Holiday: Pilot Study of Fundamental Modification of the Gut Microbiota in the Treatment of Refractory Crohn's Disease
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
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 Design
Arms and Interventions
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:
Drug: Neomycin
Oral three times daily (Days 1-3)
Other Names:
Drug: Ciprofloxacin
Oral twice daily (Days 4-14)
Other Names:
Drug: Polyethylene Glycol 3350
Dissolved in Gatorade on day 2
Other Names:
Drug: Fluconazole
Orally once daily (Day 1-14)
Other Names:
|
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:
Drug: Neomycin
Oral three times daily (Days 1-3)
Other Names:
Drug: Ciprofloxacin
Oral twice daily (Days 4-14)
Other Names:
Drug: Polyethylene Glycol 3350
Dissolved in Gatorade on day 2
Other Names:
|
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. |
Outcome Measures
Primary Outcome Measures
- 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
- 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]
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19146 |
Sponsors and Collaborators
- Children's Hospital of Philadelphia
- University of Pennsylvania
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Lindsey Albenberg, DO, Children's Hospital of Philadelphia
Study Documents (Full-Text)
More Information
Publications
None provided.- 17-014343
- 5K23DK109136-02
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Group 1-Fluconazole | Group 1-Placebo | Group 2 |
---|---|---|---|
Arm/Group Description | 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). Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 Fluconazole: Orally once daily (Day 1-14) | 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. Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. |
Period Title: Overall Study | |||
STARTED | 0 | 0 | 10 |
COMPLETED | 0 | 0 | 10 |
NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
Arm/Group Title | Group 1-Fluconazole | Group 1-Placebo | Group 2 | Total |
---|---|---|---|---|
Arm/Group Description | 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). Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 Fluconazole: Orally once daily (Day 1-14) | 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. Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. | Total of all reporting groups |
Overall Participants | 0 | 0 | 10 | 10 |
Age (Count of Participants) | ||||
<=18 years |
9
Infinity
|
9
Infinity
|
||
Between 18 and 65 years |
1
Infinity
|
1
Infinity
|
||
>=65 years |
0
NaN
|
0
NaN
|
||
Age (years) [Median (Full Range) ] | ||||
Median (Full Range) [years] |
16.5
|
16.5
|
||
Sex: Female, Male (Count of Participants) | ||||
Female |
2
Infinity
|
2
Infinity
|
||
Male |
8
Infinity
|
8
Infinity
|
||
Race and Ethnicity Not Collected (Count of Participants) | ||||
Count of Participants [Participants] |
0
NaN
|
|||
Region of Enrollment (participants) [Number] | ||||
United States |
10
Infinity
|
10
Infinity
|
||
Calprotectin (mcg/g) [Median (Full Range) ] | ||||
Median (Full Range) [mcg/g] |
1254.5
|
1254.5
|
Outcome Measures
Title | Change in FCP in Group 2 Participants |
---|---|
Description | Change in fecal calprotectin between stool samples collected at baseline and day 12 after procedure in Group 2 participants. |
Time Frame | change from baseline to day 12 |
Outcome Measure Data
Analysis Population Description |
---|
Group 1 study was not done. |
Arm/Group Title | Group 1-Fluconazole | Group 1-Placebo | Group 2 |
---|---|---|---|
Arm/Group Description | 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). Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 Fluconazole: Orally once daily (Day 1-14) | 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. Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. |
Measure Participants | 0 | 0 | 10 |
Median (Full Range) [mcg/g] |
1501
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Group 2 |
---|---|---|
Comments | ||
Type of Statistical Test | Equivalence | |
Comments | Median difference in calprotectin for controls from day 12 to baseline | |
Statistical Test of Hypothesis | p-Value | 1.0 |
Comments | ||
Method | Wilcoxon (Mann-Whitney) | |
Comments |
Title | Change in Disease Activity by Pediatric Crohn's Disease Activity Index |
---|---|
Description | 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. |
Time Frame | Baseline, Day 15 |
Outcome Measure Data
Analysis Population Description |
---|
This outcome was specific to Group 1 and we did not enroll patients into Group1as an identical study was simultaneously enrolling adult patients and results from the adult study were sufficient to make a conclusion without enrolling children. |
Arm/Group Title | Group 1-Fluconazole | Group 1-Placebo | Group 2 |
---|---|---|---|
Arm/Group Description | 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). Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 Fluconazole: Orally once daily (Day 1-14) | 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. Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. |
Measure Participants | 0 | 0 | 0 |
Title | Change in Disease Activity by Fecal Calprotectin (FCP) |
---|---|
Description | 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 | Baseline, Day 15 |
Outcome Measure Data
Analysis Population Description |
---|
This outcome was specific to Group 1 and Group 1 study was not completed. |
Arm/Group Title | Group 1-Fluconazole | Group 1-Placebo | Group 2 |
---|---|---|---|
Arm/Group Description | 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). Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 Fluconazole: Orally once daily (Day 1-14) | 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. Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. |
Measure Participants | 0 | 0 | 0 |
Title | Change in C-reactive Protein (CRP) |
---|---|
Description | 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. |
Time Frame | Baseline, Day 15 |
Outcome Measure Data
Analysis Population Description |
---|
This outcome was specific to Group 1 and Group 1 study was not completed. |
Arm/Group Title | Group 1-Fluconazole | Group 1-Placebo | Group 2 |
---|---|---|---|
Arm/Group Description | 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). Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 Fluconazole: Orally once daily (Day 1-14) | 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. Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. |
Measure Participants | 0 | 0 | 0 |
Title | Safety and Tolerability of the Treatment Regimen Based on Medication Side Effects and/or Adverse Events |
---|---|
Description | |
Time Frame | 105 days |
Outcome Measure Data
Analysis Population Description |
---|
This outcome is specific to Group 1 and Group 1 study was not completed. |
Arm/Group Title | Group 1-Fluconazole | Group 1-Placebo | Group 2 |
---|---|---|---|
Arm/Group Description | 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). Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 Fluconazole: Orally once daily (Day 1-14) | 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. Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. |
Measure Participants | 0 | 0 | 0 |
Adverse Events
Time Frame | 14 days | |||||
---|---|---|---|---|---|---|
Adverse Event Reporting Description | Group 1 study was not completed | |||||
Arm/Group Title | Group 1-Fluconazole | Group 1-Placebo | Group 2 | |||
Arm/Group Description | 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). Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 Fluconazole: Orally once daily (Day 1-14) | 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. Vancomycin: Oral suspension 4 times daily (Day 1-14) Neomycin: Oral three times daily (Days 1-3) Ciprofloxacin: Oral twice daily (Days 4-14) Polyethylene Glycol 3350: Dissolved in Gatorade on day 2 | Collect stool samples for calprotectin in patients undergoing colonoscopy for clinical care to evaluate effect of bowel lavage alone on calprotectin. | |||
All Cause Mortality |
||||||
Group 1-Fluconazole | Group 1-Placebo | Group 2 | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/0 (NaN) | 0/0 (NaN) | 0/10 (0%) | |||
Serious Adverse Events |
||||||
Group 1-Fluconazole | Group 1-Placebo | Group 2 | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/0 (NaN) | 0/0 (NaN) | 0/10 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
Group 1-Fluconazole | Group 1-Placebo | Group 2 | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/0 (NaN) | 0/0 (NaN) | 0/10 (0%) |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Lindsey Albenberg, DO |
---|---|
Organization | Children's Hospital of Philadelphia |
Phone | 267-426-0139 |
albenbergl@chop.edu |
- 17-014343
- 5K23DK109136-02