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An open-label, single-arm study of CRYO2 for tissue removal at the site of central airway obstruction or stenosis: study protocol

ABSTRACT Argon-plasma coagulation, high-frequency electrosurgical snare, laser therapy, and microwave treatment are therapeutic options to reduce tumor-related stenosis of the central airway. These treatments may cause airway fire under a high concentration of oxygen, so FiO2 levels must be ≤40%. This restriction may be dangerous when treating patients with respiratory failure. The cryosurgery unit, ERBE-CRYO2, facilitates treatment under an FiO2 level of 100%, safely reducing this risk. In Japan, CRYO2 has been approved for cryobiopsy and foreign body removal, but not for tissue removal at the site of obstruction or stenosis due to lack of sufficient evidence. Since CRYO2 may be useful for reducing airway stenosis, the present study was designed to increase indications for this unit in Japan.


INTRODUCTION
Argon-plasma coagulation (APC), high-frequency treatment, laser therapy, and microwave treatment are all therapeutic options for reducing tumor-related stenosis of the central airway. These treatments may cause airway fire under a high oxygen concentration, so FiO2 levels must be kept at 40% or less. This restriction may be dangerous when treating patients with respiratory failure, such as dyspnea and hypoxemia. The cryosurgery unit, CRYO2 (AMCO Inc., Tokyo, Japan) facilitates treatment under an FiO2 level of 100%, safely reducing this risk. However, tumorectomy with CRYO2 may induce hemorrhage from the tumor or peripheral tissue as frozen/ coagulated tissue is being removed. It has not yet been established whether the associated risk exceeds the above advantage.
In the United States and Europe, this unit was approved with the brand name "ERBE-CRYO2" in 2015 ("Erbecryo2" in 2012) for the purposes of cryobiopsy, tissue removal at the site of obstruction or stenosis, and foreign body removal. The import of this unit to Japan as a medical device was approved for cryobiopsy and foreign body removal in 2017. However, in contrast to Europe, it has not yet been approved in Japan for tissue removal at the site of obstruction or stenosis, due to lack of sufficient evidence.
According to a study in Europe, recanalization of the central airway was achieved under an oxygen concentration of 100%, and the degree of hemorrhage was moderate or slight in most cases. The present study was designed to increase indications for this unit in Japan.

METHODS / DESIGN
In order to treat central airway tumor-related stenosis, tissue removal at the stenotic site of the airway will be performed using CRYO2 under general or local anesthesia. Taking the day of surgery as Day 1, Days 2 to 7 are established as an observation period to evaluate primary endpoints and conduct clinical examinations (Refer to Figure 1). During the study period, combined therapies, such as airway-dilating procedures and aspiration for safety assurance, will be performed based on the attending physician's evaluation.

Device
Cryosurgery units supply a gas or liquid refrigerant for target-tissue heat emission through direct cryogen supply or indirect contact with a probe cooled with a cryogen. CRYO2 will be employed in the present study (refer to Figure 2 for its shape/structure). This cryosurgery unit is used in the field of respiratory medicine; a probe cooled with a cryogen is brought into contact with the site to be operated on (the bronchus and peripheral tissue of the bronchus) or objective (intra-bronchial foreign bodies, such as sputum and blood clots) for cooling/freezing, and then biopsy specimens are collected or foreign bodies are removed.

Eligibility criteria Inclusion criteria
(1) Patients with central airway mass-related stenosis of the airway requiring treatment for symptoms such as dyspnea, hypoxemia, and stridor.
(3) Those who provide (or whose legal representatives provide) written informed consent to trial participation.

Exclusion criteria
(1) Patients with unstable angina or a history of myocardial infarction within 6 months.
(2) Those with a marked bleeding tendency.
(3) Those with an aspartate transaminase or alanine aminotransferase level of ≥100 IU/L. (4) Women who are or may be pregnant.
(5) Patients who are considered to be ineligible for this trial by the principal investigator or attending physicians.

Endpoints
The primary endpoint is the incidence of moderate to severe and massive hemorrhage. The degree of hemorrhage will be evaluated using the American College of Radiology ACR Appropriateness Criteria® 1) : -Minor: blood loss volume within 24 hours, <30 cc -Moderate to severe: blood loss volume within 24 hours, 30-300 cc -Massive: blood loss volume within 24 hours, >300-400 cc Secondary endpoints include the proportion of technical success, adverse events, and proportion of subjects with an intraoperative SpO2 value ≤95. Patients with sputum excretion following its retention related to airway tumor dissection, the amelioration of airway stenosis, or successful stenting are regarded as achieving a technical success. The severity of adverse events will be evaluated using the Common Terminology Criteria for Adverse Events (Ver. 4.0).

Statistical analysis
Subjects meeting the main registration conditions and with at least one observation value after the start of the CRYO2 procedure will be regarded as a full analysis set. Furthermore, subjects in whom the CRYO2 procedure was started will be regarded as a safety analysis set.
In the full analysis set, the proportion of technical success and 95% confidence interval will be calculated. The proportion of subjects with an intraoperative SpO 2 value of ≤95 and 95% confidence interval will be calculated. In the safety analysis, the incidence of moderate or marked intraoperative hemorrhage in the safety analysis set and 95% confidence interval will be calculated. Furthermore, the incidence of moderate to severe and massive hemorrhage with respect to the presence or absence of a stent will be calculated, along with the incidence of adverse events.

Sample size
Two studies have reported the incidence of hemorrhage as an adverse event with respect to the severity in patients who underwent tissue removal with a CRYO probe at the site of obstruction or stenosis. The incidences of moderate and marked hemorrhage were 25 (10/40) 2) and 8.0% (18/225), 3) respectively. Assuming that the incidence of moderate to severe and massive hemorrhage may be 25%, 27 patients are required to establish a width from the lower limit of the 95% confidence interval to sample the estimate for the incidence of hemorrhage as <15%. Considering the possibility of dropouts, the sample size was set to 30.

DISCUSSION
The safety of CRYO2 for tissue removal at the site of obstruction or stenosis will be examined. According to a study in Europe, recanalization of the central airway was achieved under an oxygen concentration of 100%, and the degree of hemorrhage was moderate or slight in most cases. This procedure may become a new, effective treatment method for patients with central airway mass-related stenosis of the airway requiring emergency airway maintenance.