Effect of a Wide Spectrum Nutritional Supplement on Mitochondrial Function in Children With Autism Spectrum Disorder

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to evaluate the metabolic effects of a comprehensive wide-spectrum supplement for children with ASD to determine whether it physiologically targets mitochondrial pathways known to be abnormal in children with ASD.The intervention is a commonly used wide-spectrum nutritional supplement, which is theoretically designed to normalize mitochondrial function. The investigators aim to determine if the supplement does have the hypothesized effect on physiology in individuals with ASD. The investigator will enroll up to 50 children, aged 4 to 14 years of age with confirmed ASD and mitochondrial dysfunction, and participation will last 26 weeks.

Detailed Description
-----------------
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder often with life-long consequences that affects young children during critical developmental periods. The Centers for Disease Control estimates that ASD affects as many as 17 per 1000 children (1 in 59) in the United States suggesting that the prevalence is higher than previous estimates.Despite the dramatic rise in the detected prevalence of ASD over the past two decades, there is no effective medical treatment for core ASD symptoms (social communication and repetitive behavior), the closely associated problem of language impairment, or the underlying pathophysiology of ASD. Currently, the only accepted treatment for core ASD symptoms is behavior therapy, which may entail intensive one-on-one treatment over several years. The primary aims of this study are to evaluate the effect of a wide-spectrum nutritional supplement on mitochondrial function in individuals with ASD. Participants entered into the trial will have abnormalities in mitochondrial function that are known to be associated with ASD (approximately 50+% of children with ASD) but are not diagnostic of mitochondrial disease. The investigators hypothesize that nutritional supplements designed for children with ASD have a physiological action of normalizing mitochondrial function and cellular physiology throughout the body. To test whether the targeted nutritional supplement is superior to placebo, the investigators will study 50 children, between the ages of 4 years to 14 years, with confirmed ASD and known abnormal variations in mitochondrial at baseline. Participants will be randomly assigned to receive active treatment or placebo for 12-weeks under double-blind conditions and at the end of the 12 weeks switch to the opposite condition after a 2-week wash out period. Mitochondrial function will be measured at baseline and after each treatment arm in order to determine if the supplement positively influences cellular biochemistry. The investigator will also evaluate the effectiveness of the supplement on core and associated ASD symptoms using several behaviors assessments.

Official Title
-----------------
Effect of a Wide Spectrum Nutritional Supplement on Mitochondrial Function in Children With Autism Spectrum Disorder (ASD)

Conditions
-----------------
Autism Spectrum Disorder

Intervention / Treatment
-----------------
* Drug: Wide-spectrum nutritional supplement
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Weight ≥ 15 kg and ≤ 100kg; DSM-5 diagnosis of Autism Spectrum Disorder as established by formal clinical assessment which includes a gold-standard tool such as the Autism Diagnostic Observational Schedule. Current Clinical Global Impression Severity score ≥ 4 Stable educational and therapy plan (one month) with no planned changes in the intensity of treatment for 12 weeks. English is spoken in the home and at least one parent is able to read, write and speak English. Stable medication (no changes in past 6 weeks and no planned changes for the study duration. Electron Transport Chain Complex (I, II, III, IV) or Citrate Synthase Activity which is >= 2.0 Standard Deviation Above or Below Average (outside the normal range) Exclusion Criteria: Presence of serious behavioral problems (tantrums, aggression, self-injury) for which another treatment is warranted. Current Clinical Global Impression Severity score < 7 (Extremely Ill) Significant medical condition by history or by physical examination or lab tests that would be incompatible with the treatment. Children taking anticonvulsant medication for seizures or active epilepsy. Diagnosis of Mitochondrial Disease

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 17 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: Crossover Assignment
Interventional Model Description: Prospective Randomized 12-week Double-Blind Placebo-Controlled Cross-over
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Wide-spectrum nutritional supplement<br>The Wide-spectrum nutritional supplement used will be a combination of NeuroNeeds: SpectrumNeeds and QNeeds. Weight based dosing will be used. The daily serving size will be divided into two oral daily doses in the form of a powder which can be mixed into liquid or food. Together, there are 34 different dietary supplements in the products. Except for ubiquinol, all of these nutrients are provided in a powder form in SpectrumNeeds. Ubiquinol is provided separately in QNeeds gel capsules. These capsules can be swallowed whole, or cut with scissors and the contents squeezed out and added to SpectrumNeeds just before ingestion. | Drug: Wide-spectrum nutritional supplement<br>* Comprehensive powder with 33 dietary supplements and 1 dietary supplement via gel capsule.<br>* Other names: NeuroNeeds: Spectrum Needs, NeuroNeeds:Q Needs;|
| Placebo Comparator: Placebo control<br>Participants randomized to receive placebo will take placebo in an oral form divided into powder and a gel capsule in the same manner as treatment. For the second phase of the cross over, participants will be part of the opposite group they were assigned to in Phase I (Placebo or Treatment). Quantities for placebo or treatment will match across phases for each subject, utilizing the same weight based dosing. | Other: Placebo<br>* Inactive placebo comparator<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mitochondrial activity in study patients | Mitochondrial activity and redox metabolism at baseline and after the placebo and supplement arms of the study, as determined through laboratory assessment. | Baseline, Week 12, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Childhood Autism Rating Scale (CARS) score | The Childhood Autism Rating Scale is a 15-item clinician-rated scale that measures the severity of core ASD symptoms of social communication and restricted and repetitive patterns of behavior, interests, or activities. Each item is scored on a 4 point scale of severity from 1 (None/Minimal) to 4 (Severe). The measure is the total score of the 15 items in which a score of 15-27.5 reflects minimal to no severity of symptoms, 28-33.5 reflects mild to moderate severity of symptoms, and a score of 34 or higher reflects severe symptoms. | Baseline, Week 12, Week 24 | 
| Change in the Clinical Global Impression scale (CGI) score | The Clinical Global Impression - Severity scale (CGI-S) is a clinician rated 7-point measure of overall symptomatic severity of psychopathology. Scores range from 1 (Normal, not at all ill) through 4 (Moderately ill) to 7 (Among the most extremely ill patients). The Clinical Global Impression - Improvement scale (CGI-I) is the companion measure that evaluates the change in the patient's symptoms relative to baseline. Scores range from 1 (Very much improved) through 4 (No Change) to 7 (Very much worse). Ratings are reflected in a single total score, in which a score of 2 (Much Improved) or 1 (Very Much Improved) on the CGI-I will be used as a secondary measure to define positive response. | Baseline, Week 12, Week 24 | 
| Change in the Children's Yale-Brown Obsessive Compulsive Scale modified for Autism Spectrum Disorder (CYBOCS-ASD) score | The Children's Yale-Brown Obsessive Compulsive Scale modified for Autism Spectrum Disorder is a 5-item clinician-rated measure to evaluate severity of repetitive behavior in children with ASD. Each item is scored on a 5 point scale from 0 (None) to 4 (Extreme) for the severity of: Time Spent, Interference in everyday life, Distress, Resistance, and Degree of Control over the behavior. A decrease in the total score of the 5 items, ranging from 0 to 20, will be used as a secondary measure to define positive response. | Baseline, Week 12, Week 24 | 
| Change in the Aberrant Behavior Checklist (ABC) scores | The Aberrant Behavior Checklist is a 58-item caregiver questionnaire consisting of five subscales: hyperactivity, irritability, social withdrawal, stereotypic behavior and inappropriate speech in children with developmental disabilities. A higher score indicates more frequent aberrant behaviors. Our secondary measures are the subscale scores for Irritability (15 item), Social Withdrawal (16 item) and Hyperactivity (16 item). Each item rates behavior severity on a 4 point scale from 0 (Not at all a problem) to 3 (The problem is severe in degree). A decrease in the subscale scores, ranging from 0 to 45 (Irritability), 48 (Social Withdrawal) and 48 (Hyperactivity), will be used as secondary measures to define positive response. | Screening, Week 12, Week 24 | 
| Change in the Parent-rated Anxiety Scale for ASD (PRAS-ASD) score | The Parent-rated Anxiety Scale for Autism Spectrum Disorder is a 25-item scale that measures anxiety in youth with ASD. Each item rates the severity of a behavior on a 4 point scale from 0 (None/not present) to 3 (Severe/Very frequent and a major problem). A decrease in the total score of the 25 items, ranging from 0 to 75, will be used as a secondary measure to define positive response to intervention. | Baseline, Week 12, Week 24 | 
| Change in the Caregiver Strain Questionnaire (CGSQ) score | The Caregiver Strain short-form questionnaire is a 7-item measure of self-reported strain experienced by caregivers of children with behavioral disorders. Each item rates the severity of interference in the quality of the caregiver's life on a 5 point scale from 0 (Not at All) to 4 (Very Much). A decrease in the total score of the 7 items, ranging from 0 to 28, will be used as a secondary measure to define positive response. | Baseline, Week 12, Week 24 | 
| Change in the Vineland III Caregiver score | The Vineland III Caregiver is a 381-item parent-reported measure of adaptive behavior in children with developmental and intellectual disabilities. The Vineland is comprised of three sub scores for the following domains: Communication, Daily Living Skills, and Socialization. The frequency of adaptive behaviors for each item is scored on a scale from 0 (Never) to 2 (Usually). The total adaptive score is reflected as a composite score of the sub domains (which is determined by age norms) in which a higher total score reflects higher functioning. An increase in the total score or sub domain scores will be used as a secondary measure to define positive response to intervention. | Baseline, Week 12, Week 24 | 
| Evaluate intervention safety | Columbia-Suicide Severity Rating Scale: a suicide risk assessment that identifies presence and severity of suicidal ideation, planning, and behavior, as well as non-suicidal self-harm behaviors. Presence of any of these behaviors during the course of study enrollment will be considered an adverse event. | Screening, Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 | 
| Evaluate intervention safety | Routine complete blood counts will be collected to determine whether treatment-emergent basic blood chemistry is altered. Presence of any changes during the course of study enrollment will be evaluated by the treating physician and determined clinically significant or not clinically significant. If determined by the treating physician, a change will be considered an adverse event. | Screening, Week 12, Week 24 | 
| Evaluate intervention safety | Routine comprehensive blood panels will be collected to determine whether treatment-emergent basic blood chemistry is altered. Presence of any changes during the course of study enrollment will be evaluated by the treating physician and determined clinically significant or not clinically significant. If determined by the treating physician, a change will be considered an adverse event. | Screening, Week 12, Week 24 | 
| Evaluate intervention effect on cellular regulatory pathways known to be implicated in ASD | Evaluation of a variety of research biomarkers, including peripheral blood mononuclear cell, plasma, DNA, red blood cells, and oxidative stress rates. Treatment-emergent change in these biomarkers will indicate that a change has occurred at the cellular level. | Screening, Week 12, Week 24 | 
| Examine the change in attention to social stimuli | Participants will watch a video with social and non-social stimuli. Eye movements and visual fixation will be measured with eye tracking software. Change in percentage of time spent looking at social stimuli will be measured. | Baseline, Week 12, Week 24 | 
| Examine the change in cognitive ability | Differential Abilities Scale-II: cognitive abilities across core domains: verbal, nonverbal, spatial. Subtests: Verbal comprehension: 42-item domain, raw score 0-23. Naming vocabulary: 34-item domain, raw score 0-28. Word definitions: 35-item domain, raw score 0-25. Verbal similarities: 33-item domain, raw score 0-28. Picture similarities: 32-item domain, raw score 0-23. Picture similarities: 50-item domain, raw score 0-34. Matrices: 56-item domain, raw score 0-33. Pattern construction: 35-item domain, raw score 0-74. Copying: 20-item domain, raw score 0-36. Recall of designs: 22-item domain, raw score 0-43. All subdomains have a t-score range of 10-90. Verbal ability standard score ranges from 30-170. Nonverbal ability standard score ranges from 32-170. Spatial ability standard score ranges from 34-170. Total General Conceptual Ability standard score ranges from 30-170. Subtests and item sets given vary by participant age | Screening, Week 12, Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mitochondrial Dysfunction