Microbial Restoration for Individuals With One or More Recurrences of Clostridium Difficile Associated Disease (CDAD)

Study Description

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Brief Summary:

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 4 years, subject participation duration is approximately 3 years. Primary study objectives are to: 1) evaluate the safety of FMT(s) delivered by enema vs. placebo delivered by enema, 2) determine efficacy of FMT delivered by enema vs. placebo delivered by enema

Condition or disease	Intervention/treatment	Phase
Clostridial Infection; Dysbacteriosis; Probiotic Therapy	Procedure: Fecal Microbiota Transplantation (FMT); Drug: Saline	Phase 1; Phase 2

Detailed Description:

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. Study duration is 4 years, subject participation duration is approximately 3 years. Primary study objectives are to: 1) evaluate the safety of FMT(s) delivered by enema vs. placebo delivered by enema, 2) determine efficacy of FMT delivered by enema vs. placebo delivered by enema. Secondary objectives are to: 1) evaluate the sustained clinical response rate of FMTs delivered by enema vs. placebo delivered by enema, 2) evaluate the rate of recurrent CDAD, 3) evaluate the time to recurrent CDAD.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	162 participants
Allocation:	Randomized
Intervention Model:	Sequential Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	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)
Actual Study Start Date :	September 6, 2018
Estimated Primary Completion Date :	September 6, 2021
Estimated Study Completion Date :	September 6, 2022

Arms and Interventions

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Arm	Intervention/treatment
Experimental: FMT group; 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); 100 grams of thawed processed stool diluted into 250 ml of saline and delivered by retention enema
Experimental: Placebo group; 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); 100 grams of thawed processed stool diluted into 250 ml of saline and delivered by retention enema; Drug: Saline; 250 ml of saline delivered by retention enema

Outcome Measures

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Primary Outcome Measures :

1. Number of subjects with a new onset of related chronic medical condition after completing treatment for recurrent Clostridium Difficile-Associated Diarrhea (CDAD) [ Time Frame: Up to 365 days ]
2. Number of subjects with a SAE (assessed by Adverse Event Grading Scale) after completing treatment for recurrent CDAD [ Time Frame: Up to 365 days ]
3. Number of subjects with an AE (assessed by Adverse Event Grading Scale) after completing treatment for recurrent CDAD [ Time Frame: Up to 30 days ]
4. Number of subjects with newly acquired transmissible infectious diseases which are considered AESI, after completing treatment for recurrent CDAD [ Time Frame: Up to 365 days ]
5. Proportion of subjects with clinical response (no recurrence of CDAD) after randomization [ Time Frame: Up to 30 days ]

Secondary Outcome Measures :

1. Number of days from randomization until the study day when first CDAD reoccurred after randomization [ Time Frame: Up to 60 days ]
2. Number of recurrences of CDAD after completing treatment for recurrent CDAD [ Time Frame: Up to 60 days ]
3. Number of subjects with new onset of related chronic medical condition after completing treatment for recurrent CDAD [ Time Frame: Up to 1095 days ]
4. Number of subjects with SAE assessed by Adverse Event Grading Scale after completing treatment for recurrent CDAD [ Time Frame: Up to 1095 days ]
5. Proportion of subjects with sustained clinical response (response by day 30 with no recurrence of CDAD through day 60) after randomization [ Time Frame: Up to 60 days ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 99 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Providing permission to access the medical record.
2. Male or non-pregnant female 18 years or older at the time of enrollment.
3. Able to provide signed and dated informed consent.
4. = / > 2 episodes of CDAD in the past 6 months, including the last episode if present at screening*.
5. 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.
6. Controlled diarrheal symptoms (<3 unformed stools per 24 consecutive hour period).
7. Deemed likely to survive for 1 year after enrollment.
8. Women of childbearing potential** (includes females who are postmenopausal <1 year) 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.
9. Males must agree to avoid impregnation of women between Day 1 and 28 days following each administration of the study product.
10. Negative urine or serum pregnancy test within 24 hours of enrollment and randomization.
11. Is able to provide blood and fecal specimens.
12. Is able to complete a test of comprehension.

Note:

• Defined by = / > 1 confirmed positive CDAD by diagnostic methods and another occurrence substantiated by medical history.

  • 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.

Exclusion Criteria:

1. Previous FMT at any time excluding this study.
2. Use of the following drugs in last 3 months: such as monoclonal antibodies to B and T cells, anti-TNF agents, glucocorticoids*, antimetabolites**, calcineurin inhibitors***, mycophenolate mofetil.
3. Requiring antibiotics in the 30 days prior to receiving the enema for a condition other than CDAD or scheduled to be used in the upcoming 3 months.
4. Unable to tolerate enema for any reason.
5. History of any GI cancer or any actively treated malignancy.
6. Patients with a history of severe anaphylactic food allergy.
7. Any history of cirrhosis.
8. Untreated HIV disease****.
9. Other severe immunosuppression or immunodeficiency.
10. Severe OR acute disease at the time of enrollment*****.
11. Major surgery of the GI tract in the past year.
12. Having a known allergy to or any component of vancomycin, loperamide or GoLYTELY.
13. Any history of inflammatory bowel disease (IBD) including ulcerative colitis, Crohn's disease, indeterminate colitis, or celiac disease.
14. Irritable bowel syndrome (IBS) within the past 12 months or any active uncontrolled gastrointestinal disorders or diseases******.
15. Unable to comply with protocol requirements.
16. Participation in any other clinical drug research trial 60 days prior to enrollment or for the 3 year duration of the current study.

17. 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.

    Note:

    • For example, > 20 mg of prednisone (or equivalent) given daily or on alternative days for 2 weeks or more

      • azathioprine, 6-merceptopurine

        • tacrolimus, cyclosporine ****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.

          • 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.

            • 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.

Contacts and Locations

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Contacts

Contact: Nadine Rouphael	14047121435	nroupha@emory.edu

Locations

United States, Georgia
Emory Vaccine Center - The Hope Clinic	Recruiting
Decatur, Georgia, United States, 30030-1705
United States, North Carolina
Duke Human Vaccine Institute - Duke Clinical Vaccine Unit	Recruiting
Durham, North Carolina, United States, 27708
United States, Tennessee
Vanderbilt University Medical Center - Infectious Diseases	Recruiting
Nashville, Tennessee, United States, 37232-0011

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

More Information

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Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT03548051 History of Changes
Other Study ID Numbers:	13-0045; HHSN272201300017I
First Posted:	June 6, 2018
Last Update Posted:	November 16, 2018
Last Verified:	April 13, 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No
Product Manufactured in and Exported from the U.S.:		No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Clostridium difficle Associated Disease (CDAD); Efficacy; Fecal Microbiota Transplantation (FMT); Microbial Restoration	Partially-Blinded; Phase 1/2; Placebo Controlled; Safety

Additional relevant MeSH terms:

Recurrence; Clostridium Infections; Dysbiosis; Disease Attributes	Pathologic Processes; Gram-Positive Bacterial Infections; Bacterial Infections