VATS Surgery Compared to Drainage in the Treatment of Pleural Empyema

Intrapleural Fibrinolysis and DNase versus VATS for the treatment of pleural empyema: a randomized, controlled trial

BACKGROUND

Pleural empyema is a disease with an infection inside the chest cavity, often as a result of a pneumonia. In Denmark there are approximately 500 new cases per year. Patients often have longer duration of hospitalization, and the disease carries a significant morbidity and mortality rate of approximately 15%. The state of pleura empyema is characterized by the passage of three stages (I - III):

- Parapneumonic effusion (stage I)

- Fibropurulent stage (stage II)

- Chronic organizing stage (stage III)

The aim of treating the disease is to remove the infection and provide fully expansion of the lung.

In our study we want to find the optimal method for treating patients in stage II and III.

The initial treatment at the early stage of the disease (stage I) is simple drainage and the disease at later stages can be treated with surgical intervention. In clinical practice, stages II and III are treated alike. Current standard treatment for these stages is drainage with ultrasound (ULS) -guided pigtail with a minimum size of 10 F. Simultaneously with drainage, an intrapleural fibrinolyticum can be given, but the indication and evidence for this is discussed. In the MIST II study, fibrinolytic (alteplase) was combined with DNase, and the authors found a positive effect using this combination.

Previously, surgery was associated with a significant morbidity and, to a lesser extent, mortality. The surgery was conducted as open surgery using a thoracotomy. Today, it can often be performed as a Video Assisted Thoracoscopic Surgery (VATS), which can be performed with a very low morbidity and mortality. It has been advocated that patients should be operated very early in the process, but the evidence is weak. In a Cochrane review on surgical versus non-surgical treatment of pleura empyema, two studies with adult patients have been included. None of the studies have a size or methodological quality that makes it possible to determine whether VATS should be included as part of the standard treatment of these patients. In children (aged <15 years), a randomized, controlled study of 50 patients in each group was conducted. It found no difference in outcome between fibrinolyticum and VATS, but no fixed treatment algorithm has been established for this age group. Furthermore, these results cannot be generalized to an adult population.

The theoretical advantage of early surgery is that patients undergo rapid, definitive treatment and surgery can ensure optimal drain placement. The potential advantages in early surgery are reduced mortality, admission time, and fewer late complications. In addition, it is estimated that an increased number of early-operable patients may reduce the proportion of patients, who will later be thoracotomized, as early surgery may be performed as VATS. However, there is the inherent risk of an operation and thereby the increased costs of the surgical procedure when compared to simple drainage. However, this could possibly be outweighed by reduced drug consumption, reduced need for supplemental drainage, shorter duration of admission, and reduced morbidity after discharge.

Accordingly, it is necessary to determine whether early VATS should be introduced as standard therapy in patients with fibropurulent stage (stage II) and the chronic organizing stage (stage III).

Hypothesis

• Patients over 18 years with a fibropurulent stage (stage II) or a chronic organizing stage (stage III) pleural empyema will have a significantly reduced time of hospitalization, if they undergo a VATS operation compared to ULS-guided pigtail drainage and fibrinolyticum (Acitlyse® (altaplasm)) with DNase (Pulmozyne®)

Aim of study • To determine if there is a difference in outcome in patients diagnosed with fibropurulent stage (stage II) and the chronic organizing stage (stage III) empyema who are receive a primary VATS surgery or ULS guided drainage and intrapleural therapy (fibrinolytic (altaplasm) with DNase (Pulmozyne ®))

Expected improvements If this trial is positive for the primary and/or the secondary outcomes, it could potentially change and strengthen the treatment of patients with this disease, both nationally and internationally. We investigate both clinical parameters, patient satisfaction and economical aspects (cost-effectiveness) in relation to pleura empyema treatment, so it will cover many aspects of this disease. If the trial is neutral, it will provide valuable data on intervention that is currently commonly used for this disease and can guide the treating physician to choose the adequate treatment based on the local preferences.

METHODS Design

- Randomized, controlled study

- Not blinded (open label)

- National multicenter study

Inclusion and exclusion criteria

Inclusion criteria:

- > 18 years or more on the day of hospitalization

- Must be able to provide informed consent

- Acute hospitalization within the last 48 hours

- Meeting diagnostic criteria for community-induced fibropurulent stage (stage II) and the chronic organizing stage (stage III) empyema

Exclusion criteria:

- Pregnant

- Breastfeeding

- Known malignant sickness and declared terminal for this

- Previous surgery (within <1 year on the same side of the thorax as where the parapneumonic effusion / pleural empyema is located

- Previously (within <1 year) hospitalized with an empyema stage II-III

- Drainage on the same side of the thorax (excluding diagnostic pleural puncture), including a pigtail

- Use of intrapleural therapy contraindicated (e.g. allergy)

- Enrollment duration at the time of diagnostic puncture > 48 hours

- Hospitalization within 7 days prior to current hospitalization

Endpoints

Primary endpoint:

• Hospitalization time, where admission time is defined as the time from first hospitalization in the course of hospitalization and to the completion of treatment (time of discharge). (In patients who cannot be discharged due to failure to receive primary care (e.g. waiting time at the relocation site), the date where the attending physician has finished the treatment is used as the discharged date).

Secondary endpoints:

- Hospitalization time (total) when patients are stratified in subgroups (Stage, ULS score, RAPID score)

- Hospitalization time after commencement of intervention

- Percentage of patients where primary intervention could be considered as final treatment: Definitive treatment is defined as a patient receiving only invasive interventions in the form of VATS procedure or initial ULS recommended drainage and not subsequent construction of additional drainage or need for surgery during hospitalization

- Mortality during hospitalization

- 30-day mortality

- Drainage time measured in days

- Radiological regression (a.m. MIST II)

- Number of drains

- Need for additional thoracic surgery (VATS, thoracotomy) during and within 12 months after hospitalization

- Need for intensive therapy

- Consumption of painkillers during hospitalization and within 12 months after hospitalization

- Lung Physiology

- Re-admission

- Quality of life, see EQ5D

- Health related costs within 12 months after hospitalization (including costs during hospitalization, post-hospitalization (hospitalization) and sick leave etc.).

Randomization All referred patients who have parapneumonic effusion in Stage II or III who immediately comply with the inclusion criteria and which cannot be excluded from the exclusion criteria will be requested to participate in the project.

Patients will be randomized to either:

1. VATS procedure with drainage, including rinse with NaCl

2. ULS-guided pigtail catheter placement and intrapleural therapy with Actilyse and DNase, including rinse with NaCl

Block randomization with varying block size will be used to get an equal number of patients in both groups. There will be stratification for the center (Rigshospitalet, Odense University Hospital, Aalborg University Hospital and Aarhus University Hospital) in the randomization. The randomization takes place after the patient is included and is conducted via a web-based randomization program, designed in RedCap.

Blinding Patients and staff who care and treat patients will not be blinded. Data analysis and assessment of different scoring systems (e.g. ULS and radiology score) are made blind, to the extent that it is practically feasible.

Patient population and selection All patients admitted during the diagnosis of pleural empyema or pleural effusion without specification (diagnostic codes: DJ 86, DJ 86.1, DJ 86.9, DJ 90.9), Stages II and III will be potential candidates, whether they are hospitalized at a Regional Hospital or at a University Hospital. All respiratory/pulmonology medical departments and relevant common emergency services/departments in Denmark will be informed that the project is in progress and that they can contact local contact persons regarding inclusion in the project.

Patients who can be included in the project receive both written and oral information before inclusion in the study.

Practical issues regarding inclusion of patients Patients who immediately meet the criteria for inclusion and are interested in participating are informed by one of the project participants or project nurses from the thoracic surgery department or other relevant department where the patient is hospitalized. The physical location of information and randomization will vary with the local organization of hospitals and departments. If the patient is randomized to VATS, the patient is transferred to one of the four centers where there is a thoracic surgical department. If the patient is randomized to ULS guided drainage and intrapleural therapy, the patient is transferred to one of the specialized pulmonology departments participating in the project.

Intervention Drain and intrapleural therapy group Pigtail is applied at a specialized department (Pulmonary or Thoracic surgery department) as soon as possible and within 48 hours of admission. Drain placement is carried out using ULS. Operators (conductors of the procedure) must have relevant training and competencies corresponding to the specialist level within the relevant specialty and be approved by the steering committee to conduct the procedure. A pigtail catheter (minimum 10F) is inserted. Operator determines the size of drain and whether drain placement is done with one-step or Seldinger technic.

VATS group The VATS procedure must be completed as soon as possible and no later than 48 hours after admission. The surgery is performed with the patient in a 90 degree sideways position, using general anesthesia. Preferably a uniportal access, purification and possibly decortication, and insertion of one pleural drain (sizes 24 - 32F) at the end of surgery. 20 ml Marcain is used as local analgetic and applied at the incision sites or as a nerve block. In the VATS group, suction on drain (- 15 cm H20) is applied in the first day after the procedure. Operator must have relevant training and competencies corresponding to the specialist level within the relevant specialty and be registered and approved by the "steering committee".

After the procedure Randomized patients should, after treatment (VATS or pigtail), be transferred to a specialized pulmonary medical department or remain hospitalized at the Thoracic surgical department. This is decided by local agreements, competencies and practical conditions. Practical conditions are agreed locally, both in some hospitals and in each Region prior to initiation of the study.

Antibiotics

Standard antibiotics treatment is initiated as intravenous treatment. Change to oral treatment can be done when all of the following three criteria are met:

- Clinical improvement of the patient (e.g. no fever / fever, improved general condition)

- Paraclinically satisfactory response (with respect to decreases in leukocytes and CRPs)

- Drain / pigtail is removed This means that 14 days i.v. treatment will not be given as standard. The duration of i.v. antibiotic treatment will therefore be individual based on the application of the above criteria. The overall duration of treatment of antibiotic is 6 weeks as standard.

Removal of drain/pigtail

The following criteria are used for discontinuation of drain / pigtail in both groups:

- Clinical improvement of the patient (e.g. no fever / subfebril, improved general condition)

- Paraclinically satisfactory response (with respect to a decrease in leukocytes and CRPs)

- Imaging (TUS, CT or Chest X-ray (CXR) in 2 planes) without significant residual effusion

- Drain with clear pleural fluid by rinsing

Data recording Baseline patient data (admission data / baseline variable) are registered on all included patients

Surgical data:

• Side of surgery (right / left), percentage of patients where the procedure has been completed with a uniportal access, number of incisions, conversion to an open procedure, operating time, complications, name of surgeon, number of assistants, equipment usage.

ULS pigtail data:

• Side of procedure (right / left), zone, findings including "Empyem score", number of "attempts", drain size, technique used (One-Step, Seldinger, ULS identification of puncture site / real-time guidance), procedure time, medication used, vital parameters, place of where the procedure are performed (FAM, ward etc.), name of operator, number of assistants, equipment usage and complications

Costs during hospitalization:

Calculated for the two groups regarding the following expenses:

- VATS Group:

- Utensils used during surgery

- Time of the procedure

- Consumption of human/staff resources

- Hospitalization time

- Medicine

- Drain group:

- Utensils used during the procedure

- Procedure Time

- Consumption of human/staff resources

- Fibrinolyticum and DNase (amount used)

- Hospitalization time

- Medicine

Costs within the 1st year after discharge:

Calculated for the two groups regarding the following expenses:

- Re-admission

- Ambulatory services

- Medication

- Number of sick days

- Visit to a GP

Patient satisfaction and functional level:

• Data in the form of EQ5D and Sct. George is collected at the following times:

- Upon inclusion in the study

- At discharge

- Ambulant: 3 months, 6 months and 12 months.

Various parameters acquired from and after hospitalization (including ambulant outpatient visits):

- Hospitalization time, total

- Hospitalization time after commencement of intervention

- Primary intervention could be considered as final treatment

- Mortality during hospitalization

- 30 days of mortality

- Drainage time

- Radiological regression a.m. MIST II

- Number and types of drains

- Need for additional surgery (VATS, thoracotomy) during and within 12 months after hospitalization

- Need for additional intrapleural therapy (regardless of choice of drug) during and within 12 months after hospitalization

- Need for intensive therapy

- Type and total duration of antibiotic treatment

- Consumption of painkillers during hospitalization and within 12 months after hospitalization

- Place of post-procedure stay (surgical / pulmonary medicine)

- Lung function tests and walking tests

- Re-admission

- Miscellaneous paraclinical parameters (blood culture, blood to biobank, urine test etc.) A very thorough and extensive plan for all data acquired has been made.

Outpatient check/clinic after discharge In conjunction with participation in the project, in addition to any common local controls, outpatient check is carried out at the regional pulmonary/respiratory out-patient-clinic after 3, 6 and 12 months after the discharge.

Data collection Media

- REDCap (Research Electronic Data Capture), REDCap Consortium, Vanderbilt University Medical Center, Tennessee, USA

- Electronic patient record (EPJ in Region Midt, EPJ in Region North, EPJ (COSMIC) in Region South and EPJ (EPIC Health Platform) in the Capital Region and Region Zealand).

- Health related costs are retrieved via the National Patient Register (LPR).

Handling and archiving data All data is entered in a Case Report Form in RedCap. REDCap is a professional database that provides a user-friendly interface. The REDCap data management system is secure, fully compliant with all regulatory guidelines, and includes a complete audit-trail for data entry validation. Through these mechanisms, as well as relevant training for all involved parties, patient confidentiality will be safeguarded. REDCap is available for free at both Odense and Aarhus University.

When handling, processing and archiving data collected, the Data Inspectorate's guidelines are followed, which implies that all personal data are deleted at the end of the project. The collected data is stored at the Department of CardioThoracic and Vascular Surgery, Aarhus University Hospital and at Department of Pulmonology, Odense University Hospital.

Sample size and power calculation The study is based on assumptions and knowledge about admission time, both from national and international publications. The sample size calculation is therefore subject to some uncertainty. In clinical practice, stage II and III are treated alike, and the pragmatic approach is therefore that both groups are included and calculated as aggregates in connection with the primary endpoint. We calculated the sample size based on the following assumptions: The main effect target is the difference between the total time (primary endpoint) between the two groups of patients (VATS versus drainage). The distribution of the hospitalization time is expected to be skewed to the right, so that a logarithmic transformation is needed to achieve normality.

We assume a median hospitalization period in the drainage group of 12 days, a minimum clinically relevant difference in hospitalization of two days, 80% power, and Coefficient of variation (CV) of 40%.

Significance level is set to 0.05. Thus, 77 patients in each group must be included. To account for excluded patients (set at 20%), we expect to include 92 patients in each group. A total of 184 patients is to be included.

In terms of showing clinically relevant non-inferiority with a difference in hospitalization of 1 day with a 80% power, and CV of 40%, 70 patients is needed in each group. This is based on a true improvement of 1 hospitalization day.

Data analysis Data extractions are made from RedCap database. Data analysis is performed using one of the following: Microsoft® Excel® 2011 (Microsoft Corporation, Washington, USA), Prism Version 6 for Mac OS X (GraphPad Software, Inc., California, USA), STATA version 14 (StataCorp LLC, Texas , USA). Endpoints will be described for the individual group by median and percentile, assuming data is not normally distributed.

Differences between the groups in the primary endpoint are determined by t-test at the log-entry time and reported as median ratios with associated confidence intervals. Whether death before discharge affects the primary endpoint is assessed using survival analysis as sensitivity analysis. We expect that the distribution between stages II and III will be 75% and 25%, respectively, and whether there is a difference between stages II and III will be assessed as secondary analysis. When repeating measurements (e.g. quality of life), repeated measurements ANOVA are used with treatment and time as systematic effects and patient as random effect. All data are analyzed primarily according to the intention to treat principle, but there will also be one per protocol analysis regarding the above-mentioned endpoints. Comparison will take place between the two groups (drainage and VATS).

Statistical cooperation partner Bo Martin Bibby. Ass. Professor, Biostatistical Advisory Service (BIAS), Faculty of Health Sciences, Aarhus University.

Risks of participation, ethical considerations and monitoring Common clinical practice is currently very divergent and there is no national or international consensus on which of the treatments is preferable (VATS versus drainage). There is thus no safe evidence for any of the regimes.The individual patient may not immediately benefit from participating. The results of the study will primarily benefit future patients.

The project is carried out in accordance with the Helsinki II Declaration, European regulations and Good Clinical Practice Guidelines. The Scientific Ethics Committees for Denmark and the Data Inspectorate are applying for permission to complete the program. Information about the subjects is protected under the Personal Data Processing Act and the Health Act, and the trial has been reported to the Data Inspectorate / Regional office. The trial will be monitored by the regional Good Clinical Practice monitoring unit.

Interruption of the experiment Suspected Severe Adverse Reactions suspend the attempt for the individual patient. However, patient data is still used in the project according to intention to treat principles.

Earlier termination of the trial for the individual patient

- If the patient wishes to leave the study.

- If unexpected complications occur If leaving the trial, the patient will follow the department's usual procedure for treating patients treated for pleura empyema. If the patient wishes to leave the study, the collected data is not used if, as a result of unexpected complications, the patient cannot receive the intervention the patient is randomized, the patient enters the data and continues to collect data in accordance with the intention to treat principles.

Events and side effects All unintended events and adverse events throughout the treatment period and until the last call after 30 days are recorded. All Adverse Events are recorded in the patients Case Report Form.

Agreements with other departments / hospitals All involved departments have signed a document obligating them to take active part in the trial.

All Pulmonary and Thoracic Surgical departements on the four University Hospital has agreed to participate in the trial The Danish Society of Cardiothoracic Surgery and the Danish Society of Respiratory Medicine has both recommended and endorsed the study

Project collaboration and work distribution The main applicant will be the principal investigator, and primarily responsible for the overall practical feasibility, conducting and hosting of the study. The co-applicants (Morten Bendixen and Thomas Decker Christensen) is part of the steering committee and equally responsible for the conduction of the trial.

Morten Bendixen have taking part in the process of preparing and writing the protocol, organizing the study and applying for economical support. He will take part in the implementing of the study (inclusion of patients, performing surgery, practical issues etc.), analyzing and interpretation of data and writing of the manuscripts. His share of the budget is estimated to 1269400 Dkr.

Thomas Decker Christensen have taking part in the idea/concept of the study, the process of preparing and writing the protocol, organizing the study and applying for economical support. He will take part in the implementing of the study (inclusion of patients, performing surgery, practical issues etc.), analyzing and interpretation of data and reviewing the manuscripts. His share of the budget is estimated to 1269400 Dkr.

International collaborators To provide scientific input and an international perspective, we have assembled a group of international experts with great expertise and experience within pleural emphyema and clinical trials. This group includes Prof. Najib. N. Rahman, Professor, Consultant of Respiratory Medicine, Nuffield Department of Medicine, Clinical Director, Oxford Respiratory Trials Unit, University of Oxford, UK and Prof. Babu Naidu, Professor, Consultant of Thoracic Surgery, Department of Thoracic Surgery, Birmingham Heartland Hospital, Birmingham, UK

Report / applied for permission from the following institutions

- Scientific ethics committee

- Data Inspectorate / Region Midt

- Medicines Agency (Case No. 2017084202)

- www.clinicaltrials.gov

Time schedule The proposal covers a 5 years' timeline, with approximately half a year for further planning and organization of the trial, 2.5 years for patient inclusion, 1 year for follow-up and 1 year for data analyses and publications. Additional details are provided in the attached figure.

Publications and sharing of the data Both positive, negative and inconclusive results from the study will be published in international journals. The researchers' free right to publication cannot be restricted. All information will be disclosed in anonymous form. The results will also be presented at international scientific congresses.

A minimum of six manuscripts are planned from the current trial. Study findings will be published irrespective of the results. Completely de-identified data will be shared in public database after the trial to allow for other researchers to replicate the results or to test new hypotheses.

Steering committee A steering committee will be responsible for the design and conduct of the trial. The principal investigator will be Christian B Laursen (see applicant information) Additional members of the multidisciplinary steering committee will include Thomas Decker Christensen (co-applicant), Morten Bendixen (co-applicant), Peter B. Licht MD, PhD (thoracic surgery), Rene H. Petersen MD, PhD (thoracic surgery), Lars Møller MD (thoracic surgery), Jens-Ulrik Stæhr Jensen MD, PhD (pulmonologist), Vasiliki Panou MD (pulmonologist) and Søren Helbo Skaarup MD (pulmonologist).

A qualified Ph.D. fellow will be included in the steering committee and involved in the conduct of the trial.

Abbreviations used in the project description CRP: C-reactive protein CT: Computed tomography CXR: Chest X-ray EQ5D: European Quality of Life F: French Ml: Milliliter MIST: Multi-centre Intra-pleural Sepsis Trial TUS: Thoracic Ultrasound ULS: Ultrasound VATS: Video Assisted Thoracoscopic Surgery