Micronutrients for ADHD in Youth (MADDY) Study

• Sponsor: Oregon Health and Science University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03252522
• Collaborator: Ohio State University (Other), University of Lethbridge (Other), National University of Natural Medicine (Other), Foundation for Excellence in Mental Healthcare (Other), Waterloo Foundation (Other)
• Enrollment: 135
• Locations: 3
• Arms: 3
• Actual Duration (Months): 37.3
• Patients Per Site: 45
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This proposed research will use randomized control trial (RCT) methodology and compare micronutrients with placebo in 135 children with ADHD.

Condition or Disease	Intervention/Treatment	Phase
Attention Deficit Hyperactivity Disorder	Combination Product: Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants; Dietary Supplement: Placebo	Phase 1/Phase 2

Detailed Description

This study examines a broad spectrum micronutrient treatment for children with ADHD. The goal is to broaden the scope of evidence-based treatments, and to address the public desire for non-pharmacological treatment options. This study will use a randomized controlled trial design, comparing micronutrients with placebo in 135 children, ages 6-12, with ADHD plus irritability or anger based on parent-report of symptoms. The study will also collect biological samples (saliva, stool, urine, hair, and blood) from the children to examine physiological mechanisms of micronutrient effects. If the micronutrient treatment successfully diminishes symptoms, the clinical implication is to offer this as a legitimate non-pharmacological alternative to stimulant medication.

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Placebo-controlled; randomization created by statistician, all involved in the study and assessment are blinded
• Primary Purpose: Treatment
• Official Title: Evaluating the Efficacy of Supplementation With Micronutrients for ADHD in Youth (MADDY) Study
• Actual Study Start Date: Apr 23, 2018
• Actual Primary Completion Date: Jul 10, 2020
• Actual Study Completion Date: May 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intervention Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants.	Combination Product: Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants; 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks; Other Names: Daily Essential Nutrients (DEN)
Placebo Comparator: Placebo Capsules of inactive placebo.	Dietary Supplement: Placebo; 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Experimental: Open Label All participants have the option to participate in an 8-week, naturalistic, open label follow-up in which the child will take the active micronutrient treatment; capsules of broad spectrum micronutrients.	Combination Product: Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants; 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks; Other Names: Daily Essential Nutrients (DEN)

Outcome Measures

Primary Outcome Measures

1. CASI-5 Parent-rated Composite Score [Baseline and week 8]

   Primary outcome measure, defined a priori, reflecting the often-comorbid ADHD symptoms of emotional dysregulation irritable mood, anger or aggression), are the parent-rated Child and Adolescent Symptom Inventory (CASI-5). The CASI-5 is based on the DSM-5 symptom criteria. The subscales of ADHD, Oppositional Defiant Disorder (ODD), Disruptive Mood Dysregulation Disorder (DMDD) and peer conflict that will be combined into a total composite score; range is 0-3 (never, sometimes, often, very often). Higher scores represent a worse outcome.

2. Clinical Global Impression (CGI) - Number of Participants Considered a Treatment Responder (Score of 1 or 2) [Week 8]

   Second primary measure is the blinded clinician-rated CGI-Improvement (CGI-I) is a subscale of the CGI that rates overall improvement of symptoms based on all relevant data. Item range is 1-7 (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse); lower score is better. A treatment responder is defined as a participant who is rated a 1 or 2 on the CGI-I. The CGI-Severity (CGI-S) subscale will also be scored at baseline and week 8, with scores compared at the two time points. Item range is 1-7 (normal, borderline ill, mildly ill, moderately ill, markedly ill, severely ill, among the most extremely ill patients); lower score is better; most participants will be a 4 or 5 at baseline.

Secondary Outcome Measures

1. Sodium, Potassium, Chloride, Carbon Dioxide, and Anion Gap in mmol/L [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

2. Calcium, Blood Urea Nitrogen, Creatinine, Glucose, Bilirubin Total in mg/dL [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

3. Albumin, Total Protein, Hemoglobin, Mean Cell Hgb in g/dL [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

4. AST, ALT, Alkaline in U/L [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

5. RBC Count in Cells/mcL [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

6. Hematocrit, RBC Distribution, Immature Grans, Lymphocyte, Monocyte, Eosinophil in Percent [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

7. Mean Cell Volume in fL [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

8. Iron in ug/dL [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

9. WBC Count, Absolute Monocyte, Absolute Eosinophil, Platelet Count in Cells/mcL [Baseline and Week 8]

   Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.

10. Clinical Global Impression (CGI) [16 weeks]

    Second primary measure is the blinded clinician-rated CGI-Improvement (CGI-I) is a subscale of the CGI that rates overall improvement of symptoms based on all relevant data. Item range is 1-7 (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse); lower score is better. A treatment responder is defined as a participant who is rated a 1 or 2 on the CGI-I. The CGI-Severity (CGI-S) subscale will also be scored at baseline and week 8, with scores compared at the two time points. Item range is 1-7 (normal, borderline ill, mildly ill, moderately ill, markedly ill, severely ill, among the most extremely ill patients); lower score is better; most participants will be a 4 or 5 at baseline.

11. CASI-5 Parent Report [16 weeks]

    Primary outcome measure, defined a priori, reflecting the often-comorbid ADHD symptoms of emotional dysregulation irritable mood, anger or aggression), are the parent-rated Child and Adolescent Symptom Inventory (CASI-5) subscales of ADHD, Oppositional Defiant Disorder (ODD), Disruptive Mood Dysregulation Disorder (DMDD) and peer conflict. The CASI-5 is based on the DSM-5 symptom criteria. Item range is 0-3 (never, sometimes, often, very often). Higher scores represent a worse outcome. The subscales for ADHD, ODD, and DMD will be composite scores.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age inclusive of and between 6 and 12 years at the time of enrollment.

• Verbally willing to swallowing a maximum of 9-12 capsules/day with food, attend all study appointments and complete questionnaires.

• Meet criteria for ADHD as assessed by the clinical cut-off (6+ questions scored as 2's or 3's, "often," or "very often") 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 one setting, based on the Diagnostic and Statistical Manual (DSM) 5 symptom criteria, including significant impairment in functioning socially and/or academically.

• Demonstrate at least one symptom of irritability or anger as assessed by a score of 2 or 3 on one question from Category B or Rz from the CASI-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 two weeks prior to in-person study assessment. Washout will be recorded as occurring on the date reported by the parent/guardian, with a faxed copy of the progress note, visit summary or signed letter from participant's doctor.

Exclusion Criteria:

• 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 responses to category M on the CASI-5 subscale.

• Any serious medical condition, including inflammatory bowel disease, history of cancer, kidney or liver disease, hyperthyroidism, diabetes Type I or II.

• Known allergy to any ingredients of the intervention.

• Any known abnormality of mineral metabolism (e.g., Wilson's disease, hemochromatosis).

• Taking any other medication with primarily central nervous system activity, including stimulants, within the last two weeks prior to in-person assessment; participants must be off these medications for a minimum of two weeks prior to the screening.

• Severe separation anxiety that would preclude separating from parent/guardian to answer study questionnaires.

• Any disability that would interfere with participant answering questions verbally.

• Non-English speaking.

• 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 a study physician in the case of any concerns about participation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Ohio State University	Columbus	Ohio	United States	43210
2	Oregon Health & Science University	Portland	Oregon	United States	97239
3	University of Lethbridge	Lethbridge	Alberta	Canada	AB T1K 6T5

Sponsors and Collaborators

• Oregon Health and Science University
• Ohio State University
• University of Lethbridge
• National University of Natural Medicine
• Foundation for Excellence in Mental Healthcare
• Waterloo Foundation

Investigators

• Principal Investigator: Jeanette Johnstone, Oregon Health and Science University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 23, 2021

More Information

Publications

None provided.

• Responsible Party: Jeanette Johnstone, Principal Investigator, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT03252522
• Other Study ID Numbers: 16870
• First Posted: Aug 17, 2017
• Last Update Posted: Feb 9, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jeanette Johnstone, Principal Investigator, Oregon Health and Science University: ADHD; ODD; DMDD; Inattention; Impulsivity; Irritability; Anger; Micronutrients; Emotional Dysregulation
• Additional relevant MeSH terms: Attention Deficit Disorder with Hyperactivity; Micronutrients; Trace Elements; Antioxidants

Study Results

Participant Flow

Arm/Group Title	Intervention	Placebo	Open Label
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	All participants have the option to participate in an 8-week, naturalistic, open label follow-up in which the child will take the active micronutrient treatment; capsules of broad spectrum micronutrients. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks
Period Title: Overall Study
STARTED	78	57	0
COMPLETED	69	54	0
NOT COMPLETED	9	3	0

Baseline Characteristics

Arm/Group Title	Intervention	Placebo	Total
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Total of all reporting groups
Overall Participants	78	57	135
Age (Count of Participants)
<=18 years	78 100%	57 100%	135 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	21 26.9%	22 38.6%	43 31.9%
Male	57 73.1%	35 61.4%	92 68.1%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	45 57.7%	40 70.2%	85 63%
Hispanic or Latino	7 9%	1 1.8%	8 5.9%
Other	4 5.1%	3 5.3%	7 5.2%
Unknown/Did Not Report	22 28.2%	13 22.8%	35 25.9%
Race/Ethnicity, Customized (Count of Participants)
Asian	3 3.8%	0 0%	3 2.2%
African American/Black	1 1.3%	3 5.3%	4 3%
White	60 76.9%	45 78.9%	105 77.8%
Other	3 3.8%	4 7%	7 5.2%
Unknown/Not Reported	11 14.1%	5 8.8%	16 11.9%
Region of Enrollment (participants) [Number]
Canada	21 26.9%	17 29.8%	38 28.1%
United States	50 64.1%	38 66.7%	88 65.2%

Outcome Measures

1. Primary Outcome

Title	CASI-5 Parent-rated Composite Score
Description	Primary outcome measure, defined a priori, reflecting the often-comorbid ADHD symptoms of emotional dysregulation irritable mood, anger or aggression), are the parent-rated Child and Adolescent Symptom Inventory (CASI-5). The CASI-5 is based on the DSM-5 symptom criteria. The subscales of ADHD, Oppositional Defiant Disorder (ODD), Disruptive Mood Dysregulation Disorder (DMDD) and peer conflict that will be combined into a total composite score; range is 0-3 (never, sometimes, often, very often). Higher scores represent a worse outcome.
Time Frame	Baseline and week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Placebo
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	78	57
Baseline	1.49 (0.08)	1.52 (0.08)
Week 8	1.18 (0.08)	1.23 (0.08)

2. Primary Outcome

Title	Clinical Global Impression (CGI) - Number of Participants Considered a Treatment Responder (Score of 1 or 2)
Description	Second primary measure is the blinded clinician-rated CGI-Improvement (CGI-I) is a subscale of the CGI that rates overall improvement of symptoms based on all relevant data. Item range is 1-7 (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse); lower score is better. A treatment responder is defined as a participant who is rated a 1 or 2 on the CGI-I. The CGI-Severity (CGI-S) subscale will also be scored at baseline and week 8, with scores compared at the two time points. Item range is 1-7 (normal, borderline ill, mildly ill, moderately ill, markedly ill, severely ill, among the most extremely ill patients); lower score is better; most participants will be a 4 or 5 at baseline.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Participants considered in the ITT analysis

Arm/Group Title	Intervention	Placebo
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	71	55
Count of Participants [Participants]	38 48.7%	10 17.5%

3. Secondary Outcome

Title	Sodium, Potassium, Chloride, Carbon Dioxide, and Anion Gap in mmol/L
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
Sodium	139.13 (0.34)	139.16 (0.34)	139.28 (0.36)	139.42 (0.37)
Potassium	4.1 (0.10)	4.06 (0.10)	4.09 (0.10)	4.0 (0.10)
Chloride	105.07 (0.96)	104.81 (0.97)	104.88 (0.97)	105.28 (0.98)
Carbon dioxide	25.62 (0.21)	25.64 (0.22)	25.97 (0.24)	25.86 (0.25)
Anion gap	10.30 (2.83)	10.64 (2.83)	10.31 (2.83)	10.15 (2.84)

4. Secondary Outcome

Title	Calcium, Blood Urea Nitrogen, Creatinine, Glucose, Bilirubin Total in mg/dL
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
Calcium	9.47 (0.20)	9.49 (0.20)	9.47 (0.20)	9.40 (0.20)
Blood urea nitrogen (BUN)	12.48 (0.41)	13.17 (0.42)	12.56 (0.46)	12.13 (0.48)
Creatinine	0.46 (0.01)	0.49 (0.01)	0.46 (0.01)	0.46 (0.01)
Glucose	82.15 (2.36)	83.03 (2.39)	79.45 (2.44)	80.0 (2.46)
Bilirubin total	0.47 (0.03)	0.45 (0.03)	0.49 (0.03)	0.46 (0.03)

5. Secondary Outcome

Title	Albumin, Total Protein, Hemoglobin, Mean Cell Hgb in g/dL
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
Albumin	4.34 (0.17)	4.34 (0.17)	4.29 (0.17)	4.28 (0.17)
Total protein	7.15 (0.63)	8.45 (0.65)	7.07 (0.73)	7.06 (0.76)
Hemoglobin	12.99 (0.17)	12.96 (0.17)	12.99 (0.18)	12.91 (0.18)
Mean cell Hgb concentration	33.82 (0.13)	33.59 (0.13)	33.75 (0.15)	33.47 (0.15)

6. Secondary Outcome

Title	AST, ALT, Alkaline in U/L
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
AST	23.58 (1.26)	27.28 (1.28)	25.72 (1.42)	22.79 (1.46)
ALT	18.67 (3.25)	26.00 (3.27)	20.40 (3.37)	18.09 (3.41)
Alkaline phosphatase	255 (8.10)	241.33 (8.15)	252.21 (9.29)	257.93 (9.41)

7. Secondary Outcome

Title	RBC Count in Cells/mcL
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
Mean (Standard Error) [cells/mcL]	4,650,000 (0.08)	4,650,000 (0.08)	4,600,000 (0.08)	4,600,000 (0.09)

8. Secondary Outcome

Title	Hematocrit, RBC Distribution, Immature Grans, Lymphocyte, Monocyte, Eosinophil in Percent
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
Hematocrit	38.40 (0.52)	38.60 (0.52)	38.50 (0.55)	38.60 (0.55)
RBC distribution	25.03 (8.76)	25.17 (8.76)	25.29 (8.76)	25.02 (8.76)
Immature grans	0.20 (0.02)	0.18 (0.02)	0.24 (0.02)	0.19 (0.03)
Lymphocyte	43.63 (1.65)	43.53 (1.66)	40.25 (1.80)	40.65 (1.84)
Monocyte	8.03 (0.34)	8.29 (0.34)	7.78 (0.38)	8.35 (0.38)
Eosinophil	3.82 (0.63)	4.03 (0.64)	6.49 (0.73)	5.71 (0.75)

9. Secondary Outcome

Title	Mean Cell Volume in fL
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
Mean (Standard Error) [fL]	82.70 (0.44)	83.00 (0.45)	83.74 (0.49)	83.85 (0.50)

10. Secondary Outcome

Title	Iron in ug/dL
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
Mean (Standard Error) [ug/dL]	99.1 (4.65)	90.7 (4.69)	100.5 (5.35)	95.5 (5.49)

11. Secondary Outcome

Title	WBC Count, Absolute Monocyte, Absolute Eosinophil, Platelet Count in Cells/mcL
Description	Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Only participants in the US sites provided blood and urine samples. Canadian participants were not required by Health Canada to collect safety blood or urine samples, hence the lower number of participants.

Arm/Group Title	Intervention (Baseline)	Intervention (Week 8)	Placebo (Baseline)	Placebo (Week 8)
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.	Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.
Measure Participants	50	50	38	38
WBC count	5,710 (0.22)	5,730 (0.23)	6,080 (0.25)	5,990 (0.26)
Absolute monocyte	460 (0.02)	470 (0.02)	460 (0.02)	480 (0.02)
Absolute eosinophil	210 (0.04)	230 (0.04)	390 (0.04)	340 (0.05)
Platelet count	289,970 (7.54)	289,320 (7.57)	290,160 (8.62)	295,900 (8.75)

12. Secondary Outcome

Title	Clinical Global Impression (CGI)
Description	Second primary measure is the blinded clinician-rated CGI-Improvement (CGI-I) is a subscale of the CGI that rates overall improvement of symptoms based on all relevant data. Item range is 1-7 (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse); lower score is better. A treatment responder is defined as a participant who is rated a 1 or 2 on the CGI-I. The CGI-Severity (CGI-S) subscale will also be scored at baseline and week 8, with scores compared at the two time points. Item range is 1-7 (normal, borderline ill, mildly ill, moderately ill, markedly ill, severely ill, among the most extremely ill patients); lower score is better; most participants will be a 4 or 5 at baseline.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	CASI-5 Parent Report
Description	Primary outcome measure, defined a priori, reflecting the often-comorbid ADHD symptoms of emotional dysregulation irritable mood, anger or aggression), are the parent-rated Child and Adolescent Symptom Inventory (CASI-5) subscales of ADHD, Oppositional Defiant Disorder (ODD), Disruptive Mood Dysregulation Disorder (DMDD) and peer conflict. The CASI-5 is based on the DSM-5 symptom criteria. Item range is 0-3 (never, sometimes, often, very often). Higher scores represent a worse outcome. The subscales for ADHD, ODD, and DMD will be composite scores.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Baseline, week 1, week 4 and week 8
Adverse Event Reporting Description	Used the Pediatric Adverse Events Rating Scale (PAERS) to assess treatment emergent adverse events.
Arm/Group Title	Intervention		Placebo		Open Label
Arm/Group Description	Capsules of broad spectrum micronutrients: a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks		Capsules of inactive placebo. Placebo: 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.		All participants have the option to participate in an 8-week, naturalistic, open label follow-up in which the child will take the active micronutrient treatment; capsules of broad spectrum micronutrients. Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants: 60% of participants will take 3-4 capsules of broad spectrum micronutrients three times per day for eight weeks. Following the initial 8 weeks (of the RCT), all participants will have the option to participate in an open label extension, during which time the child would take the active micronutrient treatment for 8 weeks
All Cause Mortality
	Intervention		Placebo		Open Label
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/71 (0%)		0/55 (0%)		0/0 (NaN)
Serious Adverse Events
	Intervention		Placebo		Open Label
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/71 (0%)		0/55 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Intervention		Placebo		Open Label
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/71 (31%)		24/55 (43.6%)		0/0 (NaN)
Cardiac disorders
Heart racing or skipping beats	0/71 (0%)		1/55 (1.8%)		0/0 (NaN)
Gastrointestinal disorders
GI symptoms	17/71 (23.9%)		8/55 (14.5%)		0/0 (NaN)
General disorders
Tired/fatigued	2/71 (2.8%)		1/55 (1.8%)		0/0 (NaN)
Trouble falling asleep	4/71 (5.6%)		1/55 (1.8%)		0/0 (NaN)
Other	5/71 (7%)		5/55 (9.1%)		0/0 (NaN)
Metabolism and nutrition disorders
Less hungry	4/71 (5.6%)		1/55 (1.8%)		0/0 (NaN)
Lost weight	0/71 (0%)		1/55 (1.8%)		0/0 (NaN)
Dry mouth	1/71 (1.4%)		0/55 (0%)		0/0 (NaN)
Gained weight	0/71 (0%)		1/55 (1.8%)		0/0 (NaN)
Nervous system disorders
Muscle shaking, stiffness, or cramps	0/71 (0%)		1/55 (1.8%)		0/0 (NaN)
Tics	0/71 (0%)		1/55 (1.8%)		0/0 (NaN)
Headache	1/71 (1.4%)		2/55 (3.6%)		0/0 (NaN)
Psychiatric disorders
Irritability	1/71 (1.4%)		1/55 (1.8%)		0/0 (NaN)
Angry or hostile	3/71 (4.2%)		1/55 (1.8%)		0/0 (NaN)
Sad or low mood	2/71 (2.8%)		0/55 (0%)		0/0 (NaN)
Lack of interest	2/71 (2.8%)		0/55 (0%)		0/0 (NaN)
Mood swings	2/71 (2.8%)		1/55 (1.8%)		0/0 (NaN)
Anxious, tense, or uptight	3/71 (4.2%)		1/55 (1.8%)		0/0 (NaN)
Lack of self-control/ impulsive	3/71 (4.2%)		2/55 (3.6%)		0/0 (NaN)
Trouble paying attention or concentrating	2/71 (2.8%)		0/55 (0%)		0/0 (NaN)
Racing thoughts	1/71 (1.4%)		1/55 (1.8%)		0/0 (NaN)
Can't sit or stand still	3/71 (4.2%)		1/55 (1.8%)		0/0 (NaN)
Tried to hurt himself/ herself	1/71 (1.4%)		0/55 (0%)		0/0 (NaN)
Hurt someone or something	1/71 (1.4%)		1/55 (1.8%)		0/0 (NaN)
Unusually good mood or super happy	1/71 (1.4%)		1/55 (1.8%)		0/0 (NaN)
Skin and subcutaneous tissue disorders
Skin rash or irritation	1/71 (1.4%)		0/55 (0%)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

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