Clinical Investigation of a Modified Staged Treatment Algorithm Using the AeriSeal System

Study Overview
=================
Brief Summary
-----------------
A multicenter, prospective, single-arm clinical investigation to evaluate the short term and long term safety of a modified staged treatment algorithm using the AeriSeal System.

Detailed Description
-----------------
The AeriSeal-STAGE trial will be a prospective, multicenter study that intends to evaluate the safety of a modified staged treatment algorithm with an escalation of dose using the AeriSeal System in the treatment of subjects with severe emphysema in a controlled trial design setting as compared to published data from prior studies. The trial is anticipated to enroll fifteen (15) study subjects with homogeneous, or upper lobe predominant heterogeneous emphysema, in three (3) centers in Europe.

Official Title
-----------------
A Multicenter, Prospective, Single-Arm Clinical Investigation of a Modified Staged Treatment Algorithm Using the AeriSeal System - the AeriSeal-STAGE Trial

Conditions
-----------------
Emphysema

Intervention / Treatment
-----------------
* Device: AeriSeal System


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is willing and able to provide informed consent and to participate in the study Subject is ≥ 40 years of age Subject has a diagnosis of homogenous or heterogeneous upper lobe predominant emphysema confirmed by computerized tomography (CT) scan. Subject has at least two (2) non-adjacent subsegments appropriate for treatment based upon CT scan in 2 different upper lobe segments in each lung (total 4 available subsegments) Subject has clinically significant dyspnea scoring >1 on the mMRC scale of 0 - 4 Subject has a Six-Minute Walk Test (6MWT) distance ≥ 250 meters Subject has post-bronchodilator FEV1 ≤ 45% predicted Subject has Total Lung Capacity >100% predicted Subject has Residual Volume >175% predicted Subject has stopped smoking for at least 8 weeks prior to entering the study as confirmed by carboxyhemoglobin or cotinine levels Subject has received preventive vaccinations against potential respiratory infections consistent with local recommendations or policy Exclusion Criteria: Subject has severe bullous emphysema as judged by Investigator. Subject has prior lung volume reduction surgery, prior lobectomy or pneumonectomy, prior lung transplantation, prior airway stent placement, prior pleurodesis, or prior endobronchial lung volume reduction therapy of any type Subject has evidence of active respiratory infection Subject has an ongoing chronic obstructive pulmonary disease (COPD) exacerbation or bronchospasm Subject has a known allergy to the device components: Polyether block amide - PEBAX® Polyvinyl Alcohol Glutaraldehyde Subject requires ventilatory support (invasive or non-invasive) Subject has diffusing capacity of the lungs for carbon monoxide (DLco) < 20% predicted Subject has a post-bronchodilator FEV1 < 20% predicted Subject cannot tolerate corticosteroids or relevant antibiotics Subject has relevant comorbidities as judged by the Investigator, or is deconditioned and cannot tolerate the stress of post-treatment inflammatory response Subject has a history of recurrent clinically significant respiratory infections, defined as three (3) or more COPD exacerbations requiring hospitalization during the year prior to enrollment Subject has severe gas exchange abnormalities as defined by any one of the following: Partial pressure of arterial carbon dioxide (PaCO2) >55 mm Hg Partial pressure arterial oxygen (PaO2) <45 mm Hg on room air Peripheral capillary oxygen saturation (SpO2) < 90% on ≥ 4 L/min supplemental O2, at rest Subject has Pulmonary hypertension, defined as peak systolic pressure > 45 mm Hg on echocardiogram or right heart catheterization Subject use of systemic steroids >20 mg/day or equivalent and/or immunosuppressive agents in the 4 weeks prior to procedure Subject unable to temporarily interrupt use of heparins or oral anticoagulants (e.g., warfarin, dicumarol) per Institutional recommendations. Note: antiplatelet drugs including aspirin and clopidogrel are permitted Subject has alpha1 -antitrypsin serum level of <80 mg/kg (i.e. < 11 µmol/L) at Screening Subject's CT scan indicates the presence of any the following radiologic abnormalities: Pulmonary nodule on CT scan greater than 0.8 cm in diameter [Does not apply if present for 2 years or more without increase in size or if proven benign by biopsy/positron emission tomography (PET)] Radiologic picture consistent with active pulmonary infection, e.g., unexplained parenchymal infiltrate Significant interstitial lung disease Significant pleural disease Subject's baseline electrocardiogram (EKG) indicates arrhythmias or conduction abnormalities Subject has high cardiac risk after undergoing cardiac risk assessment in accordance with published guidelines or ischemic heart disease, congestive heart failure, renal failure or cerebrovascular disease Clinically significant asthma (reversible airway obstruction), chronic bronchitis, or bronchiectasis Allergy or sensitivity to medications required to safely perform bronchoscopy and the AeriSeal System treatment under general anesthesia or conscious sedation Participation in an investigational study of a drug, biologic, or device within 30 days prior to entering the study or planned during the course of the study. Body mass index (BMI) < 15 kg/m2 or > 35 kg/m2 Female subject pregnant or breast-feeding Abnormal screening laboratory test results as compared to reference lab normals at individual sites as follows: Blood urea nitrogen > 1.5 x upper limit of normal Creatinine > 1.5 x upper limit of normal Aspartate aminotransferase > 1.5 x upper limit of normal Alanine aminotransferase > 1.5 x upper limit of normal Alkaline phosphatase > 1.5 x upper limit of normal White blood cells (total) absolute < 3 x 109/L or > 1.25 x upper limit of normal Hematocrit < 34 or > 1.25 x upper limit of normal Platelets < 100 or > 450 K/µL Prothrombin time or International Normalized Ratio (INR) > 1.5 x upper limit of normal Partial thromboplastin time > 1.5x upper limit of normal Positive Beta human chorionic gonadotropin (β-HCG) Pregnancy test (if female) Subject has evidence of severe disease which in the judgment of the investigator may compromise survival for the duration of the study (24 months) e.g.: Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) Active malignancy Stroke or Transient ischemic attack (TIA) within 12 months of Screening visit Myocardial infarction within 6 months of Screening visit Congestive heart failure within 6 months of Screening visit defined as clinical evidence of right or left heart failure or left ventricular ejection fraction < 45% on echocardiogram Subject has been diagnosed with diabetes mellitus Any condition that the Investigator believes would interfere with the intent of the study or would make participation not in the best interest of the subject i.e., alcoholism, high risk for drug abuse or noncompliance in returning for follow-up visits

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AeriSeal System<br>Subjects will be treated with AeriSeal Foam. | Device: AeriSeal System<br>* Subjects will undergo two bronchoscopy procedures two months apart and will be treated with AeriSeal foam unilaterally, in two sub-segments during each bronchoscopy (4 segments treated in total).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Serious Adverse Events | Assessment of Serious Adverse Events (SAEs) To evaluate the safety of using a modified staged treatment algorithm at 3- months following the second placement of AeriSeal foam treatment in subjects with severe emphysema. The primary endpoint will be safety of AeriSeal System treatment. Safety will be assessed by monitoring the incidence of Serious Adverse Events (SAEs), during the 3-months post treatment period. Exclusively, the incidence of a prospectively specified subset of important respiratory related SAEs (COPD exacerbations requiring hospitalization or extended hospitalization, pneumonia, acute inflammatory response occurring after 30-days posttreatment, pneumothoraces), deaths and respiratory failures will be lower as compared to published data from prior studies. | 3-months post treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in one second (FEV1) | Percent mean change relative to baseline at 3-months, 6-months and 12-months for FEV1 | Baseline, 3-months, 6-months and 12-months | 
| Residual volume (RV) | Percent mean change relative to baseline at 3-months, 6-months and 12-months for RV | Baseline, 3-months, 6-months and 12-months | 
| Exercise capacity as assessed by six-minute walk test (6MWT) | Absolute change relative to baseline at 3-months, 6-months and 12-months for 6MWT | Baseline, 3-months, 6-months and 12-months | 
| Quality of life as assessed by the St George's Respiratory Questionnaire (SGRQ) | Absolute change relative to baseline at 3-months, 6-months and 12-months for SGRQ. The St. George's Respiratory Questionnaire measures health status (quality of life) in patients with diseases of airways obstruction. The questionnaire comprises of two parts: Part I: Symptoms (frequency & severity) Part II: Activities that cause or are limited by breathlessness; Impacts (social functioning, psychological disturbances resulting from airways disease) A Total score is calculated which summarizes the impact of the disease on overall health status. Scores range from 0 to 100, with higher scores indicating more limitations. | Baseline, 3-months, 6-months and 12-months | 
| Dyspnea as assessed by the Modified Medical Research Council Dyspnea Score (mMRC) | Absolute change relative to baseline at 3-months, 6-months and 12-months for mMRC. The mMRC (Modified Medical Research Council) stratifies severity of dyspnea in respiratory diseases. The severity of dyspnea is rated on a scale of 0 to 4, with higher scores indicating more limitations. | Baseline, 3-months, 6-months and 12-months | 
| Lobar volume reduction | Lobar volume reduction of the treated lobes as quantified by computerized tomography (CT) scans at 3-months | 3-months | 
| Radiological signs of complications on computerized tomography (CT) scans | Radiological signs on CT scans of complications including but not limited to pneumonias, pleural effusions and consolidation at, and outside the treatment sites and formation of lung abscesses at 3-months following the second placement of AeriSeal foam. | 3-months following the second placement of AeriSeal foam. |