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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Clostridium Difficile Infection	Device: DAV132	Not Applicable

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	260 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	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
Actual Study Start Date :	October 31, 2018
Estimated Primary Completion Date :	June 8, 2019
Estimated Study Completion Date :	June 8, 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: DAV132 group; Patients randomized to the DAV132 arm will be administered DAV132 concomitantly with fluoroquinolones.	Device: DAV132; 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.
No Intervention: No DAV132 group; Patients randomized to the No DAV132 arm will receive only fluoroquinolones, according to local standard of care.

Outcome Measures

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Primary Outcome Measures :

1. 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). [ Time Frame: 51 days after randomization ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

Inclusion Criteria. Eligible patients for the study must meet ALL the following inclusion criteria:

1. Male or female ≥18 years of age
2. 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
3. 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
4. Patients expected to stay in hospital for at least 3 days after randomization

5. 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

6. 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.

7. 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:

1. Antibacterial treatment within seven days before randomization
2. Fluoroquinolone indication other than LRTI, cUTI, or febrile neutropenia prophylaxis
3. Patients with suspected or diagnosed CDI at screening, and/or receiving a treatment effective against CDI
4. 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
5. Patients using probiotics for prevention of CDI and refusing to stop them at inclusion and during the study
6. Patients currently taking activated charcoal
7. Patients who have received a fecal microbial transplantation within the last 90 days prior to study screening
8. 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;
9. 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
10. Patients diagnosed with any cancer requiring taxane-based chemotherapy
11. Patients with digestive stoma, known conditions at risk for intestinal obstruction, or known achlorhydria
12. Contra-indication to oral therapy (eg, severe nausea/vomiting or ileus) or patient having tube feeding
13. Patients unable or expected to be unable within 48 hours to receive a medication by oral route administration
14. Known hypersensitivity to the activated charcoal, or to any of the constituents or excipients of DAV132
15. Patients taking any drug/medication acting on (eg, metronidazole; sulfasalazine) or absorbed in the colon.
16. Female patients planning a pregnancy, pregnant or breastfeeding
17. Patients already included into this study
18. Patients in an exclusion period of a previous study
19. 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
20. 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.
21. Patients under administrative or legal supervision.

Contacts and Locations

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Contacts

Contact: Marie-Noëlle Bouverne	+33 1 58 39 32 20	marie-noelle.bouverne@davolterra.com
Contact: Marina Varastet	+33 1 58 39 32 20	marina.varastet@davolterra.com

Locations

Bulgaria
Multiprofile Hospital for Active Treatment Sveti Ivan Rilski - Kozloduy EOOD Internal Department	Not yet recruiting
Kozloduy, Bulgaria, 3320
Contact: Rumen Tiholov
MHAT "Dr Nikola Vasilev " AD 1	Not yet recruiting
Kyustendil, Bulgaria, 2500
Contact: Sashka Pavlova
MHAT "Dr. Stamen Iliev" AD 4	Not yet recruiting
Montana, Bulgaria, 3400
Contact: Lidiya Nikolcheva-Todorova
Pernik EOOD Specialized Hospital for Active Treatment of Pulmonary Diseases - Phthisiatry Department	Not yet recruiting
Pernik, Bulgaria, 2300
Contact: Galina Petrova
Hosp Ruse EOOD	Not yet recruiting
Ruse, Bulgaria, 7002
Contact: Hristo Metev
Multiprofile Hospital for Active Treatment Silistra AD Department of pneumology and phtisiatry	Not yet recruiting
Silistra, Bulgaria, 7500
Contact: Mirena Sapundzhieva
Military Medical Academy, Clinic of Infectious Diseases	Not yet recruiting
Sofia, Bulgaria, 1606
Contact: Georgi Popov
UMHATEM N.I.Pirogov Department of internal diseases Clinic of internal diseases	Not yet recruiting
Sofia, Bulgaria, 1606
Contact: Diana Slaveva Mladenova
MHAT Sv. Anna Clinic of Urology	Not yet recruiting
Varna, Bulgaria, 9200
Contact: Boyan Lazarov
Germany
Universitaetsklinikum Jena Klinik für Innere Medizin IV	Not yet recruiting
Jena, Germany, 07747
Contact: Philipp Reuken
Universitätskliniken Köln (AöR) Klinik I für Innere Medizin	Not yet recruiting
Köln, Germany, 50937
Contact: Maria Vehreschild
Medizinische Universitaetsklinik Abteilung Innere Medizin I	Not yet recruiting
Tuebingen, Germany, 72076
Contact: Christoph Berg
Romania
Institutului Clinic Fundeni, Secţia Clinica Urologie III	Not yet recruiting
Bucuresti, Romania, 22328
Contact: Robert Ionut Stoica
Spitalul Clinic de Boli Infecţioase şi Tropicale Dr. Victor Babeş, Secţia Pneumologie II	Not yet recruiting
Bucuresti, Romania, 30303
Contact: Ana Maria Trăilescu
Spitalului de Boli Infectioase si Tropicale "Dr. Victor Babes" Sectia Clinica de Boli Infectioase si Tropicale VI - adult	Not yet recruiting
Bucuresti, Romania, 30303
Contact: Simin-Aysel Florescu
Institutul de Pneumoftiziologie "MariusNasta" (Pavilionul IV), Sectia Pneumologie VII	Not yet recruiting
Bucuresti, Romania, 40206
Contact: Dragos Zaharia
The Oncology Institute "Prof. Dr. Ion Chiricuţă"	Not yet recruiting
Cluj-Napoca, Romania, 400015
Contact: Delia Herghea
Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca, Secţia Clinică Pneumologie I	Not yet recruiting
Cluj-Napoca, Romania, 400371
Contact: Manuela Cosmina Magdau
Spitalul Clinic de Boli Infecţioase si Pneumoftiziologie Victor Babeş Craiova, Secţia Boli Infecţioase Adulţi II	Not yet recruiting
Craiova, Romania, 200515
Contact: Gheorge Iulian Diaconescu
Spitalului Universitar de Urgenta Elias, Clinica Universitara de Geriatrie, Gerontologie si Psihogeriatrie, Sos. Bucuresti-Ploiesti	Not yet recruiting
Otopeni, Romania, 13686
Contact: Luiza Spiru
Spitalul Clinic de Boli Infecţioase si Pneumoftiziologie "Dr. Victor Babeş" Timişoara, Clinica II Pneumologie	Not yet recruiting
Timişoara, Romania, 300310
Contact: Stefan Mihaicuta
Spitalului Clinic de Boli Infecţioase şi Pneumoftiziologie "Dr. Victor Babeş", Secţia Pneumologie II	Not yet recruiting
Timişoara, Romania, 300310
Contact: Monica Marc
Spitalului Clinic Judeţean de Urgenţă "Pius Brînzeu" Timişoara, Secţia Clinică Urologie	Not yet recruiting
Timişoara, Romania, 300736
Contact: Razvan Bardan
Serbia
Clinical Hospital Centre Bezanijska Kosa Pulmonology Department	Recruiting
Belgrad, Serbia, 11080
Contact: Vojislav Radosavljevic
Clinical Centre Kragujevac Clinic for Infectious Diseases	Recruiting
Kragujevac, Serbia, 34000
Contact: Olgica Gajovic
Clinical Centre of Nis Clinic for Lung Diseases	Recruiting
Niš, Serbia, 18000
Contact: Desa Nastasijevic-Borovac
Health Centre Uzice Department for Lung Diseases and Tuberculosis	Recruiting
Užice, Serbia, 31000
Contact: Zorica Radojevic
General Hospital Department for Lung Diseases and Tuberculosis	Recruiting
Čačak, Serbia, 32000
Contact: Julijana Antonovic

Sponsors and Collaborators

Da Volterra

Syneos Health

Investigators

Principal Investigator:	Maria J.G.T Vehreschild, MD	Uniklinik Köln

More Information

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Publications:

de Gunzburg J, Ducher A, Modess C, Wegner D, Oswald S, Dressman J, Augustin V, Feger C, Andremont A, Weitschies W, Siegmund W. Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: A proof of concept study in healthy subjects. J Clin Pharmacol. 2015 Jan;55(1):10-6. doi: 10.1002/jcph.359. Epub 2014 Jul 16.

de Gunzburg J, Ghozlane A, Ducher A, Le Chatelier E, Duval X, Ruppé E, Armand-Lefevre L, Sablier-Gallis F, Burdet C, Alavoine L, Chachaty E, Augustin V, Varastet M, Levenez F, Kennedy S, Pons N, Mentré F, Andremont A. Protection of the Human Gut Microbiome From Antibiotics. J Infect Dis. 2018 Jan 30;217(4):628-636. doi: 10.1093/infdis/jix604.

Burdet C, Sayah-Jeanne S, Nguyen TT, Hugon P, Sablier-Gallis F, Saint-Lu N, Corbel T, Ferreira S, Pulse M, Weiss W, Andremont A, Mentré F, de Gunzburg J. Antibiotic-Induced Dysbiosis Predicts Mortality in an Animal Model of Clostridium difficile Infection. Antimicrob Agents Chemother. 2018 Sep 24;62(10). pii: e00925-18. doi: 10.1128/AAC.00925-18. Print 2018 Oct.

Burdet C, Sayah-Jeanne S, Nguyen TT, Miossec C, Saint-Lu N, Pulse M, Weiss W, Andremont A, Mentré F, de Gunzburg J. Protection of Hamsters from Mortality by Reducing Fecal Moxifloxacin Concentration with DAV131A in a Model of Moxifloxacin-Induced Clostridium difficile Colitis. Antimicrob Agents Chemother. 2017 Sep 22;61(10). pii: e00543-17. doi: 10.1128/AAC.00543-17. Print 2017 Oct.

Responsible Party:	Da Volterra
ClinicalTrials.gov Identifier:	NCT03710694 History of Changes
Other Study ID Numbers:	DAV132-CL-2001; CIV-18-03-023465 ( Other Identifier: EUDAMED )
First Posted:	October 18, 2018
Last Update Posted:	November 16, 2018
Last Verified:	November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

Infection; Communicable Diseases; Fluoroquinolones; Anti-Bacterial Agents	Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action