Probiotics for Quality of Life in Autism Spectrum Disorders

Status

Completed

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02903030

Enrollment

Registered

2016-09-16

Start date

2016-08-31

Completion date

2017-12-01

Last updated

2020-02-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Anxiety, Autism Spectrum Disorders

Keywords

Gastrointestinal Microbiome

Brief summary

A randomized pilot trial of a probiotic for quality of life in autism spectrum disorder (ASD), targeting gastrointestinal (GI) symptoms.

Detailed description

The physical and mental/emotional health of people with autism spectrum disorder (ASD) are closely connected. The emerging data on immune abnormalities and gut microbiome differences, and interactions of the genome with these suggest a possible etiological link between physical and mental dysfunction, especially the gastrointestinal (GI) dysfunction and severe anxiety that many individuals with ASD manifest. The investigators have preliminary clinical evidence that children with ASD & GI symptoms differ in microbiome composition and function from neurotypical children with GI symptoms. The investigators hypothesize that altered host-microbial signals, which include altered fecal neurotransmitter gamma-aminobutyric acid (GABA) levels contribute towards anxiety and sensory over-responsivity in ASD. Our preliminary findings also show that probiotic Visbiome Extra Strength, improves GI and pain symptoms, correlating with altered gut microbiome composition and related metabolites (the macrobiome). The proposed crossover trial will explore the possibilities of this new appreciation of the microbiome-mental/physical function connection for ASD, GI dysfunction, and anxiety. If altering the gut microbiome results in better GI and emotional function, it could improve the quality of life for children with ASD and their parents. A pilot trial with 12 children with ASD will test feasibility for a proposed three-site crossover randomized clinical trial (RCT) of probiotics (beneficial bacteria including Lactobacilli & Bifidobacteria) in 60 children 3-12 years old with ASD, GI dysfunction, & anxiety. In a balanced crossover children will be randomized 1;1 to Visbiome or placebo first, 8 weeks per condition with 3 weeks washout between. The investigators have access to significant fecal microbiome and metabolome data from NIH-funded Human Microbiome Projects (HMP) on similar-age healthy and irritable-bowel children, with and without ASD. These will help leverage our understanding of macrobiome changes that correlate with functional improvement of GI and abdominal pain symptoms. Pilot study efficiency will also benefit from those HMPs having already collected and analyzed baseline stools for some children with ASD, thus saving significant costs for baseline stool analyses for the pilot.

Interventions

DRUGMaltose (placebo)

Maltose with a trace amount of silicon dioxide

DRUGVisbiome Extra Strength

It is a mix of 8 strains of beneficial bacteria that should improve gut flora, improving GI function and hopefully anxiety

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

3 Years to 12 Years

Healthy volunteers

Inclusion criteria

1. have DSM-5 ASD on clinical evaluation by a doctoral-level diagnostician, confirmed by Autism Diagnostic Interview-Revised or Autism Diagnostic Observation Schedule; 2. be between 3 and 12 years old; 3. have \>2 mo. abdominal pain, constipation, diarrhea, and/or vomiting, with an item-mean score \>2 on at least one scale of the GI module of the PedsQL scale; 4. have clinical anxiety symptoms with an item mean of \>1.0 (0-3 scale) on the new Autism Anxiety Scale. Participants will be recruited from minority, poor, inner city, or rural populations.

Exclusion criteria

1. Antibiotics in 2 months prior to enrolling; 2. Prior bowel surgery; 3. Chronic serious medical condition (e.g., diabetes); 4. Weight or height \< 3rd %ile for age; 5. Chronic anti-inflammatory use within 2 months prior to enrolling; 6. History of inflammatory bowel disease, Celiac disease, or eosinophilic disorders (e.g., eosinophilic esophagitis); 7. Already taking probiotics within the previous 6 months.

Design outcomes

Primary

Measure	Time frame	Description
Change in Gastrointestinal (GI) Module of the Pediatric Quality of Life Inventory (PedsQL) at From Baseline at Week 8	Baseline and Week 8 of Both the First and Second Intervention	A 74-item survey with 14 scales. Report forms for specific age ranges assess the parent's perception of the child's GI function and/or symptoms during the last month on a 5-point scale from 0 (never a problem) to 4 (almost always a problem). Items are reverse-scored and transformed to a 0-100 scale so lower scores reflect worse GI dysfunction. Response choices are in Likert-scale format ranging from 0 to 4 (0=Never, 1=Almost Never, 2=Sometimes, 3=Often, 4=Almost Always).

Secondary

Measure	Time frame	Description
Change in Parent Anxiety Checklist--ASD From Baseline at Week 8	Baseline and Week 8 of Both the First and Second Intervention	A 25-item single-factor scale measure of emotional stability/anxiety. Higher scores are worse for PRAS-ASD subscale, hence a negative estimate means more improvement with the probiotics compared to control. Scores range from 0-75.
Change in The Aberrant Behavior Checklist (ABC) From Baseline at Week 8	Baseline and Week 8 of Both the First and Second Intervention	The ABC is a 58-item parent rating on a 0-3 scale with five subscales: * Irritability (includes agitation, aggression, and self-injury, 15 items) with range of scores from 0-45 * Social Withdrawal (16 items) with range of scores from 0-48 * Stereotypies (7 items) with range of scores from 0-21 * Hyperactivity (16 items) with range of scores from 0-48 * Inappropriate Speech (4 items) with range of scores from 0-12. Higher scores are worse for the ABC subscale, hence a negative estimate means more improvement with the probiotics compared to control.
Change in Target Symptom Rating From Baseline at Week 8	Baseline and Week 8 of Both the First and Second Intervention	Parents are asked to name the 2 problems of most concern to them at baseline; a clinician helps the parent quantify and describe the problem (frequency, duration, severity, interference with daily life) at baseline. At subsequent visits the clinician reminds the parent of the previous description and helps them again quantify/describe the current state. A panel of blind clinicians reviews the descriptions and rates each on a 9-point scale relative to baseline, from remission (0) to disastrously worse (9), with 5=no change. These ratings are averaged, capturing the issues of most concern to parents across families. For purposes of this study, one of the 2 problems will be required to pertain to GI function, and will be analyzed separately as well as being averaged into the overall symptom rating.
Children's Sleep Habits Questionnaire (CSHQ) at Week 8	Week 8 of Both the First and Second Intervention	It includes 33 items rated retrospectively over the previous week by parents yielding a total score and eight subscales. Eight subscales include: (1) bedtime resistance (2) sleep onset latency, (3) sleep duration, (4) anxiety around sleep, (5) night awakenings, (6) sleep disordered breathing, (7) parasomnias and (8) morning waking/daytime sleepiness.Total score (summed) range of 0-99. A higher score is a better outcome for this measure.
Change in The Parenting Stress Index Short Form (PSI)	Baseline and Week 8 of Both the First and Second Intervention	The PSI is used to evaluate the degree of stress in the parent-child relationship. The Short Form has 36 items from the full length PSI, rated on a 5-point scale from 1 = strongly disagree, to 5 = strongly agree. It is completed in 10-15 minutes. The PSI may be used for parents of children up to 12 years. It yields a Total Score and three domain scores. This will detect effect on parental stress and QOL. Higher scores (ranging from 0-180) are worse for PSI, hence a negative estimate means more improvement with the probiotics compared to control.
Change in Social Responsiveness Scale (SRS) From Baseline at Week 8	Baseline and Week 8 of Both the First and Second Intervention	This 65-item rating scale measures the severity of autism spectrum symptoms as they occur in natural social settings. The SRS provides a clear picture of a child's social impairments, assessing social awareness, social information processing, capacity for reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and traits. It is appropriate for use with children from 4 to 18 years of age and will detect changes in core ASD symptoms. A higher score in this scale represents worse symptoms with raw scores summed and generated t-scores ranging from 0-110.

Countries

United States

Participant flow

Recruitment details

13 participants were screened and randomized to be in the study at the OSU Wexner Medical Center, Nisonger Center in 2016.

Pre-assignment details

13 patients were randomized to order, but 3 dropped out because of distance and transportation without providing any follow-up data, leaving 10 who progressed through to study completion. (77% retention rate)

Participants by arm

Arm	Count
Visbiome, Then Placebo Participants were randomly assigned 1:1 to Visbiome probiotic for 8 weeks, followed by a 3-week washout and an 8 week crossover treatment. (19 weeks total) Starting dose: the first 4 weeks, was a half packet twice daily mixed with food. At 4 week and 15-week visit, there was an option to increase to a full packet twice daily if no effect was noted. The probiotic mix (VISBIOME) will be mainly Bifidobacteria and Lactobacilli, in view of the previously reported encouraging clinical studies and safety data. Visbiome Extra Strength: It is a mix of 8 strains of beneficial bacteria that should improve gut flora, improving GI function and hopefully anxiety	6
Placebo, the Visbiome Particiapants were randomly assigned 1:1 to placebo for 8 weeks, followed by a 3-week washout and an 8 week crossover treatment. (19 weeks total) Starting dose: the first 4 weeks of the probiotic treatment was a half packet twice daily mixed with food. At 4 week and 15-week visit, there was an option to increase to a full packet twice daily if no effect was noted. Placebo matched to probiotic. Maltose (placebo): Maltose with a trace amount of silicon dioxide	4
Total	10

Withdrawals & dropouts

Period	Reason	FG000	FG001
First Intervention (8 Weeks)	Withdrawal by Subject	2	1

Baseline characteristics

Characteristic	Total	Visbiome, Then Placebo	Placebo, the Visbiome
Abbreviated Children's Sleep Habits Questionnaire (CSHQ)	51.63 units on a scale STANDARD_DEVIATION 15.27	43.50 units on a scale STANDARD_DEVIATION 8.02	59.75 units on a scale STANDARD_DEVIATION 13
Aberrant Behavior Checklist (ABC) (1) irritability	21.75 units on a scale STANDARD_DEVIATION 16.64	18.50 units on a scale STANDARD_DEVIATION 12.661	25.00 units on a scale STANDARD_DEVIATION 10.801
Aberrant Behavior Checklist (ABC) (2) lethargy	20.04 units on a scale STANDARD_DEVIATION 18.35	18.83 units on a scale STANDARD_DEVIATION 12.336	21.25 units on a scale STANDARD_DEVIATION 13.598
Aberrant Behavior Checklist (ABC) (3) stereotypy	9.67 units on a scale STANDARD_DEVIATION 9.57	9.33 units on a scale STANDARD_DEVIATION 4.803	10.00 units on a scale STANDARD_DEVIATION 8.287
Aberrant Behavior Checklist (ABC) (4) hyperactivity	28.83 units on a scale STANDARD_DEVIATION 15.43	22.67 units on a scale STANDARD_DEVIATION 11.639	35.00 units on a scale STANDARD_DEVIATION 10.132
Aberrant Behavior Checklist (ABC) inappropriate speech	6.79 units on a scale STANDARD_DEVIATION 5.6	5.33 units on a scale STANDARD_DEVIATION 3.327	8.25 units on a scale STANDARD_DEVIATION 4.5
Age, Categorical <=18 years	10 Participants	6 Participants	4 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	0 Participants
Gastrointestinal Module of the Pediatric Quality of Life Inventory (PedsQL)	63.17 units on a scale STANDARD_DEVIATION 18.76	66.73 units on a scale STANDARD_DEVIATION 20.193	59.60 units on a scale STANDARD_DEVIATION 17.214
Parenting Stress Index Short Form (PSI)	118.84 units on a scale STANDARD_DEVIATION 27.303	108.17 units on a scale STANDARD_DEVIATION 20.731	129.50 units on a scale STANDARD_DEVIATION 17.767
Parent-Rated Anxiety Scale for ASD (PRAS-ASD)	40.63 units on a scale STANDARD_DEVIATION 18.52	40.00 units on a scale STANDARD_DEVIATION 15.582	41.25 units on a scale STANDARD_DEVIATION 10.012
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	5 Participants	2 Participants	3 Participants
Race (NIH/OMB) More than one race	2 Participants	2 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	2 Participants	1 Participants
Region of Enrollment United States	10 participants	6 participants	4 participants
Sex: Female, Male Female	4 Participants	1 Participants	3 Participants
Sex: Female, Male Male	6 Participants	5 Participants	1 Participants
Social Responsiveness Scale (SRS)	84.585 units on a scale STANDARD_DEVIATION 9.189	82.17 units on a scale STANDARD_DEVIATION 7.859	87.00 units on a scale STANDARD_DEVIATION 4.761

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 10	0 / 10
other Total, other adverse events	6 / 10	4 / 10
serious Total, serious adverse events	0 / 10	0 / 10

Outcome results

Primary

Change in Gastrointestinal (GI) Module of the Pediatric Quality of Life Inventory (PedsQL) at From Baseline at Week 8

A 74-item survey with 14 scales. Report forms for specific age ranges assess the parent's perception of the child's GI function and/or symptoms during the last month on a 5-point scale from 0 (never a problem) to 4 (almost always a problem). Items are reverse-scored and transformed to a 0-100 scale so lower scores reflect worse GI dysfunction. Response choices are in Likert-scale format ranging from 0 to 4 (0=Never, 1=Almost Never, 2=Sometimes, 3=Often, 4=Almost Always).