An Open-Label Pilot Study of Fundamental Modification of the Gut Microbiota in the Treatment of Refractory Crohn's Disease
Overview
- Phase
- Phase 2
- Intervention
- Vancomycin
- Conditions
- Crohn Disease
- Sponsor
- Children's Hospital of Philadelphia
- Enrollment
- 10
- Locations
- 1
- Primary Endpoint
- Change in FCP in Group 2 Participants
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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.
Investigators
Eligibility Criteria
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
- •Inclusion Criteria
- •Males or females 10 years of age and older.
Arms & Interventions
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).
Intervention: Vancomycin
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).
Intervention: Fluconazole
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).
Intervention: Neomycin
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).
Intervention: Ciprofloxacin
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).
Intervention: Polyethylene Glycol 3350
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.
Intervention: Vancomycin
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.
Intervention: Neomycin
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.
Intervention: Ciprofloxacin
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.
Intervention: Polyethylene Glycol 3350
Outcomes
Primary Outcomes
Change in FCP in Group 2 Participants
Time Frame: 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
Time Frame: 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)
Time Frame: 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 Outcomes
- Change in C-reactive Protein (CRP)(Baseline, Day 15)
- Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events(105 days)