A Phase II, Randomized, Double-blind, Placebo-controlled Study of Myrosinase-enriched Glucoraphanin, a Sulforaphane Precursor System, in Autism Spectrum Disorder
Overview
- Phase
- Phase 2
- Intervention
- Sulforaphane
- Conditions
- Autism Spectrum Disorder
- Sponsor
- University of North Carolina, Chapel Hill
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Social Responsiveness Scale-2 (SRS-2) Total Score at Baseline
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
The aim of this randomized controlled trial is to determine if a nutritional supplement containing broccoli sprout and seed extracts, a rich source of sulforaphane, is effective in reducing core symptoms of autism spectrum disorder (ASD). The study will also explore the safety and tolerability of a sulforaphane supplement in young men with ASD, as well as its effects on challenging neuropsychiatric symptoms that are commonly associated with ASD, such as hyperactivity, irritability, and repetitive movements.
Detailed Description
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 68 children, including 1 in 42 boys, characterized by marked social communication impairment and restricted, repetitive behaviors and interests. Evidence-based pharmacological treatments available for the treatment of the defining symptoms of ASD are currently lacking. While the etiology of ASD is not fully understood, the pathogenesis is hypothesized to involve cellular dysfunction, including increased oxidative stress, aberrant neuroinflammation, and reduced mitochondrial capacity, leading to synaptic dysfunction in at least a subset of individuals. Sulforaphane is a powerful upregulator of antioxidant response elements and heat shock proteins, which may lead to improved redox capacity, decreased inflammation, and improved mitochondrial functioning in individuals with ASD. A trial by Singh and colleagues (2014) provided preliminary evidence suggesting that sulforaphane derived from broccoli sprout extract can have beneficial effects for improving symptoms of autism. In this study, young men ages 13-30 years old with moderate to severe autism spectrum disorder will be randomly assigned to receive either a sulforaphane supplement or placebo for a 12 week treatment treatment period, followed by a 4 week blinded discontinuation phase. The uncoated tablets each contain 125 mg broccoli seed extract and 50 mg broccoli sprout extract, corresponding to approximately 15 µmol sulforaphane per tablet. The dose will vary from 3-8 tablets daily depending upon the participant's weight. Matched placebo tablets contain only inert ingredients A serum sample will be collected prior to starting treatment and at the end of the treatment phase to quantify sulforaphane metabolites. Clinical response will be assessed through clinician- and caregiver-rated measures of autism symptoms (Social Responsiveness Scale-2; Repetitive Behavior Scale- Revised), challenging symptoms commonly observed in individuals with developmental disabilities (Aberrant Behavior Checklist), and global severity of symptoms and improvement (Clinical Global Impression Scale). A blood sample will be collected at baseline and at the end of the treatment phase to check safety labs, and a saliva sample will be collected at baseline for a future study of genetic biomarkers associated with treatment response.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Males between ages 13-30 (inclusive) at the time of the consent
- •Primary diagnosis of Autism Spectrum Disorder (ASD), confirmed by Diagnostic and Statistical Manual-5 (DSM-5) criteria and meeting the autism cut-off score of 9 or greater on the Autism Diagnostic Observation Schedule-2 (ADOS-2)
- •Participant is capable of giving written informed consent or has a legally authorized representative (LAR) with sufficient capacity to provide written informed consent on the participant's behalf.
- •Participant has a reliable informant (parent or caregiver) who has sufficient past and current knowledge of the subject and will oversee the administration of study medication and accompany the subject to each study visit.
- •Participant and caregiver have reliable means of transportation to attend study visits.
Exclusion Criteria
- •Chronic medical illness that is not stable or would pose a risk to the participant if he participates in the trial
- •History of clinical seizures within the 12 months preceding study enrollment
- •Known genetic disorder that is presumed to be the cause of autism spectrum disorder (eg., Fragile x syndrome, tuberous sclerosis)
- •Changes to psychopharmacological medications (e.g., stimulants, antidepressants, anxiolytics, antipsychotics) in the 4 weeks preceding study enrollment
- •Significant changes to non-pharmacological treatments for ASD in the 4 weeks preceding study enrollment
- •Chronic treatment with anti-inflammatory agents (e.g., ibuprofen, NSAIDs, corticosteroids)
- •Clinically significant laboratory abnormalities at Screening visit (e.g., AST/ALT\> two times the upper normal limits; serum creatinine \> 1.2 mg/dl, TSH outside normal limits)
- •Clinically significant findings on physical examination that investigator determines could increase risk of harm from participating in the study
- •Participated in another clinical interventional trial or received an investigational product in the 30 days preceding study enrollment
- •Previous therapeutic trial of sulforaphane or participation in a clinical trial in which sulforaphane was the investigational agent
Arms & Interventions
Sulforaphane
Participants will take a sulforaphane supplement 3-8 tablets daily, with dose depending upon body weight. Each tablet contains 125 mg broccoli seed powder and 50 mg broccoli sprout extract, providing approximately 15 µmol sulforaphane. The weight-based dosing schedule is as follows: 3 tablets (approx. 46.5 µmol SF) if \<100 lb; 5 tablets (approx. 77.5 µmol SF) if 100-125 lb; 6 tablets (approx. 93 µmol SF) if 126-175 lb; 7 tablets (approx. 108.5 µmol SF) if 176-199 lb; 8 tablets (approx. 124 µmol SF) if ≥ 200 lb
Intervention: Sulforaphane
Placebo
Participants in this arm will take placebo tablets that are identical in shape, size, and color to the sulforaphane tablets. The number of tablets taken per day corresponds to the weight-based schedule described for the sulforaphane arm.
Intervention: Placebo
Outcomes
Primary Outcomes
Social Responsiveness Scale-2 (SRS-2) Total Score at Baseline
Time Frame: Baseline
The Social Responsiveness Scale-2 (SRS-2) is a 65-item caregiver report that includes 5 subscales covering core symptom domains of ASD (Social Awareness, Social Cognition, Social Communication, Social Motivation, and Restricted Interests/ Repetitive Behaviors). The SRS-2 provides a T-score that is scaled such that the mean is 50 and the SD is 10. Higher scores indicate a higher presence and severity of autistic social impairment. A T-score of 76 or higher is considered "severe". T-scores between 66 and 75 are considered as "moderate". T-scores between 60 and 65 are considered "mild". A T-score below 60 is considered typical. The theoretical range of a T-score is 10 to 90. The actual range of the SRS-2 in this study is 45 to 90.
Social Responsiveness Scale-2 (SRS-2) Total Score at Week 4
Time Frame: Week 4
The Social Responsiveness Scale-2 (SRS-2) is a 65-item caregiver report that includes 5 subscales covering core symptom domains of ASD (Social Awareness, Social Cognition, Social Communication, Social Motivation, and Restricted Interests/ Repetitive Behaviors). The SRS-2 provides a T-score that is scaled such that the mean is 50 and the SD is 10. Higher scores indicate a higher presence and severity of autistic social impairment. A T-score of 76 or higher is considered "severe". T-scores between 66 and 75 are considered as "moderate". T-scores between 60 and 65 are considered "mild". A T-score below 60 is considered typical. The theoretical range of a T-score is 10 to 90. The actual range of the SRS-2 in this study is 45 to 90.
Social Responsiveness Scale-2 (SRS-2) Total Score at Week 8
Time Frame: Week 8
The Social Responsiveness Scale-2 (SRS-2) is a 65-item caregiver report that includes 5 subscales covering core symptom domains of ASD (Social Awareness, Social Cognition, Social Communication, Social Motivation, and Restricted Interests/ Repetitive Behaviors). The SRS-2 provides a T-score that is scaled such that the mean is 50 and the SD is 10. Higher scores indicate a higher presence and severity of autistic social impairment. A T-score of 76 or higher is considered "severe". T-scores between 66 and 75 are considered as "moderate". T-scores between 60 and 65 are considered "mild". A T-score below 60 is considered typical. The theoretical range of a T-score is 10 to 90. The actual range of the SRS-2 in this study is 45 to 90.
Social Responsiveness Scale-2 (SRS-2) Total Score at Week 12
Time Frame: Week 12
The Social Responsiveness Scale-2 (SRS-2) is a 65-item caregiver report that includes 5 subscales covering core symptom domains of ASD (Social Awareness, Social Cognition, Social Communication, Social Motivation, and Restricted Interests/ Repetitive Behaviors). The SRS-2 provides a T-score that is scaled such that the mean is 50 and the SD is 10. Higher scores indicate a higher presence and severity of autistic social impairment. A T-score of 76 or higher is considered "severe". T-scores between 66 and 75 are considered as "moderate". T-scores between 60 and 65 are considered "mild". A T-score below 60 is considered typical. The theoretical range of a T-score is 10 to 90. The actual range of the SRS-2 in this study is 45 to 90.
Social Responsiveness Scale-2 (SRS-2) Total Score at Week 16
Time Frame: Week 16
The Social Responsiveness Scale-2 (SRS-2) is a 65-item caregiver report that includes 5 subscales covering core symptom domains of ASD (Social Awareness, Social Cognition, Social Communication, Social Motivation, and Restricted Interests/ Repetitive Behaviors). The SRS-2 provides a T-score that is scaled such that the mean is 50 and the SD is 10. Higher scores indicate a higher presence and severity of autistic social impairment. A T-score of 76 or higher is considered "severe". T-scores between 66 and 75 are considered as "moderate". T-scores between 60 and 65 are considered "mild". A T-score below 60 is considered typical. The theoretical range of a T-score is 10 to 90. The actual range of the SRS-2 in this study is 45 to 90.
Secondary Outcomes
- Social Responsiveness Scale-2 (SRS-2) Subscale Score (Social Awareness)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Social Responsiveness Scale-2 (SRS-2) Subscale Score (Social Cognition)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Social Responsiveness Scale-2 (SRS-2) Subscale Score (Social Communication)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Social Responsiveness Scale-2 (SRS-2) Subscale Score (Social Motivation)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Social Responsiveness Scale-2 (SRS-2) Subscale Score (Restricted Interests/Repetitive Behaviors)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Aberrant Behavior Checklist (ABC) Subscale Score (Social Withdrawal)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Aberrant Behavior Checklist (ABC) Subscale Scores (Hyperactivity)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Aberrant Behavior Checklist (ABC) Subscale Score (Inappropriate Speech)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Aberrant Behavior Checklist (ABC) Subscale Score (Stereotypy)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Aberrant Behavior Checklist (ABC) Subscale Score (Irritability)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Clinical Global Impression-Severity (CGI-S) Score(Baseline, Week 4, Week 8, Week 12, Week 16)
- Number of Participants With Clinical Global Impression-Improvement (CGI-I) Score of Much Improved or Very Much Improved(Week 4, Week 8, Week 12, Week 16)
- Repetitive Behavior Scale-Revised (RBSR) Total Score(Baseline, Week 4, Week 8, Week 12, Week 16)
- Mean Red Blood Cell Value(Baseline, Week 12)
- Mean White Blood Cell Value(Baseline, Week 12)
- Mean Hemoglobin Value(Baseline, Week 12)
- Mean Hematocrit Value(Baseline, Week 12)
- Mean Corpuscular Volume Value(Baseline, Week 12)
- Mean Corpuscular Hemoglobin Value(Baseline, Week 12)
- Mean Corpuscular Hemoglobin Concentration Value(Baseline, Week 12)
- Mean Red Blood Cell Distribution Width Value(Baseline, Week 12)
- Mean Platelets Value(Baseline, Week 12)
- Mean Absolute Neutrophils Value(Baseline, Week 12)
- Mean Absolute Lymphocytes Value(Baseline, Week 12)
- Mean Absolute Monocytes Value(Baseline, Week 12)
- Mean Absolute Eosinophils Value(Baseline, Week 12)
- Mean Absolute Basophils Value(Baseline, Week 12)
- Mean Serum Chemistries (Sodium)(Baseline, Week 12)
- Mean Serum Chemistries (Potassium)(Baseline, Week 12)
- Mean Serum Chemistries (Chloride)(Baseline, Week 12)
- Mean Serum Chemistries (Bicarbonate)(Baseline, Week 12)
- Mean Serum Chemistries (Blood Urea Nitrogen)(Baseline, Week 12)
- Mean Serum Chemistries (Creatinine)(Baseline, Week 12)
- Mean Serum Chemistries (Glucose)(Baseline, Week 12)
- Mean Liver Function Tests Values (Alanine Transaminase)(Baseline, Week 12)
- Mean Liver Function Tests Values (Aspartate Transaminase)(Baseline, Week 12)
- Mean Liver Function Tests Values (Total Bilirubin)(Baseline, Week 12)
- Mean Value of Thyroid Stimulating Hormone (TSH)(Baseline, Week 12)
- Least Squares Mean of Vital Signs (Weight)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Least Squares Mean of Vital Signs (Height)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Least Squares Mean of Vital Signs (Blood Pressure)(Baseline, Week 4, Week 8, Week 12, Week 16)
- Least Squares Mean of Vital Signs (Heart Rate)(Baseline, Week 4, Week 8, Week 12, Week 16)