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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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) that is refractory to conventional, immunosuppressive therapy.

Official Title
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Fundamental Modification of the Gut Microbiota in the Treatment of Refractory Crohn's Disease

Conditions
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Crohn's Disease

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is capable of giving informed consent Males or females 18-75 years of age Normal kidney function (defined by normal serum creatinine [male: <1.27 mg/dL; female: <1.03 mg/dL]) Normal aspartate aminotransferase [AST] (<41 U/L), alanine aminotransferase [ALT] (<63 U/L), and alkaline phosphatase (<126 U/L) Active CD defined as HBI ≥ 7 CRP > 5 mg/dL or hs-CRP > 10mg/L (or 1mg/dL) or fecal calprotectin (FCP) > - - 350 mcg/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 or suspected stricturing disease producing obstructive symptoms Active Clostridium difficile infection Unwillingness to provide informed consent Allergy or intolerance to the medications used in this study History of kidney disease History of liver disease Pregnant or lactating females Baseline QTc interval on EKG > 430 in males or > 450 in females Participants 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: 18 Years
Maximum Age: 75 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: Fluconazole<br>Vancomycin 500 mg oral suspension four times daily (Day 1-14), plus neomycin 1000 mg orally three times daily (Days 1-3), plus ciprofloxacin 750 mg orally twice daily (Day 4-14), plus Polyethylene Glycol 3350 (Miralax) 238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2, plus fluconazole 400 mg orally once daily (Day 1-14). PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3). | Drug: Fluconazole<br>* 400mg orally once daily (Day 1-14)<br>* Other names: Diflucan;Drug: Vancomycin<br>* 500mg oral suspension 4 times daily (Day 1-14)<br>* Other names: Vancocin;Drug: Neomycin<br>* neomycin 1000 mg orally three times daily (Days 1-3)<br>* Other names: Neo-Fradin;Drug: Ciprofloxacin<br>* ciprofloxacin 750 mg orally twice daily (Day 4-14)<br>* Other names: Cipro;Drug: Polyethylene Glycol 3350<br>* 238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2<br>* Other names: Miralax;Drug: Promethazine<br>* PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3).<br>* Other names: Phenergan;|
| Placebo Comparator: Placebo<br>Vancomycin 500 mg oral suspension four times daily (Day 1-14), plus neomycin 1000 mg orally three times daily (Days 1-3), plus ciprofloxacin 750 mg orally twice daily (Day 4-14), plus Polyethylene Glycol 3350 (Miralax) 238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2, plus placebo for fluconazole. PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3). | Drug: Vancomycin<br>* 500mg oral suspension 4 times daily (Day 1-14)<br>* Other names: Vancocin;Drug: Neomycin<br>* neomycin 1000 mg orally three times daily (Days 1-3)<br>* Other names: Neo-Fradin;Drug: Ciprofloxacin<br>* ciprofloxacin 750 mg orally twice daily (Day 4-14)<br>* Other names: Cipro;Drug: Polyethylene Glycol 3350<br>* 238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2<br>* Other names: Miralax;Drug: Promethazine<br>* PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3).<br>* Other names: Phenergan;Drug: Fluconazole placebo<br>* Once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Disease Activity by Harvey Bradshaw Index | The primary endpoint will be the change in disease activity, as measured by Harvey-Bradshaw Index (HBI) 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 HBI is a clinical score where points are given for each category below plus number of liquid bowel movements in previous day. A score of 3 or lower is considered remission. A score of 8 or higher is considered severe disease. General Well Being Very well 0 points Slightly below par 1 point Poor 2 points Very poor 3 points Terrible 4 points Abdominal Pain None 0 points Mild 1 point Moderate 2 points Severe 3 points Abdominal Mass None 0 points Dubious 1 point Definite 2 points Definite and tender 3 points Complications None 0 points Arthralgias +1 point Uveitis +1 point Erythema Nodosum + 1 point Aphthous ulcers +1 point Pyoderma Gangrenosum + 1 point Anal fissure + 1 point New fistula + 1 | enrollment visit (baseline) and 15 days | 
| 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. | enrollment visit (baseline) and 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change in High-sensitivity C-reactive Protein (hsCRP) | A secondary outcome measure will be the change in high-sensitivity C-reactive protein between the enrollment visit and day 15. The high-sensitivity C-reactive protein is a blood test which measures systemic inflammation. | enrollment visit (baseline) and 15 days | 
| Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events (AEs). | Number of Medication Side Effects and/or Adverse Events (AEs) | 105 days |