The primary goals of this phase 2 clinical trial are to determine the feasibility, safety, and tolerability of oral Fecal Microbiota Transplantation (FMT) in adolescents (aged 13-17) with Attention-Deficit/Hyperactivity Disorder (ADHD).
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder affecting 5% to 7% of children globally, with up to 60% of cases persisting into adulthood. ADHD is characterized by persistent inattention, hyperactivity, and impulsivity, often leading to impairments in occupational, social, and academic functioning, while imposing profound socioeconomic burdens through direct medical costs and productivity losses. Due to current approved pharmacotherapy treatments yielding incomplete symptom relief or intolerable side effects there is an urgent need for innovative treatment options. Emerging evidence implicates the microbiota-gut-brain axis (MGBA) in ADHD, pointing to a unique, potentially dysbiotic gut microbiome profile in individuals with ADHD, marked by reduced alpha and beta diversity and fewer short-chain fatty acid producers. Thus, potentially driving ADHD pathology through low-grade inflammation, "leaky gut" and disrupted neurotransmitter precursor synthesis (dopamine, serotonin, GABA). Following promising results in autism spectrum disorder, fecal microbiota transplantation (FMT) presents a novel approach to address symptom management in ADHD. Unlike probiotics or dietary changes that introduce isolated strains, FMT systemically restructures the microbial network through competitive exclusion, restoring metabolic and ecological functions. Preclinical evidence strongly supports FMT's therapeutic potential as transplanting stool from humans with ADHD into germ-free mice induced ADHD-like behaviors and structural brain alterations in executive function regions. Conversely, transferring healthy donor stool into ADHD-like rodent models, reduced hyperactivity. However, clinical evidence is virtually nonexistent, with a single case report of a woman experiencing relief of her ADHD symptoms after FMT for a C. difficile infection. Pinpointing precise bidirectional MGBA mechanisms remains challenging due to confounding lifestyles, heterogeneous phenotypes, and microbiome complexity. Consequently, rigorous interventional trials are needed to establish true causality and disentangle the clinical impacts of a microbial reset from the disruptive effects of antibiotic pre-conditioning. This study will directly address this critical gap by conducting a randomized, placebo-controlled trial of oral FMT in an adolescent population with ADHD.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
64
Participants will receive active oral FMT capsules, administered over three consecutive visits with each dose spaced 24 hours apart (20 capsules per visit at Visits 3A, 3B, and 3C). This will be administered following bowel preparation to serve as the primary therapeutic intervention for the active FMT regimen.
Participants will receive oral combination therapy consisting of Nitazoxanide (500 mg administered in capsule form) taken twice daily for 6 consecutive days, administered concurrently with oral liquid Vancomycin (250 mg) twice daily for 6 days prior to dosing.
Participants will receive oral liquid Vancomycin at a dose of 250 mg, administered twice daily for 6 consecutive days. This will be taken concurrently with oral Nitazoxanide capsules (500 mg) as part of FMT pre-treatment. Placebo antibiotic receiving participants will receive a matching oral liquid vehicle placebo on the identical twice-daily, 6-day schedule.
University of Calgary
Calgary, Alberta, Canada
Feasibility: Number of Participants Enrolled
Feasibility of FMT in an Adolescent Population With ADHD will be determined by: Successful enrollment of at least 45 participants across the four trial arms
Time frame: 0-24 Weeks
Feasibility: Number of Participants Completing Study Protocol
Feasibility of FMT in an Adolescent Population With ADHD will be determined by: A minimum of 45 participants to complete study until the 24-week primary endpoint
Time frame: 0-24 weeks
Feasibility: Number of Prescribed Capsule Doses Successfully Ingested
Feasibility of FMT in an Adolescent Population With ADHD will be determined by adherence to study protocols: Receive at least 10/20 capsules per dosing visit
Time frame: 0-24 weeks
Feasibility: Number of Participants Completing Required Study Visits
Feasibility of FMT in an Adolescent Population With ADHD will be determined by the adherence to study protocols: Attend all visits - attend the baseline visit (Visit 2- V2) and at least 2 follow up visits (V4-10).
Time frame: 0-24 weeks
Feasibility: Number of Participants Providing Required Biological Samples
Feasibility of FMT in an Adolescent Population With ADHD will be determined by the adherence to study protocols: Provide biological samples at baseline visit (V2) and at least 2 follow up visits (V4-10)
Time frame: 0-24 Weeks
Safety: Number of Participants With Treatment-Emergent Adverse Events
Safety of FMT in an Adolescent Population With ADHD will be determined by: Evaluating solicited and unsolicited adverse events, including serious adverse events
Time frame: 0-24 weeks
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Participants will receive a matching oral liquid vehicle placebo, administered twice daily for 6 consecutive days.
Participants will receive matching oral placebo capsules, administered twice daily for 6 consecutive days.
Participants will undergo bowel cleansing prior to the intervention. On the evening before the first day of dosing participants will consume 1.5 sachets of Pico-Salax mixed in water, followed by eight 250 mL glasses of water over the subsequent 60 minutes to induce a bowel purge over an expected 6- to 8-hour period.
Participants will receive matching oral placebo capsules, administered over three consecutive visits with each dose spaced 24 hours apart (20 capsules per visit at Visits 3A, 3B, and 3C). This will be administered following bowel preparation to serve as the control comparator for the active FMT regimen.
Safety: Change From Baseline in Suicidality Score on the Columbia-Suicide Severity Rating Scale (C-SSRS)
Safety of FMT in an Adolescent Population With ADHD will be determined by: Monitoring suicidality using the Columbia Suicide Severity Rating Scale (C-SSRS). The suicidal ideation subscale ranges from 0 (no ideation) to 5 (active suicidal ideation with specific plan and intent), and the suicidal behavior subscale ranges from 0 (no behavior) to 5 (completed suicide). Higher scores indicate greater severity of suicidality.
Time frame: 0-24 weeks
Tolerability: Change From Baseline in Pittsburgh Side Effects Rating Scale (PSERS) Total Score
Tolerability of FMT in Adolescents With ADHD will be determined by: Evaluating stimulant side effects using the Pittsburgh Side Effects Rating Scale (PSERS). Total scores range from 0 to 45 (or average score per item ranging from 0 to 3 across 15 symptoms: 0 = absent, 1 = mild, 2 = moderate, 3 = severe). Higher scores indicate greater severity of side effects.
Time frame: 0-24 weeks
Tolerability: Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Total Score
Tolerability of FMT in Adolescents With ADHD will be determined by: Evaluating gastrointestinal symptoms following colonic preparation and capsule dosing using the Gastrointestinal Symptom Rating Scale (GSRS). The GSRS is a 15-item questionnaire assessing GI symptoms across 5 domains (abdominal pain, reflux, indigestion, diarrhea, and constipation). Individual items are rated on a 7-point Likert scale ranging from 1 (no discomfort) to 7 (very severe discomfort), with total scores ranging from 15 to 105. Higher scores indicate greater GI symptom severity.
Time frame: 0-24 weeks
Stool Samples - Microbiome Composition - Metagenomics: Change From Baseline in Gut Microbiome Alpha Diversity (Shannon Diversity Index) and Beta Diversity (Bray-Curtis Dissimilarity) via Shotgun Metagenomic Sequencing
The effect of FMT on microbiome composition will be assessed through changes from baseline (V2) to post-intervention follow-up (V4-10). Evaluated using shotgun metagenomic sequencing of stool samples analyzed via the MetaPhlAn4 bioinformatics pipeline. Species-level relative abundances are used to calculate the Shannon Diversity Index (alpha diversity) and Bray-Curtis dissimilarity (beta diversity) at each study visit. Higher Shannon values indicate greater microbial community diversity and species richness, while Bray-Curtis dissimilarity measures compositional differences between samples over time. Samples are collected at 5 time points.
Time frame: 0-24 weeks
Stool Samples - Microbiome Functional Activity - Metabolomics: Change From Baseline in Fecal Metabolite Concentrations Measured via Proton Nuclear Magnetic Resonance (1H-NMR) Spectroscopy
The effect of FMT on microbiome functional activity will be assessed through changes in the following from baseline (V2) to post-intervention follow-up (V4-10): Evaluated by quantifying fecal metabolite concentrations from stool samples using a 500 MHz 1H-NMR spectrometer and Chenomx NMR Suite library profiling. Individual target metabolites (e.g., short-chain fatty acids) are quantified across study visits. Samples are collected at 5 time points.
Time frame: 0-24 weeks
Saliva Samples - Oral Microbiome Composition - Metagenomics: Change From Baseline in Oral Microbiome Alpha Diversity (Shannon Diversity Index) and Beta Diversity (Bray-Curtis Dissimilarity) via Shotgun Metagenomic Sequencing
The effect of FMT on oral microbiome composition will be assessed through changes from baseline (V2) to post-intervention follow-up (V4-10). Evaluated using shotgun metagenomic sequencing of saliva samples analyzed via the MetaPhlAn4 bioinformatics pipeline. Species-level relative abundances are used to calculate the Shannon Diversity Index (alpha diversity) and Bray-Curtis dissimilarity (beta diversity) at each study visit. Higher Shannon values indicate greater oral microbial community diversity and species richness, while Bray-Curtis dissimilarity measures compositional differences between samples over time. Samples are collected at 5 time points.
Time frame: 0-24 weeks
Saliva Samples - Oral Microbiome Composition - Metabolomic Analysis: Change From Baseline in Salivary Metabolite Concentrations Measured via Proton Nuclear Magnetic Resonance (1H-NMR) Spectroscopy
To assess the effect of FMT on the oral microbiome through changes in the following from baseline (V2) to post intervention follow up (V4-10): Evaluates functional metabolic changes in saliva by quantifying individual metabolite concentrations using 1H-NMR spectroscopy collected at 5 time points.
Time frame: 0-24 weeks
Blood Samples - Serum Inflammatory Cytokines: Change From Baseline in Serum Cytokine Concentrations
To assess the effect of FMT on associated biomarkers seen through changes in the following from baseline (V2) to post intervention follow up (V4-10): Evaluates systemic inflammatory profile changes by measuring serum concentrations of pro- and anti-inflammatory cytokines obtained via blood samples collected at 5 time points.
Time frame: 0-24 weeks