The primary objective of the study is to assess the feasibility and safety of sequential ETLA treatment in patients with severe emphysema with hyperinflation. The secondary objective of the study is to assess efficacy of sequential ETLA treatment in…
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Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints will assess the feasibility and safety of ETLA.
Feasibility:
• % of procedures where the device operated as intended per IFU
• % of procedures and % of target regions where saline is delivered at the
predetermined volume per treatment plan
Safety:
• Incidence of serious adverse events (SAE) associated with the ETLA device
and/or procedure through 9 months post-procedure 1 as adjudicated by an
independent medical monitor
Secondary outcome
The secondary endpoints will assess the efficacy, feasibility, and safety of
ETLA.
Feasibility:
• Target Lobe Volume Reduction (TLVR) as measured by CT scan quantified by the
reduction in the volume of the targeted lobe(s) (reported in mL) at the below
time points:
o 3 months post-procedure 1 compared to baseline
o 3 months post-procedure 2 compared to the scan at 3 months post-procedure 1
• Cumulative Lobar Volume Reduction as measured by CT scan, quantified by the
summation of TLVR through both procedures (reported in mL)
Safety:
• Incidence of all adverse events associated with the ETLA device and/or
procedure through 9 months post-procedure 1
Efficacy:
The following endpoints will be compared to baseline at 3 months and 9 months
post-procedure 1 and 3 months post-procedure 2.
• RV change (mL, % change in absolute and % predicted)
• FEV1 change (mL, % change in absolute and % predicted)
• 6MWT changes
• SGRQ-C change
Background summary
Many emphysema patients remain symptomatic with worsening symptoms over time
despite optimal pharmacotherapy and pulmonary rehabilitation. Lung volume
reduction surgery improves symptoms, exercise tolerance and quality of life
beyond improvements seen with optimized medical therapy including pulmonary
rehabilitation. However, the procedure is characterized by an increase in
mortality, significant morbidity, and may involve lengthy post-operative care.
Bronchoscopic approaches to lung volume reduction (LVR) demonstrate
improvements in pulmonary function and quality of life with less morbidity and
mortality than surgery. Valve implants have been shown to induce LVR in
patients with hyperinflated diseased lobes with intactfissures (no collateral
ventilation) resulting in clinically meaningful and statistically significant
improvement in pulmonary function and quality of life. ETLA is a non-implant
with a short procedure duration that offers the potential to induce significant
LVR of hyperinflated emphysematous regions regardless of collateral ventilation
and is able to treat at a subsegmental level. ETLA may provide clinically
meaningful improvement in pulmonary function and quality of life to a broad
population of severe emphysema patients, addressing a clinical need in patients
with collateral ventilation as well as patients with significant intralobar
heterogeneity.
The preclinical safety and feasibility of ETLA for lung volume has been
established and is presented in the Investigator*s Brochure. It is anticipated
that LVR will lead to clinically meaningful improvement in pulmonary function
and quality of life. Clinical experience gathered to-date from the Australian
First in Human REDUCE study have demonstrated correlation to pre-clinical
findings for safety, efficacy, and lung volume reduction in patients regardless
of collateral ventilation at the dose proposed for this study. The REDUCE EU
Pilot study will primarily evaluate the feasibility and safety of ETLA
treatment in patients with severe emphysema. Secondarily, the study will
evaluate the efficacy of sequential ETLA treatment.
Study objective
The primary objective of the study is to assess the feasibility and safety of
sequential ETLA
treatment in patients with severe emphysema with hyperinflation.
The secondary objective of the study is to assess efficacy of sequential ETLA
treatment in patients
with severe emphysema with hyperinflation
Study design
This study is a prospective, single-arm, multi-center pilot study of sequential
treatment with endobronchial thermal liquid ablation (ETLA) to assess
feasibility, safety, and efficacy in patients with severe emphysema with
hyperinflation. ETLA is delivered sequentially over two procedures. Treatment
can be unilateral or bilateral over the two procedures, with each procedure
limited to treatment in a single lung.
The ETLA dose consists of the following parameters that will remain constant:
- Temperature at 95*C
- Flow rate of 1ml/s
- ETLA ratio of 1.75 (volume of heated saline delivered: conductive and
respiratory airway volume 1)
- Number of Subsegments Targetted (estimate) 1-4 subsegments
The cumulative ablation potential (CAP) will not exceed 15% per procedure.
Intervention
Subjects will undergo two (2) ETLA procedures separated by a minimum three (3)
month interval. Each procedure will be limited to treatment in a single lung,
with either unilateral or bilateral treatment over the two procedures.
All sub-segments are presented to the Investigator in a Treatment Region
Selection Tool (TRST). The Investigator will identify and target sub-segments
for treatment which are >= 25% destruction %-950 HU (by CT analysis).
The ETLA procedure will be performed under general anesthesia with a paralytic
according to the Instructions for Use (IFU). The ETLA generator heats and
delivers a predetermined volume of normal saline (0.9% NaCl) to targeted
emphysematous lung regions through a connected, disposable catheter.
Study burden and risks
Patients with severe emphysema suffer from a debilitating decline in pulmonary
function and have a very poor quality of life, primarily due to hyperinflation.
Therapies that reduce hyperinflation and improve pulmonary function and QOL
offer meaningful relief for patients.
ETLA treatment is anticipated to benefit a broad population of severe emphysema
patients. ETLA is not limited to only treating patients with heterogenous lobes
without collateral ventilation (CV-) from incomplete fissures (valves). ETLA
allows for treatment of all qualifying emphysematous patients with
heterogeneous disease regardless of the presence of collateral ventilation.
GOLD stage III & IV heterogeneous emphysema patients with collateral
ventilation represent a large percentage of the severe emphysema population
that currently have limited treatment options. ETLA is expected to benefit
these patients by providing safe, clinically meaningful improvements in
pulmonary function and quality of life. Additionally, ETLA can be delivered to
any eligible subsegment in a lung, allowing the investigator to treat the most
diseased regions regardless of location. The risks associated with the study
are minimized by implementing a treatment CAP that is within the established
safety threshold. A range of 5 to 15% volume treated per procedure is expected
to typically result in clinically meaningful improvement in pulmonary function
and QOL.
The intended patient population for the ETLA system are those individuals with
severe and very severe (GOLD stage III & IV) emphysema deemed to be in clinical
need of lungvolume reduction. These patients may have the following baseline
characteristics: chronic obstructive pulmonary disease with highly destructed
parenchymal subsegments, hyperinflation, reduced pulmonary function, reduced
exercise capacity, reduced oxygen saturation, reduced quality of life, fatigue,
and concomitant disease states such as vascular and/or cardiac disease. This
patient population is characterized by a severe emphysema disease state where
conservative management has failed. The medical condition and nature of the
patient population is such that medical intervention is clinically warranted
based on the treating clinician*s medical judgement and patient informed
consent. The disease state of the patient may contribute to the probability of
adverse procedural effects; however, medical intervention in this patient
population is indicated. Without appropriate management, the risks posed to
health include substantial decrease in quality of life during end-stage disease.
Valve implantation may be appropriate in highly selected patients with severe
COPD and hyperinflation if collateral ventilation from incomplete lobar
fissures can be excluded (intact fissure on imaging and Chartis negative during
bronchoscopy). Benefits of lung volume reduction in the patient population
include improved pulmonary function, reduced lung volumes and hyperinflation,
exercise capacity, dyspnea, and health-related quality of life. Current
evidence on the safety and efficacy of lung volume reduction procedures for
severe emphysema appears adequate to support the use of this procedure.
The side-effects associated with lung volume reduction in general are well
known and documented and are further discussed within this document. Valve
implantation results were used to assess the ETLA pre-clinical studies. These
studies demonstrated adequate evidence of the severity and probability of these
events to provide an overall safety profile of the ETLA system.
The safety and performance aspects of the ETLA system have been evaluated using
risk analysis techniques. Thresholds and precautions have been implemented
wherever possible to mitigate safety risks. The risks associated with the use
of the ETLA system are considered reasonable in comparison to the anticipated
benefits to patients. As the risks associated with the ETLA system are aligned
with the risk profiles of currently available bronchoscopic technologies used
to facilitate lung volume reduction in the intended patient population, the
ETLA system poses an acceptable level of risk for their intended use.
The anticipated residual risks associated with use of the ETLA system are
generally short-lasting and well tolerated. Temporary post-procedural
respiratory symptoms are expected to occur and will typically be managed with
standard of care measures. Due to the minimally invasive nature of the
procedure, the risk profile, by design, has a reduced risk compared to
traditional open surgical lung volume reduction techniques, and due to the
ability to treat patients with collateral ventilation, provide potential for
treatment for a
population with limited alternatives.
Initial assessment of early clinical data has been considered in respect to the
risks outlined. Results for these procedures have shown expected adverse
reactions that, to-date, are consistent with the frequency and severity
outlined in Section 12.2 of the Protocol. Initial clinical data also
demonstrate lung volume reduction that is expected to result in clinically
meaningful improvements in pulmonary function and quality of life. Refer to
Investigator*s Brochure for details. The risks associated with the use of the
ETLA system are considered reasonable in comparison to the anticipated benefits
to patients with severe emphysema.
Further evidence of anticipated and unanticipated risks will be assessed
through tracking of
adverse event rates through clinical studies.
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Age
Inclusion criteria
1. Age >= 40 years old
2. Diagnosis of COPD with FEV1/FVC less than 0.7 post-bronchodilation
3. Post-bronchodilator FEV1 >= 20% and <= 49% of predicted value
4. Total lung capacity TLC >= 100% predicted
5. Residual volume (RV) >= 175% predicted
6. 6MWD >= 140 meters
7. Dyspnea scoring >= 1 on the modified Medical Research Council scale (mMRC)
8. PCO2 <= 55 mmHg; PO2 > 45 mmHg on room air
9. Optimized medical management (consistent with GOLD guidelines) as confirmed
by the Investigator
10. Non-smoking for 3 months prior to study enrollment, as confirmed by:
• Negative cotinine urine analysis or serum cotinine level of <= 10 ng/ml
OR
• Negative carboxyhemoglobin (COHb) test (<= 2.5%)
Note: Carboxyhemoglobin is required for patients who are using smoking
cessation products containing nicotine at screening
11. The patient engages in physical activity beyond activities of daily living
(i.e., a walking program, pulmonary rehabilitation)
• On a regular basis for more than 6 weeks, AND
• Is continuing the activity at enrollment, AND
• Agrees to continue the activity throughout study participation
Note: Physical activity level may be based on documentation or patient
reporting.
12. Patient must meet ONE of the following criteria for distance from treating
hospital:
• Live within approximately 1 hour of the study hospital
OR
• If > 1 hour from study hospital, patient lives within approximately 1 hour of
regional care that is sufficient to handle an emergency pulmonary event in COPD
patients or must be willing to remain in the hospital for at least 5 days
post-procedure
13. Vaccinated for COVID-19, pneumococcus, and influenza (per European Union
and Member State guidelines) or documented clinical intolerance or documented
patient refusal
14. Cognitively able to provide written informed consent and willing to comply
with study requirements
15. Severe emphysematous subsegments eligible for ETLA treatment where the
volume of targeted subsegments must meet the minimum Targeted Procedure Volume
(TPV), with the total targeted volume allowing for two (2) ETLA procedures.
Eligible subsegments are defined as having >= 25% destruction %-950 HU per QCT
analysis with a heterogeneity index (HI) >1.2.
Note: Chest CT analysis by QCT Core Lab
Exclusion criteria
1. Body mass index (BMI) < 16 kg/m2 or >= 33 kg/m2
2. DLCO < 20% predicted
3. Chronic bronchitis as defined by cough and sputum production for at least 3
months per year for two consecutive years, in the absence of other conditions
that can explain these symptoms
4. 75ml or greater sputum production per day most days of the week
5. Greater than two (2) hospitalizations for COPD exacerbations and/or
pneumonia in the 12 months
prior to enrollment
6. Diagnosis of asthma that is confirmed according to the Global Initiative for
Asthma (GINA)
guidelines
7. Prior lung volume reduction via endobronchial valves(s), coil(s), vapor
and/or polymer. Patients whose valves have been removed > 3 months previously
can be treated if a baseline bronchoscopy reveals no airway obstruction or
obvious tissue granulation and the reason for valve removal was not for
complications e.g., Pneumonia, severe exacerbation, or pneumothorax
8. Pulmonary hypertension:
• History of cor pulmonale
OR
• mPAP >20mm Hg in the 12 months prior to enrollment
OR
• RV estimated systolic pressure >45 mmHg in the 12 months prior to enrollment
Note: Measurements from right heart catheterizations are considered definitive
over echocardiography. Patients with a pulmonary hypertension diagnosis must
have an echocardiogram or right heart catheterization within the past 12 months
9. Alpha-1 antitrypsin deficiency
10. Uncontrolled diabetes mellitus with an HbA1c >9.0% within 6 months of
enrollment
Note: Patients with a diagnosis of diabetes mellitus must have an HbA1c
measurement within
the past 6 months.
11. Prior heart or lung transplant
12. Myocardial infarction or stroke within the 12 months of enrollment
13. Diagnosis of heart failure: Left Ventricular Ejection Fraction (LVEF) less
than or equal to 40% within 12 months prior to enrollment.
Note: Patients with a heart failure diagnosis must have an LVEF measurement
within the past 12 months
14. Heart failure requiring hospitalization, within 6 months prior to enrollment
15. History of bleeding disorders or enhanced predisposition to bleeding
16. History of severe/massive hemoptysis defined as >200ml of blood loss in <24
hours
17. Unable to discontinue anti-coagulants or platelet inhibitors
(acetylsalicylic acid [ASA] and non-ASA, including low dose) for at least 7
days prior to each procedure (or as per physician discretion based on the
specific agent) and for at least 6 weeks after each procedure
18. Daily systemic steroids equivalent to > 15 mg prednisolone
19. Immunosuppressive drugs, such as for the treatment of cancer, autoimmune
disease, or prevention of tissue/organ rejection
20. Pregnant, lactating, or women of childbearing potential who plan to become
pregnant within the study duration
21. Currently enrolled in another trial studying an experimental treatment
22. Any disease or condition likely to limit survival to less than one year
23. Concomitant illnesses or medications that may pose a significant increased
risk for complications following treatment with ETLA
24. Any condition that would interfere with evaluation or completion of the
study including study assessments and procedures, including bronchoscopy
25. Active aspergillus infection, including chronic aspergillus infection,
aspergilloma, invasive
aspergillosis, cavitation and/or history of aspergillus cavitation(s) or
colonization confirmed by bronchoscopic culture*
26. Clinically significant bronchiectasis as determined by the Investigator
27. Radiological evidence of bronchiectasis in target region(s) and/or cystic
radiological bronchiectasis in any region of the lungs*
Note: A valid treatment plan must be feasible without targeting regions for
ETLA having radiological evidence of bronchiectasis
28. Clinically significant pulmonary fibrosis*
29. Lung nodule not proven stable unless proven to have benign pathology*
30. Large bulla (defined as > 1/3 volume of a lung)*
31. Prior Lung Volume Reduction Surgery (LVRS), bullectomy, or lobectomy*
32. Remaining lung tissue NOT targeted for ETLA treatment is too highly
diseased, defined as %-
950 >= 50%, after both ETLA procedure treatment plans are finalized, as
confirmed by QCT analysis
Note: Applies to each lung, each individually assessed, regardless of whether
the lung is targeted for
ETLA (unilateral or bilateral treatment)
Note: Chest CT analysis by QCT Core lab
33. Active respiratory infection or recent respiratory infection with
resolution < 4 weeks prior to
screening or procedure
34. Recent COPD exacerbation within < 6 weeks prior to screening or procedure
*Assessed by the Radiology Eligibility Reviewer in addition to the site.
Clinical significance stated in the criteria is determined by the Investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL85280.000.24 |
| Other | TBD |