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

Phase 2

Completed

Conditions: Crohn Disease

Interventions: Drug: Vancomycin
Drug: Neomycin
Drug: Ciprofloxacin
Drug: Polyethylene Glycol 3350
Drug: Fluconazole

Registration Number: NCT03476317

Lead Sponsor: Children's Hospital of Philadelphia

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1-Placebo	Neomycin	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.
Group 1-Fluconazole	Neomycin	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).
Group 1-Fluconazole	Vancomycin	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).
Group 1-Fluconazole	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).
Group 1-Fluconazole	Ciprofloxacin	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).
Group 1-Fluconazole	Polyethylene Glycol 3350	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).
Group 1-Placebo	Vancomycin	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.
Group 1-Placebo	Polyethylene Glycol 3350	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.
Group 1-Placebo	Ciprofloxacin	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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