28-Day Daily-dose Crossover Study of the Safety and Tolerability of SB-121 (Lactobacillus Reuteri With Sephadex® and Maltose) in Subjects, Ages 15 to 45 Years, Diagnosed With Autistic Disorder

Study Overview
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Brief Summary
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SB-121 is being developed for use in the treatment of autistic disorder (AD). This study is a multiple-dose, randomized, double-blind, placebo-controlled, cross-over single-site Phase I study. The primary objective is to evaluate the safety and tolerability of multiple doses of SB-121 in subjects ages 15 to 45 years with AD. Additionally, multiple measures of AD, as well as mechanistic biomarkers, will be assessed in order to inform later stage trials.

Official Title
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Randomized, Double-blind, Placebo-controlled, 28-Day Daily-dose Crossover Study of the Safety and Tolerability of SB-121 (Lactobacillus Reuteri With Sephadex® and Maltose) in Subjects, Ages 15 to 45 Years, Diagnosed With Autistic Disorder

Conditions
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Autistic Disorder

Intervention / Treatment
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* Drug: SB-121
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject/parent (or authorized designee) has provided written informed consent for the study. Subject is ≥15 and ≤45 years of age at the time of enrollment. Diagnosis of autistic disorder (AD) as confirmed by the gold standard clinical interview using Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria and administration of the Autism Diagnostic Observation Schedule-2. Subject, if female and of childbearing potential, is not lactating or pregnant. Subject, if female, is either not of childbearing potential or is practicing an acceptable effective method of birth control. Subject is willing to comply with all study requirements (including the requirements for stool sampling and biobanking) and to return to the study facility for the follow-up evaluations, as required. Exclusion Criteria: Subject has known allergy or significant adverse reaction to L reuteri, Sephadex®, maltose, or related compounds. Subject has previously had GI surgery, intestinal obstruction, Clostridium difficile infection or diverticulitis. Subject has travelled outside of the USA in the 30 days prior to screening. Subject has had a diarrheal illness in 30 days prior to screening. Subject currently has a fever or active/uncontrolled gastrointestinal (GI) symptoms (e.g., nausea, vomiting, diarrhea, constipation, abdominal distention, abdominal pain/cramps, flatulence) or has had these within 14 days prior to screening. If the GI symptoms are stable, in the opinion of the investigator, the subject can be enrolled. Subject has any immunological/autoimmune disorder including, but not limited to, systemic lupus erythematosis, rheumatoid arthritis, Sjögren's syndrome, inflammatory bowel disease, or immunoglobulin-deficiency disorder, that would increase the risk to the subject or interfere with the evaluation of SB-121. Subject has a documented history of human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C Subject has implanted prosthetic devices including prosthetic heart valves. Subject has taken, or is taking, any of the following prohibited medications: A proton pump inhibitor within 2 weeks prior to screening Use of supplemental probiotics within 2 weeks prior to screening except for yogurt Current use of immunosuppressive medications, including corticosteroids Treatment with monoclonal antibodies within 4 weeks prior to screening Systemic antibiotics within 2 weeks prior to screening Subject has diabetes mellitus or is prediabetic. Subject has received any IP (or investigational device) within 30 days prior to screening. Subject has any of the following laboratory test results at Screening: An absolute neutrophil count of <1.5 × 10^9/L alanine aminotransferase or aspartate aminotransferase >1.5 × upper limit normal (ULN), total bilirubin >1.5 × ULN (subjects with known Gilbert's Syndrome can be included) serum creatinine >1.5 × ULN any other abnormal laboratory test that is clinically significant in the judgment of the investigator. Subject has an unstable medical condition or is otherwise considered unreliable or incapable, in the opinion of the investigator, of complying with the requirements of the protocol. Subject tests positive for drugs of abuse in a urine drug screen at screening. Subject has a history of alcohol abuse.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 45 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SB-121<br>One dose of SB-121 daily for 28 days according to the treatment group to which they are allocated. Administration: Oral | Drug: SB-121<br>* SB-121 is a formulation of L. reuteri<br>|
| Placebo Comparator: Placebo<br>One dose of placebo daily for 28 days according to the treatment group to which they are allocated. Administration: Oral | Drug: Placebo<br>* Placebo oral formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse event of special interest (AESIs), and adverse events (AEs) leading to discontinuation from the study |  | Approximately 98 days | 
| Incidence of presence of L. reuteri and Sephadex® microspheres in the stool |  | Period 1: Days 1 (pre-dose), 28 and 35; Period 2: Days 28 and 42 (period = 28 days and 14 days wash-out) | 
| Incidence of symptomatic bacteremia with positive L. reuteri identification |  | Approximately 98 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Clinical Global Impressions Severity (CGI-S) Subscales | The clinician-rated CGI-S is rated on a 7 point Likert scale from minimally to the most severely affected, anchored to core symptoms of autistic disorder (AD). | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Clinical Global Impressions Improvement (CGI-I) Subscales | Clinical response to drug exposure will be assessed with the clinician-rated CGI-I (Guy 1976). The CGI-I is a 7-point scale designed to measure symptomatic change as compared to CGI-S at baseline. The CGI-I assessment will focus on the core symptoms of AD. CGI-I is a gold standard measure of potential change with treatment in placebo-controlled pharmacotherapy trials in AD. | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Vineland Adaptive Behavior Scales (3rd edition) | The Vineland(TM)-3 measures communication, daily living skills and socialization skills. The Vineland(TM)-3 will be administered to a subject's reliable caregiver in this study, during which the rater from the study team will ask the caregiver open ended questions relating to the subject's activities and behavior. | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Aberrant Behavior Checklist (ABC) | The ABC is an informant-based questionnaire consisting of 58 items subdivided amongst 5 scales: irritability, lethargy and social withdrawal, stereotypic behavior, hyperactivity/non-compliance, and inappropriate speech (Aman 1985). A score for each item ranges from 0 indicating no problem to 3 indicating severe problem. Scale scores are calculated by summing the items within that scale. Higher scores indicate greater impairment. | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Woodcock Johnson 3rd Edition (WJ-III) | The Spatial Relations and Auditory Attention subtests of the WJ-III will be administered. The Spatial Relations subtest will assess the visual spatial thinking domain with a task that requires the identification of parts needed to form a complete shape. Responses can be oral or motoric (pointing). The Auditory Attention subtest will assess auditory processing (speech/sound discrimination) requiring the identification of orally presented words amid increasingly intense background noise. Examinees point to a picture of the word presented. | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1(pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Repeatable Battery for Assessment of Neuropsychological Status (RBANS) | The RBANS is a neuropsychological battery for persons with neurological disorders. The RBANS covers five domains including Immediate Memory, Language, Attention, Visuospatial/Constructional, and Delayed Memory (Randolph 1998). | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Test of Attentional Performance for Children (KiTap) | The KiTap is an automated computer based assessment of attentional performance developed and normed for the pediatric population. Despite its development in pediatrics, the KiTap is well suited for use in developmental disabilities across all age ranges and has been normed specifically in Fragile X Syndrome (FXS) in adults and youth (Knox 2012). The task presents an enchanted castle animation and investigates performance in a number of areas including Alertness, Vigilance, Visual Scanning, Distractibility, Attention, Flexibility, and Sustained Attention. | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Neurophysiology Measures: electroencephalogram (EEG) resting state | EEG resting state task: Participants will complete a 5-minute resting state EEG protocol. Participants will watch a standardized silent video during data collection to facilitate cooperation and ensure wakefulness. Resting state EEG data will be analyzed across the following frequency bands: delta (1-3 Hz); theta (4-7 Hz); lower alpha (8-10 Hz); upper alpha (10-12 Hz); gamma (30-80 Hz). | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Neurophysiology Measures: auditory habituation | Auditory habituation Evoked Response Potential (ERP): ERPs will be recorded during passive listening. | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Neurophysiology Measures: chirp modulated sweep auditory evoked response | Subjects will passively listen to auditory stimuli consisting of an amplitude modulated chirps. | Period 1: Days 1 (pre-dose) and 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in eye tracking | Infrared eye tracking will be used as a measure of eye gaze and pupillary reactivity in response to visual processing of human faces and of social scenes at prior to the first dose of investigational product (IP) (baseline) and following four weeks of chronic dosing in each treatment period. | Period 1: Day 1 (pre-dose) and Day 28; Period 2: Day 1 (pre-dose) and Day 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Biomarkers: plasma oxytocin |  | Day -28 to Day 0, Period 1: Day 28; Period 2: Days 1 and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Biomarkers: plasma vasopressin |  | Day -28 to Day 0, Period 1: Day 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Biomarkers: serum high-sensitivity C-reactive protein (hs-CRP) |  | Day -28 to Day 0, Period 1: Day 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Biomarkers: tumor necrosis factor-α |  | Day -28 to Day 0, Period 1: Day 28; Period 2: Days 1 (pre-dose) and 28 (period = 28 days and 14 days wash-out) | 
| Change from baseline in Biomarkers: stool biomarkers |  | Period 1: Days 1 (pre-dose), 28 and 35; Period 2: Days 28 and 35 (period = 28 days and 14 days wash-out) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lactobacillus reuteri, autistic disorder, microbiome