parent will be send the CASI-5 screening questions to 
their email via REDCap. The screening questions come from the ADHD and DMDD/ODD sections 
of the CASI-5 (see details of this process in the Baseline Assessment section below). 
Phone screen data, including inclusion/exclusion criteria, and the CASI-5 responses will be reviewed 
and discussed by the study PIs and the research assistant. Any questions or concerns regarding 
enrollment, based on information provided by the parent/guardian or participant, may be handled 
with phone or in-person consultation with an onsite study physician. If necessary, the consultation or 
meeting enables a brief review of medical history and the opportunity to identify any potential 
concerns prior to enrollment.  
Consent and Assent   
After eligibility is established based on phone screen and CASI-5 responses, and review of medical 
records and/or site physician assessment, if necessary, the parent/guardian and child will be invited 
to meet with a research staff team member for a baseline visit, in designated office space at one of 
the three sites to discuss the study and to complete consent and assent prior to any study procedures. 
Prior to the first visit, the consent and assent forms will be sent to the parent/guardian for review in 
before the first meeting. This will facilitate the parent’s ability to formulate and ask questions in 
advance of the first visit. The consent will be signed onsite, using REDCap. 
 
As this study represents minimal risk to the child and offers potential benefit, the consent of one 
parent/guardian will be sufficient for participation. The child will be provided with information about 
the study using simple language that is appropriate for a child as young as 6 years of age. The child 
will be clearly told that s/he does not have to participate, s/he can change his/her mind at a later time. 
Provided that both the parent/guardian and child want to participate, both will provide electronic 
consent/assent via the secure, HIPAA-compliant REDCap web portal. Documentation of 
assent/consent, via an electronic signature, will be captured for each participant and parent/guardian. 
If the parent/guardian or child does not consent/assent or is excluded for any other reason, data 
already collected will be retained for the purpose of characterizing those who made contact. The 
reason for not enrolling will be noted in REDCap. Parents will be asked whether they are interested 
in communicating regarding the MADDY research study via text. A separate consent form will be 
provided and the text communication explained. 
 
Procedures 
Baseline Assessment  
Once consent and assent are given, the parent/guardian and child will complete the other baseline 
questionnaires electronically, also via the REDCap web portal. Details regarding the measures are 
noted in the section below (starting on page 13). Participant will also have weight, height and blood 
pressure measures taken and recorded electronically in the REDCap portal. Any paper-collected 
ratings data will be entered weekly.   
 

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Blood, hair, saliva, and urine samples will also be collected from the child participant at the baseline 
assessment, along with the stool sample, if possible. If the child cannot give a stool sample at the 
baseline visit, the parent will be given the collection kit and instructed to collect the sample later that 
day or the next morning, before the child begins taking the capsules. The samples will be stored as 
below, in order to examine nutrient levels, systemic inflammation, DNA methylation, metabolomics 
and microbiome markers. Except for the blood sample at baseline and week 8, the child will not be 
excluded from the study without providing any one, or all, of the biological samples (hair, saliva, 
urine or feces). Child-appropriate information sheets will be provided to the participants to explain 
the biological sample collection and receipt of parent/guardian consent and child assent will be 
documented. Aside from blood, which will be collected and stored per laboratory requirements, 
samples that are collected will be entered on a paper study sample log, by site (A1 A=Oregon, 
sample 1, saliva; etc), along with the participants ID number. For stool and hair, a record of the serial 
number of the collection container will be added to participant’s REDCap record. Hair and urine 
collection will be noted in participants’ REDCap record. 
 
Blood pressure, heart rate, height and weight will also be assessed at in-person visits by a trained 
research assistant using instruments calibrated according to hospital maintenance schedule. 
Participants will be asked to complete the VioScreen version of the Food Frequency Questionnaire 
(FFQ) at baseline and at the end of eight weeks with input from one parent/guardian.  
 
Enrollment 
Once parent/guardian has signed consent and child participant has signed assent, and following the 
completion of baseline questionnaires and recording of vitals, including blood pressure, pulse, height 
and weight, the participant will be considered to be enrolled in the study. Enrollment may be delayed 
until any questions that may have arisen during the baseline assessment are discussed with and 
answered by the study physician. Once enrolled, the participant will be randomized to a treatment, 
either active or placebo, and a notification of participation letter will be sent to the child’s primary 
care physician with the parent/guardian signature on the release of information form. Parent/guardian 
will be given study capsules for the initial 4 weeks as noted below. 
Randomization 
The randomization scheme will be generated for all three sites, as a whole, by the study statistician at 
OHSU using REDCap, with the randomization sequence arranged in permuted blocks of size 5, in a 
3 active to 2 placebo ratio. The randomization scheme will be emailed to the other two sites. Neither 
the participants nor the clinicians involved in the study will have access to the randomization until 
end of study, but access will be available to the medical oversight person at each site and Data Safety 
Monitoring Board members in event of emergency. A pharmacist or designated unblinded research 
team member at each site will prepare individual participant pill kits in advance, per the 
randomization scheme. The pill kits include 1-week pill caddy containing the capsules to be taken 
during the first week (titrated up to the full dose by Day 5), from pre-labeled and packaged bottles 
sent from the manufacturer. The pill caddy, together with the bottle of pills for the rest of the month 
will be individually labeled and put inside a white paper bag to be given to each participant. These 
kits will be sequentially numbered and allocated to placebo or micronutrients based on the 
randomization list. The pharmacy research staff at OHSU, who is unblinded, will be available 24/7 

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as per on-call schedule, to break the blind for an individual subject if medically necessary. Each 
participating family will be given the appropriate local clinician name and contact information in the 
case of a side effect or question or urgent notification for any medical emergencies. 
Micronutrient formula, titration and dosing  
The study will be using a product called Daily Essential Nutrients (DEN) from Hardy Nutritionals, 
which consists of a blend of vitamins, minerals, amino acids and antioxidants; see Appendix A for 
ingredients of both DEN and placebo, beginning on page 27. Participants will be given one pill 
caddies with 7-day sections divided into 3x/day dosing that contain the pills for the first week of the 
study and will receive instructions on how to store the caddie at home. The remaining pills will be in 
a labeled bottle with the participant’s name. Participants will be asked to take one capsule, 3 times 
each day, with plenty of food and water, and asked to increase the dose by three capsules every two 
days, up to 9 capsules per day, in 3 divided doses, for the first four weeks. For 6-8 year olds, this will 
represent the maximum dose; for 9-12 years old, up to 12 capsules per day is the maximum. At week 
one, research staff will check in with each participant’s parent/guardian via phone to see how the 
participant is responding and answer any questions. At this call and during any subsequent contact 
(other phone calls, week-4 study visit), any decision to increase dose up to a maximum of 12 
capsules for participants ages 9-12 will be made in consultation with the site PI, and will depend on 
parent/guardian/participant report of side effects, if any; participant’s ability to swallow the capsules; 
and parent/guardian/participant report of symptom profile, noting whether any improvement or 
worsening has occurred. Symptom questions from the CASI-5 eligibility questions will be used to 
ascertain any symptom change. These data will inform the site PI- or designate-rated CGI-
Improvement scale to determine if dose needs to be increased to 12 capsules/day, based on a score of 
3 or more on the CGI, for participants who are 9-12 years old. Dose can be lowered from 9 or 12 at 
any time for concerns regarding any AEs, as clinically determined by the site PI or their designate. 
Designates will be physicians or PhD-level licensed psychologists with clinical experience using 
micronutrients. At the return visit, participants will return the pill caddie and any remaining pills to 
receive the bottle of pills for the next month. The participant’s parent will be responsible for filling 
the pill caddie with a reminder from study staff. 
 
Adherence 
At the four- and eight-week visits in the RCT and the twelve- and sixteen-week visits in the open 
label phases, participants will return the pill caddies to the site coordinator with any remaining 
capsules, to assess adherence. The returned pills will be returned to the research pharmacy, and the 
pill caddies will be refilled using pills dispensed by the pharmacy or research staff (site dependent) at 
each in-person assessment. Parents will also be asked to download Medisafe, a pill reminder app and 
will receive detailed instructions on how to download it and use it.  
 
End-of-RCT, Open Label Extension, and End-of-Trial 
At the completion of the 8-week RCT, participants will come in to the research site for an in-person 
visit at each site to be re-assessed, and assessments repeated (see schedule below in Table 1). 
Participants will then enter an 8-week open-label extension in which they have the opportunity to 
knowingly take the active product.  The capsules, both active and placebo, will be donated by Hardy 
Nutritionals, Raymond, Alberta, Canada. Study participants will be eligible to purchase the product, 

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DEN, at a price of $85 per bottle (65% of current retail price) for a person of one year after the 
completion of the study. At the end of the open label trial (end of month 4, week 16), participants 
and their parent/guardian, will return to the research lab for a final in person end-of-trial assessment. 
Questionnaires to be completed are noted below. 
 
 
Post-study follow up: 30- and 60- and 365-days 
Thirty and sixty days following the completion of the open label portion of the study, participants’ 
parents will be contacted by phone to see whether the child participant is still taking the micronutrients. 
If not, parent/guardian will be asked the questions on the Treatment Cessation questionnaire.  In either 
case, parent/guardian and child will be sent, via REDCap, the assessment questions to complete: e.g. 
CASI-5, PROMIS measures and others as noted below. At 365-days after study enrollment, 
participants will be given the opportunity to come in for a visit, as described above, and to provide 
optional biological samples.  
 
Assessments 
ADHD, Emotional and Behavioral Disorder Assessment  
The Child & Adolescent Symptom Inventory-5 (CASI-5) will be used as a baseline screening and 
diagnostic tool. The CASI-5 is a behavior rating scale for DSM-5-defined emotional and behavioral 
disorders in youths between 5 and 18 years old. Subscales of the parent-version will be used. When 
the parent/guardian endorses a symptom question, s/he will be asked for an example, when a 
symptom question is answered “often” or “very often” and also asked for additional detail about the 
setting or settings in which the behavior occurs. Each symptom category includes an Impairment 
question (i.e., the degree to which symptoms interfere with the youth’s social or academic 
functioning).  Subscales to be used at baseline, end-of-RCT and end-of-Open Label are questions 
from: Categories A, B, C, Cz, D, E, G, I, Rz, K, L, M, Q. These include questions about ADHD, 
Disruptive Mood Dysregulation Disorder (DMDD), anxiety, depression, Obsessive Compulsive 
Disorder (OCD)/Post Traumatic Stress Disorder (PTSD), tics, mania, psychosis, separation anxiety, 
Autism Spectrum Disorders (ASD) (which is an exclusion), enuresis/encopresis, and Oppositional 
Defiant Disorder (ODD).  
 
Demographics 
Demographic information will also be collected including ethnicity, parent/guardians’ occupation, 
parent/guardians’ level of education, and family income so that Socioeconomic Status (SES) can be 
estimated. 
 
Study personnel-rated measures  
Completed at baseline and at assessments every 4 weeks – time: 30 minutes: 
1. Vital Signs and Body mass index-BMI - height and weight plus pulse and blood pressure, 
adverse events, will be assessed at every in-person visit. BMI will be calculated using the 
standard formula from the participant’s height and weight, as measured with a scale and 
stadiometer. Blood pressure and pulse will be measured using standardized hospital equipment.   
2. Adverse events will be measured using the Pediatric Adverse Event Rating Scale (PAERS), and 
the Columbia Suicide Severity Rating Scale (CSSRS) with questions asked of the 

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parent/guardian and participant. Both of these measures were requested by the Federal Drug 
Administration upon review of an IND application by Dr. Gracious for a similar proposed study, 
specifically to standardize reports.   
3. Pill count compliance will be monitored by the assessor at in-person visits by counting the 
remaining pills. 
Completed at end of week 8: 
4. Clinician/RA and rater blinding will be recorded to verify integrity of the blind. Clinicians and 
raters will be asked whether they believe the child is assigned to the placebo, active nutrient 
supplement, or are unsure.   
 
Clinician- reviewed measures  
Completed at baseline, at week 8 and 16: 
1. Clinical Global Impressions Scale (CGI) The CGI is a single-item rating of the clinician’s 
assessment of the severity of symptoms[50]. Its goal is to allow the clinician to rate the efficacy 
of treatment, change over time and the severity of illness. CGI-rating will be based on 1) 
participant self-report, 2) parent ratings, 3) observation by RA and, 4) overview by PI. 
Parent/guardian-rated measures  
Completed at appropriate times during trial – see Table 1 – total time: 40 minutes or less: 
1. CASI – 5: Subscales as noted above will be used from this behavior rating scale for DSM-5-defined 
emotional and behavioral disorders in youths between 5 and 18 years old 
2. PROMIS measures: The Patient-Reported Outcomes Measurement Information System 
(PROMIS) measures are simple self-reports developed by the U.S. Dept. Health and Human 
Services to be pragmatic outcome measures in clinical trials. 
(http://www.healthmeasures.net/explore-measurement-systems/promis/obtain-administer-
measures). The child’s parent/guardian will complete PROMIS scales for sleep, anxiety, peer 
relationships, anger, and depression. There are 4 to 13 Likert-style questions in each form. The 
parent/guardian answers will be used to compare to the child’s responses. 
3. Strengths and Difficulties Questionnaire (SDQ): The Strengths and Difficulties Questionnaire 
(SDQ) is a brief behavioral screening questionnaire designed to measure positive and negative 
attributes, divided between 5 scales: emotional symptoms, conduct problems, 
hyperactivity/inattention, peer relationships, and prosocial behaviors. 
4. Temperament in Middle Childhood Questionnaire (TMCQ): The Temperament in Middle 
Childhood Questionnaire (TMCQ) will be used to assess children’s reaction to a number of 
scenarios. It is divided in 17 categories: activation control, activity level, affiliation, 
anger/frustration, assertiveness/dominance, attention focusing, discomfort, fantasy/openness, 
fear, high intensity pleasure, impulsivity, inhibitory control, low intensity pleasure, perceptual 
sensitivity, sadness, shyness, and soothability/falling reactivity.  
5. Food Frequency Questionnaire (FFQ): The children’s usual dietary intake captured over 90 days, 
will be assessed using a standardized, validated VioScreen FFQ, which includes 1,200 food images 
that users may slect, based on branching logic that tracks their choices in food families.  
6. Food Insecurity Measure: A brief measure asking to what degree the family has experienced food 
insecurity in the past 12 months, asked at baseline and week 8.   

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7. Parent Target Problems: (PTP): At baseline, parents will be asked to nominate the child’s biggest 
problem. If the parent cannot select just one, two may be named. The research assistant and parent 
discuss the named problem and the RA asks questions about the frequency, duration and 
interference level of the problem. The example field allows the parent to construct a brief narrative 
of the behavior and its impact on family life. The target symptoms are reviewed and the narratives 
revised at subsequent visits. A panel of four judges, blind to treatment condition, will 
independently review the narratives to rate change from baseline on a 9-point scale: 1, normal; 2, 
markedly improved; 3, definitely improved; 4, equivocally improved; 5, no change; 6, possibly 
worse; 7, definitely worse; 8, markedly worse; 9, disastrously worse. The mean of the four raters 
will be compared with primary and key secondary ratings from the original study. 
8. Concomitant treatment measure will ask parents about any current treatments received 
(behavioral or physical), for what condition, when started and stopped, and details on dosing or 
frequency. This measure will be repeated at each in-person visit. 
9. Parent/guardian assessment of the blind will be reviewed by recording a direct query of whether 
the parent/guardian believes the child is taking the placebo or the active product, to monitor 
integrity of the blind.   
10. Treatment acceptability rating – upon study completion, the parent/guardian will be asked how 
participating in the study went, any suggestions they have to improve the study, and whether they 
would recommend the trial to others with symptoms. 
11. Treatment Review – at 30-, 60- and 365-days post-study, parent/guardian will be asked whether 
his or her child is still taking the micronutrients and if yes, dosage information. Also 
parent/guardian will be asked about any other treatments used or obtained in the time period since 
last interviewed. 
12. Treatment cessation – at 30-, 60- and 365-days post-study, parent/guardian will be asked whether 
his or her child is still taking the micronutrients. If not, the parent/guardian will complete this 
measure to report on the reasons for stopping the treatment. 
 
13. (Optional) Qualitative assessment – a smaller sample of participants will be asked whether they 
want to provide optional qualitative input regarding the study. The scripted, phone-based interview, 
will be completed a member of the study staff who will conduct all the interviews. See details of 
the qualitative assessment in separate document, included as part of IRB submission.  
 
For this qualitative component, interviews with parents of children enrolled in the clinical trial will 
be asked about their perspectives and experience of using medications and the micronutrients. 
Questions will address the following concept domains and questions: 
a. Current and past treatments/therapies used – what are the perceived benefits and limitations? 
b. Reasons for micronutrients – what are the perceived benefits? What are the facilitators and 
barriers to micronutrients as a treatment option; e.g. adherence and tolerance (# capsules/day), 
swallowing difficulties, side effects, cost, practitioner knowledge 
c. Accessibility –how would micronutrients incorporated into part of healthcare services? E.g. 
after nothing else has worked, or be the first step in treatment? 

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d. Patient oriented outcomes – what is important for parents/patients to find out from the 
research? What would be impactful for them? 
Methodology 
For this qualitative component of the study, we will use qualitative descriptive analysis 
(Sandelowski, 2000; Magilvy & Thomas, 2009) to explore the perspectives and experiences of 
parents whose child is enrolled in the clinical trial. Qualitative description is a pragmatic approach to 
qualitative data analysis that enable health research to gain preliminary insight into a specific topic 
and help to focus on the experiences of the participants (e.g. patients), gaining their views and 
insights on their interaction within the health care system (Neergaard, et al, 2009). With qualitative 
data, we will gain a deeper understanding of the issues and give patients/parents a voice. 
Furthermore, it allows us to understand the issues from a range of patients’ narratives, without 
constraints set by the researcher or by the use of narrowly focused questionnaires and pre-defined 
items (Festen et al., 2014). The findings from patients’ experiences will help to formulate new 
theories or hypotheses for further testing.  
We will interview parents of children in the current clinical trial. We chose to conduct one-on-one 
interviews in place of focus groups for two important reasons. Personal interviews allow for the 
tailoring of inquiries specific to different families and their individual experiences. Thus, interviews 
allow for in-depth questioning to solicit personal experiences, and enable for more direct, 
customized, probing questions. As well, interviews will allow parents to speak openly or freely about 
potentially intimate issues, and not be constrained as it would in a group setting (Powell & Single, 
1996).  
Data collection: Semi-structured interviews will be guided by a topic list with open-ended questions 
and probing questions (see sample below). The questions will be used to roughly structure the 
conversation, but allow for flexibility to enable interviewees to express their experiences 
(Sandelowski, 2000).  
Interview questions will be piloted to assess for language (understandability), relevance (i.e. makes 
sense to patients), comprehension (i.e. content validity), sensitivity, and the length of time to 
complete the interview. Interviews are anticipated to take about 60 minutes. The interviews may be 
conducted face-to-face at the University of Lethbridge, at the participant’s home, or by phone for 
participants outside of the Lethbridge area. A Research Associate with experience in qualitative 
interviewing techniques will conduct the interviews. [Participants will be offered a gift certificate for 
their time].  
The interview process will involve building rapport, empathic listening, probing, and asking open-
ended questions. The interviews will be conducted in a way that the interviewee will feel at ease, 
decrease social desirability, and deepen the conversation. In addition to constructing the topic list, the 
research team will discuss the expectations of participant responses, as well as acknowledge 
assumptions and biases of team members. As well, the interviewer will record thoughts and insights 
in field notes during each interview. These discussion points and field notes will help guide or adjust 
the interview process as needed. A professional transcriptionist will transcribe the interview data. 

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Child-rated measures  
In person at baseline, end of RCT, end of open label;  
Table 1 at the end of this protocol – time: 15 minutes 
1. PROMIS measures: The child will complete the PROMIS scales for sleep, anxiety, peer 
relationships, anger, and depression. There are 4 to 13 Likert-style questions in each form. 
2. Columbia Suicide Severity Rating Scale (CSSRS): The child will complete the CSSRS baseline 
or follow up version, together with a research coordinator viewing the responses to ensure safety; 
a minimum of 3 questions will be asked. Numerous studies support the psychometric properties 
of the C-SSRS. These studies attest to the scale’s divergent, convergent, predictive, and 
incremental validity, as well as to its sensitivity to change, internal consistency, inter-rater 
reliability, cross-cultural and multi-lingual application, and more. Evidence also supports the 
effectiveness of the C-SSRS as an intervention tool for preventing suicides, as well as a 
measurement tool for treatment response (http://cssrs.columbia.edu/the-columbia-scale-c-
ssrs/cssrs-for-research/). 
3. Child Target Problem- At baseline, child will be asked to nominate his or her biggest problem or 
symptom. If the child cannot select just one, two may be named. The research assistant and child 
discuss the named problem and the RA asks questions about the frequency, duration and 
interference level of the problem. The example field allows for the construction of a brief narrative 
of the behavior and its impact on family life. The target symptoms are reviewed and the narratives 
revised at subsequent visits. A panel of four judges, blind to treatment condition, will 
independently review the narratives to rate change from baseline on a 9-point scale: 1, normal; 2, 
markedly improved; 3, definitely improved; 4, equivocally improved; 5, no change; 6, possibly 
worse; 7, definitely worse; 8, markedly worse; 9, disastrously worse. The mean of the four raters 
will be compared with primary and key secondary ratings from the original study. 
4. Treatment Acceptability– upon study completion, the child participant will be asked for their 
opinion on participation and any suggestions they have to improve the study, and whether they 
would recommend the trial to others with symptoms. 
 
In person at the end of the RCT 
5. Child assessment of the blind will be captured by asking the youth whether they believe they are 
taking the placebo or real product.  
Teacher or Other Adult-rated measures 
Completed at baseline and 8 week RCT, 16-week end-of-study – time: 10 minutes: 
1. CASI-5 selected subscales (3 eligibility subscales and peer relationships) will used at baseline and 
to monitor the effectiveness of the child’s response to intervention at two other time points. 
Data and Specimens 
Blood, hair, saliva, urine, and feces collection   
Collected at baseline, 8 weeks and week 16 (end-of-study) – time: 5-10 minutes  
 
Blood collection 
Per FDA requirements, participants will be required to provide blood samples at each in-person 
visit. These samples will be used for safety measures and for research purposes. Analysis will 
include CBC, TSH, iron, a number of supplemented nutrients including B vitamins and Vit D, and 

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blood for future analysis of targeted and untargeted metabolomics and IL-6 and TNF-a. Total blood 
collection will be approximately 18ml, or 3 teaspoons. See “Blood Sample Collection Info for 
OHSU” chart included in IRB submission, for details.  
 
 
Hair Collection 
 
At least 20 strands of hair, approximately the diameter of a pencil lead will be cut close to the 
 
root from the posterior aspect of the head. The hair will be tied at the cut end to identify the most 
 
recent portion of hair growth. Samples will be wrapped in static free paper, zip-locked, placed in  a 
 
light occlusive envelope, labeled with participant’s study identification only and stored at the 
 
individual lab sites until all hair is collected. Then it will be shipped to OHSU for analyzes.  
 
Saliva collection 
Using the Oragene – DNA, OG-600 collection kit, participants will be asked to provide saliva samples 
during their visits at: baseline, 8 weeks, 16 weeks, in order for us to begin to understand the effect that 
micronutrient treatment might have on DNA methylation. They will be provided with instructions on 
how to spit into the collection tube and seal up the kit, which will be labelled with the participant’s ID 
number and recorded on a log, then stored in the lab, in a specially labelled and locked file drawer 
and/or the Clinical Research Center, until all samples are collected from participants. The specimens 
collected at the other two sites will be stored at their onsite location. Once the study finishes, and all 
samples have been collected, the saliva samples will be sent to the lab determined most appropriate for 
analyses, once funding is available.  
 
Stool sample collection 
Participants will be asked to provide three stool samples, collected in the home setting, within 48 
hours of an in-person study visit, using the OMNIgene Gut OMR-200 collection kit: at baseline, end 
of RCT (8 weeks) and end of open label (16 weeks); in order for us to begin to understand the effect 
that micronutrient treatment might have on the microbiome. These data are exploratory components 
of the study and seen as a pilot investigation because this is a very new area and there is little 
scientific literature to direct these analyses. However, a series of studies have now documented the 
impact of the gut microbiome on behavioral disorders such as autism, anxiety, and depression 
directly and indirectly. See [51] for an example. The purpose of collecting the samples for storage is 
to identify the relationship between the gut microbiome and clinical symptoms of ADHD at a later 
date, once funds are available to generate and analyze the samples. 
 
Procedures for stool sample collection 
Participants will be asked if they would be willing to provide a stool specimen. If they agree, they 
will be mailed a stool specimen collection kit and instructions, to be performed ideally within 24-48 
hours of their next visit. This kit includes a swab system and sterile tube for collection of stool 
material from tissue wipe after defecation, as well as a biohazard bag and brown paper bag for 
transportation. After defecation at home, the subject or parent will wipe the provided swab on the 
toilet paper to collect the stool specimen to be put in the tube. The swab will then be thrown away, 
and the tube sealed and brought to the research assistant at the participant’s next visit. If the 
participant is not returning for another visit, the participant will be given a mailer and instructions on 

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how to mail the sample back. After being delivered to the lab, the specimen will be frozen at -80 C 
until further processing, once funding is available. In Oregon, freezer space in the Core Lab run by 
Clive Woffendin, PhD, will be used to store the samples. Stool sample collection and storage will be 
identical at the other two sites per best practice recommendations [52]. University of Lethbridge will 
ship their samples to OHSU for storage; Ohio State will store their samples locally until sample 
generation and analyses funds are available. 
 
Urine sample collection 
 
Participants will be asked to provide three urine samples, collected in the home setting or at the  lab, 
 
first thing in the morning: at baseline, end of RCT (8 weeks) and end of open label (16 weeks) in 
 
order for us to begin to understand how metabolism of the micronutrients might impact response to 
 
treatment. Participants will be given a sterile urine specimen collection container and instructed  to 
 
fill it at least half full (a minimum of 4ml). If done at home, participant will store urine in the 
 
refrigerator until lab appointment. The urine samples will be frozen at -80 C, in the Core Lab run 
 
by Clive Woffendin, PhD, until further processing, pending available funds.  
 
 
Sharing of Results 
Due to the exploratory nature of this research and the time delay from collection to generation and 
analyzation of the samples, results from the biological samples will not necessarily be shared with 
participants’ families.  
 
However, once samples are analyzed, participants may be re-contacted, even if they have completed 
the study, if any safety concerns arise from the analyses. Participants will be asked whether they 
want to know the results. As the collected samples may or may not be analyzed by a CLIA-approved 
lab the reliability of the results may not be unknown. Participants will be advised to run further 
analyses, at their own expense. The risks associated with receiving this information include, but are 
not limited to: costs of additional medical care and testing, impact on insurability, and psychological 
risks, if you receive information that is upsetting. 
 
 
Specimen Banking and Repository 
As noted in each section pertaining to the biological samples, specimens will be stored (at each of the 
three sites, unless specified) for future generation and analyses, which will occur once sufficient 
funding is available. Specimens may be accessed by any of the named PIs or their representative. 
Permission via an email granting access will be sufficient. Study-generated identification (coded) 
information will be provided with the specimens so that the data may be matched up by treatment 
arm. Data and samples from this study may be shared with other study investigators at Ohio State or 
University of Lethbridge for future research studies.  A code number is assigned to each child, their 
cells and genetic information, as well as to information about them.  Only the investigators and 
people involved in the conduct of the study will be authorized to link the code number to the 
participant.  Other investigators or outside labs, including ZRT Laboratory, who receive samples, 
saliva/genetic information/other data for research, will be given only the code number, but not 
identifying information. 
 

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ZRT Laboratory in Beaverton, Oregon, will be analyzing approximately .5-1ml of blood and up to 2 
mls of urine for neurotransmitters, diurnal analytes, sex steroids, hormones and mineral. All samples 
will be de-identified. _ 
Data Analysis  
Our primary outcome measures defined a priori, reflecting the often co-morbid ADHD symptoms of 
irritable mood and aggression are the CASI-5 subscales and the clinician CGI. The changes from 
baseline to the end of treatment will be compared between randomized groups using repeated-
measures ANCOVA, with the baseline level as the covariate. The differences between treatment 
groups in these measures will be summarized as the mean differences and 95% confidence intervals 
generated from the ANCOVA/ANOVA models. Categorical outcomes will be compared between 
groups using Chi-square tests and will be described using odds ratios and 95% confidence intervals. 
All analyses will be undertaken on an intention-to-treat (ITT) basis that includes all randomized 
participants analyzed according to the group to which they were randomized. For those participants 
not completing the 8 weeks, data from their final assessment (last observation carried forward) will 
be used to evaluate the change scores. Secondary analyses will be undertaken on all outcomes using 
the per-protocol (completers) analysis set. All tests will be two tailed and any p values less than 0.05 
will be considered statistically significant.  
Privacy, Confidentiality, and Data Security 
All staff involved in the conduct and/or monitoring of this study will have completed the requisite 
Human Subject Protection Training for each IRB. Documentation of training will be held in locked 
cabinets or secure password protected computers at each site. Prior to implementation of any 
protocol changes, amendments will be submitted to the Institutional Review Boards for approval. 
The site PIs will be responsible for continuous data and safety monitoring of all participants enrolled 
in this study at their respective sites; discussion of any data or safety monitoring concerns will be 
routinely brought up as part of weekly study coordination meetings across sites. Overt identifying 
information will be separated from collected data and specimens.  
All information collected in this study will remain confidential. Only designated study staff will have 
access to the participant information. Electronic data and documentation of consent will be 
maintained in REDCap.  Electronic data is password protected with permissions for log-ins given 
only to the PIs and approved research assistants. Standard security measures ensure confidentiality 
including double encryption of electronic files and double locking of paper files and removal of 
identifying information from data files. The identification key will be locked in a secure office 
cabinet apart from the data. Computerized versions of the list of participants and the recruitment log 
will be encrypted and stored on the secure, HIPAA compliant REDCap system at OHSU.  
However, after study completion, the ID-key will be destroyed to anonymize the data. In the case of 
birthdates, age at time of study participation will be retained, but actual birth dates will not. No 
information that could personally identify any participant will be used in any manuscripts or reports 
on this study. In cases where there is a concern about the safety of a participant, or of others, or any 
mandatory audit, confidentiality may be breached in accordance with applicable regulations. 
 
 Data Safety Monitoring Plan (DSMP)  
All three sites place the highest priority on ensuring the safety and protection of participants in a 

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clinical trial, and the integrity of the trial data. Study participation is voluntary and participants may 
withdraw at any time without penalty; we would request permission to retain questionnaire follow-
ups in this instance to preserve the ITT analysis. Participant data collected to-date would remain part 
of the database, per FDA regulations. 
 
Data Safety and Monitoring Board  
A Data Safety and Monitoring Board (DSMB) will be created with a representative at each site. The 
members will consist of at least one person who is an expert on clinical trial safety monitoring and 
free of any conflicts of interest with this study. DSMB participants who have agreed to be on the 
board include: Dr. Sarah Feldstein Ewing, at OHSU, Dr. Bob Kowatch, at Nationwide Children’s 
Hospital/The Ohio State University, and Dr. Darren Christensen from the University of Lethbridge. 
Every six months, the DSMB will review study recruitment, subject demographics and 
characteristics, and any adverse events (AEs) and safety differences that emerge between the 
randomized arms, including looking for differences by site. We anticipate the DSMB will meet via 
Skype or teleconference. To facilitate this review, the PIs will provide the DSMB with the data 
related to safety and efficacy. If the DSMB determines that there are significant and/or serious 
emergent risks within the study for any reason, the DSMB could make a recommendation to the PIs 
and IRBs that the study be closed for accrual of participants until a more detailed review can be 
conducted. 
Risk and Benefits 
As Co-PIs, the overseeing the risk management of the project will be handled by Dr. Johnstone, Dr. 
Gracious, and Dr. Leung, in consultation with site-specific study physicians including Dr. Meg Cary 
at OHSU, Dr. Gene Arnold at Ohio State, and Dr. Megan Rodway for the University of Calgary. The 
Co-PIs have been and will be involved on all aspects of the project, and will, therefore, monitor for 
any foreseeable risks.  
 
Risk/benefit analysis 
One risk for participants, if they were taking stimulant medication that conferred a benefit in terms of 
ADHD symptoms, is that by coming off the medication, their symptoms may return. Risks to 
participants in terms of taking the micronutrients are low, but as with any intervention there are 
potential side effects. These may include transient gastrointestinal upset (loose stool, nausea), and 
headache, particularly if product is taken on an empty stomach. If these side effects are experienced 
and believe to be related to taking the micronutrients, these symptoms should go away if pills are 
taken with food and water as directed, and tend to lessen after a day or two of taking the pills, or 
when participant ceases taking the pills. Not all participants will receive the active treatment in the 
first 8-weeks, but everyone will have the opportunity to knowingly take the active treatment in the 
second 8-week, open-label phase. In terms of specific personal benefit, some participants may find 
that taking the micronutrients help with the symptoms of ADHD and irritability, as well as 
aggressive behavior. However, participants may or may not personally benefit from being in this 
study.  
 
The product to be studied has the largest amount of published research in the mental health field for a 
complex micronutrient product. Data were examined from all known published and unpublished 

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studies of the micronutrient product to be used in the study [1, 25, 46, 53].  Biological safety data 
from 237 children and adults from six datasets revealed no occurrences of negative outcomes or 
effects [38]. Further, no abnormal blood tests indicated toxicity. In an RCT of 93 children, aged 7-12 
years of age, which was completed in New Zealand in December 2016, there were no differences 
between adverse events in the micronutrient versus the placebo groups [4] Comparing tolerability 
data between a micronutrient group and a group taking psychotropic medication, those in the 
micronutrient group reported 1/6th the number of AEs, such as appetite suppression or metabolic side 
effects, than participants treated with medication [31]. Further, no abnormal blood tests could be 
attributed to toxicity. In previous studies [53, 54], the only side effect noted was transitory 
gastrointestinal difficulties (loose stool, nausea), when the product was taken on an empty stomach, 
contrary to recommendation. These difficulties reduced or disappeared when taking the capsules on a 
full stomach. As such, participants are asked to always take their capsules with food. In the extension 
phase of the child open label study [1], as well as in a child RCT just completed in NZ, a 
reformulated version of the product is being used with no gastrointestinal difficulties noted (J.J. 
Rucklidge, personal communication, December 19, 2016). This is the version of the product to be 
used in this study. Another way to prevent potential side effects is increase the dose slowly over 
several days, so participants will begin with three (3) capsules per day (one capsule 3x/day) and 
increase gradually to the full dose. The safety concerns of nutrient supplementation generally pertain 
to giving one nutrient at a time whereas this product includes 38 ingredients. Considering lowest-
observed-adverse-effect level (LOAEL), only two nutrients: niacin and magnesium, are above the 
LOAEL at 9 capsules per day (maximum dose) for 6 to 8-year-olds. See Appendix A on page 27 for 
ingredients. Given the significant issues facing children with ADHD, the possibility of reducing their 
symptomology and improving their quality of life, and the rigorous nature of our safety procedures, 
the benefits significantly outweigh the risks of this study. 
 
Risk assessment and right to withdraw 
Participant safety is the most important consideration. Participants may be discontinued from the 
study if they show adverse symptoms of either a physical or psychological nature in response to the 
treatment. Evidence of significant or poorly tolerated side-effects will stop a participant's 
participation in the study, in the judgement of the PI and in consultation with the study physicians. 
Mandatory stop concerns will include: possible or probable allergic reaction, new onset of severe and 
persistent suicidal ideation deemed related to study product, or emergence of exclusion criteria. If a 
participant’s psychological state deteriorates to a clinically significant degree during the trial, the 
investigator will discuss with the participant and parent/guardians the possibility of withdrawing 
from the study, or may decide that the participant should be withdrawn. Participants or their 
parent/guardian may request to be withdrawn from the study or withdraw consent at any time without 
penalty. If a participant, for any reason, requires treatment with certain therapeutic agents (i.e. 
antibiotics), we will note what they are taking and for how long. If a protocol exclusion violation has 
occurred (i.e. participant requires psychiatric medications), his or her involvement will be 
discontinued, but they will be followed for the duration initially anticipated for descriptive purposes. 
If any patient is discontinued from the trial, we will carry out follow-ups and appropriate referrals for 
treatment linkage, to ensure participant well-being. 
 
Human subjects’ protection  

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All participants will be required to provide informed assent should they wish to participate in the trial 
and their parents/guardians will be asked to provide written informed consent. Any side effects or 
AEs will be asked about and recorded during in-person visits using the Pediatric Adverse Events 
Rating Scale (PAERS). This measure was selected to standardize outcomes for studies using the 
proposed micronutrient treatment in a previously submitted Investigational New Drug application for 
the product. Any AEs reported during participant visits will be discussed with onsite PI, and on 
weekly calls with the study physicians at one of the three sites, for assignment as to whether they are 
related to the study product and to determine if symptoms represent unanticipated problems 
involving risk to subjects. If AE severity is mild or moderate; was not unexpected (is listed as a 
possible AE); unrelated, unlikely related, or possibly-related to study product, PI may allow research 
staff to sign off on the AE, by proxy, after discussion. Medical oversight will be provided to 
participants as needed throughout the trial by one of the medical physicians at each site. While any 
reported side effects or AEs, will be discussed with one of the study doctors weekly, any medical 
concerns or questions may be directed to the appropriate on-site physician. Consultation between PI 
and doctor will determine the appropriate action to be taken, which may include unblinding and trial 
cessation or dose change depending on the nature and severity of the symptoms. If a protocol 
exclusion violation has occurred, involvement will be discontinued, but follow-up will be carried out 
to ensure participant well-being.  
 
Definition of an Adverse Event or Serious Adverse Event 
An adverse event (AE) is a negative experience encountered by an individual during the course of a 
clinical trial that may be associated with the drug or treatment provided. An AE can include 
previously undetected symptoms, or the exacerbation of a pre-existing condition. A serious adverse 
event (SAE) is: 1) any medical occurrence that results in death; 2) is life-threatening, requires or 
prolongs hospitalization; 3) causes persistent or significant disability/incapacity; 4) or, in the opinion 
of the investigators represents other significant hazards or potentially serious harm to research 
subjects or others. An AE/SAE is considered unexpected if it is not described in the Package Insert 
or in the Investigator’s Brochure (for FDA investigational agents), in the protocol, or in the informed 
consent document. 
 
Investigational New Drug 
The product to be used has an approved Investigational New Drug application through the FDA. 
Results will be reported to the FDA, per requirements. Researchers, working closely with the FDA, 
will follow applicable Research Pharmacy policies and procedures. Plan for drug storage, handling, 
and accountability have been outlined in the appropriate sections above. The study has been 
registered as a clinical trial through clinicaltrials.gov #NCT03252522 and results will be submitted 
per requirements. 
 
Multi-Site Coordination 
Research Sites  
 
Oregon Health & Science University, Portland, OR 
Nationwide Children’s Hospital/The Ohio State University, Columbus, OH 
University of Lethbridge, Alberta, Canada 

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IRB 
Prior to participant recruitment or data collection, all study materials including consent/assent forms 
will be approved by the IRBs at all three sites. The most current version of all study materials, 
including the protocol, consent documents and HIPAA authorization will be stored on the Box, the 
OHSU-policy compliant password-secure cloud storage. The Box system is already in place and 
being used by the three named PIs. However, no participant data will be stored here. Any 
modifications will be communicated to each of the sites and approved by each sites IRB before the 
modification is implemented. Any non-compliance with study protocol or applicable requirements 
will be reported in accordance with local policy. All staff involved in the conduct and/or monitoring 
of this study will have completed the requisite Human Subject Protection Training for each IRB. 
Documentation of training will be held in locked cabinets or secure password protected computers at 
each site. Prior to implementation of any protocol changes, amendments will be submitted to the 
Institutional Review Boards for approval. All staff and volunteers working on the study will be 
registered with the appropriate institutional IRB office and must complete annual HIPAA and IRB 
compliances as required. The compliances ensure that all have passed knowledge tests regarding 
protection of data, confidentiality, and research participants.  
Cross Site Coordination 
To ensure continuity across sites, there will be weekly phone meetings amongst the three site PIs and 
investigators; common training of Research Assistants (RAs) prior to the start of the study via Skype 
meetings to ensure identical screening, assessment, and scoring procedures are used at each site; 
adherence/problem-solving meetings every 3 months or sooner if needed/requested by one of the 
PIs;a protocol which follows the same procedures and processes at each of the sites and will be 
clearly outlined using a Standard Operating Procedure applicable across sites, and operationalized by 
a Manual of Procedures, which will be tailored for each site; simultaneous access to most recent 
version via the centralized online repository, The Box; use of central data repository, REDCap, 
housed at OHSU, but accessible to other site PIs and appropriate research team members at any time 
online; recruitment and enrollment managed via REDCap, with de-identified information; use of 
identical forms/questionnaires across sites; and similar recruitment materials using same text and 
pictures, at each site. 
Investigators 
Jeanette M. Johnstone, PhD – Dr. Johnstone will serve in the lead investigator role, and will oversee 
the OHSU site and the IRB approval process. OHSU’s REDCap data collection will serve as the data 
repository for all three sites, and the study randomization for the three sites will be handled through 
OHSU’s pharmacy. Dr. Johnstone will provide oversight, support and supervision to research 
assistants and trained student volunteers on the project, being available at all times should any issues 
or difficulties arise.  Joseph Thoits, MD, a child and adolescent psychiatrist, will provide medical 
oversight.. 
Barbara L. Gracious MD – Dr. Gracious will oversee and take responsibility for the OSU site and 
the FDA IND approval process. She will provide oversight, support and supervision to research 
assistants and any other team members, including other study doctors on the project, being available 
at all times should any difficulties arise. She will oversee any safety issues including clinical 
concerns.  

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Brenda Leung, ND, PhD – Dr. Leung will oversee the University of Lethbridge site and the IRB 
approval process. She will provide oversight, support and supervision to research assistants and 
trained student volunteers on the project, being available at all times should any issues or difficulties 
arise. An affiliated physician will oversee any patient related safety issues at this site.  
Data ownership 
All data associated with the study, and all manuscripts resulting from said data, will be owned by the 
three named investigators. In the case of a disagreement, consensus will decide the outcome. Input 
from Professor Emeritus Bonnie Kaplan or Dr. Gene Arnold may be sought as needed.  
 
Resources 
A generous anonymous donor has given $125,000 to the Foundation for Excellence in Mental Health 
Care (FEMHC) to be used for the aforementioned study, with monies earmarked for Oregon Health 
& Science University. Dr. Johnstone and collaborators also won a competitive grant, issued through 
the FEMHC, of $100,000. In addition, a number of other generous donors have contributed 
additional funds to provide $100,000 to Ohio State University; and, another generous donor has 
given $95,000 (Canadian) to be used by University of Lethbridge. 
Anticipated costs 
Costs will vary by site. See associated budget for cost breakdown. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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References 
1. 
Gordon, H.A., et al., Clinically significant symptom reduction in children with attention-deficit/hyperactivity 
disorder treated with micronutrients: an open-label reversal design study. Journal of child and adolescent 
psychopharmacology, 2015. 25(10): p. 783-798. 
2. 
Norman, G.R., J.A. Sloan, and K.W. Wyrwich, Interpretation of changes in health-related quality of life: the 
remarkable universality of half a standard deviation. Medical care, 2003. 41(5): p. 582-592. 
3. 
Faraone, S.V., C. Bonvicini, and C. Scassellati, Biomarkers in the diagnosis of ADHD–promising directions. 
Current psychiatry reports, 2014. 16(11): p. 497. 
4. 
Rucklidge JJ, E.M., Johnstone JM, Darling K, Frampton C., Vitamin-mineral treatment improves aggression 
and emotional control in children with ADHD: A fully blinded, randomized, placebo-controlled trial. Journal 
of Child Psychology and Psychiatry, In Press. 
5. 
Wilmot, B., et al., Methylomic analysis of salivary DNA in childhood ADHD identifies altered DNA 
methylation in VIPR2. J Child Psychol Psychiatry, 2015. 
6. 
Gevi, F., et al., Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and 
purine metabolism. Molecular Autism, 2016. 7(1): p. 47. 
7. 
Ming, X., et al., Metabolic perturbance in autism spectrum disorders: a metabolomics study. Journal of 
proteome research, 2012. 11(12): p. 5856-5862. 
8. 
Yano, J.M., et al., Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 
2015. 161(2): p. 264-276. 
9. 
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994: 
American Psychiatric Association, Washington, DC. 
10. 
Barkley, R.A., ed. Attention-Deficit Hyperactivity Disorder: A handbook for diagnosis and treatment (3rd 
ed.). 2006, The Guilford Press: New York, NY. 
11. 
Baumgaertel, A., Alternative and controversial treatments for attention-deficit/hyperactivity disorder. 
Pediatric Clinics of North America, 1999. 46(5): p. 977-992. 
12. 
Sonuga-Barke, E.J., et al., Nonpharmacological interventions for ADHD: systematic review and meta-
analyses of randomized controlled trials of dietary and psychological treatments. American Journal of 
Psychiatry, 2013. 170(3): p. 275-289. 
13. 
Wilson, K., C. Dowson, and D. Mangin, Prevalence of complementary and alternative medicine use in 
Christchurch, New Zealand: children attending general practice versus paediatric outpatients. New Zealand 
Medical Journal, 2007. 120(1251): p. 1-9. 
14. 
Klein, R.G., et al., Clinical and functional outcome of childhood attention-deficit/hyperactivity disorder 33 
years later. Archives of General Psychiatry, 2012: p. 1-9. 
15. 
Mannuzza, S., et al., Adult Outcome of Hyperactive Boys - Educational-Achievement, Occupational Rank, and 
Psychiatric Status. Archives of General Psychiatry, 1993. 50: p. 565-576. 
16. 
Molina, B.S.G., et al., The MTA at 8 Years: Prospective Follow-up of Children Treated for Combined-Type 
ADHD in a Multisite Study. Journal of the American Academy of Child and Adolescent Psychiatry, 2009. 
48(5): p. 484-500. 
17. 
Howard, A.L., et al., ADHD is associated with a ‘Western’ dietary pattern in adolescents. Journal of Attention 
Disorders, 2011. 15(5): p. 403-411. 
18. 
Pelsser, L.M., et al., Effects of a restricted elimination diet on the behaviour of children with attention-deficit 
hyperactivity disorder (INCA study): a randomised controlled trial. The Lancet, 2011. 377(9764): p. 494-503. 
19. 
Milte, C.M., et al., Eicosapentaenoic and docosahexaenoic acids, cognition, and behavior in children with 
attention-deficit/hyperactivity disorder: A randomized controlled trial. Nutrition, 2012. 28(6): p. 670-677. 
20. 
Galler, J.R., et al., Infant malnutrition is associated with persisting attention deficits in middle adulthood. 
Journal of Nutrition, 2012. 142(4): p. 788-794. 
21. 
Mertz, W., A balanced approach to nutrition for health: The need for biologically essential minerals and 
vitamins. Journal of the American Dietetic Association, 1994. 94: p. 1259-1262. 

Child RCT Protocol 2017 
 
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22. 
Rucklidge, J.J., J. Johnstone, and B.J. Kaplan, Nutrient supplementation approaches in the treatment of 
ADHD. Expert Review of Neurotherapeutics, 2009. 9(4): p. 461-476. 
23. 
Kaplan, B.J., et al., Improved mood and behavior during treatment with a mineral-vitamin supplement: an 
open-label case series of children. Journal of Child and Adolescent Psychopharmacology, 2004. 14(1): p. 
115-22. 
24. 
Rucklidge, J.J., M. Taylor, and K. Whitehead, Effect of micronutrients on behavior and mood in adults with 
ADHD: Evidence from an 8-week open label trial with natural extension. Journal of Attention Disorders, 
2011. 15(1): p. 79-91. 
25. 
Rucklidge, J.J., D. Gately, and B.J. Kaplan, Database analysis of children and adolescents with bipolar 
disorder consuming a multinutrient formula. BMC: Psychiatry, 2010. 74(10): p. doi:10.1186/1471-244X-10-
74. 
26. 
Rucklidge, J.J. and R. Harrison, Successful treatment of Bipolar Disorder II and ADHD with a micronutrient 
formula: A case study. CNS Spectrums, 2010. 15(5): p. 289-295. 
27. 
Harding, K.L., R.D. Judah, and C. Gant, Outcome-based comparison of Ritalin versus food-supplement 
treated children with AD/HD. Alternative Medicine Review, 2003. 8(3): p. 319-30. 
28. 
Shaw, I., J.J. Rucklidge, and R.N. Hughes, A possible biological mechanism for the B Vitamins altering 
behaviour in ADHD. Pharmaceutical Medicine, 2010. 24(5): p. 1-6. 
29. 
Ames, B.N., I. Elson-Schwab, and E. Silver, High-dose vitamin therapy stimulates variant enzymes with 
decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms. 
American Journal of Clinical Nutrition, 2002. 75: p. 616-658. 
30. 
Mayer, A.B., Historical changes in the mineral content of fruits and vegetables. British Journal of Food, 
1997. 99: p. 207-211. 
31. 
Davis, D.R., Declining fruit and vegetable nutrient composition: What is the evidence? HortScience, 2009. 
44(1): p. 15-19. 
32. 
Gardner, A. and R.G. Boles, Is a "Mitochondrial Psychiatry" in the future? A review. Current Psychiatry 
Reviews, 2005. 1: p. 255-271. 
33. 
Patel, K. and L.T. Curtis, Comprehensive approach to treating autism and attention-deficit hyperactivity 
disorder: A prepilot study. Journal of Alternative and Complementary Medicine, 2007. 13(10): p. 1091-1097. 
34. 
Sinha, D. and D. Efron, Complementary and alternative medicine use in children with attention deficit 
hyperactivity disorder. Journal of Paediatrics and Child Health, 2005. 41(1-2): p. 23-26. 
35. 
Bussing, R., et al., Use of complementary and alternative medicine for symptoms of attention-deficit 
hyperactivity disorder. Psychiatric Services, 2002. 53(9): p. 1096-1102. 
36. 
Chan, E., The role of complementary and alternative medicine in attention-deficit hyperactivity disorder. 
Journal of Developmental & Behavioral Pediatrics, 2002. 23(Suppl1): p. S37-S45. 
37. 
Stubberfield, T.G., T.A. Wray, and T.S. Parry, Utilization of alternative therapies in attention-deficit 
hyperactivity disorder. Journal of Pediatric Child Health, 1999. 35: p. 450-453. 
38. 
Gately, D. and B.J. Kaplan, Database analysis of adults with bipolar disorder consuming a multinutrient 
formula. Clinical Medicine: Psychiatry, 2009. 4: p. 3-16. 
39. 
Kennedy, D.O., et al., Effects of high-dose B vitamin complex with vitamin C and minerals on subjective mood 
and performance in healthy males. Psychopharmacology, 2010. 211: p. 55-68. 
40. 
Mehl-Madrona, L., et al., A naturalistic case-control study of micronutrients versus standard medication 
management in autism. Journal of Child and Adolescent Psychopharmacology, 2010. 20(2): p. 95-103. 
41. 
Adams, J., et al., Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatrics, 
2011. 11(1): p. 111. 
42. 
Stough, C., et al., The effect of 90 day administration of a high dose vitamin B-complex on work stress. 
Human Psychopharmacology: Clinical and Experimental, 2011. 26(7): p. 470-476. 
43. 
Figueiredo, J.C., et al., Folic acid and risk of prostate cancer: Results from a randomized clinical trial. 
Journal of the National Cancer Institute, 2009. 101(6): p. 432-435. 

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44. 
Bairati, I., et al., Antioxidant vitamins supplementation and mortality: A randomized trial in head and neck 
cancer patients. International Journal of Cancer, 2006. 119(9): p. 2221-2224. 
45. 
Frazier, E., M.A. Fristad, and L.E. Arnold, Multinutrient supplement as treatment: Literature review and case 
report of a 12-year-old boy with bipolar disorder. Journal of Child and Adolescent Psychopharmacology, 
2009. 19(4): p. 453-460. 
46. 
Simpson, J.S.A., et al., Systematic review of safety and tolerability of a complex micronutrient formula used in 
mental health. BMC Psychiatry, 2011. 11(62). 
47. 
National Health and Medical Research Council, Nutrient reference values for Australia and New Zealand: 
Including recommended dietary intakes. 2006, Department of Health and Ageing, Canberra  
48. 
Kaplan, B.J., et al., Successful treatment of pill-swallowing difficulties with head posture practice. Paediatr 
Child Health, 2010. 15(5): p. e1-5. 
49. 
Gracious, B.L., et al., Randomized, placebo‐controlled trial of flax oil in pediatric bipolar disorder. Bipolar 
disorders, 2010. 12(2): p. 142-154. 
50. 
Guy, W., et al., ECDEU Assessment manual for psychopharmacology. DHEW publication (ADM) 76-338. 
1976, Washington (DC): US Department of Health, Education, and Welfare. 
51. 
Pärtty, A., et al., A possible link between early probiotic intervention and the risk of neuropsychiatric 
disorders later in childhood: a randomized trial. Pediatric research, 2015. 77(6): p. 823-828. 
52. 
Aad, G., et al., Search for magnetic monopoles in sqrt[s]=7 TeV pp collisions with the ATLAS detector. Phys 
Rev Lett, 2012. 109(26): p. 261803. 
53. 
Rucklidge, J.J., et al., Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-
blind randomised placebo-controlled trial. The British Journal of Psychiatry, 2014. 204(4): p. 306-315. 
54. 
Rucklidge, J., M. Taylor, and K. Whitehead, Effect of micronutrients on behavior and mood in adults with 
ADHD: Evidence from an 8-week open label trial with natural extension. Journal of Attention Disorders, 
2011. 15(1): p. 79-91. 
 
 
 
 
 
 

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Appendix A: Daily Essential Nutrients (DEN) Ingredients 
Unit 
1 Cap^ 
9 Caps 
12 Caps 
RDA* or AI+ 
LOAELӨ 
Vitamin A (as retinyl palmitate) 
IU 
480 
4320 
5760 
2000 
46667 
Vitamin C (as ascorbic acid) 
mg 
50 
450 
600 
45 
3000 
Vitamin D (as cholecalciferol) 
IU 
250 
2250 
3000 
600 
3800 
Vitamin E (as d-alpha tocopheryl succinate) 
IU 
30 
270 
360 
16.5 
750 
Vitamin K (as 75% phylloquinone, 25% menaquinone-7) 
mcg 
10 
90 
120 
60 
NE 
Vitamin B1 (as thiamin mononitrate) 
mg 
5 
45 
60 
0.9 
NE 
Vitamin B2 (riboflavin) 
mg 
1.5 
13.5 
18 
0.9 
NE 
Niacin - Vitamin B3 (as niacinamide) 
mg 
7.5 
67.5 
90 
12 
50 
Vitamin B6 (as pyridoxine hydrochloride) 
mg 
5.8 
52.5 
70 
1.0 
500 
Folate - B9 (as calcium L-5 methyltetrahydrofolate) 
mcg 
66.6 
600 
799.9 
300 
5000 
Vitamin B12 (as 75% adenosylcobalamin, 25%  
mcg 
75 
675 
900 
1.8 
NE 
Biotin – Vitamin H 
mcg 
90 
810 
1080 
20 
NE 
Pantothenic acid (as d-calcium pantothenate) 
mg 
2.5 
22.5 
30 
4 
NE 
Calcium (as NutraTek™ chelation complex) 
mg 
110 
990 
1320 
1300 
4000 
Iron (as NutraTek™ chelation complex ) 
mg 
1.15 
10.35 
13.8 
8 
70 
Phosphorus (as NutraTek™ chelation complex ) 
mg 
70 
630 
840 
1250 
10200 
Iodine (as NutraTek™ chelation complex ) 
mcg 
17 
153 
204 
120 
1700 
Magnesium (as NutraTek™ chelation complex ) 
mg 
50 
450 
600 
240 
360 
ӨLowest Observed Adverse Effects Level; *Recommended Daily Allowance; +Adequate Intake 
Unit measurements: mg – milligram (1,000 milligrams = 1 gram);  mcg – microgram (1,000 micrograms = 1 milligram)  

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Appendix A: DEN Ingredient List (continued) 
Unit 
1 Cap^ 
9 Caps 
12 Caps 
RDA* or AI+ 
LOAELӨ 
Zinc (as NutraTek™ chelation complex ) 
mg 
4 
36 
48 
8 
60 
Selenium (as NutraTek™ chelation complex ) 
mcg 
17 
153 
204 
40 
913 
Copper (as NutraTek™ chelation complex ) 
mg 
0.6 
5.4 
7.2 
0.7 
10 
Manganese (as NutraTek™ chelation complex ) 
mg 
0.8 
7.2 
9.6 
1.9 
15 
Chromium (as NutraTek™ chelation complex ) 
mcg 
52 
468 
624 
25 
NE 
Molybdenum (as NutraTek™ chelation complex ) 
mcg 
12 
108 
144 
34 
1500 
Potassium (as NutraTek™ chelation complex ) 
mg 
20 
180 
240 
4500 
NE 
ӨLowest Observed Adverse Effects Level; *Recommended Daily Allowance; +Adequate Intake 
Unit measurements: mg – milligram (1,000 milligrams = 1 gram);  mcg – microgram (1,000 micrograms = 1 milligram)  
DEN Proprietary blend ingredients: 
Choline bitartrate 
Alpha-lipoic acid 
Mineral wax (shilajit) 
Inositol 
Acetyl-L-carnitine  
Grape seed extract 
Ginkgo biloba leaf extract 
L-methionine  
N-acetyl-L-cysteine 
Boron (as NutraTek™ chelation complex ) 
Vanadium (as chelate) 
Lithium orotate (as chelate) 
Nickel (as chelate) 
DEN Proprietary blend ingredients (continued): 
Other ingredients: 
Gelatin capsule (Bovine derived, 100% BSE-free) 

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Microcrystalline cellulose 
Glycine  
Citric acid 
Magnesium stearate 
Silicon dioxide 
Appendix B: Placebo Formula 
INGREDIENTS 
One capsule 
9 capsules 
12 capsules  
Riboflavin Powder 
0.10 mg 
0.90 mg 
1.2 mg 
Magnesium stearate 
5 mg 
45 mg 
60 mg 
Silicon dioxide  
2.5 mg 
22.5 mg 
30 mg 
Microcrystalline cellulose ~ 650mg/capsule+ 
~ 650mg/capsule+ 
~ 650mg/capsule+ 
+ Sufficient amount to fill the capsule 

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Table 1: Schedule of Events 
ITEM or TASK 
Phone 
Scree
n 
Base- 
Line 
RCT
Wk 
4 
RCT 
Wk 8 
Open  
Wk 12 
Ope
n  
Wk 
16 
30-, and 
60-Day  
F/U 
Phone 
Call 
365-Day 
F/U Phone 
Call or in 
person 
visit* 
Phone Screen with CASI-
5 eligibility Qs  
X 
 
 
 
 
 
 
 
 
PARENT/GUARDIAN 
Consent 
 
X 
 
 
 
 
 
 
CASI-5 Subscales 
 
X 
X 
X 
X 
X 
X 
X 
PROMIS Scales 
 
X 
X 
X 
X 
X 
X 
X 
SDQ 
 
X 
 
X 
 
X 
 
X 
FFQ 
 
X 
 
X 
 
 
 
 
PTP 
 
X 
 
X 
 
X 
 
X 
Food Insecurity 
 
X 
 
X 
 
 
 
 
Temperament Q. 
 
 
X 
 
 
 
 
 
Concomitant Treatment  
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events – also at 
wk 1 
 
X 
X 
X 
X 
X 
X 
X 
Placebo Question 
 
 
 
X 
 
 
 
 
Treatment Acceptability  
 
 
 
X 
 
 
Treatment Review 
 
 
 
 
X 
X 
Treatment Discontinuation 
 
 
 
 
X 
X 
CHILD 
 
 
 
 
 
Assent 
 
X 
 
 
 
 
 
 
PROMIS Scales 
 
X 
X 
X 
X 
X 
X 
X 
PAERS  - also at week 1 
 
X 
X 
X 
X 
X 
X 
X 
CSSRS – also at week 1 
 
X 
X 
X 
X 
X 
 
 
CTP 
 
X 
X 
X 
X 
X 
 
X* 
Placebo Question 
 
 
 
X 
 
 
 
 
Trial feedback  
 
 
 
 
 
X 
 
 
RESEACH STAFF 
 
 
 
 
 
 
Pill caddy – receive 
/return 
 
X 
X 
X 
 
 
 
 
How to take your pills 
 
X 
 
 
 
 
 
 
Return unused pills  
 
 
X 
X 
X 
X 
 
 
Pedi study info.  
 
X 
 
 
 
 
 
 
Height/weight/BP 
 
X 
X 
X 
X 
X 
 
X* 
Placebo/active Question 
 
 
 
X 
 
 
 
 
TEACHER/Other Adult 
CASI-5 Subscales 
 
X 
 
X 
 
X 
 
 
CLINICIAN 
CGI  
 
X 
 
X 
 
X 
 
 
BIOLOGICAL SAMPLES 
Collection Instructs. 
 
X 
 
 
 
 
 
 
Blood 
 
X 
 
X 
 
X 
 
X 
Hair 
 
X 
 
X 
 
X 
 
X 
Urine 
 
X 
 
X 
 
X 
 
X 

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Saliva 
 
X 
 
X 
 
X 
 
X 
Stool Sample 
 
X 
 
X 
 
X 
 
X 
 
 
Table 2: Assessment Measures and Time Points 
Measures 
Construct 
Time to 
complete1 Who 
How 
When 
Ped. Adverse Events*  
AEs 
20 
P 
Q, I 
M 
CSSRS 
Suicidality 
1 min 
C 
I 
B, E x2 
Concomitant Txts 
Other txts 
5 mins 
P 
I 
B, E x2 
MediSafe App 
Adherence 
2 
P 
Q, I 
M 
CASI-5; wide range of 
subscales 
Gen. Clinical 
25 
P 
Q 
B, E x2,  
CASI-5; targeted 
symptoms subscales 
Mood, 
Irritability 
10 
P 
Q 
B, M,  
Post× 
SDQ – strengths & 
difficulties 
Difficulties 
prosocial 
10 
P 
Q 
B, E x2 
PTP – parent target 
problem 
Target 
problem 
10 
P 
Q 
B, E x2 
CTP- child target prob 
Target 
problem 
10 
C 
Q 
B, M 
Food Frequency 
Diet 
20 
P, 
Q 
B, E 
Food Insecurity 
Food Insecurity 
5 
P 
Q 
B, E 
CASI-5 subscales 
ADHD, anger 10 
T 
Q 
B, E x2 
PROMIS Anger 
Anger 
1 
P, C+ Q 
M 
PROMIS Anxiety 
Anxiety 
2 
P, C+ Q 
M 
PROMIS  Depression 
Mood 
2 
P, C+ Q 
M 
PROMIS  Peer R/Ship 
Social 
2 
P, C+ Q 
M 
PROMIS Sleep 
Sleep 
2 
P, C+ Q 
M 
Temperament 
Temperament 
15 
P 
Q 
B 
Treatment Acceptability 
Acceptability 
2 
P 
Q 
Wk 16 
Treatment Review€ 
Follow up 
5 
P 
I 
30, 60, 
365× 
Reasons for Treatment 
Discontinuation 
Discontin- 
uation  
1 
P 
Q 
30,60, 
365× 

Child RCT Protocol 2017 
“The MADDY study” 2017 Proposal 
32 | P a g e  
 
 
 
1In minutes P=parent, C=child, T=teacher, Q=questionnaire, I=interview, E=week 
8, B=baseline, x2=end of RCT and Open Label, M=monthly, + completed 
separately, € Only given if parent reports that child has stopped taking the DEN, 
×30, 60 after finishing the study and 365 days after enrollment