Clinical trial NCT01474993: Sulforaphane-rich Broccoli Sprout Extract for Autism
Official title: Sulforaphane-rich Broccoli Sprout Extract for Autism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autism
Lead sponsor: University of Massachusetts, Worcester
Sponsor class: OTHER
Collaborators: name: Johns Hopkins University
First posted: 2011-11-18
Enrollment: 44
Sex: MALE
Minimum age (years): 13
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Screening/Baseline in Social Responsiveness Scale (SRS) at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 10 weeks, 18 weeks and 22 weeks
Secondary outcomes:
measure: Change From Screening/Baseline in Aberrant Behavior Checklist (ABC) at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 10 weeks, 18 weeks, 22 weeks
measure: Ohio Autism Clinical Global Impression Scale - Severity (OACIS-S) Scale at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 10 weeks, 18 weeks, 22 weeks
measure: Ohio Autism Clinical Impressions Scale - Improvement (OACIS-I) (or CGI-I Scores) Scores at 4 Weeks, 10 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 10 weeks, 18 weeks, 22 weeks
measure: Liver Function Tests [Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase (SGPT)] at 4 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 18 weeks, 22 weeks
measure: Renal Function Tests (Serum Creatinine) at 4 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 18 weeks, 22 weeks
measure: Thyroid Stimulating Hormone (TSH) at 4 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 18 weeks, 22 weeks
measure: Red Blood Cell (RBC) Count at 4 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 18 weeks, 22 weeks
measure: White Blood Cell (WBC) Count at 4 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 18 weeks, 22 weeks
measure: Platelet Count at 4 Weeks, 18 Weeks and 22 Weeks
timeFrame: 4 weeks, 18 weeks, 22 weeks
measure: 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
timeFrame: Screening, baseline, 24 hours after first dose of study medication, 4 weeks, 10 weeks, 18 weeks, 22 weeks
measure: 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
timeFrame: Screening, 24 hours after first dose of study medication, 18 weeks, 22 weeks
Other outcomes:
Locations:
city: Lexington
country: United States
facility: Lurie Center for Autism, MassGeneral Hospital for Children
state: Massachusetts
Study officials:
affiliation: UMass Medical School
name: Andrew W. Zimmerman, M.D.
role: PRINCIPAL_INVESTIGATOR
References: