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Effect of Milk Oligosaccharides and Bifidobacteria on the Intestinal Microflora of Children With Autism

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ClinicalTrials.gov Identifier: NCT02086110
Recruitment Status : Completed
First Posted : March 13, 2014
Results First Posted : August 1, 2019
Last Update Posted : August 1, 2019
Sponsor:
Information provided by (Responsible Party):
University of California, Davis

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Basic Science
Condition Autism
Interventions Dietary Supplement: Synbiotic
Dietary Supplement: Prebiotic
Enrollment 11
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Prebiotic Only First, Then Synbiotic Synbiotic First, Then Prebiotic Only
Hide Arm/Group Description This group will receive prebiotic only (bovine milk oligosaccharides, administered orally twice per day for a daily total of 0.3 g per pound of body weight) for the first five weeks, followed by a two week break with no treatment, and then will receive the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally) for the next five weeks. This group will receive the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally) for the first five weeks, followed by a two week break with no treatment, and then will receive the prebiotic only (bovine milk oligosacharrides, administered orally twice per day for a daily total of 0.3 g per pound of body weight) for the next five weeks.
Period Title: Overall Study
Started 5 6
Completed 4 5
Not Completed 1 1
Reason Not Completed
Withdrawal by Subject             1             1
Arm/Group Title Prebiotic Only First, Then Synbiotic Synbiotic First, Then Prebiotic Only Total
Hide Arm/Group Description This group will receive prebiotic only (bovine milk oligosaccharides, administered orally twice per day for a daily total of 0.3 g per pound of body weight) for the first five weeks, followed by a two week break with no treatment, and then will receive the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally) for the next five weeks. This group will receive the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally) for the first five weeks, followed by a two week break with no treatment, and then will receive the prebiotic only (bovine milk oligosacharrides, administered orally twice per day for a daily total of 0.3 g per pound of body weight) for the next five weeks. Total of all reporting groups
Overall Number of Baseline Participants 5 6 11
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 6 participants 11 participants
<=18 years
5
 100.0%
6
 100.0%
11
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 6 participants 11 participants
Female
1
  20.0%
1
  16.7%
2
  18.2%
Male
4
  80.0%
5
  83.3%
9
  81.8%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 5 participants 6 participants 11 participants
White, non-Hispanic
3
  60.0%
5
  83.3%
8
  72.7%
African-American, non-Hispanic
1
  20.0%
0
   0.0%
1
   9.1%
White, Hispanic/Latino
1
  20.0%
1
  16.7%
2
  18.2%
African-American, Hispanic/Latino
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 5 participants 6 participants 11 participants
5
 100.0%
6
 100.0%
11
 100.0%
1.Primary Outcome
Title Stool Microbiota Composition Change During Prebiotic Only Treatment
Hide Description The stool microbiome composition will be analyzed through next generation sequencing and quantitative polymerase chain reaction. Overall bacterial composition change is reported here, as change in enterotype from before prebiotic only treatment to after prebiotic treatment, for all subjects. Enterotypes were organized into four categories for analysis: a community high in Prevotella ("Prevotella"), a community high in Bifidobacterium ("Bifidobacterium"), a community high in Bacteroides ("Bacteroides"), and a mixed community ("Mixed") that did not fall into one of the other three enterotypes but instead consisted of a varied combination of bacteria, including among others Akkermansia, Collinsela, Prevotella, and/or Bacteroides.
Time Frame Five weeks
Hide Outcome Measure Data
Hide Analysis Population Description
In the Prebiotic First group, 1 subject withdrew consent prior to providing stool sample. In the Synbiotic First group, 1 subject withdrew consent prior to starting prebiotic treatment, and 1 subject was unable to provide a stool sample for analysis.
Arm/Group Title Prebiotic Only First, Then Synbiotic Synbiotic First, Then Prebiotic Only
Hide Arm/Group Description:
This group will receive prebiotic only (bovine milk oligosaccharides, administered orally twice per day for a daily total of 0.3 g per pound of body weight) for the first five weeks, followed by a two week break with no treatment, and then will receive the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally) for the next five weeks.
This group will receive the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally) for the first five weeks, followed by a two week break with no treatment, and then will receive the prebiotic only (bovine milk oligosacharrides, administered orally twice per day for a daily total of 0.3 g per pound of body weight) for the next five weeks.
Overall Number of Participants Analyzed 4 4
Measure Type: Count of Participants
Unit of Measure: Participants
No change in enterotype
2
  50.0%
3
  75.0%
Bifidobacterium to Prevotella
1
  25.0%
0
   0.0%
Bacteroides to Bifidobacterium
1
  25.0%
0
   0.0%
Prevotella to Bifidobacterium
0
   0.0%
1
  25.0%
2.Primary Outcome
Title Stool Microbiota Composition Change During Synbiotic Treatment
Hide Description The stool microbiome composition will be analyzed through next generation sequencing and quantitative polymerase chain reaction. Overall bacterial composition change is reported here, as change in enterotype from before synbiotic treatment to after synbiotic treatment, for all subjects. Enterotypes were organized into four categories for analysis: a community high in Prevotella ("Prevotella"), a community high in Bifidobacterium ("Bifidobacterium"), a community high in Bacteroides ("Bacteroides"), and a mixed community ("Mixed") that did not fall into one of the other three enterotypes but instead consisted of a varied combination of bacteria, including among others Akkermansia, Collinsela, Prevotella, and/or Bacteroides.
Time Frame Five weeks
Hide Outcome Measure Data
Hide Analysis Population Description
In the Prebiotic First group, 1 subject withdrew consent prior to starting synbiotic treatment. In the Synbiotic First group, 1 subject withdrew consent prior to providing stool sample, and 1 subject was unable to provide a stool sample for analysis.
Arm/Group Title Prebiotic Only First, Then Synbiotic Synbiotic First, Then Prebiotic Only
Hide Arm/Group Description:
This group will receive prebiotic only (bovine milk oligosaccharides, administered orally twice per day for a daily total of 0.3 g per pound of body weight) for the first five weeks, followed by a two week break with no treatment, and then will receive the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally) for the next five weeks.
This group will receive the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally) for the first five weeks, followed by a two week break with no treatment, and then will receive the prebiotic only (bovine milk oligosacharrides, administered orally twice per day for a daily total of 0.3 g per pound of body weight) for the next five weeks.
Overall Number of Participants Analyzed 4 4
Measure Type: Count of Participants
Unit of Measure: Participants
No change in enterotype
4
 100.0%
2
  50.0%
Prevotella to Mixed
0
   0.0%
1
  25.0%
Prevotella to Bifidobacterium
0
   0.0%
1
  25.0%
3.Secondary Outcome
Title Serum Immune Profile Change During Prebiotic Only Treatment
Hide Description Luminex technology will be used to determine a serum immune profile of each participants in response to the study supplement. This profile included assessment of change in percentage of stimulated CD4+ T cells producing intracellular IL-13 before and after Synbiotic treatment ("Post-Synbiotic % IL-13"), and assessment of change in percentage of stimulated CD8+ T cells producing TNF-alpha before and after Prebiotic Only treatment ("Post-Prebiotic % TNF-alpha"). Results are reported here for all subjects regardless of treatment order assignment. Decrease in inflammatory cytokines IL-13 and TNF-alpha is interpreted as a positive outcome.
Time Frame Five weeks
Hide Outcome Measure Data
Hide Analysis Population Description
1 subject was unable to provide blood specimens throughout the study due to significant anxiety with regard to venipuncture, so only 7 subjects' serum was available for analysis.
Arm/Group Title All Subjects
Hide Arm/Group Description:
All subjects with serum samples available for analysis were included below.
Overall Number of Participants Analyzed 7
Median (95% Confidence Interval)
Unit of Measure: percentage of cytokine production
Post-Synbiotic % IL-13
-0.8
(-2.073 to -0.524)
Post-Prebiotic % TNF-alpha
-7.9
(-14.375 to -1.425)
Time Frame Adverse event data was collected from time of consent through end-of-treatment (12 weeks total).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Prebiotic Only Arm Synbiotic Arm
Hide Arm/Group Description Includes reported adverse events for all subjects while receiving prebiotic only (bovine milk oligosaccharides, administered orally twice per day for a daily total of 0.3 g per pound of body weight). Includes reported adverse events for all subjects while receiving the synbiotic (Bifidobacterium infantis (10 billion CFU) twice a day plus 0.3 g per pound body weight of bovine milk oligosaccharides in two divided doses per day orally).
All-Cause Mortality
Prebiotic Only Arm Synbiotic Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   0/10 (0.00%)      0/10 (0.00%)    
Hide Serious Adverse Events
Prebiotic Only Arm Synbiotic Arm
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/10 (0.00%)      0/10 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Prebiotic Only Arm Synbiotic Arm
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/10 (100.00%)      10/10 (100.00%)    
Gastrointestinal disorders     
Increased gassiness †  2/10 (20.00%)  2 2/10 (20.00%)  2
Stomachache †  1/10 (10.00%)  1 0/10 (0.00%)  0
Diarrhea †  2/10 (20.00%)  4 2/10 (20.00%)  4
Constipation †  2/10 (20.00%)  4 2/10 (20.00%)  4
Pain associated with bowel movements †  3/10 (30.00%)  3 3/10 (30.00%)  3
Bloating †  1/10 (10.00%)  1 2/10 (20.00%)  2
Metabolism and nutrition disorders     
Weight gain †  0/10 (0.00%)  0 2/10 (20.00%)  2
Psychiatric disorders     
Sleep disturbances †  1/10 (10.00%)  1 0/10 (0.00%)  0
Lethargy †  1/10 (10.00%)  1 0/10 (0.00%)  0
Skin and subcutaneous tissue disorders     
Hives †  0/10 (0.00%)  0 1/10 (10.00%)  1
†
Indicates events were collected by systematic assessment
Lack of a clear control group receiving a placebo, resulting in possible placebo effect (partially addressed by study's cross-over design). Study duration was short. Lack of a probiotic only arm to parse out specific treatment effects.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Kathleen Angkustsiri
Organization: University of California, Davis Health System
Phone: 916-703-0278
EMail: kangkustsiri@ucdavis.edu
Layout table for additonal information
Responsible Party: University of California, Davis
ClinicalTrials.gov Identifier: NCT02086110    
Other Study ID Numbers: 450072
First Submitted: March 7, 2014
First Posted: March 13, 2014
Results First Submitted: May 31, 2019
Results First Posted: August 1, 2019
Last Update Posted: August 1, 2019