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Sulforaphane Treatment of Children With Autism Spectrum Disorder (ASD)

This study is currently recruiting participants.
See Contacts and Locations
Verified January 2017 by Andrew Zimmerman, University of Massachusetts, Worcester
Sponsor:
Collaborators:
Congressionally Directed Medical Research Programs
Johns Hopkins University
Information provided by (Responsible Party):
Andrew Zimmerman, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier:
NCT02561481
First received: September 24, 2015
Last updated: January 10, 2017
Last verified: January 2017
  Purpose

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.


Condition Intervention Phase
Autism Spectrum Disorder Drug: Sulforaphane Drug: Placebo Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Sulforaphane Treatment of Children With Autism Spectrum Disorder (ASD)

Resource links provided by NLM:


Further study details as provided by Andrew Zimmerman, University of Massachusetts, Worcester:

Primary Outcome Measures:
  • Change in Ohio Autism Clinical Impressions Scale - Improvement (OACIS-I) average Score from baseline [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]

Secondary Outcome Measures:
  • OACIS-I response rate on aberrant behaviors subscale [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
    Response rate described as proportion of study participants who have much improved or very much improved on the OACIS-I subscale

  • OACIS-I response rate on social communication subscale [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
    Response rate described as proportion of study participants who have much improved or very much improved on the OACIS-I subscale

  • Change in total ABC score from baseline [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Change in total SRS score from baseline [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Serum glutamic oxaloacetic transaminase (SGOT) levels [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Serum glutamic-pyruvic transaminase (SGPT) levels [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Total bilirubin levels [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Serum creatinine levels [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Thyroid Stimulating Hormone (TSH) [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Transcription factor Nrf2 (Nuclear factor-erythroid factor 2) [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Oxidative stress biomarkers [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Heat shock response biomarkers [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Mitochondrial function biomarkers [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • mTOR signaling pathway biomarkers [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Immune function biomarkers [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]
  • Inflammatory biomarkers [ Time Frame: 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks ]

Estimated Enrollment: 60
Study Start Date: December 2015
Estimated Study Completion Date: March 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Sulforaphane

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
See under active arm description
Placebo Comparator: Placebo

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
See under placebo arm description

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

Ages Eligible for Study:   3 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02561481

Contacts
Contact: Andrew W Zimmerman, MD 508-856-3279 andrew.zimmerman@umassmemorial.org
Contact: Kanwaljit Singh, MD MPH 617-953-1480 kanwaljit.singh@umassmed.edu

Locations
United States, Massachusetts
University of Massachusetts Medical School Recruiting
Worcester, Massachusetts, United States, 01655
Contact: Andrew W Zimmerman, MD    508-856-3279    andrew.zimmerman@umassmemorial.org   
Contact: Kanwaljit Singh, MD MPH    617-953-1480    kanwaljit.singh@umassmed.edu   
Sponsors and Collaborators
University of Massachusetts, Worcester
Congressionally Directed Medical Research Programs
Johns Hopkins University
Investigators
Principal Investigator: Andrew W Zimmerman, MD University of Massachusetts, Worcester
  More Information

Responsible Party: Andrew Zimmerman, Clinical Professor of Pediatrics and Neurology, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier: NCT02561481     History of Changes
Other Study ID Numbers: H00007832
AR140087 ( Other Grant/Funding Number: Congressionally Directed Medical Research Programs )
Study First Received: September 24, 2015
Last Updated: January 10, 2017

Additional relevant MeSH terms:
Disease
Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Pathologic Processes
Neurodevelopmental Disorders
Mental Disorders
Sulforafan
Anticarcinogenic Agents
Protective Agents
Physiological Effects of Drugs
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 19, 2017