Clinical trial NCT03710694: Safety and Efficacy of DAV132 in Patients at High-Risk for Clostridium Difficile Infection (CDI)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Clostridium Difficile Infection
Lead sponsor: Da Volterra
Sponsor class: INDUSTRY
Collaborators: name: Syneos Health
First posted: 2018-10-18
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility 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.

Primary outcomes:
measure: 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).
timeFrame: 51 days after randomization
Secondary outcomes:
measure: Safety endpoint: Number of AEs and proportion of patients with at least one AE
timeFrame: 51 days after randomization
measure: Efficacy/performance endpoint, clinical:Proportion of patients with CDI
timeFrame: 51 days after randomization
measure: Efficacy/performance endpoint, clinical: Proportion of patients with AAD
timeFrame: 51 days after randomization
measure: Efficacy/performance endpoint, clinical: Plasma levels of FQs
timeFrame: Day 4
measure: Efficacy/performance endpoint, biological: Level of free fecal concentrations of FQs
timeFrame: Day 1, Day 4, Day 6, 10 days after the end of FQs
measure: Efficacy/performance endpoint, biological: Level of α-diversity of the intestinal microbiota
timeFrame: Day 1, Day 6, 10 days after the end of FQs, and 30 days after the end of FQs
measure: Efficacy/performance endpoint, biological: Change from D1 of α-diversity of the intestinal microbiota
timeFrame: Day 6, 10 days after the end of FQs, and 30 days after the end of FQs
measure: Efficacy/performance endpoint, biological: Levels of β-diversity of the intestinal microbiota
timeFrame: Day 6, 10 days after the end of FQs, and 30 days after the end of FQs
measure: Efficacy/performance endpoint, biological: Proportion of patients with resistant bacteria and/or yeasts in feces
timeFrame: Baseline and up to 10 days after the end of FQs
measure: Efficacy/performance endpoint, biological: Proportion of patients with at least one occurrence of resistant bacteria and yeasts in feces (among patients negative at baseline)
timeFrame: up to 10 days after the end of FQs
measure: Efficacy/performance endpoint, biological: Proportion of patients with acquisition of intestinal colonization by C. difficile (among patients negative at baseline)
timeFrame: up to 10 days after the end of FQs
Other outcomes:
Locations:
city: Kozloduy
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Sveti Ivan Rilski - Kozloduy EOOD Internal Department
city: Kyustendil
country: Bulgaria
facility: MHAT "Dr Nikola Vasilev " AD 1
city: Montana
country: Bulgaria
facility: MHAT "Dr. Stamen Iliev" AD 4
city: Pernik
country: Bulgaria
facility: Pernik EOOD Specialized Hospital for Active Treatment of Pulmonary Diseases - Phthisiatry Department
city: Ruse
country: Bulgaria
facility: Hosp Ruse EOOD
city: Silistra
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Silistra AD Department of pneumology and phtisiatry
city: Sofia
country: Bulgaria
facility: Military Medical Academy, Clinic of Infectious Diseases
city: Sofia
country: Bulgaria
facility: UMHATEM N.I.Pirogov Department of internal diseases Clinic of internal diseases
city: Varna
country: Bulgaria
facility: MHAT Sv. Anna Clinic of Urology
city: Frankfurt am Main
country: Germany
facility: Universitaetsklinikum Frankfurt, Medizinische Klinik II
city: Jena
country: Germany
facility: Universitaetsklinikum Jena Klinik für Innere Medizin IV
city: Köln
country: Germany
facility: Universitätskliniken Köln (AöR) Klinik I für Innere Medizin
city: Tuebingen
country: Germany
facility: Medizinische Universitaetsklinik Abteilung Innere Medizin I
city: Bucuresti
country: Romania
facility: Institutului Clinic Fundeni, Secţia Clinica Urologie III
city: Bucuresti
country: Romania
facility: Spitalul Clinic de Boli Infecţioase şi Tropicale Dr. Victor Babeş, Secţia Pneumologie II
city: Bucuresti
country: Romania
facility: Spitalului de Boli Infectioase si Tropicale "Dr. Victor Babes" Sectia Clinica de Boli Infectioase si Tropicale VI - adult
city: Bucuresti
country: Romania
facility: Institutul de Pneumoftiziologie "MariusNasta" (Pavilionul IV), Sectia Pneumologie VII
city: Cluj-Napoca
country: Romania
facility: The Oncology Institute "Prof. Dr. Ion Chiricuţă"
city: Cluj-Napoca
country: Romania
facility: Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca, Secţia Clinică Pneumologie I
city: Craiova
country: Romania
facility: Spitalul Clinic de Boli Infecţioase si Pneumoftiziologie Victor Babeş Craiova, Secţia Boli Infecţioase Adulţi II
city: Otopeni
country: Romania
facility: Spitalului Universitar de Urgenta Elias, Clinica Universitara de Geriatrie, Gerontologie si Psihogeriatrie, Sos. Bucuresti-Ploiesti
city: Timişoara
country: Romania
facility: Spitalul Clinic de Boli Infecţioase si Pneumoftiziologie "Dr. Victor Babeş" Timişoara, Clinica II Pneumologie
city: Timişoara
country: Romania
facility: Spitalului Clinic de Boli Infecţioase şi Pneumoftiziologie "Dr. Victor Babeş", Secţia Pneumologie II
city: Timişoara
country: Romania
facility: Spitalului Clinic Judeţean de Urgenţă "Pius Brînzeu" Timişoara, Secţia Clinică Urologie
city: Belgrad
country: Serbia
facility: Clinical Hospital Centre Bezanijska Kosa Pulmonology Department
city: Kragujevac
country: Serbia
facility: Clinical Centre Kragujevac Clinic for Infectious Diseases
city: Niš
country: Serbia
facility: Clinical Centre of Nis Clinic for Lung Diseases
city: Užice
country: Serbia
facility: Health Centre Uzice Department for Lung Diseases and Tuberculosis
city: Čačak
country: Serbia
facility: General Hospital Department for Lung Diseases and Tuberculosis
Study officials:
affiliation: Universitaetsklinikum Frankfurt
name: Maria J.G.T Vehreschild, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: de Gunzburg J, Ghozlane A, Ducher A, Le Chatelier E, Duval X, Ruppe E, Armand-Lefevre L, Sablier-Gallis F, Burdet C, Alavoine L, Chachaty E, Augustin V, Varastet M, Levenez F, Kennedy S, Pons N, Mentre 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.
citation: 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, Mentre 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):e00925-18. doi: 10.1128/AAC.00925-18. Print 2018 Oct.
citation: Burdet C, Sayah-Jeanne S, Nguyen TT, Miossec C, Saint-Lu N, Pulse M, Weiss W, Andremont A, Mentre 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):e00543-17. doi: 10.1128/AAC.00543-17. Print 2017 Oct.