Tunnelled catheters for palliative care outcomes: study protocol for a prospective, multicentre observational study (PRO ASEPT)

Introduction

Accumulation of fluid within the pleural or abdominal cavity results in pleural effusion or ascites, respectively. There are numerous non-malignant and malignant causes of pleural effusion and ascites (1-3). The most frequent causes of pleural effusions are pleural infection, heart failure, and malignancy. The incidence of pleural effusion is 100–500/100,000 (4,5) and it is estimated that approximately 15 percent of all patients with cancer develop malignant pleural effusions (6). Common problems in these patients are dyspnoea and other symptoms; those include chest pain, dry cough, or early feeling of satiety due to the pressure exerted by the pleural fluid on the stomach. Inevitably, these clinical symptoms impair the quality of life (QoL) of patients (7).

Therefore, control of symptoms and improvement of QoL are central therapeutic goals with a preference of minimally invasive procedures. These include initial thoracentesis, the use of tunnelled catheters, chemical pleurodesis, and more invasive surgical options, such as pleurectomy (8).

Similarly, ascites involves the accumulation of fluid, specifically in the peritoneal cavity, and can occur in the advanced stages of both benign and malignant diseases. Ascites can cause painful abdominal distention, early satiety, and nausea, with patients often also experiencing shortness of breath, limited mobility, and lower extremity oedema, all of which significantly impact QoL (9). Therefore, selecting an appropriate treatment method tailored to the patient’s medical condition and palliative care needs is crucial. Likewise for pleural effusion there are various treatment options for ascites include diuretic therapy, paracentesis for fluid drainage, transjugular intrahepatic portosystemic shunt (TIPS) placement and tunnelled peritoneal catheters for recurrent ascites. Guidelines by several medical and surgical societies support each option for the appropriate patient population (10,11). The outstanding advantage of tunnelled catheters compared to other modalities is that they can be inserted in an out-patient setting thereby reducing hospitalization, increasing time spent at home, and requiring fewer subsequent thoracentesis or paracentesis to obtain symptom palliation (12).

Although tunnelled catheters enable a rapid symptom relief—especially dyspnoea—they are a radical event for patients concerned with. Only a few studies have evaluated the QoL and outpatient management of tunnelled catheters (i.e., PleurX, Ewimed GmbH, Hechingen, Germany; Rocket, Rocket medical plc., Washington, UK; and ASEPT^® Catheters, PFM medical GmbH, Cologne, Germany) in palliative patients (13-16). Our study aims to give further insight in the patients’ palliative care outcome and QoL 6 weeks after implantation compared to baseline using the tunnelled ASEPT^® Catheters in a larger cohort of patients suffering from ascites or pleural effusion. Furthermore, additional data about safety and application will be evaluated. We present this article in accordance with the SPIRIT reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-24-147/rc).

Methods

Study aims

The aim of this study is to evaluate changes in patients palliative care outcome and QoL 6 weeks after implantation of the ASEPT^® Catheters compared to baseline in a cohort of patients’ suffering from ascites or pleural effusion. It will be assessed by changes in the validated German version of the Palliative Care Outcome Scale (POS) questionnaire reflecting the patients’ palliative care and QoL. The POS was developed by Hearn and Higginson as a multidimensional outcome measure for patients with advanced cancer (17). The scale encompasses physical, psychological, spiritual, practical, emotional and psychosocial concerns of both patients and family. The POS is available in different languages. Bausewein et al. validated the German version of the POS in 2002 and 2003 (18). Furthermore, the data of the clinical application, the handling of tunnelled catheter in the home environment, and the rate and type of short- and long-term complications will be evaluated.

Study design

This prospective, single-arm multicentre study was registered at the German Clinical Trial Register (DRKS) with the registration number DRKS00031242. Participants are recruited from five hospitals [Lungclinic Grosshansdorf, Oberhavel Clinic, Marienhospital Gelsenkirchen, University Clinic Rheinisch-Westfälische Technische Hochschule (RWTH), and Helios Clinic Berlin Buch] specialized in thoracic surgery and palliative care in Germany. It is anticipated that 150 patients will be enrolled in this study. Inclusion of patients has been started in May 2023 and the recruitment phase is planned for 18 months.

All patients included in the study receive the tunnelled ASEPT^® Catheter. No control group and randomization are intended. The devices under investigation are tunnelled catheters designed for implantation in either the pleural cavity (pleural effusion) or in the peritoneal cavity (ascites). These soft silicone tubes are suitable for short- and long-term use especially in home care, enabling patients a better management of the symptoms such as respiratory distress caused by recurrent malignant pleural effusions or ascites. For catheter implantation video-assisted thoracoscopic surgery (VATS), laparoscopy or Seldinger technique is commonly used. The chosen implantation technique depends on patients’ general condition, and whether additional surgical procedures are needed for the diagnostic process (e.g., histological specimen). They are suitable for short- and long-term use and serves the drainage of accumulated fluid from the pleural cavity to alleviate the symptoms of pleural effusions or serves the drainage of accumulated fluid from the abdomen. Patients will be discharged after successful implantation and are cared for by the homecare team.

Investigating patient-reported palliative care outcome, the POS will be recorded before surgery, and 2 and 6 weeks after implantation (follow-up visits; Table 1). During the follow-up visits, clinical use, and the complication rate are also analysed.

The homecare team will assess and follow-up patients during home care visit which take place either in person or via telephone call. The questionnaire exists in three versions which can be filled in by the patient, the medical staff or the family members. The primary endpoint is the comparison of the POS questionnaire between before and 6 weeks after implantation.

After 6 months we planned an additional follow-up investigating the safety of the tunnelled catheters due to an official directive of the German technical inspection association.

Outcome measurements

The study investigates changes in patients palliative care outcome and QoL 6 weeks after implantation of the ASEPT^® Catheters compared to baseline in a cohort of patients’ suffering from ascites or pleural effusion. The primary endpoint will be assessed by changes in the POS questionnaire reflecting the patients’ palliative care. An improvement is indicated by a decrease in the respective scores. Furthermore, a descriptive analysis includes the clinical application at surgery, the complication rate within the 6-month period and the handling of ASEPT^® Drainage Kit change in the home environment is investigated. The use of an ASEPT^® system includes two major groups, patients suffering from ascites or pleural effusion, diagnosed either malignant or non-malignant. Therefore, subgroup analysis will be performed if enough patients for each subgroup can be included.

Study population and recruitment

Before inclusion to the study, each patient will be informed detailed by the investigator and a patient information is handed out. Afterwards a written informed consent must be obtained and signed from all individual participants. The participants have the right to withdraw at any time.

Patient inclusion is determined based on the medical necessity for a peritoneal or pleural tunnelled catheter to continuously manage ascites or pleural effusion using the investigational product. Eligible patients must be 18 years or older with a life expectancy exceeding 2 months. Median survival following diagnosis ranges from 3 to 12 months and is dependent on the stage and type of the underlying malignancy (11,13,14). In order to ensure a 6 weeks follow-up, a life expectancy of at least 2 months was defined.

Inclusion criteria are follows:

• Indication for drainage of symptomatic, recurrent pleural effusions, including malignant pleural effusions and other types, or drainage of symptomatic ascites.
• The patient must be able to understand the nature, significance, and implications of the clinical study.
• Age of 18 years or older.
• Life expectancy greater than 2 months.

Exclusion criteria include:

• Contraindications as specified in the manufacturer’s instructions for use: sepsis or infection, coagulopathy or other haemorrhagic tendency, the anatomy does not suffice for the insertion of a catheter, allergy to materials compositions, or chylous effusion.
• Patient is institutionalized by court or official order or is participating in another surgical clinical study related to the ASEPT^® Pleural Drainage System or ASEPT^® Peritoneal Drainage System.

If an enrolled patient does not meet the inclusion criteria before the device implantation, or if the investigator deems the device inappropriate, the patient must be withdrawn from the study as a “screening failure”. After device implantation, all enrolled patients will be considered part of the “treated patients” group. Patients will be excluded from the study as a “drop out” if they withdraw their consent or if the drainage system needs to be removed (Figure 1).

Figure 1 Flowchart of the study. DSMB, Data Safety Monitoring Board; FU, follow up.

Data collection and management

All data generated during this study will be entered into the Electronic Data Capture (EDC) system.

However, there are different data sources which were collected by: (I) the clinical investigator and delegated medical staff; (II) study patients (questionnaire on patient satisfaction).

All data reported must be traceable to source data documents. In general, source data are the patient records at the study site including validated paper-filled questionnaire on patient satisfaction. In case of telephone contact as source of data entered into the EDC system the respective electronic Case Report Form may be provided as print. Authorised personnel must verify by a dated signature that the print contains the original information. These certified copies will become part of the source data at the study sites. For each patient, data will be collected on medical history (age, weight, gender, treatment status, living situation, previous therapies), surgical procedure (implantation technique, duration, location of procedure), a 2-week follow-up (POS), a 6-week follow-up (POS) and when necessary adverse events.

All patients will be pseudonymised and will be remained anonymous to the sponsor and the public. The data will be stored in both an electronic database and a locked cabinet. This study will be conducted under the supervision of monitors and Data Safety Monitoring Board (DSMB). Check for logical data entry will be performed to identify missing data and inconsistencies.

Archiving of the study database (EDC system), database exports and reports follow standard operating procedures. After completion of the analysis by the responsible biostatistician, the principal investigator will prepare and sign the final report and a publication containing the results of the study jointly with the biostatistician. It is planned to publish the study results in appropriate journals and conferences.

Monitoring

There will be an on-site monitoring: initiation visit, first regular visit after the tenth patient is included, routine monitoring visits to check patient enrolment, documentation/data collection and compliance of the study centre, and close-out of the study centre after the last patient’s 6 weeks follow up (FU).

Additionally, a DSMB will be installed. The DSMB is a group of experts who monitor patient safety and treatment efficacy data while a clinical investigation is ongoing. They give an independent assessment of (serious) adverse events [(S)AEs] and protocol deviations that may occur during the clinical investigation with respect to categorisation, assessment of severity and device relatedness. If there is evidence for unanticipated or increased risks for subjects, the study may be suspended or terminated by the investigator, sponsor, the DSMB, or the local ethic committee. In case of premature termination, ‘treated patients’ must be followed-up and should be informed if the premature termination of the investigation has any clinical implication.

Statistical analysis and sample size calculation

The sample size is calculated based on the assumed measurement of a detectable change in the palliative care outcome. The sample size calculation was based on reference values from similar studies reported in the literature (19-28). Assuming a 50% loss to follow-up or death, a power of 0.80, an alpha of 0.01, and an effect size of 0.4 (Cohen’s D), a minimum of 150 patients were to be enrolled. The effect size calculated by the MCID and the standard deviation from literature is 0.5—which is also the typical value when choosing Cohen’s D to represent a ‘medium’ sized effect. In the sample size calculations, 0.4 was chosen as effect size to allow detecting smaller effects in order to account for the heterogeneity of the data found in literature. This study is designed without blinding and randomization procedures.

Statistical analysis is presented using the mean and standard deviation for normally distributed data, the median and interquartile range for non-normally distributed data, and frequencies with percentages for categorical variables.

Considering the primary endpoint, a paired two-sided t-test will be conducted to assess significant changes in response patterns between baseline and the 6-week follow-up visits in palliative care outcomes. The basis of the analysis is a two-sided test for matched pairs—like the paired Student’s t-test or the Wilcoxon signed-rank test for non-parametric data. The normality assumption is tested graphically using a Q-Q-plot and by applying a statistical test such as the Kolmogorov-Smirnov test. Missing data can have an impact on the primary endpoint. One option is testing the impact of missing data in the POS by comparing the results of the complete cases, i.e., only cases with no missing data towards an analysis including imputation of missing data by last observation carried forward imputation, if applicable.

All patients will receive the same medical devices: the ASEPT^® Pleural Drainage System, the ASEPT^® Peritoneal Drainage System, the ASEPT^® Drainage Kit, or the ASEPT^® Drainage Kit L. To avoid bias, the study population will be described in detail using descriptive statistics to ensure generalizability.

Safety

(S)AEs will be counted and percentages for each type of (S)AE are reported. The percentage of patients among the whole safety set who experienced at least one (S)AE will be calculated and reported. The relationship of (S)AEs with the device under investigation or the study procedure as judged by the DSMB will be assessed.

Ethics

Prior to the start of the study, the protocol, informed consent and other relevant documents were submitted to the local ethics committee for approval. Any change of the study protocol will be reported to the local ethics committee. The study has been approved by the ethics committees of the University of Lübeck (No. 2023-202), Westfalen-Lippe (No. 2023-329-b-S), Brandenburg (No. 2023-75-BO) and University of Aachen (No. EK 23-344). The local ethics committee of Berlin follows the decision of the ethics committee of the University of Lübeck. Furthermore, this study will be conducted in accordance with the Declaration of Helsinki (as revised in 2013 and ISO-14155).

Discussion

We are conducting this prospective, single-arm multi-centre study to provide essential information for using the tunnelled ASEPT^® Catheters in the clinical routine. The focus is on patient-reported palliative care outcome using the POS questionnaire. Most patients with pleural effusion and symptomatic ascites are affected with symptoms such as dyspnoea, chest pain and dry cough which may be severe and lead to hospitalisation or adversely impact QoL. Two previous studies by Dhaliwal et al. (13) and Mitchell et al. (14) have already investigated the patients’ QoL and could show a relevant improvement. Besides these issues, it is aimed to gain knowledge concerning the clinical use of tunnelled catheters, and the drainage kits application in the home environment, and to confirm the safety and performance in clinical routine in Germany. We anticipate that this study will provide more information on the QoL and care of patients with an indwelling tunnelled catheter in the outpatient palliative setting. Additional our study also includes patients suffering from ascites, in contrast to the existing studies in this field.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-24-147/rc

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-147/prf

Funding: This study is funded by the pfm medical gmbh, Germany. The company is involved in the study set-up, data collection and data analyses, especially of the safety data. All patients’ data will be remained anonymous to pfm medical gmbh. The investigators are free to use another procedure treating pleura effusion or ascites.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-147/coif). S.T. is an employee of pfm medical gmbh and the pfm medical covers the article processing charges. D.B.E. receives consulting fees from pfm medical gmbh, travel support from Metronic gmbh, Germany and is participant on an advisory board by Cosinuss Gmbh, Germany. S.v.W. receives consulting fees from pfm medical gmbh, travel support from Astra Zeneca Livsmed, MSD and BMS; and is a participant on a Data Safety Monitoring Board of pfm medical gmbh, and at the Advisory Board of MSD and BMS. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Prior to the start of the study, the protocol, informed consent and other relevant documents were submitted to the local ethics committee for approval. Any change of the study protocol will be reported to the local ethics committee. The study has been approved by the ethics committees of the University of Lübeck (No. 2023-202), Westfalen-Lippe (No. 2023-329-b-S), Brandenburg (No. 2023-75-BO) and University of Aachen (No. EK 23-344). The local ethics committee of Berlin follows the decision of the ethics committee of the University of Lübeck. This study will be conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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