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| ID | Type | Description | Link |
|---|---|---|---|
| AR140087 | Other Grant/Funding Number | Congressionally Directed Medical Research Programs |
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| Name | Class |
|---|---|
| Congressionally Directed Medical Research Programs | FED |
| Johns Hopkins University | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sulforaphane | Drug | See under active arm description |
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| OACIS-I Response Rate on Aberrant Behaviors Subscale | See above in the primary outcome measure for a description of OACIS-I scale. This section describes the change from baseline of the OACIS-I subdomain of aberrant behaviors. This subdomain has a range of 1 to 7 - 1 is extremely improved from baseline, 7 is extremely worse from baseline, and 4 is no change. 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. |
| Measure | Description | Time Frame |
|---|---|---|
| NQO1: NAD(P)H:Quinone Oxidoreductase-1 | Cytoprotective enzyme regulated by nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of cellular redox homeostasis and an inhibitor of a key pro-inflammatory pathway, of which both functions are critical factors in the neuropathology of ASD. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andrew W Zimmerman, MD | University of Massachusetts, Worcester | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Massachusetts Medical School | Worcester | Massachusetts | 01655 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25313065 | Result | 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. | |
| 32242086 | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. Sulforaphane: See under active arm description |
| FG001 | 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. Placebo: See under placebo arm description |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pilot Trial |
| |||||||||||||
| Main Trial - Double Blind Phase |
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| Main Trial - Open Label Phase |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. Sulforaphane: See under active arm description |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Patients started dropping out at subsequent visits so the number analyzed at latter visits is less | Posted | Mean | Standard Deviation | score on a scale | 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks |
The pilot study took place over 2 weeks for each of 10 participants. The main study took place over 2 years, 6 months; 1/1/16 - 6/30/18 for 45 participants, each of whom was assessed from screening (time 0), 7, 15, 22 and up to 36 weeks for the final visit. Participants in the pilot study were followed for adverse events during regular clinical visits for at least 12 months after the study and none were reported.
Adverse event reporting followed clinicaltrials.gov Definitions.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. Sulforaphane: See under active arm description |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hashimoto thyroiditis | Endocrine disorders | Systematic Assessment | Participant was found to have elevated TSH. He was withdrawn from the study and was taking placebos. He was treated and followed by a pediatric endocrinologist, who determined that this was unrelated to his participation in the study. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| insomnia | Nervous system disorders | Systematic Assessment | sleep disturbance |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Andrew Zimmerman, MD | Univ of Massachusetts Medical School | 4109350488 | andrew.zimmerman@umassmemorial.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 3, 2019 | Feb 10, 2020 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jul 3, 2019 | Feb 10, 2020 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000067877 | Autism Spectrum Disorder |
| ID | Term |
|---|---|
| D002659 | Child Development Disorders, Pervasive |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C016766 | sulforaphane |
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| Drug |
See under placebo arm description |
|
| 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks |
| OACIS-I Response Rate on Social Communication Subscale | See above in the primary outcome measure for a description of OACIS-I scale. This section describes the change from baseline of the OACIS-I subdomain of social communication. This subdomain has a range of 1 to 7 - 1 is extremely improved from baseline, 7 is extremely worse from baseline, and 4 is no change. 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 |
| Change in Total Aberrant Behavior Checklist Score From Baseline | Aberrant Behavior Checklist (ABC) is a 58 item scale that primarily evaluates how aberrant or abnormal a patient's daily behaviors are. The items evaluate behaviors as they pertain to irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech. Each item is scored on a scale of 0 to 3, with 0 being better outcome and 3 being worse outcome. The score from each item is added up to calculate a total score. This outcome describes change in total ABC score from baseline at each follow up visit. The scores from all items are added to calculate a total score (0 to 174). This outcome describes change in total ABC score from baseline at each follow up visit. | 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks |
| Change in Total SRS-2 Score From Baseline | The Social Responsiveness Scale-2 (SRS-2) is a 65-item scale that measures total scores as well as subscales: four social behaviors (awareness, cognition, communication and motivation) and autistic mannerisms. Each item is rated from 1 to 4 (not true to almost always true) on worksheets that are blinded to the rater with respect to values. Total and subscale scores are calculated as raw scores and can be converted to T-scores. Raw scores (range 0-180) are reported here (unadjusted for general population, since all children had ASD). Higher or lower values at follow up visits compared to baseline indicated worsening or improvement, respectively. | 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks |
| Dithiocarbamate Plasma Concentration Detected by Cyclocondensation at Each Visit | Sulforaphane (and other isothiocyanates, ITC) are conjugated by glutathione (GSH) which then undergoes further enzymatic modifications to give rise sequentially to the cysteinylglycine-, cysteine- and N-acetylcysteine-ITC conjugates, all of which are dithiocarbamates (DTC) and are detected in the cyclocondensation reaction-HPLC assay. | Week 0, Week 7, Week 15, Week 22, Week 30, Week 36 |
| Comparison of Free Reduced Glutathione (GSH), Total GSH, Oxidized Glutathione (GSSG) at Week 0 and 15 | F-statistic calculated by comparison of Free Reduced GSH, Total GSH and oxidized Glutathione (GSSG) of Week 15 to Week 0. | Week 0 and Week 15 |
| Free GSH:GSSG and Total GSH:GSSG Ratios at Week 15 | Ratios of free GSH:GSSG and total GSH:GSSG were calculated by obtaining ratios of f-statistic scores from baseline to week 15 between free reduced GSH and GSSG and between total GSH and GSSG. | Week 15 |
| Week 0, Week 15, Week 30 |
| xCT | xCT (SLC7A11): Cystine/glutamate antiporter encoded by the SLC7A11 gene.Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | Week 0, Week 15, Week 30 |
| HO-1 (Heme Oxygenase 1) | HO-1 (heme oxygenase 1): an essential and Nrf2-dependent enzyme in heme catabolism. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | Week 0, Week 15, Week 30 |
| HSP70 | HSP70 (Heat shock protein 70) was examined because it is upregulated by SF in vitro. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | Week 0, Week 15, Week 30 |
| HSP27 | HSP27 (Heat shock protein 27) was examined because it is upregulated by SF in vitro. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | Week 0, Week 15, Week 30. |
| IL-6 | IL-6 (interleukin 6) cytokine gene expression, a nuclear factor-kappa B - regulated inflammatory biomarker. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | Week 0, Week 15, Week 30 |
| IL-1β | IL-1β: Interleukin-1 beta cytokine gene expression, a nuclear factor-kappa B - regulated inflammatory biomarker. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | Week 0, Week 15, Week 30 |
| Cox-2 | Cox-2 (cyclooxygenase-2): a nuclear factor-kappa B - regulated inflammatory biomarker. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | Week 0, Week 15, Week 30 |
| TNF-α | TNF-α (Tumor necrosis factor alpha), a cytokine as inflammatory biomarker. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | Week 0, Week 15, Week 30 |
| 34034808 | Derived | 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. |
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| BG001 | 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. Placebo: See under placebo arm description |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | 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. Sulforaphane: See under active arm description |
| OG001 | 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. Placebo: See under placebo arm description |
|
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| Secondary | OACIS-I Response Rate on Aberrant Behaviors Subscale | See above in the primary outcome measure for a description of OACIS-I scale. This section describes the change from baseline of the OACIS-I subdomain of aberrant behaviors. This subdomain has a range of 1 to 7 - 1 is extremely improved from baseline, 7 is extremely worse from baseline, and 4 is no change. 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. | Patients started dropping out at subsequent visits so the number analyzed at latter visits is less | Posted | Mean | Standard Deviation | score on a scale | 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks |
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| Secondary | OACIS-I Response Rate on Social Communication Subscale | See above in the primary outcome measure for a description of OACIS-I scale. This section describes the change from baseline of the OACIS-I subdomain of social communication. This subdomain has a range of 1 to 7 - 1 is extremely improved from baseline, 7 is extremely worse from baseline, and 4 is no change. 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. | Patients started dropping out at subsequent visits so the number analyzed at latter visits is less | Posted | Mean | Standard Deviation | score on a scale | 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks |
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| Secondary | Change in Total Aberrant Behavior Checklist Score From Baseline | Aberrant Behavior Checklist (ABC) is a 58 item scale that primarily evaluates how aberrant or abnormal a patient's daily behaviors are. The items evaluate behaviors as they pertain to irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech. Each item is scored on a scale of 0 to 3, with 0 being better outcome and 3 being worse outcome. The score from each item is added up to calculate a total score. This outcome describes change in total ABC score from baseline at each follow up visit. The scores from all items are added to calculate a total score (0 to 174). This outcome describes change in total ABC score from baseline at each follow up visit. | Patients started dropping out at subsequent visits so the number analyzed at later visits is less | Posted | Mean | Standard Deviation | score on a scale | 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks |
|
|
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| Secondary | Change in Total SRS-2 Score From Baseline | The Social Responsiveness Scale-2 (SRS-2) is a 65-item scale that measures total scores as well as subscales: four social behaviors (awareness, cognition, communication and motivation) and autistic mannerisms. Each item is rated from 1 to 4 (not true to almost always true) on worksheets that are blinded to the rater with respect to values. Total and subscale scores are calculated as raw scores and can be converted to T-scores. Raw scores (range 0-180) are reported here (unadjusted for general population, since all children had ASD). Higher or lower values at follow up visits compared to baseline indicated worsening or improvement, respectively. | Patients dropped out (or families did not return forms) at subsequent visits so the number analyzed at later visits is less. | Posted | Mean | Standard Deviation | score on a scale | 7 weeks, 15 weeks, 22 weeks, 30 weeks, 36 weeks |
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| Secondary | Dithiocarbamate Plasma Concentration Detected by Cyclocondensation at Each Visit | Sulforaphane (and other isothiocyanates, ITC) are conjugated by glutathione (GSH) which then undergoes further enzymatic modifications to give rise sequentially to the cysteinylglycine-, cysteine- and N-acetylcysteine-ITC conjugates, all of which are dithiocarbamates (DTC) and are detected in the cyclocondensation reaction-HPLC assay. | Number analyzed varied due to participants who dropped out, their blood samples could not be obtained, or data could not be obtained from the assay. | Posted | Mean | Standard Deviation | nmol DTC (Dithiocarbamates)/ml | Week 0, Week 7, Week 15, Week 22, Week 30, Week 36 |
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| Secondary | Comparison of Free Reduced Glutathione (GSH), Total GSH, Oxidized Glutathione (GSSG) at Week 0 and 15 | F-statistic calculated by comparison of Free Reduced GSH, Total GSH and oxidized Glutathione (GSSG) of Week 15 to Week 0. | Posted | Number | F-statistic | Week 0 and Week 15 |
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| Secondary | Free GSH:GSSG and Total GSH:GSSG Ratios at Week 15 | Ratios of free GSH:GSSG and total GSH:GSSG were calculated by obtaining ratios of f-statistic scores from baseline to week 15 between free reduced GSH and GSSG and between total GSH and GSSG. | Posted | Number | F-statistic | Week 15 |
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| Other Pre-specified | NQO1: NAD(P)H:Quinone Oxidoreductase-1 | Cytoprotective enzyme regulated by nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of cellular redox homeostasis and an inhibitor of a key pro-inflammatory pathway, of which both functions are critical factors in the neuropathology of ASD. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure. | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30 |
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| Other Pre-specified | xCT | xCT (SLC7A11): Cystine/glutamate antiporter encoded by the SLC7A11 gene.Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure. | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30 |
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| Other Pre-specified | HO-1 (Heme Oxygenase 1) | HO-1 (heme oxygenase 1): an essential and Nrf2-dependent enzyme in heme catabolism. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30 |
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| Other Pre-specified | HSP70 | HSP70 (Heat shock protein 70) was examined because it is upregulated by SF in vitro. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure. | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30 |
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| Other Pre-specified | HSP27 | HSP27 (Heat shock protein 27) was examined because it is upregulated by SF in vitro. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30. |
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| Other Pre-specified | IL-6 | IL-6 (interleukin 6) cytokine gene expression, a nuclear factor-kappa B - regulated inflammatory biomarker. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure. | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30 |
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| Other Pre-specified | IL-1β | IL-1β: Interleukin-1 beta cytokine gene expression, a nuclear factor-kappa B - regulated inflammatory biomarker. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure. | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30 |
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| Other Pre-specified | Cox-2 | Cox-2 (cyclooxygenase-2): a nuclear factor-kappa B - regulated inflammatory biomarker. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure. | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30 |
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| Other Pre-specified | TNF-α | TNF-α (Tumor necrosis factor alpha), a cytokine as inflammatory biomarker. Total cellular RNA was isolated from peripheral blood mononuclear cells (PBMCs) and complementary DNAs (cDNA) were synthesized. Quantitative real-time PCR analysis was performed using the Applied Biosystems QuantStudio™ 3 Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA). Relative mRNA expression was normalized to GAPDH. Gene expression was calculated using the comparative 2-ΔΔCT method. | N varies due to missing data, variable clinic visits or assay failure | Posted | Mean | Standard Deviation | log fold change | Week 0, Week 15, Week 30 |
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| 0 |
| 32 |
| 0 |
| 32 |
| 8 |
| 32 |
| EG001 | 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. Placebo: See under placebo arm description | 0 | 23 | 1 | 23 | 0 | 23 |
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| irritability | Nervous system disorders | Systematic Assessment |
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| taste/smell | General disorders | Systematic Assessment | unable to tolerate taste/smell of tablets |
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| gastrointestinal upset | Gastrointestinal disorders | Systematic Assessment |
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Not provided
Not provided
Not provided
| 15 weeks |
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| 22 weeks |
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| 30 weeks |
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| 36 weeks |
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| 15 weeks |
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| 22 weeks |
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| 30 weeks |
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| 36 weeks |
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| 15 weeks |
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| 22 weeks |
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| 30 weeks |
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| 36 weeks |
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| 15 weeks |
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| 30 weeks |
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| 36 weeks |
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