Sulforaphane-rich Broccoli Sprout Extract for Autism

Study Overview
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Brief Summary
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The primary objectives of this study are to answer whether there is evidence of measurable effects on social responsiveness (primary outcome) and other behavioral symptoms after treatment of autistic male adolescents and adults with orally administered sulforaphane-rich Broccoli Sprout Extract (efficacy). The secondary objectives of this study are to answer whether treatment of male adolescents and adults with autism using orally administered sulforaphane-rich Broccoli Sprout Extract within a specified dose range is safe (toxicity); treatment with sulforaphane-rich Broccoli Sprout Extract is well tolerated (side effects and adverse events); key cellular biomarkers support the hypothesized mechanisms (proof of principle).

Detailed Description
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Behavioral improvements occur transiently during febrile illnesses in autism, and include decreased repetitive behaviors and improved speech. These changes have been recorded in 38% of autistic children in a clinical survey and 83% in an observational study, respectively. The cellular basis for this fever effect is unknown but is likely to involve heat shock proteins (HSP) and cellular stress responses (CSR) that lead to changes in synaptic function and network connectivity. Sulforaphane (1-isothiocyanato-4R- (methylsulfinyl)butane) is an isothiocyanate that is delivered by lyophilized extracts of 3-day-old broccoli sprouts. Broccoli sprouts are widely consumed as a food item all over the world by very large numbers of individuals, without any reports of adverse effects. Our preliminary work in vitro shows that sulforaphane stimulates HSP and mitochondrial biogenesis in several genetic disorders. This study of sulforaphane-rich Broccoli Sprout Extract in autism is a randomized, double-blinded, placebo-controlled, phase II single site trial, designed to ensure safety and obtain efficacy data, with a focus on changes in social responsiveness, a core feature of autism. Its hybrid design, incorporating double masking, placebo control, and randomization, enhances the robustness of early outcome data. The study duration will be 2 years. Recruitment of subjects will be 50% by 8 months and complete by 14 months. All subjects in the study will be followed for 22 weeks. Treatment (18 weeks) will be started as patients are entered into the study and receive baseline testing. All treatment will be completed by 20 months and data analysis and presentation of results by 24 months. Forty-five male adolescents (13-18 years) and adults (19-30 years) with autism will be randomly assigned to receive either sulforaphane-rich Broccoli Sprout Extract (n = 30) or placebo (n = 15). The 2:1 randomization schedule will be produced by the study statistician using permuted random blocks and stratification by history of positive behavioral effects of fever. Treatment assignments will be performed by the research pharmacy at MGH. Females will be excluded for homogeneity of the sample and because males have higher incidence of autism than females (4:1). We will seek to enroll up to 50% of the subjects having a history of positive behavioral effects of fever, which will be recorded from caregivers' recall of incidents and graded on the CGI-Improvement (CGI-I) 7-point scale. There will be in total 7 study visits for each subject: the screening visit, enrollment visit, a blood draw visit at 24 hours after the first dose of study medication (for mitochondrial/heat shock protein analysis), 4 week (follow-up) visit, 10 week (follow-up) visit, 18 week visit (last treatment visit), and the final closeout visit one month after the study drug stops (22 weeks). Even though the treatment will stop at 18 weeks, we will follow subjects for additional 4 weeks after study medication stops (the 22 week visit) to ensure safety after study drug stops. Additional visits may be conducted in case any side effects are reported at any stage of the study.

Official Title
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Sulforaphane-rich Broccoli Sprout Extract for Autism

Conditions
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Autism

Intervention / Treatment
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* Drug: Sulforaphane-rich Broccoli Sprout Extract
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Autism diagnosis. Quantitative autism traits and severity for diagnosis of autism will be assessed using the ADOS-G (Modules 1-4 and Severity), Social Responsiveness Scale (SRS; child and adult forms), Clinical Global Impression-Severity (CGI-S) and Aberrant Behavior Checklist-Withdrawal subscale (ABC-W). Exclusion Criteria: Absence of a parent or legal guardian and consent Unavailability for all visits and adherence to study regimen Seizure within 2 years of screening Impaired renal function (serum creatinine > 1.2 mg/dl), impaired hepatic function (AST/ALT > 2x upper limit of normal), impaired thyroid function (TSH outside normal limits) Current infection or treatment with antibiotics; AND Chronic medical disorder (e.g., cardiovascular disease, stroke or diabetes) or major surgery within 3 months prior to enrollment. A diagnosis of autism spectrum disorder other than autism, for example, Asperger's, PDD-NOS etc.

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>inactive placebo. | Drug: Placebo<br>* 15 subjects will be randomly selected to receive inactive placebo (Gelcaps identical in appearance to that of active medication and containing microcrystalline cellulose)<br>|
| Experimental: Interventional<br>sulforaphane-rich Broccoli Sprout Extract. | Drug: Sulforaphane-rich Broccoli Sprout Extract<br>* 30 subjects will be randomly selected to receive sulforaphane-rich Broccoli Sprout Extract. The medication will be supplied and dispensed as No.1 size gelcaps (each gelcap containing   250 mg sulforaphane rich Broccoli Sprout Extract, equivalent to   50 µmol of sulforaphane). The dosage of sulforaphane will depend on subject's body weight: Subjects with body weight less than 101 lbs will receive   50 micromol sulforaphane per day (1 gelcap to be taken once a day) Subjects with body weight 101 lbs to 199 lbs will receive   100 micromol sulforaphane per day (2 gelcaps to be taken once a day) Subjects with bidy weight > 199 lbs will receive   150 micromol sulforaphane per day (3 gelcaps to be taken once a day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Screening/Baseline in Social Responsiveness Scale (SRS) at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks | The Social Responsiveness Scale is a parent- and/or teacher-reported 65 question scale. Each question on the scale inquires about an observed aspect of reciprocal social behavior that is rated on the scoring sheet on a scale from 0 to 3, where 0 is best possible behavior and 3 is the worst possible behavior. The total SRS score may range from 0 to 195 where higher values represent the worse outcome. For the purposes of this study, SRS scores were obtained at both screening (the day study participants were first seen and consent obtained) and the baseline visits (the day study medication was first started, within a month of the screening visit). The screening and baseline scores were then averaged and these average SRS scores were used to calculate the change in scores at 4 weeks, 10 weeks, 18 weeks and 22 weeks respectively. | 4 weeks, 10 weeks, 18 weeks and 22 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Screening/Baseline in Aberrant Behavior Checklist (ABC) at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks | The Aberrant Behavior Checklist has 58 questions rated by parents or teachers on a scale of 0 to 3, where a score of 0 for particular behavior is not a problem at all, 1 indicates that the behavior is a problem but slight in degree, 2 indicates that the problem is moderately serious, and 3 indicates that the problem is severe in degree. The possible ABC scores may range from 0 to 174, where higher values represent the worse outcome. For the purposes of this study, ABC scores were obtained at both screening (the day study participants were first seen and consent obtained) and the baseline visits (the day study medication was first started, within a month of the screening visit). The screening and baseline scores were then averaged and these average ABC scores were used to calculate the change in scores at 4 weeks, 10 weeks, 18 weeks and 22 weeks respectively. | 4 weeks, 10 weeks, 18 weeks, 22 weeks | 
| Ohio Autism Clinical Global Impression Scale - Severity (OACIS-S) Scale at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks | OACIS-S is a 10 domain scale that requires the clinician to rate the severity of the patient's autism symptoms at the time of assessment. The 10 domains cover different aspects of patients' behavior, including global autism severity, social interaction, aberrant behavior, repetitive or ritualistic behaviors, verbal communication, non-verbal communication, hyperactivity/inattention, anxiety, sensory sensitivities and restricted/narrow interests. Each domain is rated on a scale of 1 to 7 where 1 is normal, 2 is some symptoms sometimes affecting individual and family, 3 is mild symptoms affecting individual daily and sometimes family, 4 is moderate symptoms affecting individual and family daily, 5 is marked symptoms affecting individual daily and sometimes family, 6 is severe symptoms affecting individual daily and sometimes family, and 7 is severe symptoms affecting individual and family daily. | 4 weeks, 10 weeks, 18 weeks, 22 weeks | 
| Ohio Autism Clinical Impressions Scale - Improvement (OACIS-I) (or CGI-I Scores) Scores at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks | The Ohio Autism Clinical Impressions Improvement Scale (OACIS-I) is a 10 domain scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to the baseline state at the beginning of the intervention. The 10 domains cover different aspects of patients' behavior, including global autism severity, social interaction, aberrant behavior, repetitive or ritualistic behaviors, verbal communication, non-verbal communication, hyperactivity/inattention, anxiety, sensory sensitivities and restricted/narrow interests. Each domain is rated on a scale of 1 to 7, where 1 is very much improved; 2 is much improved; 3 is minimally improved; 4 is no change; 5 is minimally worse; 6 is much worse; or 7 is very much worse. | 4 weeks, 10 weeks, 18 weeks, 22 weeks | 
| Liver Function Tests [Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase (SGPT)] at 4 Weeks, 18 Weeks and 22 Weeks |  | 4 weeks, 18 weeks, 22 weeks | 
| Renal Function Tests (Serum Creatinine) at 4 Weeks, 18 Weeks and 22 Weeks |  | 4 weeks, 18 weeks, 22 weeks | 
| Thyroid Stimulating Hormone (TSH) at 4 Weeks, 18 Weeks and 22 Weeks |  | 4 weeks, 18 weeks, 22 weeks | 
| Red Blood Cell (RBC) Count at 4 Weeks, 18 Weeks and 22 Weeks |  | 4 weeks, 18 weeks, 22 weeks | 
| White Blood Cell (WBC) Count at 4 Weeks, 18 Weeks and 22 Weeks |  | 4 weeks, 18 weeks, 22 weeks | 
| Platelet Count at 4 Weeks, 18 Weeks and 22 Weeks |  | 4 weeks, 18 weeks, 22 weeks | 
| Change From Screening and Baseline in Urinary Isoprostane F2α-VI Levels at 24 Hours After First Dose, at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks | *Due to lack of resources, only the results on change from screening at the final intervention visit (18 weeks) are reported. | Screening, baseline, 24 hours after first dose of study medication, 4 weeks, 10 weeks, 18 weeks, 22 weeks | 
| Change From the Screening Visit in Heat Shock Protein Gene Expression (Relative Maximum Gene Expression) at 24 Hours After First Dose, 18 Weeks and 22 Weeks | Due to lack of resources, only the results on change from screening at the final intervention visit (18 weeks) are reported. | Screening, 24 hours after first dose of study medication, 18 weeks, 22 weeks |