Tolerability and Functional Assessment of a Novel Children's Synbiotic

Study Overview
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Brief Summary
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Recent data support the use of specific probiotic strains in a pediatric population. However, given the wide number of commercial products available, and contradictory data in the literature, healthcare providers and consumers are uncertain about whether or not to use probiotics in children and which one(s) to choose. While much progress has been made in understanding the gastrointestinal microbiota and its role in the balanced development of the infant immune system, the tolerability and efficacy of introducing beneficial microbes into the pediatric gastrointestinal tract remain underexplored. The purpose of this study is to investigate the effect of a 9 strain synbiotic consortium comprised of strains with previous pediatric clinical data for use in modulating airway sensitivity, gastrointestinal discomfort, dermatological inflammation, and reduction in the duration and severity of upper respiratory tract infections in a pediatric population.

Detailed Description
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During infancy and childhood, environmental factors including the maternal vaginal and skin microbiomes, breast milk microbiota, breast milk, geographic location, and use of antibiotics will exert significant influence over the offspring's microbiota and have a determinant impact on their health later in life. Unfavorable environmental exposures, coupled with an immature immune system in early life can, therefore, confer suboptimal immune responses that can lead to the development of extra-gastrointestinal conditions such as allergic rhinitis, asthma, and atopic dermatitis-which affects 15-20% of the world's population. Furthermore, while the indiscriminate use of antibiotics has decreased, they remain standard-of-care for most childhood infections, and unfortunately, often result in short- or long-term disruption of the patient's microbiome. Constipation is a common childhood gastrointestinal disorder, with a worldwide prevalence between 0.7-29.6%. Its etiology is multifactorial and usually not due to underlying conditions. Few studies have explored the implications of the intestinal or fecal microbiota in childhood constipation, yet some have shown benefits of various probiotic compositions in reducing transit time and improving bowel movement frequency. Dysbiosis of the gut microbiome may play an important role in functional constipation. PDS-08™ is a novel synbiotic, comprised of nine probiotic bacterial strains and fructooligosaccharide with inulin (FOS-inulin) as a prebiotic. A synbiotic is defined as a probiotic (live microorganisms that, when administered in adequate amounts, confer a health benefit on the host) plus an established prebiotic (a substrate that is selectively utilized by host microorganisms conferring a health benefit)-or, an untested live microbe co-administered with a substrate that it selectively utilizes. The selected probiotics and prebiotic in the PDS-08 formulation have shown to improve antibiotic-associated diarrhea, gastrointestinal and respiratory tract infections, allergic rhinitis, atopic dermatitis, irritable bowel syndrome (IBS) symptoms, and/or microbiota modulation. The positive outcomes of these respective studies warrants further investigation of the strains as part of a probiotic consortium with the potential to modulate the microbiota, regulate dysbiosis, and confer a benefit to host health. There is a need for additional systematic studies on probiotic administration in pediatric populations, with a focus on measuring shifts in the fecal microbiota and markers of gut health and function. Therefore, the objective of this study is to assess the efficacy, tolerability, and safety of a novel synbiotic in healthy children with occasional constipation, over 12 weeks, as compared to a sensory-matched placebo. This is a randomized, 12-week study to compare the efficacy and tolerability of PDS-08 in a cohort of 100 healthy children with constipation. 50 subjects will receive PDS-08™ over 12 weeks, and 50 subjects will receive a placebo. Subjects will provide stool samples at baseline and week 12. Safety is a paramount concern in the study design and will be monitored carefully throughout the study. Parents or direct relative guardians of study subjects will receive extensive education on synbiotic use.

Official Title
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A 12-week Randomized, Double-Blind Controlled Trial to Evaluate the Tolerability and Gastrointestinal Response of a Novel, Multi-Strain Synbiotic (PDS-08™) in Children Ages 3-17

Conditions
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Constipation, Signs and Symptoms, Digestive Signs and Symptoms, Infrequent or Difficult Evacuation

Intervention / Treatment
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* Dietary Supplement: PDS-08
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The parent(s) or direct relative guardian(s) of the participant must be willing and able to give informed assent/consent for participation in the study. Participant must be in good health as determined from participant's medical history. Males & Females between 3-17 years old. Normal weight or overweight (BMI between the age- and sex-specific 5th percentile and 95th percentile). Children with constipation (defined as less than 4 bowel movements per week) and/or baseline Bristol Stool Form Scale score of 1 or 2. Participant's parent(s) must be willing and able (in the PI's opinion) to comply with all study requirements. Children with healthy skin or eczema and/or acne. Females of childbearing potential (post-menarche) and/or their parents must make a written and/or verbal statement prior to randomization indicating that they are not pregnant and adhere to a pregnancy prevention method (abstinence or barrier method plus spermicidal foam or oral or implanted contraceptive). Consistent use of medications not listed in the exclusion criteria. Participant is under the care of a parent or direct relative guardian. Exclusion Criteria: Underweight (BMI<5th percentile for age) or obese (BMI above the 95th percentile on the Centers for Disease Control and Prevention growth charts). Participants are taking, and plan to continue taking, medications (including over the counter (OTC), such as simethicone for gas), home remedies (such as juice for constipation), herbal preparations, or rehydration fluids that might affect GI tolerance. Participants taking laxatives. Participants using probiotics, antibiotics, or antifungals during the course of the study or within the past 1 month. Participants receiving administration of any investigational drug within the past 1 month. Participants who are pregnant, lactating, or planning a pregnancy during the course of the study. Participants with compromised immunity. Participants with GI disease (e.g., inflammatory bowel disease, celiac disease, prior intestinal resection, SIBO/small intestinal bacterial growth, irritable bowel syndrome, functional abdominal pain, or lactose intolerance). Participants are taking medication such as antipsychotics, antidepressants, mood stabilizers, medications for Attention Deficit Hyperactivity Disorder, anti-anxiety medications (Anxiolytics), or related medication. Participants on medically prescribed diets or supplements other than a standard multivitamin. Participants with plans to travel outside the USA during the study. Alcohol or drug abuse. Participants using any oral over the counter or prescription medications for acne or atopic dermatitis. Participants who have recently tested positive for COVID-19 or who live with adults with an active COVID-19 infection. Participants are under the care of someone other than a parent or direct relative guardian.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Multi-Strain Synbiotic (PDS-08)<br>PDS-08 is a rationally defined microbial consortium consisting of 9 strains, with FOS-inulin as prebiotic. Participants will be instructed to take 1 sachet daily for the duration of the trial. | Dietary Supplement: PDS-08<br>* PDS-08 is a novel synbiotic comprised of nine probiotic bacterial strains and FOS-inulin as a prebiotic.<br>|
| Placebo Comparator: Placebo<br>Placebo sachets for PDS-08 will contain potato or tapioca maltodextrin matched for color and texture. Participants will be instructed to take 1 sachet daily for the duration of the trial. | Other: Placebo<br>* Placebo sachets will contain potato or tapioca maltodextrin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who are spontaneous bowel movement responders, defined as having an average of ≥ 4 complete spontaneous bowel movements (CSBMs) per week and an average increase of ≥ 1 CSBM from baseline, by age group: 3-6, 7-12, 13-17 years. | Assessed as the change from baseline and compared to placebo for the continuous variable estimated using a linear mixed model. | Baseline-Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average increase from baseline of Bristol Stool Form Scale (BSFS) score by ≥ 1 point (stool characterized as an increase to either type 2 or 3 or 4) in the intervention group, compared to the placebo group. | Assessed by daily stool characteristics reported using the seven-point ordinal BSFS score. The BSFS classifies human stool into seven types and scores them accordingly. Type 1: Separate hard lumps (hard to pass) Type 2: Sausage-shaped and lumpy Type 3: Like a sausage but with cracks on its surface Type 4: Like a sausage, smooth and soft Type 5: Soft blobs with clear cut edges (passed easily) Type 6: Fluffy pieces with ragged edges, a mushy stool Type 7: Watery, no solid pieces, entirely liquid. Types 1 and 2 indicate constipation, with 3 through 5 represent the ideal stool form, and 6 and 7 tend towards diarrhea. For a given assessment week, the weekly stool consistency is defined as the sum of non-missing stool consistency score for spontaneous bowel movements during that week divided by the number of non-missing stool consistency scores for spontaneous bowel movements during that week. The parameter will be analyzed using a linear mixed model. | Baseline-Day 84 | 
| Decrease of ≥ 10% in time spent emptying bowel from beginning to end of bowel movement, compared to baseline. |  | Baseline-Day 84 | 
| Changes in subjective assessment of gut tolerability as reported by parents or direct relative guardians, indicated by sustained (longer than 7 days of) abdominal pain, severe bloating, heartburn, acid reflux, or indigestion. | Assessed by online daily symptom-tracking of stool-quality, regularity, ease of expulsion, bloating, and flatulence. | Baseline-Day 84 | 
| Maintenance or increase of diversity within the PDS-08 treatment group. | Microbiota composition will be identified through fecal samples for total genomic DNA extraction in participants supplemented with PDS-08 or placebo. Metagenomic sequencing will yield a total observable species count and maintenance will be defined as within 20% of the total observed species count when compared to baseline. | Baseline-Day 84 | 
| Significant increase in QoL measured by the KINDL questionnaire with respect to mean change from baseline score (p<0.05). |  | Baseline-Day 84 | 
| Exploratory: number of respiratory tract infections in the PDS-08 group compared to placebo. |  | Baseline-Day 84 | 
| Exploratory: number and percent of participants with reduction in number of acne lesions from baseline as measured by global count of blemishes. |  | Baseline-Day 84 | 
| Exploratory outcomes: changes in fecal calprotectin, histamine, bacterial enzymes (β-glucosidase and β-glucuronidase), β-defensin (hBD2) and short chain fatty acids in treatment group compared to the placebo group. |  | Baseline-Day 84 |