Probiotics and Oxytocin Nasal Spray on Social Behaviors of Autism Spectrum Disorder (ASD) Children

The Effects of Probiotics and Oxytocin Nasal Spray on Social Behaviors of ASD Children- A Pilot Study

Because oral probiotics reported to potentially induce endogenous Oxytocin, and Oxytocin has been reported to improve social behaviors, the investigators will conduct a pilot trial to compare the effects of probiotics and Oxytocin on social behavioral changes in ASD children. Additionally, the investigators will check oxytocin levels, and perform brain fMRI in some subjects, in order to determine which treatment is more efficient, sustainable, and practical, and whether both treatments in combination are better than either treatment alone. If the trial is conclusive, the investigators will conduct a trial in large scale to understand more the mechanism of ASD behaviors and corresponding effective interventions.

Study Overview

• Status: Completed
• Conditions: Autism Spectrum Disorder
• Intervention / Treatment: Drug: intranasal oxytocin; Dietary supplement: oral probiotics; Dietary supplement: oral placebo

Detailed Description

This study description is in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines that are published for the evaluation of randomized controlled trials. This clinical trial is a randomized, double-blind placebo controlled study. Subjects will be randomized to 2 groups:

Phase 1: a. oral placebo, and b. oral probiotics; Phase 2: a. intranasal Oxytocin(OXT) + oral placebo, and b. intranasal OXT + oral probiotics

The treatment will proceed for a total of 28 weeks. In the first phase (16 weeks), all the patients will be randomly and proportionally divided into two groups: Group A (30 subjects) receives oral probiotics while Group B (30 subjects) receives an oral placebo. In the second phase, subjects in Group A and Group B will continue their respective oral probiotics or placebo administration as in Phase 1. In addition, both groups will be simultaneously administered with intranasal OXT spray.

Testing will be performed 3 times total (before, during, and after treatment). The tests include behavioral surveys, cognitive tests, clinical autonomic tests, and blood tests for oxytocin levels. Investigators plan to select up to 10 subjects from each group to conduct a series of MRI studies at week 0, week 16 and week 28.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age between 3-25years old;
2. Pre-existing diagnosis of autism; subjects may be asked to provide documentation confirming diagnosis by DSM-V-TR criteria, ADOS, ADI-R, or other clinical forms
3. A care provider who can reliably bring the participant to study visits;
4. No planned changes in medications or psychosocial interventions during trial (stable medications within the last 2 weeks);
5. Willingness to provide blood samples

Exclusion Criteria:

1. Pregnant woman (before or during the study).
2. Comorbidity of other neurological and/or psychiatric disorders such as unstable seizures, schizophrenia, schizoaffective disorder, bipolar disorders or history of substance abuse.
3. Psychotropic medication use
4. Subjects with active cardiovascular disease that is not controlled by medication.
5. Oxytocin, antibiotic, or probiotic use within the last 30 days.
6. Regular nasal obstruction or nosebleeds
7. Significant hearing, vision, or motor impairments
8. Habitual consumption of large volumes of water
9. Started taking new medications within the last 2 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: oral probiotics and oxytocin spray; Subjects will receive oral probiotics, 2 pills per day, for 28 weeks. For the last 12 weeks, subjects will also receive intranasal oxytocin spray at the following dose: 4 IU in week 1, 8 IU in week 2, 16 IU in week 3, and 24 IU in weeks 4-12.	Drug: intranasal oxytocin; 4-24 IU per day, dosage gradually increases; Other Names: Novartis Syntocinon; Dietary supplement: oral probiotics; 200 million cfu per day
Placebo Comparator: oral placebo and oxytocin spray; Subjects will receive oral placebo, 2 pills per day, for 28 weeks. For the last 12 weeks, subjects will also receive intranasal oxytocin spray at the following dose: 4 IU in week 1, 8 IU in week 2, 16 IU in week 3, and 24 IU in weeks 4-12.	Drug: intranasal oxytocin; 4-24 IU per day, dosage gradually increases; Other Names: Novartis Syntocinon; Dietary supplement: oral placebo; 2 pills per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Social Responsiveness Scale (SRS) Edition 2	social communication and behavior - The scoring is based on T-score which is based on the sum of responses as follows (76 to higher - severe, 66 to 75- moderate deficiencies, 60 to 65 - mild deficiencies, 59 and below is not clinically significant for ASD).	change from baseline at 0, 16, and 28 weeks
Aberrant Behavior Checklist (ABC) Edition 2	social behavior test - The total score is calculated based on 5 sub-scales (Irritability, Social Withdrawal, Stereotypic Behavior, Hyperactive/Noncompliance, and Inappropriate Speech). There are 58 questions that are scored on a 0-3 scale 0 -"not at all a problem", 1- "the behavior is a problem but slight in degree", 2- "the problem is moderately serious" and 3- "the problem is severe in degree". Based on this sub-scores are calculated and added to get the total score.	change from baseline at 0, 16, and 28 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuroinflammation and Oxytocin levels	neuroendocrine biomarker measured in blood ( Melatonin, Oxytocin, Tumour Necrosis Factor alpha, testosterone and Interleukin 6)	change from baseline at 0, 16, and 28 weeks
structural MRI	The software Freesurfer will be used to calculate volume of brain regions and diffusion parameters (e.g. fractional anisotropy and mean diffusivity) from structural T1 and diffusion tensor images respectively. T-tests will be applied for group comparisons.	change from baseline at 0, 16, and 28 weeks
Functional MRI (resting state)	Correlation analysis will be used to calculate the connectivity across different brain regions. T-tests will be used for group comparisons.	change from baseline at 0, 16, and 28 weeks
Functional MRI (task based)	General linear modeling will be used to calculate brain responses to the tasks. T-tests will be used for group comparisons.	change from baseline at 0, 16, and 28 weeks
Autonomic indices 1	Blood volume pulse	change from baseline at 0, 16, and 28 weeks
Autonomic indices 2	heart rate	change from baseline at 0, 16, and 28 weeks
Autonomic indices 3	peripheral skin temperature	change from baseline at 0, 16, and 28 weeks
Autonomic indices 4	skin electrodermal activity	change from baseline at 0, 16, and 28 weeks
Autonomic indices 5	blood oxygen saturation	change from baseline at 0, 16, and 28 weeks
Microbiome	16s metagenomic sequencing of the microbiome	change from baseline at 0, 16, and 28 weeks
Eye tracking and Behavioral task (joint attention)	joint attention - Conduct T-tests and calculate P values for total and average fixation values for each area of interest	change from baseline at 0, 16, and 28 weeks
Eye tracking and behavioral task (emotion response)	emotion response - The accuracy and reaction time will be calculated for each time point. Then an ANOVA will be used to compare the results.	change from baseline at 0, 16, and 28 weeks
Eye tracking and behavioral task (eye behavior)	eye behavior - Conduct T-tests and calculate P values for total and average fixation values for each area of interest	change from baseline at 0, 16, and 28 weeks

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Xue-Jun Kong, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Sherman HT, Liu K, Kwong K, Chan ST, Li AC, Kong XJ. Carbon monoxide (CO) correlates with symptom severity, autoimmunity, and responses to probiotics treatment in a cohort of children with autism spectrum disorder (ASD): a post-hoc analysis of a randomized controlled trial. BMC Psychiatry. 2022 Aug 8;22(1):536. doi: 10.1186/s12888-022-04151-3.
• Kong XJ, Liu J, Li J, Kwong K, Koh M, Sukijthamapan P, Guo JJ, Sun ZJ, Song Y. Probiotics and oxytocin nasal spray as neuro-social-behavioral interventions for patients with autism spectrum disorders: a pilot randomized controlled trial protocol. Pilot Feasibility Stud. 2020 Feb 12;6:20. doi: 10.1186/s40814-020-0557-8. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2018
• Primary Completion (Actual): October 2, 2019
• Study Completion (Actual): October 2, 2019

Study Registration Dates

• First Submitted: October 31, 2017
• First Submitted That Met QC Criteria: November 7, 2017
• First Posted (Actual): November 8, 2017

Study Record Updates

• Last Update Posted (Actual): March 4, 2020
• Last Update Submitted That Met QC Criteria: March 3, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Probiotics, Oxytocin
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Physiological Effects of Drugs; Reproductive Control Agents; Oxytocics; Oxytocin
• Other Study ID Numbers: 2017P001667

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no plan to share data with researchers not involved in this study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes