Safety and Efficacy of FMT in Individuals With One or More Recurrences of Clostridium Difficile Associated Disease (CDAD)

Study Overview
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Brief Summary
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Multi-center, randomized, placebo controlled, partially blinded trial comparing the safety and efficacy of fecal microbiota transplantation versus placebo both delivered by rectal enema in subjects 18 years of age or older with recurrent Clostridium difficile Associated Disease (CDAD). 162 male or female subjects will be enrolled in the study. Enrolled subjects will be randomized at each site to receive either FMT by enema or placebo by enema in a 2:1 ratio. Study duration is 3 years, subject participation duration is approximately 1 year. The primary study objectives are: 1) to evaluate the safety of FMT(s) delivered by enema vs. placebo delivered by enema and 2) to determine efficacy of FMT delivered by enema vs. placebo delivered by enema.

Detailed Description
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This is a multi-center, randomized, placebo controlled, partially blinded trial comparing the safety and efficacy of fecal microbiota transplantation versus placebo both delivered by rectal enema in subjects 18 years of age or older with recurrent Clostridium difficile Associated Disease (CDAD). 162 (108 in the FMT group, 54 in the placebo group) male or female subjects will be enrolled in the study. Subjects must have had treatment for most recent CDAD with at least 10 days of either metronidazole po/IV (500 mg tid), oral vancomycin (at least 125 mg qid), or oral fidaxomicin (200 mg bid) and have no diarrheal symptoms (<3 unformed stools per 24 hour period) off antibiotics during the washout period. Enrolled subjects will be randomized at each site to receive either FMT by enema or placebo by enema in a 2:1 ratio. The study is described as partially blinded because by design subjects are to be blinded only to a certain point. Subjects will be followed for clinical response (efficacy) and safety. The study duration is 3 years, subject participation duration is approximately 1 year. The primary study objectives are: 1) to evaluate the safety of FMT(s) delivered by enema vs. placebo delivered by enema and 2) to determine efficacy of FMT delivered by enema vs. placebo delivered by enema. Secondary objectives: 1) to evaluate the sustained clinical response rate of FMTs delivered by enema vs. placebo delivered by enema, 2) to evaluate the rate of recurrent CDAD, and 3) to evaluate the time to recurrent CDAD.

Official Title
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Phase 1/2 Placebo Controlled, Partially-Blinded Clinical Trial to Assess the Safety and Efficacy of Microbial Restoration by Enema With Banked and Thawed Processed Stool in Individuals With One or More Recurrences of Clostridium Difficile Associated Disease (CDAD)

Conditions
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Clostridial Infection, Dysbiosis, Probiotic Therapy

Intervention / Treatment
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* Procedure: Fecal Microbiota Transplantation (FMT)
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Providing permission to access the medical record. Male or non-pregnant female 18 years or older at the time of enrollment. Able to provide signed and dated informed consent. = / > 2 episodes of Clostridium difficile Associated Disease (CDAD) in the past 12 months, including the last episode if present at screening*. *Defined by = / > 1 confirmed positive CDAD by diagnostic methods and another occurrence substantiated by medical history. Completed treatment course of at least 10 days of oral vancomycin, oral/IV metronidazole, or oral fidaxomicin for the most recent episode prior to enrollment. Controlled diarrheal symptoms (<3 unformed stools per 24 consecutive hour period). Deemed likely to survive for 1 year after enrollment. Women of childbearing potential* in sexual relationships with men must use an acceptable method of contraception** from 30 days prior to enrollment until 4 weeks after completing study treatment. *Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or < 1 year of the last menses if menopausal. Also includes females who are postmenopausal < 1 year. **Includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study enrollment), intercourse with men who underwent vasectomy. Males must agree to avoid impregnation of women between Day 1 and 28 days following each administration of the study product. Negative urine or serum pregnancy test within 24 hours of enrollment and randomization. Is able to provide blood and fecal specimens. Is able to complete a test of comprehension. Exclusion Criteria: Previous fecal microbiota transplantation (FMT) within the previous 12 months prior to study enrollment. Any heart, lung, pancreas, or intestinal transplant recipient or any HIV positive transplant recipient.* *not excluded from the trial are subjects who are kidney, liver, or liver/kidney transplant recipients AND are more than 6 months from transplantation AND have not had a rejection episode in the past 6 months AND have been stable on immunosuppressive regimen for the past 6 months (any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, will not be considered a deviation of this criterion) Requiring antibiotics in the past 2 weeks prior to receiving the enema for a condition other than CDAD or scheduled to be used in the upcoming 2 weeks. Unable to tolerate enema for any reason. Any GI cancer in the past 6 months or any actively treated malignancy.*,** *Not excluded from the trial are subjects with actively treated basal and squamous cell cancers without any systemic treatment. **Subjects with recently treated malignancy (past 2 months) should have an absolute neutrophil count = / > 1000 /µL since treatment. Subjects with leukemia can not be enrolled in the study. Patients with a history of severe anaphylactic food allergy. Patients with decompensated cirrhosis.* *Decompensated cirrhosis is defined as cirrhosis with any history of the following: variceal hemorrhage, ascites, spontaneous bacterial peritonitis, hepatocellular carcinoma, hepatorenal syndrome, or hepatopulmonary syndrome. Untreated HIV disease.* *If no HIV screening results are available in the medical record from within the last six months, a HIV screening test will be performed during screening. Other severe immunosuppression or immunodeficiency conditions.* *not excluded from the trial are, subjects who take daily dose of systemic corticosteroid equivalent to <20mg prednisone for any duration, or = / > 20 mg prednisone for <14 days, or alternate-day corticosteroid therapy at any dose, OR methotrexate < / = 0.4 mg/kg/week, OR azathioprine < / = 3 mg/kg/day, OR 6-mercaptopurine < / = 1.5 mg/kg/day. Severe OR acute disease at the time of enrollment.* *Temperature >100.4 degrees Fahrenheit (38.0 degrees Celsius) or heart rate less than 45 bpm or greater than 130 bpm, or systolic blood pressure less than 80 mm Hg or greater than 155 mm Hg, or diastolic blood pressure greater than 100 mm Hg, or at the discretion of the investigator. Major surgery of the GI tract in the past 2 months. Having a non tolerance* to or any component of vancomycin, loperamide or GoLYTELY. *tolerance is defined as the absence of immunoglobulin E-mediated allergy (e.g., urticaria, angioedema, bronchospasm, or anaphylaxis) and the absence of severe allergy (e.g., Stevens-Johnson syndrome/toxic epidermal necrolysis). Active* inflammatory bowel disease (IBD) including ulcerative colitis, Crohn's disease, indeterminate colitis or celiac disease. *Active IBD is defined as any IBD requiring any steroid use in the past 6 months OR any increase in dose or frequency of medications in the past 6 months (any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, will not be considered a deviation of this criterion). Uncontrolled irritable bowel syndrome (IBS)* or any active uncontrolled gastrointestinal disorders or diseases.** *Uncontrolled IBS refers to any IBS with diarrhea on average more than once a week for the past 3 months prior to last CDAD episode. **GI obstruction, ileus, gastric retention, bowel perforation, toxic colitis or toxic megacolon, persistent infectious gastroenteritis, persistent or chronic diarrhea of unknown etiology, or refractory/severe Clostridium difficile infection (severe CDAD identified as leukocytosis with a white blood cell count greater than 15,000 cells/mL or an increase in the serum creatinine level to 1.5 times the premorbid level), chronic diarrhea of unknown cause for 6 weeks or more. Unable to comply with protocol requirements. Participation in any other clinical drug research trial within 30 days prior to enrollment or for 1 year after enrollment that might interfere with the safety and efficacy assessment. A condition that would jeopardize the safety or rights of the subject, would make it unlikely for the subject to complete the study, or would confound the results of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FMT group<br>100 grams of thawed processed stool diluted into 250 ml of saline and delivered by retention enema given 1-3 hours after loperamide 4 mg po x 1, n=108 | Procedure: Fecal Microbiota Transplantation (FMT)<br>* 100 grams of thawed processed stool diluted into 250 ml of saline and delivered by retention enema<br>|
| Experimental: Placebo group<br>250 ml of saline delivered by retention enema given 1-3 hours after loperamide 4 mg po x 1; if no improvement followed by FMT (100 grams of thawed processed stool diluted into 250 ml of saline and delivered by retention enema given 1-3 hours after loperamide 4 mg po x 1) x 2, n=54 | Procedure: Fecal Microbiota Transplantation (FMT)<br>* 100 grams of thawed processed stool diluted into 250 ml of saline and delivered by retention enema<br>Drug: Saline<br>* 250 ml of saline delivered by retention enema<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a New Onset of Related Chronic Medical Condition After Completing Treatment for Recurrent Clostridium Difficile-Associated Diarrhea (CDAD) | New onset of related chronic medical conditions (NOCMCs) through 365 days after completing treatment for recurrent CDAD were reported. NOCMCs were defined as any new ICD-10 diagnosis that is applied to the participant during the duration of the study, after receipt of the study agent, that is expected to continue for at least 3 months and requires continued health care intervention. | Day 1 through Day 365 | 
| Number of Participants With a Serious Adverse Event (SAE) After Completing Treatment for Recurrent Clostridium Difficile-Associated Diarrhea (CDAD) | SAEs included any adverse event or suspected adverse reaction which, in the view of the investigator or sponsor, resulted in any of the following: death, life threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a congenital anomaly/birth defect, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life function. | Day 1 through Day 365 | 
| Number of Participants With an Adverse Event (AE) After Completing Treatment for Recurrent Clostridium Difficile-Associated Diarrhea (CDAD) | Adverse events were defined as any noxious, pathologic, or unintended change in anatomic, physiologic, or metabolic functions, as indicated by physical signs, symptoms, and/or laboratory changes occurring in any phase of the clinical trial, regardless of their relationship to investigational product. | Day 1 through Day 30 | 
| Number of Participants With Newly Acquired Transmissible Infectious Diseases Which Are Considered Adverse Events of Special Interest (AESI), After Completing Treatment for Recurrent Clostridium Difficile-Associated Diarrhea (CDAD) | Adverse Events of Special Interest were defined as newly acquired transmissible infectious agents or infectious diseases related to study product and the following agents: HIV type 1 and 2, Hepatitis A, B, C, Treponema pallidum, HTLV-1, -2, Cyclospora, Salmonella, Shigella, Campylobacter, E. coli 0157:H7, Shiga-toxin producing E. coli, Ova and enteric parasites including Isospora, Vancomycin-resistant Enterococcus (VRE), extended spectrum beta-lactamase (ESBL), carbapenemase producing gram-negative rods, methicillinresistant Staphylococcus aureus (MRSA), Helicobacter pylori, Rotavirus, Adenovirus, Norovirus, Vibrio, Giardia lamblia, Cryptosporidium, and Microsporidia. | Day 1 through Day 365 | 
| Proportion of Participants With Clinical Response (Defined as no Recurrence of Clostridium Difficile-Associated Diarrhea (CDAD)) | Clinical response was defined as those subjects who have no recurrence of CDAD through Day 30 after completing treatment for recurrent CDAD. CDAD was defined as bowel movements as determined by >=3 unformed stools (soft or watery) within 24 consecutive hours and a positive PCR test for Clostridium difficile. | Day 1 through Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Recurrences of Clostridium Difficile-Associated Diarrhea (CDAD) After Completing Treatment for Recurrent CDAD | Recurrence was defined as the re-establishment of diarrhea (frequency of passed unformed stools, >=3 unformed stools within 24 consecutive hours) with a positive PCR test for C. difficile. | Day 1 through Day 30 | 
| Number of Recurrences of Clostridium Difficile-Associated Diarrhea (CDAD) After Completing Treatment for Recurrent CDAD | Recurrence was defined as the re-establishment of diarrhea (frequency of passed unformed stools, >=3 unformed stools within 24 consecutive hours) with a positive PCR test for C. difficile. | Day 1 through Day 60 | 
| Proportion of Participants With Sustained Clinical Response | Sustained clinical response is defined as those subjects who responded by Day 30 with no recurrence of CDAD through Day 60 after randomization. | Day 1 through Day 60 | 
| Time to First Clostridium Difficile-Associated Diarrhea (CDAD) Reoccurrence (Using the Date of First Positive PCR Post-enema) | The time (in weeks) until first CDAD recurrence was calculated as time from randomization to the end of the interval of ascertainment. Participants without a recurrence were censored at their last known contact date or their Day 60 visit, whichever occurred first. | Day 1 through Day 60 visit windows reported as Weeks 1 through 8, respectively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clinical Trial, Clostridium difficile, Clostridium difficle Associated Disease (CDAD), Efficacy, Fecal Microbiota Transplantation (FMT), Microbial Restoration, Partially-Blinded, Placebo, Safety, Stool