Sulforaphane Treatment of Children With Autism Spectrum Disorder (ASD)

NCT02561481 | Completed Phase 1 Results DMC

• 2 other identifiers: H00007832AR140087
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Autism Spectrum Disorder

Outcome Measures

Primary Outcomes (1)

• Change in Ohio Autism Clinical Impressions Scale - Improvement (OACIS-I) Average Score From Baseline

  The Ohio Autism Clinical Impressions Scale-Severity (OACIS-S) rates severity of symptoms in 10 categories: general level of autism, social interaction, aberrant and repetitive behavior, verbal and nonverbal communication, hyperactivity, anxiety, sensory sensitivities and restricted and narrow interests. Each category is rated from 1 (normal) to 7 (most severe). The OACIS-S was a reference at follow up visits when the OACIS-Improvement was compared to the OACIS-S, from 1 to 7: 4 was no change; 3 to 1 minimal to marked improvement and 5 to 7 minimal to marked worsening. The numerical score of the OACIS-S is independent and unrelated quantitatively to the OACIS-I. For analysis, the OACIS-I general score and subscale values were recoded, in which 4 (no change) was recoded as 0; 3 to 1 were recoded as +1 to +3 to denote improvement, and 5 to 7 were recoded as -1 to -3 for worsening.

  7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks

Secondary Outcomes (7)

• OACIS-I Response Rate on Aberrant Behaviors Subscale

  7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks

• OACIS-I Response Rate on Social Communication Subscale

  7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks

• Change in Total Aberrant Behavior Checklist Score From Baseline

  7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks

• Change in Total SRS-2 Score From Baseline

  7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks

• Dithiocarbamate Plasma Concentration Detected by Cyclocondensation at Each Visit

  Week 0, Week 7, Week 15, Week 22, Week 30, Week 36

Other Outcomes (9)

• NQO1: NAD(P)H:Quinone Oxidoreductase-1

  Week 0, Week 15, Week 30

• xCT

  Week 0, Week 15, Week 30

• HO-1 (Heme Oxygenase 1)

  Week 0, Week 15, Week 30

Study Arms (2)

Sulforaphane

ACTIVE COMPARATOR

Sulforaphane (SF) will be administered once a day orally in an approximate dose of 1 µmol/lb (2.2 kg µmol/kg) body weight. Each SF tablet will contain 125 mg broccoli seed powder (equivalent to \~ 15 µmol SF). The total dose per day will depend on participants' body weight: 30-50 lb: 3 tablets (45 µmol/day) 50-70 lb: 4 tablets (60 µmol/day) 70-90 lb: 6 tablets (90 µmol/day) 90-110 lb: 7 tablets (105 µmol/day) 110-130 lb: 8 tablets (120 µmol/day) For pilot study, all participants (n=10) will receive SF for 14 days. For main clinical trial, 25 participants will randomly receive SF for 15 weeks (phase 1). During phase 2, a single-arm crossover from placebo to sulforaphane arm will take place, and all participants will receive SF from 15-30 weeks.

Drug: Sulforaphane

Placebo

PLACEBO COMPARATOR

Placebo tablets identical in size and similar in appearance to the active tablets will be used. Number of placebo tablets will be equivalent to the active tablets depending on participants' body weight. For the main clinical trial, 25 participants will be randomly allocated to receive placebo for 15 weeks (phase 1). During phase 2, a single-arm crossover from placebo arm to sulforaphane arm will take place, and all participants will receive sulforaphane from 15-30 weeks.

Drug: Placebo

Interventions

Sulforaphane DRUG

See under active arm description

Sulforaphane

Placebo DRUG

See under placebo arm description

Placebo

Eligibility Criteria

• Age: 3 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• Absence of a parent or legal guardian and consent
• Inability to speak/understand English language
• 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

Sponsors & Collaborators

• University of Massachusetts, Worcester: lead
• Congressionally Directed Medical Research Programs: collaborator
• Johns Hopkins University: collaborator

Study Sites (1)

University of Massachusetts Medical School

Worcester, Massachusetts, 01655, United States

Location

Related Publications (3)

• 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.

  PMID: 25313065 RESULT

• 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.

  PMID: 32242086 RESULT

• 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.

  PMID: 34034808 DERIVED

MeSH Terms

Conditions

Autism Spectrum Disorder

Interventions

sulforaphane

Condition Hierarchy (Ancestors)

Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders

Limitations and Caveats

The sample size was limited to 45 children with ASD and we could not impute missing data for those participants who were lost to follow up.

Results Point of Contact

• Title: Andrew Zimmerman, MD
• Organization: Univ of Massachusetts Medical School

andrew.zimmerman@umassmemorial.org

4109350488

Study Officials

• Andrew W Zimmerman, MD

  University of Massachusetts, Worcester

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Professor of Pediatrics and Neurology

Study Record Dates

• First Submitted: September 24, 2015
• First Posted: September 28, 2015
• Study Start: December 1, 2015
• Primary Completion: December 1, 2018
• Study Completion: January 1, 2020
• Last Updated: December 17, 2020
• Results First Posted: November 25, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)