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This study will randomized hematology oncology patients with active diarrhea and a NAAT positive/toxin EIA negative to either 14 days of oral vancomycin capsules or placebo. The study is designed to include 30 patients (15 per arm).
Outcomes will include C. difficile load using qPCR, VRE loads, structural and functional microbiome changes and frequency of bowel movements. All endpoints will be measured at several time points including days 0, 14, 21 and 90.
The adverse health consequences resulting from antibiotic overtreatment of NAAT(+), toxin(-) patients may be particularly important in transplant recipients. The usual treatment prescribed for CDI at the Froedtert Memorial Lutheran Hospital is oral vancomycin. While this drug has excellent activity against C. difficile and commonly suppresses its growth to non-detection, it does not eradicate carriage and its use results in marked and prolonged disruption of the lower intestinal microbiota. Meanwhile, the degree of lower intestinal microbiota disruption at the time of HSCT engraftment has been demonstrated to be an independent predictor (controlling for other markers of underlying disease) of overall and transplant-related 3-year mortality.14 In addition, recent findings suggest that bone marrow suppressive effects of antibiotics, in this case potentially unnecessary oral vancomycin (which is not appreciably absorbed), may be solely mediated via microbiota disruption. All these data supports the notion that antibiotic treatment of NAAT(+), toxin(-) C. difficile patients might have significant negative repercussions without a clear clinical benefit.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vancomycin treated group | Active Comparator | This group will be given vancomycin oral capsules, 125 mg, every 6 hours, for 14 days. |
|
| Placebo group | Placebo Comparator | This group will be given placebo oral capsules every 6 hours for 14 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Vancomycin Oral Capsule | Drug | We have chosen oral vancomycin capsules as it is currently a standard of care for Clostridium difficile infections, is poorly absorbed by the intestines, and is easier to blind compared to oral vancomycin solution. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Clostridium Difficile Bacterial Loads in the Stool | Changes in Clostridium difficile bacterial counts from stool as determined by quantitative polymerase chain reaction (PCR). Values obtained from initial sample (pre-treatment) were compared with values from the last sample obtained for each patient. | First sample versus last stool sample collected, up to 90 days |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Silvia Munoz-Price, M.D., Ph.D. | Medical College of Wisconsin | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Froedtert and the Medical College of Wisconsin | Milwaukee | Wisconsin | 53226 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26061850 | Background | Lessa FC, Winston LG, McDonald LC; Emerging Infections Program C. difficile Surveillance Team. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015 Jun 11;372(24):2369-70. doi: 10.1056/NEJMc1505190. No abstract available. | |
| 26956066 | Background | Martin JS, Monaghan TM, Wilcox MH. Clostridium difficile infection: epidemiology, diagnosis and understanding transmission. Nat Rev Gastroenterol Hepatol. 2016 Apr;13(4):206-16. doi: 10.1038/nrgastro.2016.25. Epub 2016 Mar 9. |
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Participant data to be shared would consist of age categories, genders, treatment groups, Clostridium difficile status, microbiome profile and metabolic profile. The data will be anonymized to prevent the identification of individual patients from the data provided. The data would be made available through contacting the principal investigator directly.
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| ID | Title | Description |
|---|---|---|
| FG000 | Vancomycin Treated Group | This group will be given vancomycin oral capsules, 125 mg, every 6 hours, for 14 days. Vancomycin Oral Capsule: We have chosen oral vancomycin capsules as it is currently a standard of care for Clostridium difficile infections, is poorly absorbed by the intestines, and is easier to blind compared to oral vancomycin solution. |
| FG001 | Placebo Group | This group will be given placebo oral capsules every 6 hours for 14 days. Placebo Oral Capsule: A capsule containing gelatin, polyethylene glycol, titanium dioxide, iron oxide, and FD&C blue No. 2. Contains the inactive ingredients of the vancomycin oral capsule, as mixed by the Froedtert Health Research Pharmacy. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Vancomycin Treated Group | This group will be given vancomycin oral capsules, 125 mg, every 6 hours, for 14 days. Vancomycin Oral Capsule: We have chosen oral vancomycin capsules as it is currently a standard of care for Clostridium difficile infections, is poorly absorbed by the intestines, and is easier to blind compared to oral vancomycin solution. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes in Clostridium Difficile Bacterial Loads in the Stool | Changes in Clostridium difficile bacterial counts from stool as determined by quantitative polymerase chain reaction (PCR). Values obtained from initial sample (pre-treatment) were compared with values from the last sample obtained for each patient. | Only 4 participants in the vancomycin group were analyzed given that one failed to give stool samples. In the placebo group all first samples were available for all 4 participants; however, only 2 participants provided a follow up sample ("last sample"). | Posted | Mean | Standard Deviation | CFUs | First sample versus last stool sample collected, up to 90 days |
|
The time frame spanned from enrollment to off treatment (up to 90 days) or withdrawal from study, whatever happened first.
Our definition mirrored clinicaltrials.gov
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Vancomycin Treated Group | This group will be given vancomycin oral capsules, 125 mg, every 6 hours, for 14 days. Vancomycin Oral Capsule: We have chosen oral vancomycin capsules as it is currently a standard of care for Clostridium difficile infections, is poorly absorbed by the intestines, and is easier to blind compared to oral vancomycin solution. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| sepsis | Infections and infestations | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| abdominal pain | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| L. Silvia Munoz-Price, MD, PhD Enterprise Epidemiologist Professor of Medicine | Medical College of Wisconsin | 414-955-0483 | smunozprice@mcw.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 7, 2019 | Oct 13, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003015 | Clostridium Infections |
| D006402 | Hematologic Diseases |
| ID | Term |
|---|---|
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D014640 | Vancomycin |
| ID | Term |
|---|---|
| D006020 | Glycopeptides |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D010455 | Peptides |
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Patients will be divided into two groups, one receiving oral vancomycin capsules, the other receiving oral placebo capsules.
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The allocation status of patients within this study will be held in sealed envelopes by the unblinded research pharmacist on the team. Neither the main care provider, study physicians, or the patient will know of their group, until either the end of the study (after data analysis). We will also have a blinded pharmacist.
|
| Placebo Oral Capsule | Drug | A capsule containing gelatin, polyethylene glycol, titanium dioxide, iron oxide, and FD&C blue No. 2. Contains the inactive ingredients of the vancomycin oral capsule, as mixed by the Froedtert Health Research Pharmacy. |
|
| 24445449 | Background | Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM, Li B, Huffnagle GB, Z Li J, Young VB. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114. doi: 10.1038/ncomms4114. |
| 27239562 | Background | Theriot CM, Bowman AA, Young VB. Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine. mSphere. 2016 Jan 6;1(1):e00045-15. doi: 10.1128/mSphere.00045-15. eCollection 2016 Jan-Feb. |
| 19929371 | Background | Sethi AK, Al-Nassir WN, Nerandzic MM, Bobulsky GS, Donskey CJ. Persistence of skin contamination and environmental shedding of Clostridium difficile during and after treatment of C. difficile infection. Infect Control Hosp Epidemiol. 2010 Jan;31(1):21-7. doi: 10.1086/649016. |
| 27943501 | Result | Aldrete SD, Kraft CS, Magee MJ, Chan A, Hutcherson D, Langston AA, Greenwell BI, Burd EM, Friedman-Moraco R. Risk factors and epidemiology of Clostridium difficile infection in hematopoietic stem cell transplant recipients during the peritransplant period. Transpl Infect Dis. 2017 Feb;19(1):10.1111/tid.12649. doi: 10.1111/tid.12649. |
| 27707993 | Result | Isaac S, Scher JU, Djukovic A, Jimenez N, Littman DR, Abramson SB, Pamer EG, Ubeda C. Short- and long-term effects of oral vancomycin on the human intestinal microbiota. J Antimicrob Chemother. 2017 Jan;72(1):128-136. doi: 10.1093/jac/dkw383. Epub 2016 Oct 5. |
| 26348734 | Result | Polage CR, Gyorke CE, Kennedy MA, Leslie JL, Chin DL, Wang S, Nguyen HH, Huang B, Tang YW, Lee LW, Kim K, Taylor S, Romano PS, Panacek EA, Goodell PB, Solnick JV, Cohen SH. Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era. JAMA Intern Med. 2015 Nov;175(11):1792-801. doi: 10.1001/jamainternmed.2015.4114. |
| BG001 |
| Placebo Group |
This group will be given placebo oral capsules every 6 hours for 14 days. Placebo Oral Capsule: A capsule containing gelatin, polyethylene glycol, titanium dioxide, iron oxide, and FD&C blue No. 2. Contains the inactive ingredients of the vancomycin oral capsule, as mixed by the Froedtert Health Research Pharmacy. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo Group | This group will be given placebo oral capsules every 6 hours for 14 days. Placebo Oral Capsule: A capsule containing gelatin, polyethylene glycol, titanium dioxide, iron oxide, and FD&C blue No. 2. Contains the inactive ingredients of the vancomycin oral capsule, as mixed by the Froedtert Health Research Pharmacy. |
|
|
| 0 |
| 5 |
| 2 |
| 5 |
| 5 |
| 5 |
| EG001 | Placebo Group | This group will be given placebo oral capsules every 6 hours for 14 days. Placebo Oral Capsule: A capsule containing gelatin, polyethylene glycol, titanium dioxide, iron oxide, and FD&C blue No. 2. Contains the inactive ingredients of the vancomycin oral capsule, as mixed by the Froedtert Health Research Pharmacy. | 0 | 4 | 1 | 4 | 4 | 4 |
| Leukocytosis | Blood and lymphatic system disorders | Systematic Assessment |
|
| Hyperglycemia | Endocrine disorders | Systematic Assessment |
|
| Changes in hepatic function | Hepatobiliary disorders | Systematic Assessment | Hepatic lab disorders |
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| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Anorexia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Creatinine increase | Renal and urinary disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
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| Edema | General disorders | Systematic Assessment |
|
| Epistaxis | Blood and lymphatic system disorders | Systematic Assessment |
|
| Fever | Infections and infestations | Systematic Assessment |
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| Weakness | General disorders | Systematic Assessment |
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| Headache | General disorders | Systematic Assessment |
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| Hyperglycemia | Endocrine disorders | Systematic Assessment |
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| Hypernatremia | Metabolism and nutrition disorders | Systematic Assessment |
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| Hyponatremia | Metabolism and nutrition disorders | Systematic Assessment |
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| Hypophosphatemia | Metabolism and nutrition disorders | Systematic Assessment |
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| Mucositis | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| White count changes | Blood and lymphatic system disorders | Systematic Assessment | Either leukopenia or leukocytosis |
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| Vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Weight loss | General disorders | Systematic Assessment |
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| Platelet count abnormalities | Cardiac disorders | Systematic Assessment | Either increased or decreased levels beyond normal range |
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| Hypertension | Cardiac disorders | Systematic Assessment |
|
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| D006425 | Hemic and Lymphatic Diseases |
| D000602 |
| Amino Acids, Peptides, and Proteins |