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

NCT03252522 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 16870
• Study Type: interventional
• Target: 135
• Locations: 2 countries
• Sites: 3

Brief Summary

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

Conditions

Attention Deficit Hyperactivity Disorder

Keywords

ADHD; ODD; DMDD; Inattention; Impulsivity; Irritability; Anger; Micronutrients; Emotional Dysregulation

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (11)

• Sodium, Potassium, Chloride, Carbon Dioxide, and Anion Gap in mmol/L

  Baseline and Week 8

• Calcium, Blood Urea Nitrogen, Creatinine, Glucose, Bilirubin Total in mg/dL

  Baseline and Week 8

• Albumin, Total Protein, Hemoglobin, Mean Cell Hgb in g/dL

  Baseline and Week 8

• AST, ALT, Alkaline in U/L

  Baseline and Week 8

• RBC Count in Cells/mcL

  Baseline and Week 8

Study Arms (3)

Intervention

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Capsules of inactive placebo.

Dietary Supplement: Placebo

Open Label

EXPERIMENTAL

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

Interventions

Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants COMBINATION_PRODUCT

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

Also known as: Daily Essential Nutrients (DEN)

Intervention; Open Label

Placebo DIETARY_SUPPLEMENT

40% of participants will take 3-4 capsules of inactive placebo three times per day for eight weeks.

Placebo

Eligibility Criteria

• Age: 6 Years - 12 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Oregon Health and Science University: lead
• Ohio State University: collaborator
• University of Lethbridge: collaborator
• National University of Natural Medicine: collaborator
• Foundation for Excellence in Mental Health Care: collaborator
• The Waterloo Foundation: collaborator

Study Sites (3)

The Ohio State University

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

University of Lethbridge

Lethbridge, Alberta, AB T1K 6T5, Canada

Location

Related Publications (4)

• Robinette LM, Hatsu IE, Adetona O, Wu CM, Johnstone JM, Bruton AM, Ast HK, Odei JB, Ziouzenkova O, Leung BMY, Arnold LE. Multinutrients Decrease Oxidative Stress in Children With ADHD: Mediation/Moderation Analysis of Randomized Controlled Trial Data. J Atten Disord. 2025 Dec;29(14):1290-1306. doi: 10.1177/10870547251355998. Epub 2025 Aug 7.

  PMID: 40772654 DERIVED

• Leung BMY, Srikanth P, Gracious B, Hatsu IE, Tost G, Conrad V, Johnstone JM, Arnold LE. Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study. Curr Med Res Opin. 2022 Sep;38(9):1595-1602. doi: 10.1080/03007995.2022.2096333. Epub 2022 Jul 11.

  PMID: 35770861 DERIVED

• Johnstone JM, Hatsu I, Tost G, Srikanth P, Eiterman LP, Bruton AM, Ast HK, Robinette LM, Stern MM, Millington EG, Gracious BL, Hughes AJ, Leung BMY, Arnold LE. Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youths: A Placebo-Controlled Randomized Clinical Trial. J Am Acad Child Adolesc Psychiatry. 2022 May;61(5):647-661. doi: 10.1016/j.jaac.2021.07.005. Epub 2021 Jul 22.

  PMID: 34303786 DERIVED

• Johnstone JM, Leung B, Gracious B, Perez L, Tost G, Savoy A, Hatsu I, Hughes A, Bruton A, Arnold LE. Rationale and design of an international randomized placebo-controlled trial of a 36-ingredient micronutrient supplement for children with ADHD and irritable mood: The Micronutrients for ADHD in Youth (MADDY) study. Contemp Clin Trials Commun. 2019 Oct 26;16:100478. doi: 10.1016/j.conctc.2019.100478. eCollection 2019 Dec.

  PMID: 31763491 DERIVED

MeSH Terms

Conditions

Attention Deficit Disorder with Hyperactivity; Impulsive Behavior

Interventions

Minerals; Amino Acids; Antioxidants

Condition Hierarchy (Ancestors)

Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders; Behavior

Intervention Hierarchy (Ancestors)

Inorganic Chemicals; Amino Acids, Peptides, and Proteins; Biological Factors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Protective Agents; Physiological Effects of Drugs; Specialty Uses of Chemicals

Results Point of Contact

• Title: Jeanette Johnstone, PhD
• Organization: Oregon Health & Science University

jojeanet@ohsu.edu

5034943700

Study Officials

• Jeanette Johnstone

  Oregon Health and Science University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Placebo-controlled; randomization created by statistician, all involved in the study and assessment are blinded
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 26, 2017
• First Posted: August 17, 2017
• Study Start: April 23, 2018
• Primary Completion: July 10, 2020
• Study Completion: May 31, 2021
• Last Updated: February 8, 2023
• Results First Posted: February 9, 2022

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2); CA (1)