Fundamental Modification of the Gut Microbiota in the Treatment of Refractory Crohn's Disease
Overview
- Phase
- Phase 2
- Intervention
- Fluconazole
- Conditions
- Crohn's Disease
- Sponsor
- University of Pennsylvania
- Enrollment
- 8
- Locations
- 1
- Primary Endpoint
- Change in Disease Activity by Harvey Bradshaw Index
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
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.
Investigators
Lindsey Albenberg
Assistant Professor of Pediatrics
University of Pennsylvania
Eligibility Criteria
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
Arms & Interventions
Fluconazole
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).
Intervention: Fluconazole
Fluconazole
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).
Intervention: Vancomycin
Fluconazole
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).
Intervention: Neomycin
Fluconazole
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).
Intervention: Ciprofloxacin
Fluconazole
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).
Intervention: Polyethylene Glycol 3350
Fluconazole
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).
Intervention: Promethazine
Placebo
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).
Intervention: Vancomycin
Placebo
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).
Intervention: Neomycin
Placebo
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).
Intervention: Ciprofloxacin
Placebo
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).
Intervention: Polyethylene Glycol 3350
Placebo
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).
Intervention: Promethazine
Placebo
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).
Intervention: Fluconazole placebo
Outcomes
Primary Outcomes
Change in Disease Activity by Harvey Bradshaw Index
Time Frame: enrollment visit (baseline) and 15 days
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
Change in Disease Activity by Fecal Calprotectin (FCP)
Time Frame: enrollment visit (baseline) and 15 days
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 Outcomes
- The Change in High-sensitivity C-reactive Protein (hsCRP)(enrollment visit (baseline) and 15 days)
- Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events (AEs).(105 days)