Crohn Disease
Conditions
Brief summary
The purpose of this study is to determine the effect of a novel gut microbiota-targeted therapeutic regimen (bowel lavage and antibiotics with or without an antifungal) in the management of active Crohn's Disease (CD) or indeterminate colitis (IBDU) that is refractory to conventional, immunosuppressive therapy. In addition, the study will determine the effect of PEG lavage alone on fecal calprotectin and gut microbiota in patients who are undergoing a PEG lavage for clinical care.
Detailed description
Investigators will evaluate the efficacy of a novel treatment regimen, employing non-immunosuppressive medications, in the management of refractory CD or IBDU. Refractory patients include those patients who have experienced loss of responsiveness (LOR) or primary nonresponse to an immunomodulator or a biologic. Investigators will treat participants with a combination of gut microbiota-targeted therapies to restore a healthy gut microbiome composition. Investigators believe that this strategy will both treat the gut inflammation associated with inflammatory bowel disease (IBD) as well as salvage response to immune suppressive therapies. Investigators will also evaluate the effect of PEG lavage alone on fecal calprotectin and gut microbiota. Participants in this arm, will be undergoing a PEG lavage in preparation for a endoscopy for clinical care. They will be asked to provide stool samples, prior to and after their PEG lavage. Participants will not be receiving any investigational treatments.
Interventions
DRUGVancomycin
Oral suspension 4 times daily (Day 1-14)
DRUGNeomycin
Oral three times daily (Days 1-3)
DRUGCiprofloxacin
Oral twice daily (Days 4-14)
DRUGPolyethylene Glycol 3350
Dissolved in Gatorade on day 2
DRUGFluconazole
Orally once daily (Day 1-14)
Sponsors
University of Pennsylvania
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Group 1 Inclusion Criteria: * Males or females 6-18 years of age * Current weight \>10 kg (or 22 lb) * Ability to swallow pills * Normal kidney function * Normal Aspartate transaminase (AST), Alanine transaminase (ALT), and alkaline phosphatase * Active CD or IBDU defined as PCDAI ≥ 30 * C-Reactive Protein (CRP) ≥ 15mg/L (or 1.5mg/dL) or fecal calprotectin (FCP)\>350mcg/g (within one month of enrollment) * Have been treated with one of the following therapies for at least 8 weeks with primary nonresponse or an initial response, followed by loss of response \[LOR\] (self-reported worsening of symptoms for ≥ 7 days): azathioprine, 6-mercaptopurine, methotrexate, adalimumab, certolizumab, golimumab, infliximab, natalizumab, vedolizumab, or ustekinumab \*\*These medications must have been administered at standard, therapeutic dosages.
Exclusion criteria
* Known allergy or intolerance to aminoglycosides or any of the medications used in this study * Current use of one or more of the following medications: 5-fluorouracil, digoxin, anticoagulants, theophylline, phenytoin, probenecid, duloxetine, clozapine, sildenafil, hydrochlorothiazide, cyclosporine, hypoglycemics, terfenadine, tacrolimus, rifabutin, midazolam, and voriconazole * Known diagnosis of diabetes mellitus * Known or suspected structuring disease producing obstructive symptoms * Active Clostridium difficile infection * Prolonged QTc interval as seen on enrollment EKG * Current use of antibiotics * Starting or increasing the dose of an IBD related medication within 4 weeks of screening Group 2 Inclusion Criteria * Males or females 10 years of age and older. * Patients undergoing a clinical GI endoscopy due to suspicion for active intestinal inflammation determined by physician global assessment (PGA). * Undergoing a bowel preparation as part of clinical care. * Parental/guardian permission (informed consent) and if appropriate, child assent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in FCP in Group 2 Participants | change from baseline to day 12 | Change in fecal calprotectin between stool samples collected at baseline and day 12 after procedure in Group 2 participants. |
| Change in Disease Activity by Pediatric Crohn's Disease Activity Index | Baseline, Day 15 | The primary endpoint will be the change in disease activity, as measured by Pediatric Crohn's Disease Activity Index (PCDAI) score, between the enrollment visit and Day 15. All participants who withdraw for any reason prior to day 15 will be considered treatment failures. The Pediatric Crohn's Disease Activity Index is a clinical score which takes into account general well being, degree of abdominal pain, number of liquid stools per day, abdominal physical examination, and Crohn's disease complications. |
| Change in Disease Activity by Fecal Calprotectin (FCP) | Baseline, Day 15 | The second primary outcome measure will be the change in disease activity, as measured by fecal calprotectin, between the enrollment visit and day 15. The fecal calprotectin is a stool test which measures intestinal inflammation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in C-reactive Protein (CRP) | Baseline, Day 15 | A secondary outcome measure will be the change in C-reactive protein between the enrollment visit and day 15. The C-reactive protein is a blood test which measures systemic inflammation. |
| Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events | 105 days | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1-Fluconazole Vancomycin oral suspension four times daily (Day 1-14), plus neomycin orally three times daily (Days 1-3), plus ciprofloxacin orally twice daily (Day 4-14), plus Polyethylene Glycol 3350 (Miralax) dissolved in Gatorade on day 2, plus fluconazole orally once daily (Day 1-14).
Vancomycin: Oral suspension 4 times daily (Day 1-14)
Neomycin: Oral three times daily (Days 1-3)
Ciprofloxacin: Oral twice daily (Days 4-14)
Polyethylene Glycol 3350: Dissolved in Gatorade on day 2
Fluconazole: Orally once daily (Day 1-14) | 0 |
| Group 1-Placebo Vancomycin oral suspension four times daily (Day 1-14), plus neomycin orally three times daily (Days 1-3), plus ciprofloxacin orally twice daily (Day 4-14), plus Polyethylene Glycol 3350 (Miralax) dissolved in Gatorade on day 2, plus placebo.
Vancomycin: Oral suspension 4 times daily (Day 1-14)
Neomycin: Oral three times daily (Days 1-3)
Ciprofloxacin: Oral twice daily (Days 4-14)
Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | 0 |
| Group 2 Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Group 2 | Total |
|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants |
| Age, Continuous | 16.5 years | 16.5 years |
| Calprotectin | 1254.5 mcg/g | 1254.5 mcg/g |
| Race and Ethnicity Not Collected | — | 0 Participants |
| Region of Enrollment United States | 10 participants | 10 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 | 0 / 10 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 10 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 10 |
Outcome results
Primary
Change in Disease Activity by Fecal Calprotectin (FCP)
The second primary outcome measure will be the change in disease activity, as measured by fecal calprotectin, between the enrollment visit and day 15. The fecal calprotectin is a stool test which measures intestinal inflammation.
Time frame: Baseline, Day 15
Population: This outcome was specific to Group 1 and Group 1 study was not completed.
Primary
Change in Disease Activity by Pediatric Crohn's Disease Activity Index
The primary endpoint will be the change in disease activity, as measured by Pediatric Crohn's Disease Activity Index (PCDAI) score, between the enrollment visit and Day 15. All participants who withdraw for any reason prior to day 15 will be considered treatment failures. The Pediatric Crohn's Disease Activity Index is a clinical score which takes into account general well being, degree of abdominal pain, number of liquid stools per day, abdominal physical examination, and Crohn's disease complications.
Time frame: Baseline, Day 15
Population: This outcome was specific to Group 1 and we did not enroll patients into Group1as an identical study was simultaneously enrolling adult patients and results from the adult study were sufficient to make a conclusion without enrolling children.
Primary
Change in FCP in Group 2 Participants
Change in fecal calprotectin between stool samples collected at baseline and day 12 after procedure in Group 2 participants.
Time frame: change from baseline to day 12
Population: Group 1 study was not done.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 2 | Change in FCP in Group 2 Participants | 1501 mcg/g |
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Change in C-reactive Protein (CRP)
A secondary outcome measure will be the change in C-reactive protein between the enrollment visit and day 15. The C-reactive protein is a blood test which measures systemic inflammation.
Time frame: Baseline, Day 15
Population: This outcome was specific to Group 1 and Group 1 study was not completed.
Secondary
Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events
Time frame: 105 days
Population: This outcome is specific to Group 1 and Group 1 study was not completed.