Pilot Study of Fundamental Modification of the Gut Microbiota in the Treatment of Refractory Crohn's Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-Label Pilot Study of Fundamental Modification of the Gut Microbiota in the Treatment of Refractory Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: Vancomycin
* Drug: Neomycin
* Drug: Ciprofloxacin
* Drug: Polyethylene Glycol 3350
* Drug: Fluconazole


Participation Criteria
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Eligibility Criteria
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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. Exclusion Criteria Antibiotic use within the past 30 days. Current presence of an ostomy bag. Patients undergoing a non- polyethylene glycol 3350 cleanout. Unwillingness to provide informed consent. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1-Fluconazole<br>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). | Drug: Vancomycin<br>* Oral suspension 4 times daily (Day 1-14)<br>* Other names: Vancocin;Drug: Neomycin<br>* Oral three times daily (Days 1-3)<br>* Other names: Neo-Fradin;Drug: Ciprofloxacin<br>* Oral twice daily (Days 4-14)<br>* Other names: Cipro;Drug: Polyethylene Glycol 3350<br>* Dissolved in Gatorade on day 2<br>* Other names: Miralax;Drug: Fluconazole<br>* Orally once daily (Day 1-14)<br>* Other names: Diflucan;|
| Placebo Comparator: Group 1-Placebo<br>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. | Drug: Vancomycin<br>* Oral suspension 4 times daily (Day 1-14)<br>* Other names: Vancocin;Drug: Neomycin<br>* Oral three times daily (Days 1-3)<br>* Other names: Neo-Fradin;Drug: Ciprofloxacin<br>* Oral twice daily (Days 4-14)<br>* Other names: Cipro;Drug: Polyethylene Glycol 3350<br>* Dissolved in Gatorade on day 2<br>* Other names: Miralax;|
| No Intervention: Group 2<br>Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | change from baseline to day 12 | 
| 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. | Baseline, Day 15 | 
| 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. | Baseline, Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Day 15 | 
| Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events |  | 105 days |