Safety and Efficacy of DAV132 in Patients at High-Risk for Clostridium Difficile Infection (CDI)

Study Overview
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Brief Summary
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The purpose of this study is to determine the safe use and evaluate the efficacy/performance of DAV132 in hospitalized patients at high risk for Clostridium difficile infection (CDI) and who receive fluoroquinolones (FQs) for the treatment of acute infections or for prophylaxis of febrile neutropenia.

Detailed Description
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Da Volterra develops DAV132, a novel therapeutic option preserving the intestinal microbiota, to prevent potentially life-threatening conditions such as CDI or emergence of antibiotic-resistant bacteria. Prevention of CDI remains critical unmet need, especially for patients at high risk of developing such infection.

Official Title
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A European Multicenter, Randomized, Parallel-group Study to Evaluate the Safety and Efficacy/Performance of DAV132 in Hospitalized Patients at High Risk for Clostridium Difficile Infection and Who Receive Fluoroquinolones for the Treatment of Acute Infections

Conditions
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Clostridium Difficile Infection

Intervention / Treatment
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* Device: DAV132


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria. Eligible patients for the study must meet ALL the following inclusion criteria: Male or female ≥18 years of age Hospitalized patients requiring a systemic antibiotic treatment for a proven or strongly suspected bacterial infection (lower respiratory tract infection [LRTI], complicated urinary tract infection [cUTI]) or prophylactic treatment of febrile neutropenia for neutropenic patient Patients who are intended to receive one of the following FQs: moxifloxacin, levofloxacin, or ciprofloxacin, by oral or parenteral route, for an intended duration of 5 days (minimum) to 21 days (maximum), in monotherapy Patients expected to stay in hospital for at least 3 days after randomization Patients with the following conditions: - Previous history of CDI (no more than 2 episodes) within six months prior to study inclusion OR - Patient aged ≥65 years, and presenting with at least two of the following: Previous cumulated exposure of at least 5 days to any antibiotics within the last 90 days Patients who have at least one concurrent severe comorbidity among the following: malignant disease, chronic renal failure, cardiopulmonary condition (such as chronic congestive heart failure or severe arterial hypertension), diabetes mellitus, or liver cirrhosis Previous hospitalization of more than 72h within the last 90 days, or patient receiving long-term nursing care for more than one month within the last 90 days Female patients participating in the study must be: - of non-childbearing potential: surgically sterilized at least 3 months prior to inclusion, or postmenopausal (menopause is defined as being aged >60 years, or aged between 45 and 60 years and being amenorrheic for ≥2 years) OR - of childbearing potential, and: • using an efficient double contraception from inclusion up to 24 hours after the end of the treatment period: hormonal contraception (including patch, contraceptive ring, etc.), intra-uterine device, or other mechanical contraception method AND condom, or diaphragm or cervical/vault cap, or spermicide AND must have a negative urine pregnancy test prior to inclusion to the study. Patients who have given their written informed consent prior to undertaking any study-related procedure. Exclusion Criteria: Eligible patients for this study will be excluded if any of the following conditions are present: Antibacterial treatment within seven days before randomization Fluoroquinolone indication other than LRTI, cUTI, or febrile neutropenia prophylaxis Patients with suspected or diagnosed CDI at screening, and/or receiving a treatment effective against CDI Patients with diarrhea corresponding to Bristol stool chart types 5-7, combined with a stool frequency of at least three stools in 24 or fewer consecutive hours, regardless of its etiology Patients using probiotics for prevention of CDI and refusing to stop them at inclusion and during the study Patients currently taking activated charcoal Patients who have received a fecal microbial transplantation within the last 90 days prior to study screening A critically ill patient for whom transfer to an intensive care unit is scheduled, or patient who may likely have critical clinical deterioration within 48 hours; Patients with serious, uncontrolled disease, including but not limited to neutropenia expected to last >7 days (Investigator discretion) or with an estimated life expectancy shorter than 6 months Patients diagnosed with any cancer requiring taxane-based chemotherapy Patients with digestive stoma, known conditions at risk for intestinal obstruction, or known achlorhydria Contra-indication to oral therapy (eg, severe nausea/vomiting or ileus) or patient having tube feeding Patients unable or expected to be unable within 48 hours to receive a medication by oral route administration Known hypersensitivity to the activated charcoal, or to any of the constituents or excipients of DAV132 Patients taking any drug/medication acting on (eg, metronidazole; sulfasalazine) or absorbed in the colon. Female patients planning a pregnancy, pregnant or breastfeeding Patients already included into this study Patients in an exclusion period of a previous study Patients with any social or logistical condition which in the opinion of the Investigator, may interfere with the conduct of the study, such as incapacity to understand well, not willing to collaborate, or cannot easily be contacted after discharge Patients not covered by a health insurance system where applicable and in compliance with the recommendations of the national laws in force relating to biomedical research. Patients under administrative or legal supervision.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DAV132 group<br>Patients randomized to the DAV132 arm will be administered DAV132 concomitantly with fluoroquinolones. | Device: DAV132<br>* DAV132: Dosage: 15 g/day activated charcoal (22.5 g/day DAV132) Route: Oral Duration: duration of fluoroquinolone treatment + 2 days DAV132 is regulated as a medical device in Europe and as a drug in the United States of America.<br>|
| No Intervention: No DAV132 group<br>Patients randomized to the No DAV132 arm will receive only fluoroquinolones, according to local standard of care. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoint: Proportion of patients having at least one adverse event (AE) related to DAV132 and/or to fluoroquinolones (FQs) and which relationship to product (DAV132 or FQ) is confirmed by the Independent Adjudication Committee (IAC). | The IAC will review AEs according to the IAC charter, including Clostridium difficile infection (CDI) and antibiotic-associated diarrhea (AAD), in a blinded manner across both treatment groups, and confirm whether each AE is related or not to DAV132 and/or to the FQ received by the patient. | 51 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoint: Number of AEs and proportion of patients with at least one AE |  | 51 days after randomization | 
| Efficacy/performance endpoint, clinical:Proportion of patients with CDI |  | 51 days after randomization | 
| Efficacy/performance endpoint, clinical: Proportion of patients with AAD |  | 51 days after randomization | 
| Efficacy/performance endpoint, clinical: Plasma levels of FQs |  | Day 4 | 
| Efficacy/performance endpoint, biological: Level of free fecal concentrations of FQs | Duration of treatment with FQs ranges from 5 to 21 days, at the discretion of the Investigator | Day 1, Day 4, Day 6, 10 days after the end of FQs | 
| Efficacy/performance endpoint, biological: Level of α-diversity of the intestinal microbiota | Duration of treatment with FQs ranges from 5 to 21 days, at the discretion of the Investigator | Day 1, Day 6, 10 days after the end of FQs, and 30 days after the end of FQs | 
| Efficacy/performance endpoint, biological: Change from D1 of α-diversity of the intestinal microbiota | Duration of treatment with FQs ranges from 5 to 21 days, at the discretion of the Investigator | Day 6, 10 days after the end of FQs, and 30 days after the end of FQs | 
| Efficacy/performance endpoint, biological: Levels of β-diversity of the intestinal microbiota | Duration of treatment with FQs ranges from 5 to 21 days, at the discretion of the Investigator | Day 6, 10 days after the end of FQs, and 30 days after the end of FQs | 
| Efficacy/performance endpoint, biological: Proportion of patients with resistant bacteria and/or yeasts in feces | Duration of treatment with FQs ranges from 5 to 21 days, at the discretion of the Investigator | Baseline and up to 10 days after the end of FQs | 
| Efficacy/performance endpoint, biological: Proportion of patients with at least one occurrence of resistant bacteria and yeasts in feces (among patients negative at baseline) | Duration of treatment with FQs ranges from 5 to 21 days, at the discretion of the Investigator | up to 10 days after the end of FQs | 
| Efficacy/performance endpoint, biological: Proportion of patients with acquisition of intestinal colonization by C. difficile (among patients negative at baseline) | Duration of treatment with FQs ranges from 5 to 21 days, at the discretion of the Investigator | up to 10 days after the end of FQs |