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

• ClinicalTrials.gov Identifier: NCT03710694
• Recruitment Status: Completed
• First Posted: October 18, 2018
• Last Update Posted: August 30, 2019
• Sponsor: Da Volterra
• Collaborator: Syneos Health
• Information provided by (Responsible Party): Da Volterra

Study Description

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

• Study Type: Interventional (Clinical Trial)
• Actual 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
• Actual Primary Completion Date: August 9, 2019
• Actual Study Completion Date: August 9, 2019

Arms and Interventions

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

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

• 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

Locations

Bulgaria

Multiprofile Hospital for Active Treatment Sveti Ivan Rilski - Kozloduy EOOD Internal Department

Kozloduy, Bulgaria, 3320

MHAT "Dr Nikola Vasilev " AD 1

Kyustendil, Bulgaria, 2500

MHAT "Dr. Stamen Iliev" AD 4

Montana, Bulgaria, 3400

Pernik EOOD Specialized Hospital for Active Treatment of Pulmonary Diseases - Phthisiatry Department

Pernik, Bulgaria, 2300

Hosp Ruse EOOD

Ruse, Bulgaria, 7002

Multiprofile Hospital for Active Treatment Silistra AD Department of pneumology and phtisiatry

Silistra, Bulgaria, 7500

Military Medical Academy, Clinic of Infectious Diseases

Sofia, Bulgaria, 1606

UMHATEM N.I.Pirogov Department of internal diseases Clinic of internal diseases

Sofia, Bulgaria, 1606

MHAT Sv. Anna Clinic of Urology

Varna, Bulgaria, 9200

Germany

Universitaetsklinikum Frankfurt, Medizinische Klinik II

Frankfurt am Main, Germany, 60590

Universitaetsklinikum Jena Klinik für Innere Medizin IV

Jena, Germany, 07747

Universitätskliniken Köln (AöR) Klinik I für Innere Medizin

Köln, Germany, 50937

Medizinische Universitaetsklinik Abteilung Innere Medizin I

Tuebingen, Germany, 72076

Romania

Institutului Clinic Fundeni, Secţia Clinica Urologie III

Bucuresti, Romania, 22328

Spitalul Clinic de Boli Infecţioase şi Tropicale Dr. Victor Babeş, Secţia Pneumologie II

Bucuresti, Romania, 30303

Spitalului de Boli Infectioase si Tropicale "Dr. Victor Babes" Sectia Clinica de Boli Infectioase si Tropicale VI - adult

Bucuresti, Romania, 30303

Institutul de Pneumoftiziologie "MariusNasta" (Pavilionul IV), Sectia Pneumologie VII

Bucuresti, Romania, 40206

The Oncology Institute "Prof. Dr. Ion Chiricuţă"

Cluj-Napoca, Romania, 400015

Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca, Secţia Clinică Pneumologie I

Cluj-Napoca, Romania, 400371

Spitalul Clinic de Boli Infecţioase si Pneumoftiziologie Victor Babeş Craiova, Secţia Boli Infecţioase Adulţi II

Craiova, Romania, 200515

Spitalului Universitar de Urgenta Elias, Clinica Universitara de Geriatrie, Gerontologie si Psihogeriatrie, Sos. Bucuresti-Ploiesti

Otopeni, Romania, 13686

Spitalul Clinic de Boli Infecţioase si Pneumoftiziologie "Dr. Victor Babeş" Timişoara, Clinica II Pneumologie

Timişoara, Romania, 300310

Spitalului Clinic de Boli Infecţioase şi Pneumoftiziologie "Dr. Victor Babeş", Secţia Pneumologie II

Timişoara, Romania, 300310

Spitalului Clinic Judeţean de Urgenţă "Pius Brînzeu" Timişoara, Secţia Clinică Urologie

Timişoara, Romania, 300736

Serbia

Clinical Hospital Centre Bezanijska Kosa Pulmonology Department

Belgrad, Serbia, 11080

Clinical Centre Kragujevac Clinic for Infectious Diseases

Kragujevac, Serbia, 34000

Clinical Centre of Nis Clinic for Lung Diseases

Niš, Serbia, 18000

Health Centre Uzice Department for Lung Diseases and Tuberculosis

Užice, Serbia, 31000

General Hospital Department for Lung Diseases and Tuberculosis

Čačak, Serbia, 32000

Sponsors and Collaborators

Da Volterra

Syneos Health

Investigators

• Principal Investigator: Maria J.G.T Vehreschild, MD; Universitaetsklinikum Frankfurt

More Information

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
• Other Study ID Numbers: DAV132-CL-2001; CIV-18-03-023465 ( Other Identifier: EUDAMED )
• First Posted: October 18, 2018
• Last Update Posted: August 30, 2019
• Last Verified: August 2019

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; Clostridium Infections; Gram-Positive Bacterial Infections; Bacterial Infections