Evaluation of Transcranial Photobiomodulation in Autism Spectrum Disorder

Study Overview
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Brief Summary
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The purpose of this 8-week double-blind randomized placebo-controlled study is to assess the tolerability, safety, and efficacy of tPBM in adult patients with ASD.

Detailed Description
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by variable presentation of difficulties with socialization, reciprocal communication, and restrictive/repetitive behaviors. An increasingly higher prevalence of ASD is documented in each successive epidemiological survey and the disorder is now estimated to affect up to 2% of youth in the general population. This rise in prevalence is in part attributed to improved recognition of autism in intellectually capable populations. Currently, there exists no approved treatments for core features of ASD. Instead, available treatment interventions target other psychiatric disorders that frequently co-occur with ASD, including attention, anxiety, and mood disorders. Transcranial Photobiomodulation (tPBM) is a novel treatment approach based on application of an invisible, non-ionizing electromagnetic wave that results in metabolic modulation in tissues targeted. This intervention consists of exposing bilaterally the frontal brain to the electromagnetic wave that penetrates the skin and skull into brain tissue, is non-invasive and minimally dissipated as thermal energy. The benefits of tPBM are wavelength specific. Electromagnetic wave at 850nm is absorbed by cytochrome c oxidase, a specific chromophore in mitochondria and is associated with increased adenosine triphosphate (ATP) production through the respiratory chain. Ultimately, the increased ATP production leads to increased energy metabolism and activity for the cell, and it is hypothesized that a signaling cascade is also activated promoting cellular plasticity and cytoprotection. These properties of the tPBM have led to novel therapeutic applications in neurology. In acute ischemic stroke subjects, acute treatment with the tPBM led to significantly better outcome as compared to sham. These results were confirmed in a different cohort of stroke patients with mild to moderate severity of illness. Both studies on stroke subjects showed no significant difference in rate of adverse events, as well as serious adverse events, between the tPBM and sham treated subjects. The tPBM has also been used as a treatment of alopecia and in animal models for methanol-induced retinal toxicity. The tPBM is already widely used for non-invasive assessment of brain function, replacing functional magnetic resonance imaging (fMRI), in studies of infants and young adults, under the name of Near Infrared Spectroscopy) underscoring the relatively low risk of tPBM. The major risk of tPBM when using a laser as the light source is associated with accidental retinal exposure, when beams are projected through the lens, with increased risk of macular degeneration. Light emitting diode (LED) light does not share the same risk level as laser light sources and this clinical trial will have multiple protections to safeguard against this risk. Proposed treatment with tPBM has been previously studied in patients with Major Depressive Disorder (MDD). MDD has been associated with deficits in brain bioenergetic metabolism. In an experimental model of depression, the mitochondrial respiratory chain was found to be inhibited by chronic stress. Depressed subjects have also significantly lower production of ATP (an energy vector) in their muscle tissue and greater incidence of deletions in their mitochondrial DNA. Data from magnetic resonance spectroscopy in subjects with MDD showed that response to the augmentation of a selective serotonin reuptake inhibitor (SSRI) with triiodothyronine (a thyroid hormone) is associated with restoration of the levels of ATP in the brain. A preliminary open study in 10 depressed subjects has shown that the tPBM was safe, effective and well tolerated. More recently, efficacy and safety of tPBM was also explored in treatment of ASD with promising results and no serious adverse events. In that study, 40 participants received eight 5-min laser light applications to the base of the skull and temporal areas across 4-week period (2 applications per week). A pulsed laser of 635nm was compared to placebo (very weak LEDs) and was shown to be associated with significant improvement in ASD symptoms. Tissue penetration varies at different wavelengths, with 800-850nm range penetrating into deep tissue compared to that of 635nm. More recently, the investigators completed a prospective, 8-week open-label treatment trial of tPBM in 10 adult patients with moderate to severe level of ASD. Short-term tPBM was well tolerated and was effective in reducing symptom severity of ASD and comorbid ADHD. In addition, tPBM treatment was associated with improvements in executive functions, specifically in functional domains of cognitive flexibility and emotional control, planning and organization, response inhibition and significant improvement in overall function. Treatment with tPBM was well tolerated, and there were no serious adverse events. One subject experienced headache 8 hours after first treatment, and another patient had insomnia after the first treatment episode. Both patients recovered spontaneously and required no changes to study treatments. Current project involves a double-blind randomized clinical trial of tPBM in adult patients with ASD. The main aim of this 8-week, prospective, placebo (sham) controlled study is to evaluate the efficacy, safety, and tolerability of tPBM with near-infrared light in intellectually capable adults with ASD. Because the tPBM is a non-ionizing radiation, multiple sessions are expected to be safe. The tPBM treatment can be completed in the comfort of participants' homes, while monitoring their safety and response during scheduled visits. This clinical trial will answer whether tPBM has an effect on ASD symptoms and whether it is safe and acceptable among patients with ASD, for whom frequent visits otherwise would be prohibitive or render it inaccessible. The advantage of the tPBM treatment approach as compared to pharmacotherapy is that adherence can be easily monitored with device recordings, and the patient is not required to ingest any substance. This proposed study will contribute to answer the question of whether tPBM has an effect on ASD symptoms and whether it is acceptable in minority populations, thus justifying further studies and investments.

Official Title
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Evaluation of Transcranial Photobiomodulation in Autism Spectrum Disorder: Double-Blind, Placebo-Controlled, Randomized Clinical Study of a Novel Approach

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Device: Transcranial Photobiomodulation (tPBM)
* Device: Placebo/ Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants between 18 and 59 years of age (inclusive) Fulfills Diagnostic and Statistical Manual-5th edition diagnostic criteria for autism spectrum disorder as established by the clinical diagnostic interview. Participants with at least moderately severity of ASD symptoms as demonstrated by SRS raw score ≥ 85 and CGI-ASD severity score ≥ 4 Participants must understand the nature of the study. Participants must be deemed not to have impaired decision-making capacity and must have the capacity to provide direct informed consent. Participants must sign an Institutional Review Board-approved informed consent form before initiation of any study procedures. Participants must have a level of understanding sufficient to communicate with the investigator and study coordinator, and to cooperate with all tests and examinations required by the protocol. Participant experiencing a major psychiatric disorder will be allowed to participate in the study provided they do not meet any exclusionary criteria. Women of child-bearing potential must use a double-barrier method for birth control (e.g. condoms with spermicide) if sexually active. The subject is willing to participate in this study. Exclusion Criteria: Impaired intellectual capacity (clinically determined). Participants' intellectual capacity will be assessed during the clinical evaluation and determination will be based on intact communicative language, ability to take personal care, history of holding a job and completion of high school (or equivalency credential), and no history of intellectual disability. Participant is unable to communicate due to delay in, or total lack of, spoken language development (grossly impaired language skills) Clinically unstable psychiatric conditions or judged to be at serious safety risk to self (suicidal risk) or others (within past 30 days). Subjects currently (within past 30 days) experiencing significant symptoms of major psychiatric disorders as clinically determined. Subjects with an unstable medical condition (that requires clinical attention). Active suicidal or homicidal ideation, as determined by clinical screening. The subject has a significant skin condition at the procedure sites (i.e., hemangioma, scleroderma, psoriasis, rash, open wound or tattoo). The subject has an implant of any kind in the head (e.g. stent, clipped aneurysm, embolised arteriovenous malformation, implantable shunt - Hakim valve). Any use of light-activated drugs (photodynamic therapy) within 14 days prior to study enrollment (verteporfin - for age related macular degeneration; Aminolevulinic Acid- for actinic keratoses; Photofrin (porfimer sodium) - for esophageal cancer, non-small cell lung cancer; Levulan Kerastick (aminolevulinic acid HCl) - for actinic keratosis; 5-aminolevulinic acid (ALA)- for non-melanoma skin cancer) Current treatment with a psychotropic medication on a dose that has not been stable for at least 4 weeks prior to initiating study treatment. Investigator and his/her immediate family, defined as the investigator's spouse, parent, child, grandparent, or grandchild.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Transcranial Photobiomodulation (tPBM) Treatment<br>Transcranial Photobiomodulation--a noninvasive intervention in which near-infrared light is applied to forebrain. | Device: Transcranial Photobiomodulation (tPBM)<br>* Transcranial Photobiomodulation (tPBM) is a novel treatment approach based on application of an invisible, non-ionizing electromagnetic wave that results in metabolic modulation in tissues targeted. This intervention consists of exposing bilaterally the frontal brain to the electromagnetic wave that penetrates the skin and skull into brain tissue, is non-invasive and minimally dissipated as thermal energy. Other Names: Niraxx G1 Headband<br>|
| Sham Comparator: Placebo/ Sham Treatment<br>The sham treatment will mimic the tPBM procedure, while delivering no light. | Device: Placebo/ Sham<br>* The sham treatment will consist of applying all the procedures for the delivery of tPBM, but will not deliver light.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ASD symptoms as measured by change through study completion, on the Clinical Global Impression of Improvement of Autism Spectrum Disorder (CGI-ASD-I) | Primary outcome measure of efficacy will be change in ASD symptoms as measured by change through study completion, an average of 8 weeks, on the clinician-rated CGI-ASD-I. Responders will be defined as those who demonstrate a ≥25% change in Social Responsiveness Scale-2nd Edition total score and a score of 2 or 1 on the CGI-ASD-Improvement subscale (much or very much improved). | through study completion, an average of 8 weeks | 
| ASD symptoms as measured by change through study completion on the Social Responsiveness Scale-2nd Edition (SRS-2) | Primary outcome measure of efficacy will be change in ASD symptoms as measured by change through study completion, an average of 8 weeks, on the SRS-2. Responders will be defined as those who demonstrate a ≥25% change in SRS-2 total score and a score of 2 or 1 on the CGI-ASD-Improvement subscale (much or very much improved). | through study completion, an average of 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related changes in social cognition functions | Treatment-related changes in associated social cognition will be assessed by change in total score on Massachusetts General Hospital Social Emotional Competence Scale (MGH-SEC Scale) on which higher scores mean more severe clinical presentation | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated executive functions | Treatment-related changes in associate executive functions will be assessed by Behavior Rating Inventory of Executive Function-Adult Self Report Version (BRIEF-A) on which higher scores mean more severe clinical presentation | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated psychopathology (Attention Deficit Hyperactivity Disorder, ADHD) | Treatment-related changes in associated ADHD will be assessed by Adult ADHD Self-Report Scale (ASRS) on which higher scores mean more severe clinical presentation | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated psychopathology (Attention Deficit Hyperactivity Disorder, ADHD) | Treatment-related changes in associated ADHD will be assessed by Adult ADHD Investigator Symptom Report Scale (AISRS) on which higher scores mean more severe clinical presentation | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated psychopathology (Attention Deficit Hyperactivity Disorder, ADHD) | Treatment-related changes in associated ADHD will be assessed by Clinical Global Impression of Improvement in ADHD scale (CGI-ADHD-I) on which lower score means improvement | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated psychopathology (depression) | Treatment-related changes in associated depression will be assessed by Hamilton Depression Scale on which higher scores mean more severe clinical presentation | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated psychopathology (depression) | Treatment-related changes in associated depression will be assessed by Clinical Global Impression of Improvement in Depression scale (CGI-Depression-I) on which lower score means improvement | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated psychopathology (anxiety) | Treatment-related changes in associated depression will be assessed by Hamilton Anxiety Scale on which higher scores mean more severe clinical presentation | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated psychopathology (anxiety) | Treatment-related changes in associated depression will be assessed by Clinical Global Impression of Improvement in Anxiety scale (CGI-Anxiety-I) on which lower score means improvement | through study completion, an average of 8 weeks | 
| Treatment-related changes in associated psychopathology | Treatment-related changes in associated psychopathology will be measured by Adult Behavior Checklist (ABCL) on which higher scores mean more severe clinical presentation | through study completion, an average of 8 weeks | 
| Treatment-related changes in quality of life | Treatment-related changes in quality of life will be measured by Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) on which higher scores mean greater satisfaction and enjoyment | through study completion, an average of 8 weeks | 
| The monitoring of treatment-emergent adverse events | Safety and tolerability will be assessed by Treatment-emergent Adverse Events Log (CTAE) | through study completion, an average of 8 weeks | 
| The monitoring of treatment-emergent adverse events | Safety and tolerability will be assessed by tPBM Self-Report Questionnaire (TSRQ) on which higher scores mean more severe discomfort | through study completion, an average of 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autism, Transcranial Photobiomodulation