ATAPAC Study (TauroLock Activity in Adult Cancer Patients)

The purpose of this study is to compare the efficacy of a lock taurolidine-citrate solution vs standard saline solution for primary prevention of central venous catheter-associated bloodstream infection in adult patients treated with intra-venous therapy for a solid tumor

The central venous catheter (CVC)-associated bloodstream infection (CLABSI) represent a serious and persistent health problem in cancer patients with an implantable CVC receiving an intravenous (IV) anti-tumor therapy. The CLABSI include the CVC-associated bacteremia and the negative bloodstream local or generalized infections. CLABSI significantly increase morbidity and hospital costs. They can lead also to discontinuation of IV anti-tumor treatment, a severe sepsis, a septic shock or a death. Microbial colonization and biofilm development, which are resistant to antibiotic therapy, often lead to CVC replacement. CLABSI prevention is a key measure to improve clinical outcomes, particularly in patients at high risk. For this reason, CLABSI prevention is a national priority of the healthcare program. Taurolidine \[bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4) methane\] is an antimicrobial agent which kills and inhibits a wide range of micro-organisms in vitro, including multidrug resistant bacteria. A catheter lock solution was developed containing 1.35% taurolidine and 4% citrate. Due to the anti-adhesion activity of the taurolidine and anti-thrombotic properties of the citrate, this lock solution can disrupt bacterial adhesion to the inner surface of the implantable CVC preventing the production of biofilm. This lock solution showed a substantial reduction in the formation of biofilm and bacterial colonization of the inner surface of the implantable CVC is several prospective trials.

In a study of pediatric cancers receiving IV anti-tumor treatment, the use of a lock solution of taurolidine-citrate resulted in a reduction of Gram-positive CLABSI as compared to a control group of patients treated with a standard heparin lock solution. In another study of 71 pediatric patients, taurolidine-citrate solution reduced CLABSI compared with heparin (0.3 vs 1.3 infections per 1000 catheter-days, p: 0.03). Microbial colonization was found in 25.4% of the catheters. Regarding the toxicity, 7 patients only in the taurolidine-citrate group (20%) experienced side effects, the most being nausea, vomiting and abnormal sensations of taste.

Some clinical trials have also demonstrated the efficacy of taurolidine-citrate in terms of CLABSI reduction in patients on home total parenteral nutrition and in hemodialysis patients.

According to the French guidelines, an anti-bacterial lock therapy (preferably taurolidine) may be used as prevention in patients at increased risk of serious CLABSI complications. However, the effectiveness of the lock taurolidine-citrate solution for adult patients with solid tumors receiving an anti-tumor treatment via a totally implantable CVC is actually unknown and it remains to be assessed.

PRIMARY OBJECTIVE

- To compare the efficacy of a lock taurolidine-citrate solution vs standard saline solution for primary prevention of CLABSI in adult patients treated with IV anti-tumor therapy for a solid tumor.

SECONDARY OBJECTIVES

* To compare the impact of CLABSI in the 2 groups in terms of days of hospitalisation, delay of IV anti-tumoral treatment, costs of CVC removal and CLABSI-management
* To evaluate the adverse effects of the lock taurolidine-citrate solution in adult patients receiving an IV anti-tumor therapy for solid tumor PRIMARY ENDPOINT: Incidence rates of CLABSI per 1000 catheter-days

SECONDARY ENDPOINTS

* Days of CLABSI-related hospitalisation
* Anti-tumor treatment CLABSI-related delay
* Total CVC-removal for CLABSI
* Costs associated with the CLABSI management in the perspective of health insurance
* Evaluation of the taurolidine-citrate solution-related adverse effects

METHODOLOGY

* Single-center prospective, randomized, open-label, controlled, clinical phase IV trial
* 1:1 randomization

Stratification:

* Metastatic vs (neo) adjuvant
* Age ≤ 70 years vs \> 70 years

PROCEDURES During a standard clinical visit for IV anti-tumor treatment administration, the investigator informs the patient of the study procedures and check the eligibility criteria. At the beginning of the next cure, he collects his informed consent and performs randomisation. The patient is then included in the TauroLock ™ or saline arm.

At the beginning of each course, a nurse removes the lock TauroLock ™ and / or makes rinsing the CVC. At the end of each course, she rinses again the CVC and instills TauroLock ™ solution for patients in the TauroLock ™ arm. Patients will be followed for each treatment, according to the same rhythm of their anti-tumor treatment program up to the end of the study: the end of the IV anti-tumor treatment, the CVC removal for mechanical reasons or a CLABSI.

A follow-up visit will be performed 7-30 days after the study end.

PATIENTS NUMBER Based on surveillance data of nosocomial infections at our institution, the incidence of CLABSI in the control group is expected to about 3 per 1000 catheter-days.

Assuming that the use of TauroLock ™ will reduce at least this rate by three (expected 1 per 1000 in the treated group rate), which is consistent with literature data, 9785 days must be followed in each group (α and β risk at 5% and 10%, respectively).

Considering a mean follow-up of 4 months, we need for 81 patients pour any treatment group, 162 patients for the 2 groups.

TRIAL TIME

Duration of the inclusion period:

- 6 months

Duration of participation for each patient:

- Duration of IV anti-tumor treatment + 1 month of follow-up

STATISTICAL ANALYSIS Verification of the homogeneity of the groups for major confounding factors: WHO performance status, indication for anti-tumor treatment (metastatic vs (neo)-adjuvant cancer), age, duration of follow-up, type of anti-tumor treatment (weekly, every 15 or 21 days) and type of hospitalisation (full vs day-hospital). Qualitative variables will be compared between the 2 groups by Chi-square test or Fisher exact test if the normality conditions are not met. Quantitative variables are compared by Student's t test or non parametric Wilcoxon test if the normality conditions are not met.

Primary endpoint: the incidence of CLABSI will be compared between groups by a logistic regression test with adjustment for stratification and confounding factors, if necessary.

Secondary endpoints: the qualitative criteria will be compared between the 2 groups by Chi-square test or Fisher exact test if the conditions of normality are not met. The quantitative criteria will be compared by Student's t test or non parametric Wilcoxon test if the conditions of normality are not met.

The α risk is set at 5%.

EXPECTED BENEFITS The expected benefits are a direct reduction of CLABSI for adult cancer patients receiving IV anti-tumor treatment via a CVC leading to a direct reduction of morbidity and mortality. In addition, a better control of CLABSI should allow a cost savings. A literature review by the Centers for Disease Control and Prevention (Atlanta, USA) estimated between $ 29,156 and 7288 the cost of CLABSI. Similarly, a report by the Institute for Research and Documentation in Health Economics (IRDES), based on the PMSI (Program of medicalization of information systems) data, estimated that CLABSI entailed an additional cost of € 10,950 (+ / - 1690) and a extending of the hospitalisation of 14.7 days (+ / - 1.84). Finally, a reduction of the CLABSI should globally lead to a less use of antibiotics and to a consequently reduced probability of resistant organisms selection.

QUALITY ASSURANCE PLAN Data will be recorded in a paper case report form from medical records.

The accuracy and completeness of data will be monitored by a study coordinator :

* 100% inform consent, eligibility criteria and safety data
* 20% data recorded in CRF (case report form) Data will be registered in Microsoft Office ACCESS 2003 Base. It's a single-center study so thre're no special procedures to address registry operations and analysis activities. Safety data like reporting for adverse event will be made by fax with The CRPV (centre régional de pharmacovogilance de Nancy).

The security of the data transfer is assured by the french "Méthodologie de Référence MR001" (Comission Nationale Informatique et Liberté).

Eligibility Criteria:
Inclusion Criteria:

* Patients older than 18 years
* Performance Index (WHO score) ≤ 2
* Patient with a solid cancer receiving an IV anti-tumor treatment
* Presence of a totally implantable CVC
* Anti-tumoral therapy administered by a totally implantable CVC
* Metastatic and / or (neo) adjuvant treatment
* Full hospitalised and / or day-hospital patients
* Informed written consent
* Social Health security insurance

Exclusion Criteria:

* Hematological cancer patients
* HIV-positive patients and/ or patients receiving an active immunosuppressive therapy
* Patients presenting a febrile episode within 4 days prior to randomisation
* Patients with neutropenia grade ≥ 2 (ANC ≤ 1000/mm3) on a blood testing older than 7 days
* Patients on IV antibiotic therapy
* Patients on total and / or peripheral parental nutrition
* Patients with a previous CLABSI history
* Allergy to citrate or taurolidine
* Patients who are not able to give an informed consent
* Patients under guardianship
* Patients under judicial protection
* Pregnant or breastfeeding woman