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

Clostridium Difficile Infection Clinical Trial

— SHIELD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03710694
• Other study ID #: DAV132-CL-2001
• Secondary ID: CIV-18-03-023465
• Status: Completed
• Phase: N/A
• Start date: October 31, 2018
• Est. completion date: August 9, 2019

Study information

• Verified date: August 2019
• Source: Da Volterra
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 260
• Est. completion date: August 9, 2019
• Est. primary completion date: August 9, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Clostridium Difficile Infection
• Clostridium Infections
• Communicable Diseases
• Infection

Intervention

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.

Locations

Country	Name	City	State
Bulgaria	Multiprofile Hospital for Active Treatment Sveti Ivan Rilski - Kozloduy EOOD Internal Department	Kozloduy
Bulgaria	MHAT "Dr Nikola Vasilev " AD 1	Kyustendil
Bulgaria	MHAT "Dr. Stamen Iliev" AD 4	Montana
Bulgaria	Pernik EOOD Specialized Hospital for Active Treatment of Pulmonary Diseases - Phthisiatry Department	Pernik
Bulgaria	Hosp Ruse EOOD	Ruse
Bulgaria	Multiprofile Hospital for Active Treatment Silistra AD Department of pneumology and phtisiatry	Silistra
Bulgaria	Military Medical Academy, Clinic of Infectious Diseases	Sofia
Bulgaria	UMHATEM N.I.Pirogov Department of internal diseases Clinic of internal diseases	Sofia
Bulgaria	MHAT Sv. Anna Clinic of Urology	Varna
Germany	Universitaetsklinikum Frankfurt, Medizinische Klinik II	Frankfurt am Main
Germany	Universitaetsklinikum Jena Klinik für Innere Medizin IV	Jena
Germany	Universitätskliniken Köln (AöR) Klinik I für Innere Medizin	Köln
Germany	Medizinische Universitaetsklinik Abteilung Innere Medizin I	Tuebingen
Romania	Institutul de Pneumoftiziologie "MariusNasta" (Pavilionul IV), Sectia Pneumologie VII	Bucuresti
Romania	Institutului Clinic Fundeni, Sectia Clinica Urologie III	Bucuresti
Romania	Spitalul Clinic de Boli Infectioase si Tropicale Dr. Victor Babes, Sectia Pneumologie II	Bucuresti
Romania	Spitalului de Boli Infectioase si Tropicale "Dr. Victor Babes" Sectia Clinica de Boli Infectioase si Tropicale VI - adult	Bucuresti
Romania	Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca, Sectia Clinica Pneumologie I	Cluj-Napoca
Romania	The Oncology Institute "Prof. Dr. Ion Chiricuta"	Cluj-Napoca
Romania	Spitalul Clinic de Boli Infectioase si Pneumoftiziologie Victor Babes Craiova, Sectia Boli Infectioase Adulti II	Craiova
Romania	Spitalului Universitar de Urgenta Elias, Clinica Universitara de Geriatrie, Gerontologie si Psihogeriatrie, Sos. Bucuresti-Ploiesti	Otopeni
Romania	Spitalul Clinic de Boli Infectioase si Pneumoftiziologie "Dr. Victor Babes" Timisoara, Clinica II Pneumologie	Timisoara
Romania	Spitalului Clinic de Boli Infectioase si Pneumoftiziologie "Dr. Victor Babes", Sectia Pneumologie II	Timisoara
Romania	Spitalului Clinic Judetean de Urgenta "Pius Brînzeu" Timisoara, Sectia Clinica Urologie	Timisoara
Serbia	Clinical Hospital Centre Bezanijska Kosa Pulmonology Department	Belgrad
Serbia	General Hospital Department for Lung Diseases and Tuberculosis	Cacak
Serbia	Clinical Centre Kragujevac Clinic for Infectious Diseases	Kragujevac
Serbia	Clinical Centre of Nis Clinic for Lung Diseases	Niš
Serbia	Health Centre Uzice Department for Lung Diseases and Tuberculosis	Užice

Sponsors (2)

Lead Sponsor	Collaborator
Da Volterra	Syneos Health

Countries where clinical trial is conducted

Bulgaria,  Germany,  Romania,  Serbia, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Safety endpoint: Number of AEs and proportion of patients with at least one AE		51 days after randomization
Secondary	Efficacy/performance endpoint, clinical:Proportion of patients with CDI		51 days after randomization
Secondary	Efficacy/performance endpoint, clinical: Proportion of patients with AAD		51 days after randomization
Secondary	Efficacy/performance endpoint, clinical: Plasma levels of FQs		Day 4
Secondary	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
Secondary	Efficacy/performance endpoint, biological: Level of a-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
Secondary	Efficacy/performance endpoint, biological: Change from D1 of a-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
Secondary	Efficacy/performance endpoint, biological: Levels of ß-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
Secondary	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
Secondary	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
Secondary	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