FOT-vent
Research type
Research Study
Full title
Clinical validation, safety & efficacy study of an advanced auto-titrating non-invasive ventilator in patients with severe chronic obstructive pulmonary disease
IRAS ID
279564
Contact name
Nicholas Hart
Contact email
Sponsor organisation
Guy's and St Thomas' NHS Foundation Trust
Clinicaltrials.gov Identifier
Duration of Study in the UK
1 years, 5 months, 1 days
Research summary
Patients with chronic obstructive pulmonary disease (COPD) can eventually progress to respiratory failure, where they cannot adequately exchange oxygen and carbon dioxide, leading to worsening breathlessness, frequent hospitalisations and death. Non-invasive ventilation (NIV) is a ventilator therapy that is used in COPD patients who suffer from respiratory failure. Studies have demonstrated that using NIV at night regularly can result in improved clinical outcomes.
Adherence to this therapy is variable, however. This can be due to poor synchrony between the device and the lungs. A novel ventilator has been designed that delivers NIV but is also incorporated with technology to assess for aberrations in respiratory physiology and correct them, breath-by-breath.
We aim to assess the efficacy, safety and tolerability of this novel ventilator. The primary research question is whether the novel ventilator can improve adherence to therapy, when compared with the usual ventilator.
Patients with COPD who use ventilation at home will be screened for inclusion in the study. Participation will involve a screening visit, and a further two visits to the Lane Fox Respiratory Unit. The first will require a two-night admission and the second a single-night admission. They will undergo detailed assessment of their daytime and overnight respiratory and sleep physiology during these admissions. These visits will be separated by a six-week period during which they will be asked to use the novel ventilator at home.
Patients will be recruited into a sub-study to evaluate the performance of the ventilator in a daytime physiological assessment. This will involve detailed invasive physiological assessment of expiratory flow limitation and how the machine is able to adjust settings to optimise respiratory support.
The study is funded by Phillips Respironics.
Summary of results
: Introduction
This report is submitted at the conclusion of the Phase 2 A40 EFL study at Guy’s and St Thomas’ NHS Foundation Trust following the previous progress report of 21. September 2022. It outlines the objectives of the study, the protocol, subject recruitment, events surrounding the suspension of the study on 4. July 2022 and the decision to terminate the study communicated by Philips Respironics during the project meeting on 19. December 2023.
Primary objective
To determine the safety of the A40 EFL non-invasive ventilator and its efficacy in improving adherence to ventilator therapy, compared with standard NIV therapy, in patients with COPD and chronic respiratory failure.
Secondary objectives
• To assess the effect of A40 EFL on sleep quality
• To assess the effect of A40 EFL on nocturnal hypoventilation
• To assess the effect of A40 EFL on pulmonary mechanics
• To assess the effect of A40 EFL on health-related quality of life and physical activity
• To assess the ability of A40 EFL to detect and abolish tidal breathing expiratory flow limitation.
Primary outcome
Ventilator adherence after 6 weeks on the novel ventilator compared with 6 weeks of standard therapy
Secondary outcomes:
• Mean and maximum nocturnal transcutaneous CO2
• Abolition of expiratory flow limitation using the novel ventilator through automated titration of EPAP
• Change in sleep parameters (including gaseous exchange) and sleep architecture (total sleep time, sleep efficiency, wake after sleep onset, time in rapid eye movement/non rapid eye movement sleep, apnoea/hyponoea index, 4% oxygen desaturation index)
• Inspiratory capacity following 6 weeks of NIV therapy
• Forced expiratory volume in 1 second (FEV1)
• Health-related quality of life
• Daytime physical activity
Summary of protocol
Recruitment data
Clinical study
In total, 14 patients were screened and 10 patients recruited. Recruitment was suspended on on 6. July 2022 due to concerns regarding over-pressurisation by the ventilator due to issues with the algorithm that detects EFLT and abolishes it through application of auto-titrated EPAP.
There have been no eligibility violations. Two patients were withdrawn from the study by the study investigators prior to completion of the protocol due to suspension of the study.
All 10 completed the first 2 nights of monitoring, with 8 patients completing the protocol at 6 weeks. Initial analysis from an abstract submitted to the European Respiratory Society indicated that patients’ sleep efficiency improved while carbon dioxide oxygen levels remained unchanged. Baseline data for the patients who have completed the study protocol are displayed below.
Parameter Mean (SD)
Age (yrs) 65 (7)
Body mass index (kg/m2) 24.5 (4.0)
ABG
pH 7.39 (0.03)
PaCO2 (kPa) 6.63 (0.70)
PaO2 (kPa) 7.75 (1.01)
HCO3 mmol/L 30.44 (3.00)
Respiratory physiology
FEV1 (L) 0.60 (0.08)
FVC (L) 1.92 (0.28)
Sniff nasal inspiratory pressure (cmH2O) 46 (11)
Forced Oscillation Technique
DeltaXRs (sitting) (cmH2O/L/s) 6.5 (2.0)
Delta XRs (supine) (cmH2O/L/s) 7.2 (1.9)
COPD Questionnaires
COPD Assessment Tool 29 (6)
Modified MRCD 4 (1)
Data collection summary
The following data have been collected:
• Respiratory system reactance using Resmon Pro and A40 EFL in screening mode
• Age, height, weight, neck/waist/hip circumference, BMI
• Pack year history
• Comorbidities
• Spirometry – FEV1, FVC, IC
• Respiratory muscle strength (SNIP, MIP MEP)
• Short physical performance battery
• Neural respiratory drive
• Breathlessness scales (modified Medical Research Council Dyspnoea [eMRCD] score and Modified Borg Dyspnoea Scale, Multidimensional dyspnea profile)
• Health-related quality of life questionnaires
o COPD-specific (COPD Assessment Tool)
o Ventilator-dependent tool (Severe Respiratory Insufficiency)
o Ventilator comfort (visual analogue scale for overnight ventilator comfort
o Sleep quality (Pittsburgh Sleep Quality Index, Visual analogue scale for sleep quality)
• Epworth Sleepiness Scale
• Objective sleep architecture
• Overnight oximetry
• Overnight capnography
• 14-day activity
• 14-day Sleep quantity (sleep diary)
• Ventilator asynchrony questionnaires
Safety concerns
There have been material concerns regarding the integrity of the ventilator algorithm that controls the auto-titration of ventilator pressures on the novel A40 EFL device.
As part of the physiological study, we conducted a detailed comparison of the within-breath changes in reactance (ΔXrs) measured by the A40 EFL device with those measured independently at the mouth. ΔXrs is the substrate for auto-titration of EPAP by the A40 EFL algorithm: when ΔXrs exceeds 2.8 cmH2O/L/s, EFLT is present and the ventilator algorithm increases EPAP by 0.1cmH2O. When ΔXrs falls below 2.8 cmH2O/L/s, EFLT has been abolished and the EPAP is reduced by 0.1cmH2O.
We noted that the A40 EFL algorithm, under certain circumstances, over-estimates ΔXrs. This appears to occur for the following reasons:
1) The quality of the ventilator-generated oscillations required to measure ΔXrs accurately diminishes markedly in inspiration during pressure support ventilation.
2) As a result, the ventilator algorithm generates “zero points” during inspiration, i.e. values of inspiratory Xrs that are discarded in the calculation of ΔXrs. The data points that are of sufficient quality to be used in the calculation of inspiratory Xrs tend to be higher than if the whole of the inspiratory phase were to be used to calculate inspiratory Xrs.
3) The quality of ventilator-generated oscillations are of good quality during expiration. Expiratory Xrs is usually lower (more negative) that inspiratory Xrs. If inspiratory Xrs is over-estimated due to the issues described above and inspiratory Xrs is accurately measured, then the magnitude of ΔXrs will be over-estimated.
Consequently, the ventilator algorithm increases EPAP based on an over-estimate of ΔXrs.
As EPAP increases, the inspiratory phase shortens, further degrading the quality of the inspiratory oscillations upon which the calculation of ΔXrs is based, leading to ongoing over-estimation of inspiratory Xrs and further uncontrolled increases in EPAP. Thus it appears in several patients that EPAP increases beyond that required to abolish EFLT.
We have identified this phenomenon occurring at some point in most patients trialled on the A40 EFL device.
Such over-pressurisation is likely to lead to discomfort, lung hyperinflation, and increased work of breathing.
The physiological studies that identified this issue were performed between 29. June and 1. July 2022. Preliminary data analyses highlighting deficiencies in the ventilator algorithm were carried out on 1-4. July 2022. As consequence, the study was suspended with immediate effect on 4. July 2022. A meeting was convened with colleagues from Philips Respironics on 5. July 2022 and we advised that the study had been suspended and the UK national medical devices regulator (MHRA) informed.
The research ethics committee and the GSTT R&D department were informed of the study suspension on 6. July 2022.
Participants who were enrolled in the study but who had not completed the study protocol (N=2) were withdrawn immediately and asked to revert to their original ventilators, and all participants who had already completed the study protocol were asked to revert to their original ventilators – these actions were complete by 12. July 2022. All participants were questioned as to whether any harm had arisen – no harm was identified. All participants were offered an urgent clinical review if required.
An amendment was sought from and granted by the REC to write to participants’ GPs informing them of the study suspension. All GPs have been informed.
A virtual online meeting was held with colleagues from Philips Respironics on 2. August 2022, and in person at the European Respiratory Society Congress in Barcelona on 5. September 2022. We agreed the following action plan with a view to completing the study.
1) Collaborate with Philips Respironics and Raffaele Dellaca (Politecnico di Milano) to adjust and validate the algorithm:
a. Philips to optimise blower performance through software changes (Mike Kissel, Chuck Cain and team)
b. Philips to validate algorithm internally against:
i. Prototype BiPAP synchrony EFL device (from original experiments Suh et al ERJ 2020)
ii. Reactance measurements made at the mouth (Raffaele)
Dr Eui-Sik Suh agreed to attend data discussions during these internal experiments virtually from the UK.
2) While experiments in US were planned such that colleagues at Philips Respironics, Politecnico di Milano and Guy’s and St Thomas’ NHS Foundation Trust are satisfied that algorithm functions appropriately:
a. GSTT team agreed to complete a major amendment and re-budgeting to re-commence recruitment to include:
i. Research fellow time
ii. Consumables – oesophageal catheter electrodes, wet gel electrodes, PSG consumables
iii. Travel expenses for Milan colleagues to complete experiments in London
b. Complete data entry and analysis:
i. Clinical study
1. Analysis of nightly and hourly changes in EPAP and other secondary outcomes
2. Analysis of primary outcomes for patients who have completed protocol
ii. Physiological study
1. Analysis of neural respiratory drive responses to over-pressurisation of the ventilator
c. Guidance was obtained from the Trial Steering Committee for the study regarding trial sample size on 26. August 2022. A broad consensus was reached that the full cohort of 28 patients would be recruited for the study using the .
d. Repeat physiological studies in 2, 3 and 5 patients over 3 experimental sessions.
e. Recommence clinical study once physiological evaluations were complete.
Colleagues from Philips Respironics, Politecnico di Milano and Guy’s and St Thomas’ NHS Foundation Trust met virtually throughout 2023 to plan the clinical evaluation of the optimised ventilator algorithm, including refinement of the protocol.
There were concerns that the requirement for EUMDR certification of the optimised device would give rise to further delays. Therefore, at a face-to-face meeting on 9. September 2023 at the European Respiratory Congress in Milan, it was agreed by colleagues from Philips Respironics (Gary Lotz, Chuck Cain), Politecnico di Milano (Raffaele Dellaca) and Guy’s and St Thomas’ NHS Foundation Trust (Eui-Sik Suh) that a protocol amendment would be submitted to the Research Ethics Committee to enable the study to proceed with the optimised ventilator as an investigational medical device.
Advice was sought from the MHRA between September and December 2023 to obtain a letter of no objection from them, before the amendment was submitted. However, for business reasons, a decision was made to terminate the study as the A40 ventilator platform was planned to be withdrawn from the market.
Discussions are ongoing with colleagues at Philips Respironics regarding publication and dissemination of study data.
Conclusion
This study has faced many challenges. Having been conceived in 2018, we were able to begin recruitment only in March 2020, at the onset of the COVID pandemic. Recruitment of patients to the clinical study in the immediate post-pandemic phase was difficult, but through colleagues’ efforts, we achieved reasonable recruitment rates. Restrictions on international travel meant that the physiological study could begin only in the summer of 2022, but this study quickly revealed the issues with over-pressurisation due to over-detection of expiratory flow limitation by the ventilator algorithm. Finally, the withdrawal of the A40 EFL device for business reasons meant that the study could not continue.
Nonetheless, we have demonstrated that recruitment into studies of this type were possible in the post-pandemic era. We have performed robust physiological studies to identify deficiencies in the ventilator algorithm. And as a broader research team across Philips Respironics, Politecnico di Milano and Guy’s and St Thomas’ NHS Foundation Trust, we have acted with scientific rigour, demonstrated integrity in the face of challenging situations, and worked collaboratively in such a way as to paint a bright future for subsequent studies with the EFL technology.REC name
West Midlands - Solihull Research Ethics Committee
REC reference
21/WM/0009
Date of REC Opinion
15 Mar 2021
REC opinion
Further Information Favourable Opinion