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

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

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.

Study Overview

• Status: Completed
• Conditions: Crohn Disease
• Intervention / Treatment: Drug: Vancomycin; Drug: Neomycin; Drug: Ciprofloxacin; Drug: Polyethylene Glycol 3350; Drug: Fluconazole

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19146
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Vancomycin; Oral suspension 4 times daily (Day 1-14); Other Names: Vancocin; Drug: Neomycin; Oral three times daily (Days 1-3); Other Names: Neo-Fradin; Drug: Ciprofloxacin; Oral twice daily (Days 4-14); Other Names: Cipro; Drug: Polyethylene Glycol 3350; Dissolved in Gatorade on day 2; Other Names: Miralax; Drug: Fluconazole; Orally once daily (Day 1-14); Other Names: Diflucan
Placebo Comparator: 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.	Drug: Vancomycin; Oral suspension 4 times daily (Day 1-14); Other Names: Vancocin; Drug: Neomycin; Oral three times daily (Days 1-3); Other Names: Neo-Fradin; Drug: Ciprofloxacin; Oral twice daily (Days 4-14); Other Names: Cipro; Drug: Polyethylene Glycol 3350; Dissolved in Gatorade on day 2; Other Names: Miralax
No Intervention: Group 2; 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?

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

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Pennsylvania
• Investigators: Principal Investigator: Lindsey Albenberg, DO, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2018
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: January 8, 2018
• First Submitted That Met QC Criteria: March 19, 2018
• First Posted (Actual): March 26, 2018

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: February 8, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Gastrointestinal Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Laxatives; Cytochrome P-450 CYP2C19 Inhibitors; Vancomycin; Ciprofloxacin; Neomycin; Fluconazole; Polyethylene glycol 3350
• Other Study ID Numbers: 17-014343; 5K23DK109136-02 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes