Inflammatory Bowel Diseases, Ulcerative Colitis, Crohn Disease
Conditions
Keywords
Colitis, Fecal Microbiota Transplant, Ulcerative colitis, inflammatory bowel disease, Crohn's Disease
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALFecal 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.
BIOLOGICALPlacebo
Placebo administration will consist of both a placebo retention enema and placebo capsules.
Sponsors
Stacy A. Kahn
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
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: 1. Have UC (PUCAI \>9) or CD (PDCAI \>10) and have failed, are intolerant to, or have refused first-line maintenance therapy. 2. Have had visual or histologic evidence of inflammation confirmed through colonoscopy no more than 105 days prior to randomization. 3. Have negative test results for Hepatitis B (HBV), Hepatitis C (HCV), and Human Immunodeficiency Virus (HIV). 4. Have a negative urine hCG test if female of childbearing potential. 5. Able to swallow antibiotic, FMT or placebo capsules. 6. Able to give informed consent and/or assent as appropriate (patients 12-17 will be asked to provide written assent, patients 5-11 will be observed for assent or dissent behaviorally, or with verbal/written communication) 7. Willing and able to participate in the study requirements, including serial stool collection, survey completion and clinic visits. 8. Willing to undergo telephone follow-up to assess for safety and adverse events. 9. Must be free of any known food allergy. 10. Agrees and willing to have an enema for purposes of induction therapy. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1. Safety and Tolerability of Universal Donor FMT Compared to Placebo: FMT-related Adverse Events Grade 2 or Above | At 8 weeks after start of FMT up to 6 months post treatment, an average of 10 months | Number of participants with FMT-related adverse events grade 2 or above experienced in each arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission of Disease | At all intermediate timepoints until 6 month follow up post intervention, an average of 10 months | Remission as defined by a PUCAI score of less than 9 (for UC) or by a PCDAI score of less than 10 (for CD) |
| Improvement in Inflammatory Biomarkers | At End of Treatment (8 weeks) and at 6 month post treatment | Improvement in inflammatory biomarkers (stool calprotectin, serum ESR, CRP, albumin, hematocrit) compared to baseline. |
| Percentage of Donor Microbiome Present in Transplant Recipient | At two weeks and seven weeks post induction enema | 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. |
| Number of Participants With Improvement in Disease Activity | At 8 weeks after start of FMT | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 8 |
| 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. | 5 |
| Total | 13 |
Baseline characteristics
| Characteristic | Fecal Microbiota Transplant (FMT) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 5 Participants | 13 Participants |
| Region of Enrollment United States | 8 participants | 5 participants | 13 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 5 |
| other Total, other adverse events | 6 / 12 | 1 / 5 |
| serious Total, serious adverse events | 3 / 12 | 0 / 5 |
Outcome results
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.
Time frame: At 8 weeks after start of FMT up to 6 months post treatment, an average of 10 months
Population: Participants who received FMT or placebo, completed the study, and follow up data is available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fecal Microbiota Transplant (FMT) | 1. Safety and Tolerability of Universal Donor FMT Compared to Placebo: FMT-related Adverse Events Grade 2 or Above | 4 Participants |
| Placebo | 1. Safety and Tolerability of Universal Donor FMT Compared to Placebo: FMT-related Adverse Events Grade 2 or Above | 0 Participants |
Secondary
Improvement in Inflammatory Biomarkers
Improvement in inflammatory biomarkers (stool calprotectin, serum ESR, CRP, albumin, hematocrit) compared to baseline.
Time frame: At End of Treatment (8 weeks) and at 6 month post treatment
Population: Participants who received FMT or placebo, completed the study, and follow up data is available.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fecal Microbiota Transplant (FMT) | Improvement in Inflammatory Biomarkers | Decrease in ESR at 8 weeks | 0 Participants |
| Fecal Microbiota Transplant (FMT) | Improvement in Inflammatory Biomarkers | Decrease in Fecal Calprotectin at 6 months | 1 Participants |
| Fecal Microbiota Transplant (FMT) | Improvement in Inflammatory Biomarkers | Decrease in ESR at 6 months | 2 Participants |
| Fecal Microbiota Transplant (FMT) | Improvement in Inflammatory Biomarkers | Decrease in CRP at 8 weeks | 1 Participants |
| Fecal Microbiota Transplant (FMT) | Improvement in Inflammatory Biomarkers | Decrease in CRP at 6 months | 1 Participants |
| Fecal Microbiota Transplant (FMT) | Improvement in Inflammatory Biomarkers | Decrease in Fecal Calprotectin at 8 weeks | 1 Participants |
| Placebo | Improvement in Inflammatory Biomarkers | Decrease in Fecal Calprotectin at 8 weeks | 3 Participants |
| Placebo | Improvement in Inflammatory Biomarkers | Decrease in ESR at 8 weeks | 0 Participants |
| Placebo | Improvement in Inflammatory Biomarkers | Decrease in CRP at 6 months | 0 Participants |
| Placebo | Improvement in Inflammatory Biomarkers | Decrease in CRP at 8 weeks | 2 Participants |
| Placebo | Improvement in Inflammatory Biomarkers | Decrease in ESR at 6 months | 0 Participants |
| Placebo | Improvement in Inflammatory Biomarkers | Decrease in Fecal Calprotectin at 6 months | 0 Participants |
| Fecal Microbiota Transplant (FMT) Ulcerative Colitis | Improvement in Inflammatory Biomarkers | Decrease in ESR at 6 months | 0 Participants |
| Fecal Microbiota Transplant (FMT) Ulcerative Colitis | Improvement in Inflammatory Biomarkers | Decrease in Fecal Calprotectin at 8 weeks | 1 Participants |
| Fecal Microbiota Transplant (FMT) Ulcerative Colitis | Improvement in Inflammatory Biomarkers | Decrease in Fecal Calprotectin at 6 months | 2 Participants |
| Fecal Microbiota Transplant (FMT) Ulcerative Colitis | Improvement in Inflammatory Biomarkers | Decrease in CRP at 6 months | 1 Participants |
| Fecal Microbiota Transplant (FMT) Ulcerative Colitis | Improvement in Inflammatory Biomarkers | Decrease in ESR at 8 weeks | 0 Participants |
| Fecal Microbiota Transplant (FMT) Ulcerative Colitis | Improvement in Inflammatory Biomarkers | Decrease in CRP at 8 weeks | 0 Participants |
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.
Time frame: At 8 weeks after start of FMT
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fecal Microbiota Transplant (FMT) | Number of Participants With Improvement in Disease Activity | UC Participants with improved disease scores as defined in outcome measure description | 2 Participants |
| Fecal Microbiota Transplant (FMT) | Number of Participants With Improvement in Disease Activity | CD Participants with improved disease scores as defined in outcome measure description | 1 Participants |
| Fecal Microbiota Transplant (FMT) | Number of Participants With Improvement in Disease Activity | UC and CD participants that did not meet improved disease activity score definitions | 3 Participants |
| Placebo | Number of Participants With Improvement in Disease Activity | UC Participants with improved disease scores as defined in outcome measure description | 0 Participants |
| Placebo | Number of Participants With Improvement in Disease Activity | CD Participants with improved disease scores as defined in outcome measure description | 0 Participants |
| Placebo | Number of Participants With Improvement in Disease Activity | UC and CD participants that did not meet improved disease activity score definitions | 5 Participants |
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.
Time frame: At two weeks and seven weeks post induction enema
Population: Participants who received FMT or placebo, completed the study, and follow up data is available.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Fecal Microbiota Transplant (FMT) | Percentage of Donor Microbiome Present in Transplant Recipient | Engraftment at 2 weeks | 74.8 percentage of donor microbiome present |
| Fecal Microbiota Transplant (FMT) | Percentage of Donor Microbiome Present in Transplant Recipient | Engraftment at 7 weeks | 68.3 percentage of donor microbiome present |
| Placebo | Percentage of Donor Microbiome Present in Transplant Recipient | Engraftment at 2 weeks | 41.8 percentage of donor microbiome present |
| Placebo | Percentage of Donor Microbiome Present in Transplant Recipient | Engraftment at 7 weeks | 47.9 percentage of donor microbiome present |
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)
Time frame: At all intermediate timepoints until 6 month follow up post intervention, an average of 10 months
Population: Participants who received FMT or placebo, completed the study, and follow up data is available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fecal Microbiota Transplant (FMT) | Remission of Disease | 1 Participants |
| Placebo | Remission of Disease | 0 Participants |
| Fecal Microbiota Transplant (FMT) Ulcerative Colitis | Remission of Disease | 2 Participants |
| Placebo Ulcerative Colitis | Remission of Disease | 0 Participants |