STRENGTHS AND LIMITATIONS OF THIS STUDY
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This is a prospective, controlled, randomised, multicentre, open-label study.
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A data safety monitoring board is established to monitor patient safety.
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The trial is part of the decision-making process regarding health insurance reimbursement in routine care in Germany. A total of 224 participants are planned to be enrolled in the trial at 15 study sites aiming to explore to what extent bronchoscopic thermal vapour ablation treatment can ensure sufficient, safe and cost-effective care for emphysema patients.
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Not sham controlled.
Introduction
Chronic obstructive pulmonary disease (COPD) can lead to lung emphysema, which is characterised by the destruction of lung tissue, reduced gas exchange and consecutive hyperinflation.1–3 Non-pharmacological treatments of COPD complement pharmacotherapy to improve symptoms and quality of life, prevent disease progression, and improve survival.1 Non-pharmacological COPD treatments include endoscopic lung volume reduction (ELVR), used to treat patients with severe emphysema and hyperinflation.4 These endoscopic techniques aim to reduce lung hyperinflation by removing or blocking damaged parts of the lung, improving overall lung function, exercise capacity and quality of life for patients. At present, more than three different types of ELVR procedures exist, including implantation of endobronchial valves, endobronchial coils and bronchial thermal vapour ablation.
Endobronchial valves are small, one-way devices that are placed inside the airways to block off diseased areas of the lung after collateral ventilation has been excluded. Complete lobar occlusion prevents air from entering these regions during inspiration and the valves redirect airflow to healthier lung tissue, reducing hyperinflation.5 Endobronchial coils, on the other hand, are tiny metal coils that are bronchoscopically inserted into the lungs as a non-occlusive procedure to compress damaged parenchyma and thereby induce LVR.6 Bronchial thermal vapour ablation involves delivering heated water vapour to the targeted areas of the lung, causing controlled damage by inflammation and subsequent volume reduction.7
ELVR procedures have shown promising results in improving lung function, exercise capacity and quality of life for selected patients with advanced emphysema. These procedures are generally considered for patients who still experience symptoms and have reduced quality of life, despite optimal pharmacological management.8
At present, endobronchial valve placement is the most studied and used technique. The procedure is usually recommended for patients with severe emphysema, intact interlobar fissures, and thus the absence of collateral ventilation, and significant dyspnoea despite optimal medical management.9 The success of endobronchial valve placement depends on the collateral ventilation between the lobes.9 Unfortunately, many patients have incomplete fissures—and thus collateral ventilation—and are therefore not qualified for a valve placement. While endobronchial valves are generally safe, there are potential complications associated with the procedure. These include pneumothorax, valve migration, valve obstruction and respiratory infections.10
There is a clear medical need for additional techniques. Bronchoscopic thermal vapour ablation (BTVA) offers the advantage of selectively targeting diseased lung regions while preserving healthy lung tissue. By precisely delivering heated water vapour to the targeted areas, BTVA causes controlled damage to the diseased lung parenchyma, leading to volume reduction. This can result in improved lung function, increased exercise capacity and improved respiratory symptoms. The procedure can be tailored to target specific lung segments of the upper lobes, based on the distribution of the disease. This flexibility enables a personalised treatment plan, optimising outcomes for individual patients.
Already published data have shown the procedure’s efficacy but the evidence needs to be strengthened.7 While further research is needed to establish its long-term efficacy and refine patient selection criteria, BTVA offers a valuable alternative to surgical interventions and other non-occlusive treatment modalities. With continued advancements and experience, BTVA has the potential to revolutionise the management of COPD, benefiting patients worldwide.
Objectives
The BENTO trial aims to demonstrate that the BTVA treatment is an effective and safe treatment option and also can ensure sufficient, appropriate and cost-effective care for emphysema patients, taking into account evidence-based medical knowledge.
Methods and analysis
Legal background
The BENTO trial is commissioned by the German Federal Joint Committee (G-BA) to evaluate a new method in the German healthcare system. The trial is part of the decision-making process regarding health insurance reimbursement in routine care. As a part of this process, the G-BA provided the framework for the study design and defined the patient population and primary endpoint (BENTO – Bronchoskopische Lungenvolumenreduktion beim schweren Lungenemphysem mittels Thermoablation – Gemeinsamer Bundesausschuss (g-ba.de)). The BENTO study is funded by the G-BA, based on the corresponding trial guideline. The treatment costs of the study participants for the intervention and control group are covered by the health insurance companies.
Study design
The BENTO trial is a prospective, controlled, randomised, multicentre, open-label study striving to evaluate the patient-relevant benefit of bronchoscopic LVR using thermal vapour ablation in patients with severe upper lobe emphysema. The intervention consists of a maximum of two partial BTVA procedures. A total of 224 participants are planned to be enrolled in the trial at 15 study sites in Germany. A full list of the planned study sites is provided in online supplemental 1. This trial was registered on ClinicalTrials.gov on 8 February 2023 (NCT05717192). The study is planned to start on 1 January 2024, with a projected end date of 1 January 2027, after 2 years of recruitment and 1 year of follow-up.
Supplemental material
Inclusion/exclusion criteria
The inclusion and exclusion criteria are based on the specifications for patient selection of the instruction for use of the InterVapor system as well as on the design paper of the STEP-UP study.11 The treatment is indicated for patients with heterogeneous, upper lobe predominant emphysema who are symptomatic despite optimal medical management. All available pharmacological and non-pharmacological options for the patients should be considered and reviewed, including other LVR treatments. The inclusion and exclusion criteria are provided in online supplemental 2.
Supplemental material
Randomisation
At the baseline visit, after signing the written informed consent, patients will be randomised centrally 2:1 into BTVA intervention with the standard of care versus standard of care alone. Randomisation is done block-wise, stratified by the study site. The standard conservative therapy will be conducted in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.12
InterVapor system
The InterVapor system uses heated water vapour to ablate the airways and parenchyma within targeted regions of the lung. Lung remodelling occurs after an initial localised inflammatory response and subsequent healing and repair. The remodelling of the tissue results in reductions in tissue and air volume in the targeted regions of the lung. The remodelled lung tissue does not reinflate as a result of collateral ventilation.
The LVR of diseased hyperinflated lung segments after InterVapor treatment is expected to increase elastic recoil by reducing the most compromised segments of the lung, decompressing segments of healthier lung tissue and thus facilitating alveolar recruitment and improving the mechanical efficiency of the respiratory muscles. These mechanical changes are expected to improve lung function, exercise capacity and quality of life.
Study flow
Subjects will be randomised in a 2:1 ratio to either the intervention arm (BTVA+standard therapy) or the control arm (standard therapy without the use of BTVA). The test subjects in the control arm will not be exposed to the additional stress of a so-called sham intervention. Although standard therapy will be determined on a patient-by-patient basis, it will always be in accordance with the actual treatment recommendations of the Global Initiative for GOLD guidelines to ensure that standard therapy does not differ relevantly between study arms.12
Intervention
The study intervention is vapour ablation treatment (BTVA, InterVapor, Uptake Medical, California, USA) in addition to standard pharmacological treatment, as mentioned above in accordance with the GOLD guidelines. The intervention includes a maximum of two partial treatments, with the optional second treatment occurring between 6 and 12 weeks after the first one.
Control
Standard conservative therapy in accordance with the present pharmacological treatment recommendations GOLD guidelines without the use of a BTVA.
The total follow-up period for each subject will be 12 months. The primary endpoint (patient-reported, disease-specific quality of life as measured by the St George’s Respiratory Questionnaire for COPD patients (SGRQ-C)) will be assessed as the change between the 9-month visit and baseline (randomisation) questionnaires. Specifically, the follow-up time points for the collection of all endpoints are 3 months, 9 months and 12 months. The follow-up period begins at randomisation for both study arms. A detailed overview is provided in figure 1.
Study flow chart. BTVA, bronchoscopic thermal vapour ablation; GOLD, Global Initiative for Chronic Obstructive Lung Disease.
Outcome measures
Primary endpoint
The primary endpoint is a change in the patient-reported, disease-specific quality of life measured by St. George Respiratory Questionnaire, SGRQ-C- between baseline (randomisation) and 9-month follow-up. The SGRQ-C is a shortened version of the SGRQ, derived from the original version after a detailed analysis of data from large COPD studies. It is a validated questionnaire that has already been used in numerous studies and is, therefore, ideally suited as a research and testing tool. This includes the STEP-UP study, which was able to demonstrate the efficacy and benefit of the tested product in patients with heterogeneous upper lobe emphysema.7
Secondary endpoints
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Change in residual volume (RV) (time frame: 3, 9 and 12 months).
Change in RV in litres and per cent predicted
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Vital status (time frame: 3, 9 and 12 months)
alive/dead
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Change in forced expiratory volume in 1 s (FEV1) (time frame: 3, 9 and 12 months).
Change in FEV1 in litres and per cent predicted.
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Change in patient-reported, disease-specific quality of life (time frame: 3 and 12 months).
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Serious adverse events (time frame: 3, 9 and 12 months).
Rate of serious adverse events
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6-min walk test (6MWT) (time frame: 3, 9 and 12 months).
Measures the distance (metre) in a 6MWT
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Severe exacerbations (time frame: 3, 9 and 12 months).
Rate of severe exacerbations
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Mortality (time frame: 3, 9 and 12 months).
All-cause mortality
Sample size calculation
Data from the STEP-UP study show that the primary endpoint ‘change in disease-specific quality of life (SGRQ-C)’ had a group difference of −6.1 points (95% CI 1.3 to 13.7; p=0.1089) after 6 months. After 12 months, the difference was −8.4 points (95% CI 0.7 to 17.5; p=0.0721).7
Assumptions and specifications:
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An expected group difference in SGRQ-C of at least six points with an SD of 14 is assumed.
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One-sided t-test.
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Significance level 2.5%.
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Power 80%.
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15% loss to follow-up (LTF).
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If randomised in a 2:1 ratio:
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n=195 (130:65) subjects to be analysed.
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Considering an LTF rate of 15%, N=224 (150:74) subjects to be included in the clinical trial.
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Data analysis and management
Statistical analysis
The analysis of the primary hypothesis will be based on the intention-to-treat (ITT) population, that is, on the data of all randomised subjects from whom the primary endpoint is available. Subjects assigned to a study arm by randomisation will be analysed as members of that arm, regardless of their concordance with the actual treatment course, for example, cross-over.
A supporting per-protocol analysis of the primary hypothesis will be conducted, that is, a subset of subjects from the above ITT population in which no relevant protocol violations have been documented. Thus, the efficacy potential of the intervention can be estimated under optimised conditions.
Descriptive analysis
All data are analysed using descriptive statistical methods.
Analysis of primary endpoint
The statistical question of whether the intervention is superior to controls with respect to the primary endpoint is tested using the two-sample t-test one-sided with a significance level of 0.025. For this analysis, the ITT population is used.
In addition to the test result, CIs for the QoL difference are calculated according to SGRQ-C.
Details on checking statistical data prerequisites for this analysis and possible consequences will be specified in the statistical analysis plan.
Although a life expectancy of <12 months was defined as an exclusion criterion, it is not assured that equal rates of death are to be expected in both study arms. Therefore, as a sensitivity analysis, the primary endpoint in the ITT population including deceased patients is tested. Thereby the QoL of the deceased is set to the computationally possible minimum.
Analysis of secondary endpoints
For all secondary endpoints, an estimate of the effects of the intervention compared with standard care is provided by appropriate methods (HRs for all-cause mortality, difference estimates for continuous endpoints, ORs for binary endpoints). For the resulting estimators, their 95% CIs are reported.
No formal statistical hypothesis tests are performed. Except for missing information on the date of death, no imputations are performed for missing data.
Safety analysis
Cumulative incidence functions of all serious kinds of events are calculated in the total safety population, taking into account mortality as a competing risk. Graphical representations are supplemented by two-tailed Gray’s tests for differences between study arms.
Adverse events and their outcome are summarised for the total population of all included subjects.
Data monitoring
To ensure high-quality and regulatory compliance, the overall conduct of the trial will be monitored. Adequate monitoring of the clinical trial will be ensured by the monitors who will verify investigator compliance with the clinical trial protocol and regulatory requirements. The planning of monitoring visits (on-site or remote) will be risk-based to ensure that the trial is conducted in accordance with the protocol and maintenance of the highest data quality. The sponsor will develop a detailed monitoring plan that specifies the timing and scope of monitoring visits and responsibilities.
Collecting, assessing, reporting and managing adverse events is described in the study-specific safety management plan.
Trial organisation
The BENTO trial is designed, implemented and supervised by a steering committee of experts in the field. The Thoraxklinik at the University of Heidelberg is responsible for the scientific advice and coordination of the study. The study and data management (details are managed in a data management plan) will be carried out by the CRO IHF (Ludwigshafen), which is also the legal sponsor. Furthermore, to ensure patient safety, a data safety monitoring board (DSMB) is established to monitor patient safety (details are managed in a DSMB Charter).
Since the trial has been commissioned by the G-BA with the intention to implement BTVA into routine care if the trial meets the primary endpoint, the funding of the study consists of two paths. Study-related costs will be covered by the sponsor. Further, all costs that may become part of routine care in the future will be covered by the respective general health insurance of a study participant. The manufacturer is not involved in any aspect of study design, conduct, data analysis or reporting. The manufacturer is only responsible for pretrial training, technical assistance and resolution of technical questions.
Patient and public involvement
The BENTO trial is commissioned by the G-BA to evaluate a new method in the German healthcare system. The trial is part of the decision-making process regarding health insurance reimbursement in routine care. As a part of this process, the G-BA provided the framework for the study design and defined the patient population and primary endpoint. No patients were involved.
Ethics and dissemination
Ethics approval and consent to participate
The current trial protocol was approved by the leading Ethics Committee at the Medical Faculty of the University of Heidelberg (DIMDI-Nr: 00014660).
Additional regional approval will be obtained at each site before study activities are conducted. Before their participation in the trial, oral and written explanations will be provided to all patients, and then written consent will be obtained by the investigator. It is not planned to enrol patients who are not able to provide consent. If there is any amendment to the study protocol that could affect the participant’s decision to participate, the principal investigator will inform the participants and confirm their intent to continue their participation in the trial.
Dissemination
The results of the BENTO trial will be disseminated by publication in a peer-reviewed journal and will be made available to healthcare providers, policy-makers and patients via presentations at local and national meetings.
Discussion
The goal of the BENTO trial is to investigate whether patients with severe emphysema and hyperinflation benefit from bronchoscopic LVR using thermoablation in addition to conservative standard therapy. Thermoablation, also known as BTVA, involves the targeted introduction of hot water vapour into the damaged lung tissue. This leads to a local inflammatory reaction and, over time, to a shrinkage of the non-functioning, overinflated lung tissue. This should leave more space available for the functional parts of the lungs.
There are currently little data on the use of BTVA for the treatment of patients with emphysema. The current evidence suggests that bronchoscopic LVR for severe emphysema using thermoablation has the potential to be an efficient treatment alternative. The efficacy of BTVA has been demonstrated in a few randomised clinical trials for heterogeneous upper lobe emphysema. In the randomised controlled trial, STEP-UP patients with predominant upper lobe emphysema experienced a clinically significant improvement in lung function and quality of life compared with the control group receiving standard pharmacological therapy.7 13
The inclusion and exclusion criteria for the BENTO trial are designed to ensure adequate patient selection. Due to the multicentre design of the study, centres with experience in BTVA-treatments are selected for participation.
The trial will, therefore, help to demonstrate the benefit of BTVA treatment as an effective and safe therapeutic option in order to provide emphysema patients with adequate, appropriate and economical care, taking into account evidence-based medical knowledge.
Supplemental material
Ethics statements
Patient consent for publication
This post was originally published on https://bmjopen.bmj.com