Clinical trial NCT02561481: Sulforaphane Treatment of Children With Autism Spectrum Disorder (ASD)
Official title: Sulforaphane Treatment of Children With Autism Spectrum Disorder (ASD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Autism Spectrum Disorder
Lead sponsor: University of Massachusetts, Worcester
Sponsor class: OTHER
Collaborators: name: Congressionally Directed Medical Research Programs
name: Johns Hopkins University
First posted: 2015-09-28
Enrollment: 60
Sex: ALL
Minimum age (years): 3
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: ASD is a diverse disorder starting in early childhood and characterized by social communication impairment as well as restricted interests and repetitive behaviors. It affects 1:68 children and is an enormous medical and economic problem for which there is no established, mechanism-based treatment. Sulforaphane is an isothiocyanate derived from broccoli, and has potent activity in transcriptionally up-regulating genes that control mechanisms whereby aerobic cells protect themselves against oxidative stress, mitochondrial dysfunction, and inflammation.

This study is a clinical trial of oral sulforaphane (as broccoli seed powder) in 50 boys and girls (3-12 years) with ASD in 3 phases over 36 weeks. In Phase 1, 25 children will receive active drug and 25 will receive placebo for 15 weeks; in Phase 2, all children will receive sulforaphane from 15-30 weeks; in Phase 3, children will receive no treatment for 6 weeks. Study visits will take place at screening, 7, 15, 22, 30 and 36 weeks, when the Ohio Autism Clinical Clinical Impressions Scale - Severity and Improvement (OACIS-S and OACIS-I), Aberrant Behavior Checklist (ABC) and Social Responsiveness Scale (SRS) will be recorded. Children will be monitored with physical examinations and for toxicity with clinical laboratory studies and examine possible biomarkers: Nuclear factor-erythroid factor 2 (Nrf2), oxidative stress and mitochondrial function, the mechanistic target of rapamycin (mTOR) pathway and cytokine expression. In addition, prior to the main clinical trial, a pilot study will be carried out in 10 children with ASD, 6-12 years of age, who will receive sulforaphane, 2.2 micromoles/kg daily for 14 days. Blood and urine samples before and at the end of treatment will be collected, in order to measure several parameters that are likely to demonstrate expected effects of sulforaphane, to standardize the assays and procedures, and to determine the most effective measures.

Detailed description: Background: ASD is a diverse disorder starting in early childhood and characterized by social communication impairment as well as restricted interests and repetitive behaviors. It affects 1:68 children and is an enormous medical and economic problem for which there is no established, mechanism-based treatment. Sulforaphane is an isothiocyanate derived from broccoli, and has potent activity in transcriptionally up-regulating genes that control mechanisms whereby aerobic cells protect themselves against oxidative stress, mitochondrial dysfunction, and inflammation.

Hypothesis: Based on the observation that fever is frequently associated with behavioral improvements in children with ASD, it is hypothesized that sulforaphane might lead to functional improvements in ASD because it can up-regulate cell-protective responses, such as heat shock proteins and related mechanisms that are also up-regulated during fever. These mechanisms are central to multiple cellular processes in the central nervous system, including synaptic transmission, and may improve long-range cerebral cortical connectivity, which is depressed in ASD.

Specific aims: The 3 specific aims in this study are: 1) To determine if there are measurable effects on social responsiveness and problem behaviors during treatment of children with sulforaphane; 2) To determine if treatment with sulforaphane in children is safe and well tolerated; and 3) To elucidate cellular biomarkers that respond to treatment with sulforaphane.

Design: This is a randomized, double blind, single-arm crossover phase 1/2 clinical trial of orally administered sulforaphane (as broccoli seed powder) in 50 boys and girls (3-12 years) with ASD in 3 phases over 36 weeks.

In Phase 1, 25 children will receive active drug and 25 will receive placebo for 15 weeks; in Phase 2, all children will receive sulforaphane from 15-30 weeks; in Phase 3, children will receive no treatment for 6 weeks. Study visits will take place at screening, 7, 15, 22, 30 and 36 weeks, when the Ohio Autism Clinical Clinical Impressions Scale - Severity and Improvement (OACIS-S and OACIS-I), Aberrant Behavior Checklist (ABC) and Social Responsiveness Scale (SRS) will be recorded.

The children will be monitored with physical examinations and for toxicity with clinical laboratory studies and examine possible biomarkers: Nrf2, oxidative stress and mitochondrial function, mTOR pathway and cytokine expression.

In addition, prior to the main clinical trial, a pilot study will be performed in 10 children with ASD, 6-12 years of age, who will receive sulforaphane, 2.2 micromoles/kg daily for 14 days. Blood and urine samples before and at the end of treatment will be collected, in order to measure several parameters that are likely to demonstrate expected effects of sulforaphane, to standardize the assays and procedures, and to determine the most effective measures.

Eligibility criteria: Inclusion Criteria:

* Autism Spectrum Disorder (ASD) diagnosis of moderate or greater severity
* Age 3 through 12 years inclusive

Exclusion Criteria:

* Absence of a parent or legal guardian and consent
* Inability to speak/understand English language
* Seizure within 1 year of screening: This exclusion is based on the theoretical concern that cellular activation by sulforaphane might exacerbate seizures in patients with known seizure disorders. As noted in our previous trial of sulforaphane in young adult males, a seizure occurred in each of 2 participants: one during treatment (in a participant with a previously undisclosed seizure), the other 3 weeks after discontinuing sulforaphane.
* Impaired renal function (serum creatinine \> 1.2 mg/dl), impaired hepatic function (SGOT/SGPT\> 2x upper limit of normal), impaired thyroid function (Thyroid Stimulating Hormone (TSH) outside normal limits): This exclusion is based on a theoretical possibility of activation of underlying cellular metabolic abnormalities by sulforaphane. Current infection or treatment with antibiotics: this exclusion is to avoid complications of inter-current illness that may occur due to the clinical trial or obscure possible effects of sulforaphane.
* Medications that may modify the course or testing of ASD parameters (e.g., prednisone): This exclusion is necessary in order not to interfere with or complicate effects of sulforaphane.
* Chronic medical disorder (e.g., cardiovascular disease, stroke or diabetes) or major surgery within 3 months prior to enrollment: Serious medical illness in the child may be complicated by the clinical trial and make it difficult to discern a change in ASD associated with treatment.
* Less than 3 years or more than 13 years of age: this age range was selected to cover the ages from usual diagnosis of ASD up to adolescence.
* A diagnosis of autism spectrum disorder of mild severity (for example, earlier categories of Asperger disorder, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS)), according to Autism Diagnostic Observation Schedule (ADOS) criteria.
* Prisoners
* Pregnant women

Primary outcomes:
measure: Change in Ohio Autism Clinical Impressions Scale - Improvement (OACIS-I) Average Score From Baseline
timeFrame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks
Secondary outcomes:
measure: OACIS-I Response Rate on Aberrant Behaviors Subscale
timeFrame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks
measure: OACIS-I Response Rate on Social Communication Subscale
timeFrame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks
measure: Change in Total Aberrant Behavior Checklist Score From Baseline
timeFrame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks
measure: Change in Total SRS-2 Score From Baseline
timeFrame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks
measure: Dithiocarbamate Plasma Concentration Detected by Cyclocondensation at Each Visit
timeFrame: Week 0, Week 7, Week 15, Week 22, Week 30, Week 36
measure: Comparison of Free Reduced Glutathione (GSH), Total GSH, Oxidized Glutathione (GSSG) at Week 0 and 15
timeFrame: Week 0 and Week 15
measure: Free GSH:GSSG and Total GSH:GSSG Ratios at Week 15
timeFrame: Week 15
Other outcomes:
measure: NQO1: NAD(P)H:Quinone Oxidoreductase-1
timeFrame: Week 0, Week 15, Week 30
measure: xCT
timeFrame: Week 0, Week 15, Week 30
measure: HO-1 (Heme Oxygenase 1)
timeFrame: Week 0, Week 15, Week 30
measure: HSP70
timeFrame: Week 0, Week 15, Week 30
measure: HSP27
timeFrame: Week 0, Week 15, Week 30.
measure: IL-6
timeFrame: Week 0, Week 15, Week 30
measure: IL-1β
timeFrame: Week 0, Week 15, Week 30
measure: Cox-2
timeFrame: Week 0, Week 15, Week 30
measure: TNF-α
timeFrame: Week 0, Week 15, Week 30
Locations:
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
Study officials:
affiliation: University of Massachusetts, Worcester
name: Andrew W Zimmerman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, Zimmerman AW. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15550-5. doi: 10.1073/pnas.1416940111. Epub 2014 Oct 13.
citation: Liu H, Zimmerman AW, Singh K, Connors SL, Diggins E, Stephenson KK, Dinkova-Kostova AT, Fahey JW. Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder. Sci Rep. 2020 Apr 2;10(1):5822. doi: 10.1038/s41598-020-62714-4.
citation: Zimmerman AW, Singh K, Connors SL, Liu H, Panjwani AA, Lee LC, Diggins E, Foley A, Melnyk S, Singh IN, James SJ, Frye RE, Fahey JW. Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder. Mol Autism. 2021 May 25;12(1):38. doi: 10.1186/s13229-021-00447-5.