Bezlotoxumab (BEZLO) In Addition To Standard Of Care (SOC) Vancomycin For The Treatment of Multi-Recurrent Clostridium Difficile Infection

Study Overview
=================
Brief Summary
-----------------
This is a research study to collect information from people that have Clostridium difficile infection (CDI) and are treated with a standard antibiotic treatment in which the antibiotic dose is gradually reduced over 6 weeks and bezlotoxumab (BEZLO), an approved monoclonal antibody targeting C. difficile toxin, which has shown to reduce CID recurrence when used in combination with standard antibiotic treatment.

Detailed Description
-----------------
Clostridium difficile (C. diff) is a type of bacteria which causes diarrhea in some people who receive antibiotics for other infections. The current antibiotics used to treat C diff infection (CDI) are usually successful in treating the initial episode of CDI, but may not prevent recurrent infection. To prevent recurrent CDI, standard oral antibiotic treatment with vancomycin is extended by gradually reducing the dose over 4-8 weeks. This is called antibiotic taper. Bezlotoxumab (BEZLO), a monoclonal antibody targeting C. difficile toxin B, is an approved medication that has also been shown to reduce CDI recurrence in patients receiving antibacterial drug treatment of CDI. In this study, approximately 12 people with multi-recurrent CDI will be treated with BEZLO in combination with standard oral tapered vancomycin. Study participation will last 16 weeks. The rate of CDI recurrence in this group will be compared to information collected from approximately 72 historical patients with multi-recurrent CDI treated with oral tapered vancomycin only.

Official Title
-----------------
Historically-controlled Clinical Trial of the Efficacy and Safety of Bezlotoxumab (BEZLO) in Addition to Standard of Care (SOC) Vancomycin for the Treatment of Multi-recurrent Clostridium Difficile Infection (CDI)

Conditions
-----------------
Clostridium Difficile Infection Recurrence

Intervention / Treatment
-----------------
* Drug: bezlotoxumab
* Drug: Vancomycin Oral


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (Interventional): i) age 18 years or older; ii) diagnosis of multi-recurrent CDI, defined as passage of 3 or more loose stools in 24 hours or less for at least 2 consecutive days and a positive stool test for toxigenic C. difficile (nucleic acid amplification test [NAAT] and toxin enzyme immunoassay [EIA] positive), with 2 or more confirmed prior CDI episodes; iii) receiving or planning to receive a 10- to 14-day course of SOC therapy with oral VAN followed by a tapered VAN regimen for at least 4 weeks; iv) patient highly unlikely to become pregnant due to being female and not of reproductive potential or female of reproductive potential agreeing to be abstinent or using 2 acceptable methods of birth control starting at enrollment and through the 16-week study period; and v) patient or legal representative voluntarily agreeing to participate by providing written informed consent after the nature of the study has been fully explained. Inclusion Criteria (Historical Control): i) age 18 years or older ii) diagnosis of multi-recurrent CDI iii) received 10- to 14-day course of SOC therapy with oral VAN followed by a tapered VAN regimen. Exclusion Criteria: i) active chronic diarrheal illness, such as (but not limited to) ulcerative colitis or Crohn's disease or with a condition such that they routinely pass loose stool ii) planned surgery for CDI within 24 hours iii) positive pregnancy test in the 48 hours before the infusion or unwilling to undergo pregnancy testing if a pre-menopausal female who is not sterilized and therefore has the potential to bear a child iv) breastfeeding or planning to breastfeed prior to the completion of the study period v) previous receipt of BEZLO vi) receipt of immune globulin within 6 months prior to enrollment or planning to receive immune globulin prior to completion of the 16-week study period vii) receipt of non-SOC CDI therapy within 14 days prior to enrollment viii) planned treatment with SOC therapy for longer than 6 weeks ix) receipt of medications to control diarrhea such as loperamide, diphenoxylate hydrochloride/atropine sulfate at any time prior to completion of the 16-week study period x) medical history of decompensated congestive heart failure

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The intervention group will consist of a single arm of patients treated with BEZLO + SOC oral VAN pulse/taper for multi-recurrent CDI, with a planned enrollment of 12 patients. To achieve the aim of the proposed study, we will compare the efficacy of BEZLO + SOC oral VAN pulse/taper to a historical cohort of patients treated with SOC oral VAN pulse/taper only. These patients will be matched 1:6 on criteria previously outlined in this proposal (BEZLO + SOC, n=12; SOC comparator, n=72; total number of patients in study, n=84).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: BEZLO + SOC taper<br>Single arm of patients treated with BEZLO + SOC oral VAN pulse/taper. | Drug: bezlotoxumab<br>* Adding BEZLO to SOC oral VAN pulse/taper<br>* Other names: Zinplava;Drug: Vancomycin Oral<br>* SOC vancomycin pulse/taper<br>* Other names: Firvanq;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of CDI reoccurrence at 12 weeks | If diarrhea resolves (defined as <2 loose stools per day for at least 2 consecutive days) and subsequently begins again (3 or more loose stools in 24 hours or less for at least 2 consecutive days), this will represent a new episode of diarrhea. If there is a new episode of diarrhea at any time during the 12-week study period, an unscheduled visit will be conducted. A stool sample will be provided for any new episode of diarrhea which occurs and a stool test for toxigenic C. difficile (NAAT plus EIA) will be performed. CDI reoccurrence will be defined as new episode of diarrhea and positive stool test for toxigenic C. difficile (NAAT plus EIA). | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
C.diff, Clostridium Difficile, recurrence, Bezlotoxumab, CDI