Micronutrients for Attention-Deficit Hyperactivity Disorder in Youth (MADDY) Study

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

Detailed Description
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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.

Official Title
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Evaluating the Efficacy of Supplementation With Micronutrients for ADHD in Youth (MADDY) Study

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Combination Product: Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>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<br>* 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<br>* Other names: Daily Essential Nutrients (DEN);|
| Placebo Comparator: Placebo<br>Capsules of inactive placebo. | Dietary Supplement: Placebo<br>* 40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.<br>|
| Experimental: Open Label<br>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<br>* 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<br>* Other names: Daily Essential Nutrients (DEN);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CASI-5 Parent-rated Composite Score | 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. | Baseline and week 8 | 
| Clinical Global Impression (CGI) - Number of Participants Considered a Treatment Responder (Score of 1 or 2) | 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. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sodium, Potassium, Chloride, Carbon Dioxide, and Anion Gap in mmol/L | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| Calcium, Blood Urea Nitrogen, Creatinine, Glucose, Bilirubin Total in mg/dL | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| Albumin, Total Protein, Hemoglobin, Mean Cell Hgb in g/dL | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| AST, ALT, Alkaline in U/L | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| RBC Count in Cells/mcL | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| Hematocrit, RBC Distribution, Immature Grans, Lymphocyte, Monocyte, Eosinophil in Percent | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| Mean Cell Volume in fL | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| Iron in ug/dL | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| WBC Count, Absolute Monocyte, Absolute Eosinophil, Platelet Count in Cells/mcL | Collect blood and urine samples at two time points. The samples are being collected per a request from the FDA for safety screening. | Baseline and Week 8 | 
| Clinical Global Impression (CGI) | 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. | 16 weeks | 
| CASI-5 Parent Report | 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. | Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Impulsivity, ODD, ADHD, DMDD, Inattention, Irritability, Anger, Micronutrients, Emotional Dysregulation