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

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

Primary outcomes

• Change in Disease Activity by Harvey Bradshaw Index [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) [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]: 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.
• Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events (AEs). [105 days]: Number of Medication Side Effects and/or Adverse Events (AEs)

Sex: All, ages: 18 Years to 75 Years

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

Participant flow

Outcome results

• Change in Disease Activity by Harvey Bradshaw Index (Primary), Median, score on a scale: Fluconazole -5 (-7 to 0); Placebo -3 (-8 to -2)
• Change in Disease Activity by Fecal Calprotectin (FCP) (Primary), Median, mcg/g: Fluconazole -16.5 (-116.48 to 94); Placebo -380.5 (-1234 to -1)
• The Change in High-sensitivity C-reactive Protein (hsCRP) (Secondary), Median, mg/dL: Fluconazole 4.1 (1.1 to 8.3); Placebo -2 (-2.9 to 1.6)
• Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events (AEs). (Secondary), Number, Events: Fluconazole 31; Placebo 12

Adverse events

Time frame: 105 days

Other adverse events by term

Limitations and caveats: Recruitment was difficult due to intensive methods with large number of/frequent study visits required. Small sample size is a major limitation.

• Study Protocol and Statistical Analysis Plan (PDF, 2017-08-11)

• Lindsey Albenberg, DO, Principal investigator, University of Pennsylvania
• James D Lewis, MD, MSCE, Principal investigator, University of Pennsylvania