Eat2beNICE Vitamins and Nutrients as Supplementation for Impulsivity, Irritability, and Compulsivity

Study Overview
=================
Brief Summary
-----------------
Impulsivity, irritability and compulsivity are cross-disorder symptom domains, which affect a significant proportion of adolescents. Predominately as part of attention deficit hyperactivity disorder (ADHD) but also as symptom domains without a diagnosis of ADHD, impulsivity and irritability cause serious burden. Furthermore, treatment options and their effects are limited. Previous studies with different study designs assessing micronutrients for the treatment of impulsivity / ADHD in children and adults have reported positive benefits as well as a very good tolerability. However, more research is required; in particular controlled studies with adolescents, cross-disorder approaches and studies investigating long-term effects are missing. The focus of this study is to investigate the effect of micronutrients on impulsivity, irritability and compulsivity in children and adolescents between 11 and 18 years of age with a high level of impulsivity and irritability with or without a diagnosis of attention deficit hyperactivity disorder (ADHD). The investigators intend to include 210 children and adolescents (n=110 in Germany) with a high level of impulsivity and irritability. The study is divided in two phases. An initial 10-week double blind, placebo-controlled treatment phase with broad-spectrum micronutrients is followed by a 10-week open-label treatment phase. The study assessments will be performed during five study visits and a follow-up visit.

Official Title
-----------------
Eat2beNICE Vitamins and Nutrients as Supplementation for Impulsivity, Irritability, and Compulsivity

Conditions
-----------------
Impulsive Behavior

Intervention / Treatment
-----------------
* Other: broad-spectrum micronutrient
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged 11;0 - 17; 6 years at initial inclusion Subjects with a high level of impulsivity/ irritability based on a CGI-S-score ≥ 4 and a parent-rated Affective Reactivity Index (ARI) score ≥ 5 indicating a high level of multi-dimensional irritability Subjects with or without a research diagnosis of attention deficit hyperactivity disorder (ADHD). ADHD has to be confirmed by structured diagnostic interview (ADHD section of Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS)) Deemed reliable and compliant with the protocol (including the ingestion of as many capsules as prescribed by the investigator) Ability to comprehend and speak the native language of the country in which the assessments take place Signed informed consent by parents or legal representative Signed informed assent by child or adolescent (indicating that the subject is aware of the investigational nature and the core aspects of the study and the study is run in accordance with the ICH GCP guideline E6 (R2) (2016)) Exclusion Criteria: Subject is being treated with a medication that might, in the opinion of the investigator, pose a safety risk for the subject when participating in this study Intellectual disability (based on available IQ or the clinical opinion of the investigator, taking into account relevant psychosocial information, e.g. educational level) Any known abnormality of mineral metabolism (e.g., Wilson's disease, haemochromatosis) History of or present clinically relevant somatic or psychiatric acute or chronic disorder that, in the opinion of the investigator, might confound the results of tolerability/safety assessment, or prohibit the patients from completing the study, or would not be in the best interest of the patient. Subject has taken any kind of food supplement containing vitamins, minerals and/or trace elements within 30 days prior to entering the study Subject has unstable treatment conditions (current changes in medication and/or psychotherapy) that might in the opinion of the investigator confound the results of the study with respect to impulsivity/irritability. Subject has a documented allergy, hypersensitivity, or intolerance to any of the ingredients of the investigational product Subject has taken another investigational product or taken part in a clinical study within 30 days prior to entering the study

Ages Eligible for Study
-----------------
Minimum Age: 11 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double-blind placebo controlled following open label phase
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: broad-spectrum micronutrients<br>broad-spectrum micronutrients description: capsules containing a blend of Vitamin B3 (NADH), Vitamin B6 (pyridoxal-5-phosphate), folic acid (5-MTHF), Vitamin B12 (methylcobalamin), Vitamin D3 (25-hydroxyvitamin D3), Magnesium (magnesium oxide), Zinc (zinc methionine), Iron (ferric phosphate), Selenium (selenomethionine), Phospholipids, L-carnitine (L-carnitine-L-tartrate) | Other: broad-spectrum micronutrient<br>* daily intake of capsules containing a blend of Vitamin B3 (NADH), Vitamin B6 (pyridoxal-5-phosphate), folic acid (5-MTHF), Vitamin B12 (methylcobalamin), Vitamin D3 (25-hydroxyvitamin D3), Magnesium (magnesium oxide), Zinc (zinc methionine), Iron (ferric phosphate), Selenium (selenomethionine), Phospholipids, L-carnitine (L-carnitine-L-tartrate)<br>|
| Placebo Comparator: placebo<br>capsules containing placebo | Other: placebo<br>* daily intake of capsules<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response rate at end of placebo-controlled phase defined as CGI-I score with focus on impulsivity of 1 or 2 [=very much improved or much improved] plus reduction in Affective Reactivity Index (ARI) total score of at least 30% compared to baseline | The primary objective is to investigate the double-blind placebo controlled (10 weeks) effects of broad-spectrum micronutrients in highly impulsive children and adolescents (10-18 years; N=180 in total) with a high level of impulsivity with or without diagnosis of attention deficit hyperactivity disorder (ADHD). The primary outcome measure is the response rate at the end of the placebo-controlled phase. Response is defined as a Clinical Global Impression - Improvement score (CGI-I, Guy 1976; NIMH 1985) with a focus on impulsivity of 1 or 2 [=very much improved or much improved] plus a reduction in the Affective Reactivity Index (ARI, parent-rated, Stringaris et al. 2012) total score of at least 30% compared to baseline. | 10 weeks (end of placebo-controlled phase) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinician rating of compulsivity | Children´s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS, Scahill et al., 1997) | every 10 weeks over the whole study period of 20 weeks (10 weeks placebo-controlled phase followed by 10 weeks open label) | 
| Change in the rating of irritability | Perceived Stress Scale (PSS-10, Taylor 2015) | every 10 weeks over the whole study period of 20 weeks (10 weeks placebo-controlled phase followed by 10 weeks open label) | 
| Change in sleep problems | Sleep problems (5-item questionnaire, self-rating of sleep problems) | every 10 weeks over the whole study period of 20 weeks (10 weeks placebo-controlled phase followed by 10 weeks open label) | 
| change in motor activity (optional) | mHealth (movisens DataAnalyzer software) | at baseline and after 10 weeks of study participation | 
| Change in ADHD symptom severity total score | Swanson, Nolan and Pelham Rating Scale (SNAP, Swanson et al. 2001) | every 10 weeks over the whole study period of 20 weeks (10 weeks placebo-controlled phase followed by 10 weeks open label) | 
| change in rating of aggression | Retrospective Modified Overt Aggression Scale (R-MOAS, Blader et al. 2010) | every 5 weeks over the whole study period of 20 weeks (10 weeks placebo-controlled phase followed by 10 weeks open label) | 
| Rates of adverse events of the treatment groups in comparison to placebo group | Compare rates of adverse events of the treatment groups to placebo group to assess safety and tolerability | every 5 weeks over the whole study period of 20 weeks (10 weeks placebo-controlled phase followed by 10 weeks open label) | 
| change in treatment adherence | assessed by Attitudes Towards Treatment questionnaire; total score 0-108; better Outcome: lower score | every 10 weeks over the whole study period of 20 weeks (10 weeks placebo-controlled phase followed by 10 weeks open label) |