ADHD, ADHD - Attention Deficit Disorder With Hyperactivity, ADHD - Combined Type
Conditions
Keywords
microbiome, microbiota transplants, fecal microbiota transplantation, gut microbiome therapy, gut microbiome, gut microbiota, neurodevelopmental disorders, neurodevelopment, ADHD, Attention Deficit Hyperactivity Disorder, gut brain axis, FMT, adolescent psychiatry, psychiatry, neuroscience
Brief summary
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).
Detailed description
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.
Interventions
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.
DRUGVancomycin 250mg BID
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.
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.
DRUGPico-Salax
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.
DRUGPlacebo Fecal Microbiota Transplantation (FMT)
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.
Sponsors
University of Calgary
Hotchkiss Brain Institute, University of Calgary
Alberta Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Phase 1 (Interventional - Weeks 0-24): Double-blind phase. Participants, care providers, investigators, and outcomes assessors are fully blinded to the 1:1:1:1 allocation (active/placebo antibiotics and active/placebo FMT). Phase 2 (Observational - Optional long term follow up - Weeks 24-48+): Single blind phase. Staff and investigators are unblinded for primary analysis and safety monitoring. Participants and their study partners remain blinded through the optional long-term follow-up to minimize bias. Due to outcomes rely on self- and parent-administered questionnaires, staff unblinding is not expected to affect data integrity. Individually sealed allocation envelopes and master codes are maintained securely by the FMT capsule manufacturer - The University of Calgary Infection Prevention & Control Research Laboratories. Only the unblinded lab technician preparing the interventions has access to these files.
Intervention model description
This is a 2-phase, randomized, placebo-controlled, factorial-design trial evaluating the feasibility, safety, and tolerability of Fecal Microbiota Transplantation (FMT) in 64 adolescents with ADHD on stable first-line pharmacological treatment. Phase 1 (Double-Blinded Interventional): Participants are randomized 1:1:1:1 into four parallel groups (n=16 per group) to evaluate the individual and combined impact of the interventions: Group 1 (Active Antibiotics + Bowel Prep + Active FMT), Group 2 (Active Antibiotics + Bowel Prep + Placebo FMT), Group 3 (Placebo Antibiotics + Bowel Prep + Active FMT), and Group 4 (Placebo Antibiotics + Bowel Prep + Placebo FMT). Phase 2 (Single-Blinded Observational): Following the interventional period, participants transition into a single-blinded observational phase to monitor long-term safety, tolerability, and maintenance of outcomes
Eligibility
Sex/Gender
ALL
Age
13 Years to 18 Years
Healthy volunteers
Yes
Inclusion criteria
1. Between 13-17 years of age with consent of a legal guardian: Participants should be at least 13 years old and not older than 17 years at the day of screening (V1). 2. Have a primary diagnosis of ADHD as confirmed by the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID). 3. Be on a stable appropriate dose of an appropriate first-line pharmacological treatment for at least 8 weeks prior to the day of screening (V1). a. First line pharmacotherapy treatment will be defined based on the CADDRA guidelines \[63\] and include the following Amphetamine-based psychostimulants: i. Mixed amphetamine salts (amphetamine and dextroamphetamine) ii. Lisdexamfetamine dimesylate Methylphenidate-based psychostimulants: i. Methylphenidate hydrochloride, Methylphenidate hydrochloride (extended release, multilayer release capsules) ii. Methylphenidate hydrochloride (extended release, OROS tablets) iii. Methylphenidate hydrochloride (controlled release, multi-layer beat capsules) iv. Methylphenidate hydrochloride (extended-release oral suspension) 4. Have a score of ≥ 18 on the inattention subset (questions 1-9) and/or the hyperactivity/impulsivity subset (questions 10-18) of the SNAP-IV 26-Item Parent Rating Scale on the day of screening (V1) and the baseline visit (V2). 5. Able to communicate and complete study assessments in English. 6. Able to comply with all protocol procedures. 7. Consenting guardian
Exclusion criteria
1. Participant meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Criteria for the following conditions according to the MINI-KID: 1. Diagnosis of a Substance Use Disorder within the last 3 months prior to screening. \*(Criteria should include Alcohol and Non-Alcohol substances except Cannabis) 2. Moderate or severe Substance Use Disorder for Cannabis use in the last 3 months 3. Currently active high suicidality. Eligibility of Participants who meet criteria for moderate suicidality is determined by clinical judgment of Principal Investigator. 4. Active Anorexia Nervosa or Bulimia Nervosa in the last 3 months. 5. Tic Disorders 6. Psychosis 7. Obsessive Compulsive Disorder 8. Bipolar Disorder 9. Conduct Disorder 2. Participant has a score of ≥ 8 on the oppositional defiant subset of the SNAP-IV 26-Item Parent Rating Scale (questions 19-26) on the day of screening (V1). 3. Intellectual or learning disability based on previous documented diagnosis or clinical judgment of Principal Investigator. 4. Documented diagnosis of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). 5. Documented diagnosis of schizophrenia or schizoaffective disorder. 6. Documented diagnosis of Autism Spectrum Disorder (ASD) or currently undergoing assessment for suspected ASD. 7. Use of systemic antibiotics for medical purposes within the last 3 months prior to the day of screening (V1). 8. Use of prebiotics or probiotics for medical purposes for more than 2 weeks within the last 3 months prior to the day of screening (V1). a) Eligibility and required washout period of participants with use of over-the-counter prebiotics or probiotics will be determined by clinical judgment of Principal Investigator. 9. Use of experimental drugs in the last 3 months prior to the day of screening (V1). 10. Documented clinical diagnosis of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and/or celiac disease. 11. Documented diagnosis of conditions causing immunosuppression and/or currently receiving immunosuppressive treatments. 12. Documented clinical diagnosis of significant bleeding disorders. 13. History of oropharyngeal dysphagia or other swallowing disorder, and/or self or study partner reported difficulty with taking oral capsules or pills. 14. Breastfeeding, pregnant or seeking to get pregnant during the course of this study. Female participants of childbearing age should be using an acceptable method of birth control (implants, injectable, combined oral contraceptives, IUDs, barrier contraceptives, sexual abstinence, or a vasectomized partner) for the duration of their participation in the trial. 15. Participants who are currently hospitalized or institutionalized. 16. Reported allergy to Vancomycin or Nitazoxanide 17. Hepatic dysfunction: A) Documented history or current diagnosis of an acute or chronic hepatic disease (e.g., cirrhosis, hepatitis, hepatic impairment) OR B) Abnormal - Liver Function Tests (LFTs): Screening laboratory results indicating clinically significant hepatic dysfunction: * Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥3 the Upper Normal Limit (UNL) * Total Bilirubin \> 1.5 × ULN (except in cases of documented Gilbert's Syndrome) 19. Renal dysfunction: A) Diagnosed Renal Disease: Any documented medical history or current diagnosis of kidney disease, acute kidney injury, or other clinically significant renal impairment. OR B) Abnormal Renal Function Tests: Screening laboratory results indicating significant renal dysfunction. Creatinine \> 1.5 × ULN\* * Potential participants presenting with mild, non-clinically significant laboratory abnormalities (e.g., AST/ALT between 1.0 and 3.0 × ULN, or isolated borderline creatinine variations confirmation of enrollment into the study will be dependent of the study physician.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Change From Baseline in Suicidality Score on the Columbia-Suicide Severity Rating Scale (C-SSRS) | 0-24 weeks | 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. |
| Tolerability: Change From Baseline in Pittsburgh Side Effects Rating Scale (PSERS) Total Score | 0-24 weeks | 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. |
| Tolerability: Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Total Score | 0-24 weeks | 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. |
| Feasibility: Number of Participants Enrolled | 0-24 Weeks | 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 |
| Feasibility: Number of Participants Completing Study Protocol | 0-24 weeks | 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 |
| Feasibility: Number of Prescribed Capsule Doses Successfully Ingested | 0-24 weeks | 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 |
| Feasibility: Number of Participants Completing Required Study Visits | 0-24 weeks | 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). |
| Feasibility: Number of Participants Providing Required Biological Samples | 0-24 Weeks | 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) |
| Safety: Number of Participants With Treatment-Emergent Adverse Events | 0-24 weeks | Safety of FMT in an Adolescent Population With ADHD will be determined by: Evaluating solicited and unsolicited adverse events, including serious adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stool Samples - Microbiome Functional Activity - Metabolomics: Change From Baseline in Fecal Metabolite Concentrations Measured via Proton Nuclear Magnetic Resonance (1H-NMR) Spectroscopy | 0-24 weeks | 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. |
| Saliva Samples - Oral Microbiome Composition - Metabolomic Analysis: Change From Baseline in Salivary Metabolite Concentrations Measured via Proton Nuclear Magnetic Resonance (1H-NMR) Spectroscopy | 0-24 weeks | 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. |
| Blood Samples - Serum Inflammatory Cytokines: Change From Baseline in Serum Cytokine Concentrations | 0-24 weeks | 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. |
| 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 | 0-24 weeks | 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. |
| 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 | 0-24 weeks | 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. |
Countries
Canada
Contacts
CONTACTCleo E Hendrickson, BSc
CONTACTAsem Bala, BDS, MSc, CCRP, CCRA
PRINCIPAL_INVESTIGATORThomas J Raedler, MD
University of Calgary
Outcome results
None listed