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

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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Fluconazole; 400mg orally once daily (Day 1-14); Other Names: Diflucan; Drug: Vancomycin; 500mg oral suspension 4 times daily (Day 1-14); Other Names: Vancocin; Drug: Neomycin; neomycin 1000 mg orally three times daily (Days 1-3); Other Names: Neo-Fradin; Drug: Ciprofloxacin; ciprofloxacin 750 mg orally twice daily (Day 4-14); Other Names: Cipro; Drug: Polyethylene Glycol 3350; 238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2; Other Names: Miralax; Drug: Promethazine; PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3).; Other Names: Phenergan
Placebo Comparator: 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).	Drug: Vancomycin; 500mg oral suspension 4 times daily (Day 1-14); Other Names: Vancocin; Drug: Neomycin; neomycin 1000 mg orally three times daily (Days 1-3); Other Names: Neo-Fradin; Drug: Ciprofloxacin; ciprofloxacin 750 mg orally twice daily (Day 4-14); Other Names: Cipro; Drug: Polyethylene Glycol 3350; 238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2; Other Names: Miralax; Drug: Promethazine; PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3).; Other Names: Phenergan; Drug: Fluconazole placebo; Once daily

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Children's Hospital of Philadelphia; Crohn's and Colitis Foundation
• Investigators: Principal Investigator: Lindsey Albenberg, DO, University of Pennsylvania; Principal Investigator: James D Lewis, MD, MSCE, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: May 2, 2016
• First Submitted That Met QC Criteria: May 3, 2016
• First Posted (Estimated): May 6, 2016

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 2, 2024
• Last Verified: February 1, 2024

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; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Anesthetics; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Anti-Bacterial Agents; Hypnotics and Sedatives; Cytochrome P-450 Enzyme Inhibitors; Anesthetics, Local; Protein Synthesis Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Laxatives; Cytochrome P-450 CYP2C19 Inhibitors; Vancomycin; Diphenhydramine; Promethazine; Ciprofloxacin; Neomycin; Fluconazole; Polyethylene glycol 3350
• Other Study ID Numbers: 823635