NCT03252522: MADDY

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

Completed Phase 1, PHASE2 Results posted Last updated 8 February 2023

What this trial tests

Phase 1, PHASE2 trial testing Broad Spectrum Micronutrients; a 36-ingredient blend of vitamins, minerals, amino acids, and antioxidants in Attention Deficit Hyperactivity Disorder in 135 participants. Completed in 31 May 2021.

Timeline

23 April 2018

Primary endpoint
10 July 2020

31 May 2021

Quick facts

Lead sponsor	Oregon Health and Science University
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	135
Start date	23 April 2018
Primary completion	10 July 2020
Estimated completion	31 May 2021
Sites	3 locations across Canada, United States

Drugs / interventions tested

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

Conditions studied

• Attention Deficit Hyperactivity Disorder — all drugs for Attention Deficit Hyperactivity Disorder →

Sponsor

Oregon Health and Science University

Who can join

Adults 6 to 12, any sex, with Attention Deficit Hyperactivity Disorder. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

CASI-5 Parent-rated Composite Score Primary · 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.

Baseline

Group	Value	95% CI
Intervention	1.49	± 0.08
Placebo	1.52	± 0.08

Week 8

Group	Value	95% CI
Intervention	1.18	± 0.08
Placebo	1.23	± 0.08

Clinical Global Impression (CGI) - Number of Participants Considered a Treatment Responder (Score of 1 or 2) Primary · 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, moderat

Group	Value	95% CI
Intervention	38
Placebo	10

Sodium, Potassium, Chloride, Carbon Dioxide, and Anion Gap in mmol/L Secondary · 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.

Sodium

Group	Value	95% CI
Intervention (Baseline)	139.13	± 0.34
Intervention (Week 8)	139.16	± 0.34
Placebo (Baseline)	139.28	± 0.36
Placebo (Week 8)	139.42	± 0.37

Potassium

Group	Value	95% CI
Intervention (Baseline)	4.1	± 0.10
Intervention (Week 8)	4.06	± 0.10
Placebo (Baseline)	4.09	± 0.10
Placebo (Week 8)	4.0	± 0.10

Chloride

Group	Value	95% CI
Intervention (Baseline)	105.07	± 0.96
Intervention (Week 8)	104.81	± 0.97
Placebo (Baseline)	104.88	± 0.97
Placebo (Week 8)	105.28	± 0.98

Carbon dioxide

Group	Value	95% CI
Intervention (Baseline)	25.62	± 0.21
Intervention (Week 8)	25.64	± 0.22
Placebo (Baseline)	25.97	± 0.24
Placebo (Week 8)	25.86	± 0.25

Anion gap

Group	Value	95% CI
Intervention (Baseline)	10.30	± 2.83
Intervention (Week 8)	10.64	± 2.83
Placebo (Baseline)	10.31	± 2.83
Placebo (Week 8)	10.15	± 2.84

Calcium, Blood Urea Nitrogen, Creatinine, Glucose, Bilirubin Total in mg/dL Secondary · 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.

Calcium

Group	Value	95% CI
Intervention (Baseline)	9.47	± 0.20
Intervention (Week 8)	9.49	± 0.20
Placebo (Baseline)	9.47	± 0.20
Placebo (Week 8)	9.40	± 0.20

Blood urea nitrogen (BUN)

Group	Value	95% CI
Intervention (Baseline)	12.48	± 0.41
Intervention (Week 8)	13.17	± 0.42
Placebo (Baseline)	12.56	± 0.46
Placebo (Week 8)	12.13	± 0.48

Creatinine

Group	Value	95% CI
Intervention (Baseline)	0.46	± 0.01
Intervention (Week 8)	0.49	± 0.01
Placebo (Baseline)	0.46	± 0.01
Placebo (Week 8)	0.46	± 0.01

Glucose

Group	Value	95% CI
Intervention (Baseline)	82.15	± 2.36
Intervention (Week 8)	83.03	± 2.39
Placebo (Baseline)	79.45	± 2.44
Placebo (Week 8)	80.0	± 2.46

Bilirubin total

Group	Value	95% CI
Intervention (Baseline)	0.47	± 0.03
Intervention (Week 8)	0.45	± 0.03
Placebo (Baseline)	0.49	± 0.03
Placebo (Week 8)	0.46	± 0.03

Albumin, Total Protein, Hemoglobin, Mean Cell Hgb in g/dL Secondary · 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.

Albumin

Group	Value	95% CI
Intervention (Baseline)	4.34	± 0.17
Intervention (Week 8)	4.34	± 0.17
Placebo (Baseline)	4.29	± 0.17
Placebo (Week 8)	4.28	± 0.17

Total protein

Group	Value	95% CI
Intervention (Baseline)	7.15	± 0.63
Intervention (Week 8)	8.45	± 0.65
Placebo (Baseline)	7.07	± 0.73
Placebo (Week 8)	7.06	± 0.76

Hemoglobin

Group	Value	95% CI
Intervention (Baseline)	12.99	± 0.17
Intervention (Week 8)	12.96	± 0.17
Placebo (Baseline)	12.99	± 0.18
Placebo (Week 8)	12.91	± 0.18

Mean cell Hgb concentration

Group	Value	95% CI
Intervention (Baseline)	33.82	± 0.13
Intervention (Week 8)	33.59	± 0.13
Placebo (Baseline)	33.75	± 0.15
Placebo (Week 8)	33.47	± 0.15

AST, ALT, Alkaline in U/L Secondary · 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.

AST

Group	Value	95% CI
Intervention (Baseline)	23.58	± 1.26
Intervention (Week 8)	27.28	± 1.28
Placebo (Baseline)	25.72	± 1.42
Placebo (Week 8)	22.79	± 1.46

ALT

Group	Value	95% CI
Intervention (Baseline)	18.67	± 3.25
Intervention (Week 8)	26.00	± 3.27
Placebo (Baseline)	20.40	± 3.37
Placebo (Week 8)	18.09	± 3.41

Alkaline phosphatase

Group	Value	95% CI
Intervention (Baseline)	255	± 8.10
Intervention (Week 8)	241.33	± 8.15
Placebo (Baseline)	252.21	± 9.29
Placebo (Week 8)	257.93	± 9.41

RBC Count in Cells/mcL Secondary · 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.

Group	Value	95% CI
Intervention (Baseline)	4,650,000	± 0.08
Intervention (Week 8)	4,650,000	± 0.08
Placebo (Baseline)	4,600,000	± 0.08
Placebo (Week 8)	4,600,000	± 0.09

Hematocrit, RBC Distribution, Immature Grans, Lymphocyte, Monocyte, Eosinophil in Percent Secondary · 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.

Hematocrit

Group	Value	95% CI
Intervention (Baseline)	38.40	± 0.52
Intervention (Week 8)	38.60	± 0.52
Placebo (Baseline)	38.50	± 0.55
Placebo (Week 8)	38.60	± 0.55

RBC distribution

Group	Value	95% CI
Intervention (Baseline)	25.03	± 8.76
Intervention (Week 8)	25.17	± 8.76
Placebo (Baseline)	25.29	± 8.76
Placebo (Week 8)	25.02	± 8.76

Immature grans

Group	Value	95% CI
Intervention (Baseline)	0.20	± 0.02
Intervention (Week 8)	0.18	± 0.02
Placebo (Baseline)	0.24	± 0.02
Placebo (Week 8)	0.19	± 0.03

Lymphocyte

Group	Value	95% CI
Intervention (Baseline)	43.63	± 1.65
Intervention (Week 8)	43.53	± 1.66
Placebo (Baseline)	40.25	± 1.80
Placebo (Week 8)	40.65	± 1.84

Monocyte

Group	Value	95% CI
Intervention (Baseline)	8.03	± 0.34
Intervention (Week 8)	8.29	± 0.34
Placebo (Baseline)	7.78	± 0.38
Placebo (Week 8)	8.35	± 0.38

Eosinophil

Group	Value	95% CI
Intervention (Baseline)	3.82	± 0.63
Intervention (Week 8)	4.03	± 0.64
Placebo (Baseline)	6.49	± 0.73
Placebo (Week 8)	5.71	± 0.75

Mean Cell Volume in fL Secondary · 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.

Group	Value	95% CI
Intervention (Baseline)	82.70	± 0.44
Intervention (Week 8)	83.00	± 0.45
Placebo (Baseline)	83.74	± 0.49
Placebo (Week 8)	83.85	± 0.50

Iron in ug/dL Secondary · 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.

Group	Value	95% CI
Intervention (Baseline)	99.1	± 4.65
Intervention (Week 8)	90.7	± 4.69
Placebo (Baseline)	100.5	± 5.35
Placebo (Week 8)	95.5	± 5.49

WBC Count, Absolute Monocyte, Absolute Eosinophil, Platelet Count in Cells/mcL Secondary · 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.

WBC count

Group	Value	95% CI
Intervention (Baseline)	5,710	± 0.22
Intervention (Week 8)	5,730	± 0.23
Placebo (Baseline)	6,080	± 0.25
Placebo (Week 8)	5,990	± 0.26

Absolute monocyte

Group	Value	95% CI
Intervention (Baseline)	460	± 0.02
Intervention (Week 8)	470	± 0.02
Placebo (Baseline)	460	± 0.02
Placebo (Week 8)	480	± 0.02

Absolute eosinophil

Group	Value	95% CI
Intervention (Baseline)	210	± 0.04
Intervention (Week 8)	230	± 0.04
Placebo (Baseline)	390	± 0.04
Placebo (Week 8)	340	± 0.05

Platelet count

Group	Value	95% CI
Intervention (Baseline)	289,970	± 7.54
Intervention (Week 8)	289,320	± 7.57
Placebo (Baseline)	290,160	± 8.62
Placebo (Week 8)	295,900	± 8.75

Clinical Global Impression (CGI) Secondary · 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, moderat

Group	Value	95% CI
Open Label (Week 8 to Week 16)	103

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline, week 1, week 4, week 8 and week 16. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Intervention

Serious: 0/69 (0%)

Deaths: 0/69

Placebo

Serious: 0/54 (0%)

Deaths: 0/54

Open Label

Serious: 0/99 (0%)

Deaths: 0/99

Other adverse events (28 terms — click to expand)

Reaction	System	Intervention	Placebo	Open Label
GI symptoms	Gastrointestinal disorders	—	—	—
Other	General disorders	—	—	—
Trouble falling asleep	General disorders	—	—	—
Less hungry	Metabolism and nutrition disorders	—	—	—
Angry or hostile	Psychiatric disorders	—	—	—
Sad or low mood	Psychiatric disorders	—	—	—
Anxious, tense, or uptight	Psychiatric disorders	—	—	—
Lack of self-control/ impulsive	Psychiatric disorders	—	—	—
Can't sit or stand still	Psychiatric disorders	—	—	—
Lack of interest	Psychiatric disorders	—	—	—
Mood swings	Psychiatric disorders	—	—	—
Trouble paying attention or concentrating	Psychiatric disorders	—	—	—
Tired/fatigued	General disorders	—	—	—
Unusually good mood or super happy	Psychiatric disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Irritability	Psychiatric disorders	—	—	—
Racing thoughts	Psychiatric disorders	—	—	—
Tried to hurt himself/ herself	Psychiatric disorders	—	—	—
Hurt someone or something	Psychiatric disorders	—	—	—
Lost weight	Metabolism and nutrition disorders	—	—	—
Dry mouth	Metabolism and nutrition disorders	—	—	—
Gained weight	Metabolism and nutrition disorders	—	—	—
Muscle shaking, stiffness, or cramps	Nervous system disorders	—	—	—
Tics	Nervous system disorders	—	—	—
Skin rash or irritation	Skin and subcutaneous tissue disorders	—	—	—
Heart racing or skipping beats	Cardiac disorders	—	—	—
Chest Pain	General disorders	—	—	—
Dizzy or light-headed	General disorders	—	—	—

Data from ClinicalTrials.gov NCT03252522 adverse events section.

Sponsor's own description

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youths: A Placebo-Controlled Randomized Clinical Trial.
   Johnstone JM, Hatsu I, Tost G, Srikanth P, et al · · 2022 · cited 48× · PMID 34303786 · DOI 10.1016/j.jaac.2021.07.005
2. 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.
   Johnstone JM, Leung B, Gracious B, Perez L, et al · · 2019 · cited 20× · PMID 31763491 · DOI 10.1016/j.conctc.2019.100478
3. Development of a Composite Primary Outcome Score for Children with Attention-Deficit/Hyperactivity Disorder and Emotional Dysregulation.
   Johnstone JM, Leung BMY, Srikanth P, Hatsu I, et al · · 2020 · cited 9× · PMID 32101469 · DOI 10.1089/cap.2019.0179
4. Pain sensitivity and perceptual sensitivity are associated with severity of emotional dysregulation in children with ADHD: a cross-sectional analysis using the Temperament in Middle Childhood Questionnaire.
   Bruton AM, Senders A, Tost G, Ast H, et al · · 2023 · cited 7× · PMID 35271401 · DOI 10.1080/09638288.2022.2043946
5. Problems most concerning to parents of children with ADHD and emotional dysregulation in a randomized controlled trial of multinutrients: MADDY secondary analysis.
   Tost G, Srikanth P, Bruton A, Hatsu IE, et al · · 2024 · cited 6× · PMID 38819662 · DOI 10.1007/s00787-024-02463-1
6. Gut microbiome changes with micronutrient supplementation in children with attention-deficit/hyperactivity disorder: the MADDY study.
   Ast HK, Hammer M, Zhang S, Bruton A, et al · · 2025 · cited 5× · PMID 39963956 · DOI 10.1080/19490976.2025.2463570
7. Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study.
   Leung BMY, Srikanth P, Gracious B, Hatsu IE, et al · · 2022 · cited 1× · PMID 35770861 · DOI 10.1080/03007995.2022.2096333
8. Association Between Trace Mineral Concentrations and Oxidative Stress in Children with ADHD Supplemented with Multinutrients.
   Robinette LM, Hatsu IE, Wu CM, Adetona O, et al · · 2026 · PMID 41776068 · DOI 10.1007/s12011-026-05017-5