Crohn's Disease
Conditions
Brief summary
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.
Interventions
DRUGFluconazole
400mg orally once daily (Day 1-14)
DRUGVancomycin
500mg oral suspension 4 times daily (Day 1-14)
DRUGNeomycin
neomycin 1000 mg orally three times daily (Days 1-3)
DRUGCiprofloxacin
ciprofloxacin 750 mg orally twice daily (Day 4-14)
DRUGPolyethylene Glycol 3350
238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2
DRUGPromethazine
PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3).
DRUGFluconazole placebo
Once daily
Sponsors
Children's Hospital of Philadelphia
Crohn's and Colitis Foundation
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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).
Fluconazole: 400mg orally once daily (Day 1-14)
Vancomycin: 500mg oral suspension 4 times daily (Day 1-14)
Neomycin: neomycin 1000 mg orally three times daily (Days 1-3)
Ciprofloxacin: ciprofloxacin 750 mg orally twice daily (Day 4-14)
Polyethylene Glycol 3350: 238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2
Promethazine: PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3). | 4 |
| 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).
Vancomycin: 500mg oral suspension 4 times daily (Day 1-14)
Neomycin: neomycin 1000 mg orally three times daily (Days 1-3)
Ciprofloxacin: ciprofloxacin 750 mg orally twice daily (Day 4-14)
Polyethylene Glycol 3350: 238 g dissolved in 64 ounces of Gatorade or Crystal Lite on day 2
Promethazine: PRN (as needed) Promethazine 12.5mg up to every four hours (Days 1-3).
Fluconazole placebo: Once daily | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Placebo | Total | Fluconazole |
|---|---|---|---|
| Age, Continuous | 32.5 years | 39.5 years | 44 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 4 participants | 8 participants | 4 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 4 / 4 | 3 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
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.
Time frame: enrollment visit (baseline) and 15 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fluconazole | Change in Disease Activity by Fecal Calprotectin (FCP) | -16.5 mcg/g |
| Placebo | Change in Disease Activity by Fecal Calprotectin (FCP) | -380.5 mcg/g |
Primary
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
Time frame: enrollment visit (baseline) and 15 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fluconazole | Change in Disease Activity by Harvey Bradshaw Index | -5 score on a scale |
| Placebo | Change in Disease Activity by Harvey Bradshaw Index | -3 score on a scale |
Secondary
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)
Time frame: 105 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events (AEs). | 31 Events |
| Placebo | Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events (AEs). | 12 Events |
Secondary
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.
Time frame: enrollment visit (baseline) and 15 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fluconazole | The Change in High-sensitivity C-reactive Protein (hsCRP) | 4.1 mg/dL |
| Placebo | The Change in High-sensitivity C-reactive Protein (hsCRP) | -2 mg/dL |