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The primary aims of this phase I/II, randomized, placebo controlled study are the assessment of safety and tolerability of universal donor FMT compared to placebo in pediatric and young adult subjects (ages 5 years through 30 years) with active ulcerative colitis (UC) or active Crohn's colitis (CD) who have failed, are intolerant to, or have refused traditional first-line maintenance therapy. Secondary objectives include the identification biomarkers in both donor and recipient that may confer a clinical response and to establish whether or not ongoing FMT maintenance therapy is required for maintenance of clinical benefit in pediatric UC or pediatric CD.
This is a single-center pilot, phase I/II, randomized, prospective, double-blinded, placebo-controlled study of FMT in the treatment of active pediatric UC and active pediatric CD. The primary aim is to assess safety and feasibility of a weekly FMT maintenance therapy. A total of 10 patients with active UC (as defined by PUCAI score of >9) and 10 patients with active CD (as defined by PDCAI score of >10) will be enrolled and randomized to receive FMT or placebo-FMT (study treatment) by retention enema for 1 week and oral, frozen encapsulated inocula/placebo for 7 weeks. After the first 8 weeks, subjects on FMT who improve or subjects on placebo-FMT who do not improve will have the option to continue on study treatment or switch to open-label FMT until the end of 4 months from study initiation. Subjects will be followed by telephone to assess adverse events for a total of 6 months after their last FMT dose.
An initial subset of no more than 20 subjects will be enrolled in the study (will be limited to only those patients 12 years of age or older and to those who have mild to moderate disease) and randomized to receive FMT or placebo. We'd expect short term adverse events to occur within 7 days of FMT administration. Individual subject safety data will be reviewed by the PI to assess whether FMT appears to be safe in the subject before continuing the subject towards open-label use of FMT.
Patient metadata and stool samples will be collected at key time points. The patient-reported metadata collection technique will allow for numerous clinical correlations to be parsed out using the random forest machine learning capabilities of synthetic learning in microbial ecology (SLiME) to identify taxonomic features associated with important clinical parameters.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fecal Microbiota Transplant (FMT) | Experimental | Induction retention enema for the first week of treatment followed by once weekly administration of 15 capsules of study treatment (the equivalent of 7.5 grams of human stool) will be (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study treatment, study subjects on FMT who have shown improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks of once weekly FMT capsule administration. |
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| Placebo | Placebo Comparator | Induction placebo enema for the first week of treatment followed by once weekly administration of 15 capsules of study placebo (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study placebo, study subjects on placebo who DO NOT demonstrate improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks, beginning with a FMT induction enema followed by 7 weeks of weekly FMT capsule administration. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fecal Microbiota Transplant (FMT) | Biological | The study intervention consists of frozen, bottled or encapsulated fecal microbiota preparations that have been screened and prepared to a uniform and rigorous standard by OpenBiome. FMT is performed by patients receiving a retention enema and swallowing capsules, introducing stool from a healthy donor into their intestinal tract. |
| Measure | Description | Time Frame |
|---|---|---|
| 1. Safety and Tolerability of Universal Donor FMT Compared to Placebo: FMT-related Adverse Events Grade 2 or Above | Number of participants with FMT-related adverse events grade 2 or above experienced in each arm. | At 8 weeks after start of FMT up to 6 months post treatment, an average of 10 months |
| Measure | Description | Time Frame |
|---|---|---|
| Remission of Disease | Remission as defined by a PUCAI score of less than 9 (for UC) or by a PCDAI score of less than 10 (for CD) | At all intermediate timepoints until 6 month follow up post intervention, an average of 10 months |
| Improvement in Inflammatory Biomarkers |
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Male and female children and young adults, aged 5 years to 30 years, who meet the following inclusion criteria, will be enrolled in the study.
Two initial subsets will be created: an initial subset of 20 subjects limited to patients greater than or equal to 12 years of age with mild to moderate ulcerative colitis (i.e., PUCAI < 65) patients with mild to moderate Crohn's disease (i.e., PDCAI less than or equal to 30).
All patients must satisfy below criteria:
Patients who have disease that has required other medications (including steroids, immunosuppressives, and biologics) will be included.
Exclusion Criteria:
Subjects who fall into any of the following exclusion criteria at the time of screening are not eligible for enrollment into the study.
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| Name | Affiliation | Role |
|---|---|---|
| Stacy A Kahn, MD | Boston Childrens Hospital - GI & Nutrition | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boston Children's Hospital | Boston | Massachusetts | 02115 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Fecal Microbiota Transplant (FMT) | Induction retention enema for the first week of treatment followed by once weekly administration of 15 capsules of study treatment (the equivalent of 7.5 grams of human stool) will be (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study treatment, study subjects on FMT who have shown improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks of once weekly FMT capsule administration. Fecal Microbiota Transplant (FMT): The study intervention consists of frozen, bottled or encapsulated fecal microbiota preparations that have been screened and prepared to a uniform and rigorous standard by OpenBiome. FMT is performed by patients receiving a retention enema and swallowing capsules, introducing stool from a healthy donor into their intestinal tract. |
| FG001 | Placebo | Induction placebo enema for the first week of treatment followed by once weekly administration of 15 capsules of study placebo (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study placebo, study subjects on placebo who DO NOT demonstrate improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks, beginning with a FMT induction enema followed by 7 weeks of weekly FMT capsule administration. Placebo: Placebo administration will consist of both a placebo retention enema and placebo capsules. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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There were two participants that were removed from the study after providing informed consent but before receiving any treatment. As a result, these participants were not included in the analysis and were not followed for adverse events.
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| ID | Title | Description |
|---|---|---|
| BG000 | Fecal Microbiota Transplant (FMT) | Induction retention enema for the first week of treatment followed by once weekly administration of 15 capsules of study treatment (the equivalent of 7.5 grams of human stool) will be (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study treatment, study subjects on FMT who have shown improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks of once weekly FMT capsule administration. Fecal Microbiota Transplant (FMT): The study intervention consists of frozen, bottled or encapsulated fecal microbiota preparations that have been screened and prepared to a uniform and rigorous standard by OpenBiome. FMT is performed by patients receiving a retention enema and swallowing capsules, introducing stool from a healthy donor into their intestinal tract. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 1. Safety and Tolerability of Universal Donor FMT Compared to Placebo: FMT-related Adverse Events Grade 2 or Above | Number of participants with FMT-related adverse events grade 2 or above experienced in each arm. | Participants who received FMT or placebo, completed the study, and follow up data is available. | Posted | Count of Participants | Participants | At 8 weeks after start of FMT up to 6 months post treatment, an average of 10 months |
|
The adverse event data was collected for 1 year post treatment, up to approximately 1 year and 4 months.
The definitions do not differ.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Fecal Microbiota Transplant (FMT) | Adverse events are reported for participants during and after receiving FMT in either blinded or open-label treatment. Induction retention enema for the first week of treatment followed by once weekly administration of 15 capsules of study treatment (the equivalent of 7.5 grams of human stool) will be (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study treatment, study subjects on FMT who have shown improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks of once weekly FMT capsule administration. Fecal Microbiota Transplant (FMT): The study intervention consists of frozen, bottled or encapsulated fecal microbiota preparations that have been screened and prepared to a uniform and rigorous standard by OpenBiome. FMT is performed by patients receiving a retention enema and swallowing capsules, introducing stool from a healthy donor into their intestinal tract. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Grade 3 Sinus Tachycardia | Cardiac disorders | Systematic Assessment | Hypersensitivity reaction from FMT induction enema resulting in sinus tachycardia and an ED admission. Inpatient for 2 days following |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Epiploic Appendagitis | Gastrointestinal disorders | Systematic Assessment | AE was not related to study intervention. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Stacy A. Kahn | Boston Children's Hospital | 617-355-6058 | stacy.kahn@childrens.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 11, 2018 | Mar 16, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D015212 | Inflammatory Bowel Diseases |
| D003093 | Colitis, Ulcerative |
| D003424 | Crohn Disease |
| D003092 | Colitis |
| ID | Term |
|---|---|
| D005759 | Gastroenteritis |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D007410 | Intestinal Diseases |
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| ID | Term |
|---|---|
| D000069467 | Fecal Microbiota Transplantation |
| ID | Term |
|---|---|
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
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| Placebo | Biological | Placebo administration will consist of both a placebo retention enema and placebo capsules. |
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Improvement in inflammatory biomarkers (stool calprotectin, serum ESR, CRP, albumin, hematocrit) compared to baseline. |
| At End of Treatment (8 weeks) and at 6 month post treatment |
| Percentage of Donor Microbiome Present in Transplant Recipient | We will assess changes in microbial composition and the extent of microbial engraftment from the donor in the recipient by comparing the similarity of the microbiomes at two weeks at seven weeks after the induction enema. | At two weeks and seven weeks post induction enema |
| Number of Participants With Improvement in Disease Activity | 5a. For UC - Improvement of Pediatric Ulcerative Colitis Activity Index (PUCAI) by 20 points or more. Improvement in disease status as measured by improvement of PUCAI score by 20 points or more. 5b. For CD - Improvement of Pediatric Crohn's Disease Activity Index (PCDAI) by 12.5 points or more. Improvement of disease status as measured by improvement of PCDAI score by 12.5 points or more. | At 8 weeks after start of FMT |
| BG001 | Placebo | Induction placebo enema for the first week of treatment followed by once weekly administration of 15 capsules of study placebo (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study placebo, study subjects on placebo who DO NOT demonstrate improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks, beginning with a FMT induction enema followed by 7 weeks of weekly FMT capsule administration. Placebo: Placebo administration will consist of both a placebo retention enema and placebo capsules. |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| OG001 | Placebo | Induction placebo enema for the first week of treatment followed by once weekly administration of 15 capsules of study placebo (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study placebo, study subjects on placebo who DO NOT demonstrate improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks, beginning with a FMT induction enema followed by 7 weeks of weekly FMT capsule administration. Placebo: Placebo administration will consist of both a placebo retention enema and placebo capsules. |
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| Secondary | Remission of Disease | Remission as defined by a PUCAI score of less than 9 (for UC) or by a PCDAI score of less than 10 (for CD) | Participants who received FMT or placebo, completed the study, and follow up data is available. | Posted | Count of Participants | Participants | At all intermediate timepoints until 6 month follow up post intervention, an average of 10 months |
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| Secondary | Improvement in Inflammatory Biomarkers | Improvement in inflammatory biomarkers (stool calprotectin, serum ESR, CRP, albumin, hematocrit) compared to baseline. | Participants who received FMT or placebo, completed the study, and follow up data is available. | Posted | Count of Participants | Participants | At End of Treatment (8 weeks) and at 6 month post treatment |
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| Secondary | Percentage of Donor Microbiome Present in Transplant Recipient | We will assess changes in microbial composition and the extent of microbial engraftment from the donor in the recipient by comparing the similarity of the microbiomes at two weeks at seven weeks after the induction enema. | Participants who received FMT or placebo, completed the study, and follow up data is available. | Posted | Mean | Full Range | percentage of donor microbiome present | At two weeks and seven weeks post induction enema |
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| Secondary | Number of Participants With Improvement in Disease Activity | 5a. For UC - Improvement of Pediatric Ulcerative Colitis Activity Index (PUCAI) by 20 points or more. Improvement in disease status as measured by improvement of PUCAI score by 20 points or more. 5b. For CD - Improvement of Pediatric Crohn's Disease Activity Index (PCDAI) by 12.5 points or more. Improvement of disease status as measured by improvement of PCDAI score by 12.5 points or more. | There were 1 CD and 5 UC participants in the FMT group that completed the study protocol and follow up. There were 2 CD and 3 UC participants that completed the Placebo and were eligible for 8 weeks of Open-Label FMT that completed the study protocol and follow up. | Posted | Count of Participants | Participants | At 8 weeks after start of FMT |
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| 0 |
| 12 |
| 3 |
| 12 |
| 6 |
| 12 |
| EG001 | Placebo | Adverse events are reported for participants during receipt of placebo treatment. Induction placebo enema for the first week of treatment followed by once weekly administration of 15 capsules of study placebo (administered within 60 minutes of thawing once weekly) for 7 weeks. After completing 8 weeks of blinded study placebo, study subjects on placebo who DO NOT demonstrate improvement will be given the option to receive open-label maintenance FMT weekly for an additional 8 weeks, beginning with a FMT induction enema followed by 7 weeks of weekly FMT capsule administration. Placebo: Placebo administration will consist of both a placebo retention enema and placebo capsules. | 0 | 5 | 0 | 5 | 1 | 5 |
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| Grade 3 Colitis | Gastrointestinal disorders | Systematic Assessment | Increase in symptoms like abdominal pain, blood in stool and or watery stool, high frequency of stooling, nausea/vomiting, and dehydration |
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| Abnormal Lab Values | Immune system disorders | Systematic Assessment | Decreased WBC, increased bilirubin, increase Alkaline phosphatase, and increased lymphocyte count were all present but were determined to be not related or present at baseline. |
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| Fever | General disorders | Systematic Assessment | Fever, dizziness, flushing, and chills were reported as probably related and resolved without sequelae |
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| Eczema/Rash | Skin and subcutaneous tissue disorders | Systematic Assessment | Eczema and rash unrelated to the study treatment were reported |
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| Sore Throat | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Sore Throat |
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| Non-Cardiac Chest Pain | General disorders | Systematic Assessment | Non-Cardiac Chest Pain |
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| Upper Respiratory Infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Upper Respiratory Infection |
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| Eye Disorder/Blurred Vision | Eye disorders | Systematic Assessment |
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| D003108 | Colonic Diseases |
| Decrease in CRP at 8 weeks |
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| Decrease in CRP at 6 months |
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| Decrease in ESR at 8 weeks |
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| Decrease in ESR at 6 months |
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| CD Participants with improved disease scores as defined in outcome measure description |
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| UC and CD participants that did not meet improved disease activity score definitions |
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