Clinical trial NCT06378671: Single-center Clinical Study on the Safety and Effect of Bronchoscopic Cryotherapy in Patients With Chronic Cough
Official title: Single-center Clinical Study on the Safety and Effect of Bronchoscopic Cryotherapy in Patients With Chronic Cough
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Chronic Cough
Keywords: Chronic Cough
Cryotherapy treatment via bronchoscopy
Lead sponsor: Guangzhou Medical University
Sponsor class: OTHER
Collaborators: name: Ningbo SensCure Biotechnology Co., Ltd.
First posted: 2024-04-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: a prospective, single-center, double-blind ,randomized controlled clinical trial
Primary purpose: TREATMENT

Brief summary: Chronic cough is one of the most common complaints in respiratory specialty clinics, imposing significant economic burden on patients and severely affecting their quality of life. Currently, the pathogenesis of chronic refractory cough remains incompletely understood, and treatment remains a major challenge in clinical practice. Cryotherapy treatment via bronchoscopy has shown efficacy in certain airway diseases, but there is currently no research reporting its effects on chronic refractory cough.

The goal of this clinical trial is to learn if Cryotherapy treatment works to treat individuals with chronic cough. It will also learn about The safety and effectiveness of the cryotherapy treatment system produced by Ningbo SensCure Biotechnology Co., Ltd.. The main questions it aims to answer are:

* Does cryotherapy treatment lower the frequency and severity of cough and enhance quality of life?
* Will there be safety or operational performance issues when using this cryotherapy treatment system? Researchers will compare cryotherapy treatment with no treatment to determine if cryotherapy treatment is effective for treating chronic cough.

Participants will:

* Take routine bronchoscopy examination, lavage, and mucosal biopsy ,with/without cryotherapy treatment locally (around the left and right main bronchi, upper trachea, and carina)
* undergo a screening period of approximately 28 days. Follow-up visits and necessary examinations will be scheduled for the 3rd day after treatment initiation and at weeks 1, 2, 4, 8, and 12 thereafter.
* Monitor vital signs and clinical manifestations.

Detailed description: 1. Objective The objective is to treat patients with chronic cough using the cryotherapy treatment system (including cryotherapy ablation equipment and associated cryotherapy ablation catheters) to improve cough symptoms and enhance patient quality of life. Additionally, to evaluate the safety and effectiveness of the cryotherapy treatment system produced by Ningbo SensCure Biotechnology Co., Ltd., and to provide scientifically reliable data for further formal clinical trials.
2. content This is a prospective, randomized, controlled, small-sample clinical trial, with plans to enroll 20 participants. The experimental device is the cryotherapy treatment system developed and manufactured by Ningbo SensCure Biotechnology Co., Ltd. (including cryotherapy ablation equipment and associated cryotherapy ablation catheters). Safety evaluation criteria (including the incidence of device/procedure-related serious adverse events, device/procedure adverse event rate, incidence of serious adverse events, and device defect rate) and effectiveness evaluation criteria (including cough visual analog scale score, number of coughs within 2 hours, modified cough score scale, Leicester Cough Questionnaire, and cough sensitivity testing) will be used to assess the safety and effectiveness of the cryotherapy treatment system for treating patients with chronic cough.
3. Criteria and Procedures for Withdrawal/Termination of Trial Treatment

Subjects may prematurely terminate treatment or withdraw from the study due to any of the following, but not limited to:

1. Medical or safety reasons deemed necessary by the investigator for the subject to withdraw from the study;
2. Failure to meet inclusion criteria or meeting exclusion criteria after enrollment;
3. Subject's unwillingness to continue participating in the study for any reason;
4. Loss to follow-up (the investigator is unable to contact the subject to return to the clinic for primary endpoint assessment and examination);
5. Termination of the study requested by the investigator or the company for any reason.

For all subjects who prematurely terminate the study, the investigator should obtain the reason for withdrawal as much as possible, such as adverse events, correction of ineffective treatment, withdrawal from the trial based on the investigator's decision, or other reasons, and the withdrawal reason should be recorded in the Case Report Form (CRF).

4．Expected Duration of Participation for Each Subject The expected duration of participation for each subject is defined as the time from the subject's signing of the informed consent form to the end of the final follow-up visit. According to the trial design, the visit schedule for each subject is as follows: Visit 1 (screening period, pre-operative -28 days to treatment period), Visit 2 (treatment period, Day 0), Visit 3 (Day 3 ± 1 day), Visit 4 (Week 1 ± 1 day), Visit 5 (Week 2 ± 3 days), Visit 6 (Week 4 ± 3 days), Visit 7 (Week 8 ± 7 days), and Visit 8 (Week 12 ± 7 days).

5．Monitoring Plan Executor: Monitor. Monitoring Content: Whether the trial protocol is followed; whether all Case Report Form (CRF) entries are correct, complete, and consistent with the original documents such as medical records and physical examination reports, and whether there are any errors or omissions in the data. Since most of the data in the CRF are transcribed from original sources such as medical records and physical examination reports, much of the content is secondary data. Therefore, during monitoring, the content of the CRF needs to be meticulously cross-checked with the original documents to ensure that the data in the CRF are completely consistent with the original data. This process is also known as Source Data Verification (SDV).

6．Data Management and Statistical Analysis Methods A separate data folder will be established for each participant, and dedicated personnel will be responsible for data collection and entry. Adhering to Good Clinical Practice (GCP) principles, it is essential to ensure the authenticity and traceability of the data, retaining all raw data for verification purposes. Statistical analysis of the data will be conducted using SAS 9.4 or higher software.

Eligibility criteria: Inclusion Criteria(To be eligible, all of the following criteria must be met):

* Age between 18 and 65 years, regardless of gender;
* Patients with cough of unknown etiology or cause, lasting for more than 8 weeks;
* Cough Visual Analogue Scale (VAS) score ≥ 50；
* Willingness to provide voluntary informed consent and agree to follow-up;
* The investigator believes that the overall status of the subjects does not affect the evaluation and completion of the trial.

Exclusion Criteria(Any one of the following criteria must not be met to be eligible):

* Presence of other diseases that may affect treatment efficacy and prognosis.
* Severe underlying conditions such as heart, brain, or lung diseases.
* Inability to tolerate bronchoscopy procedures and painless anesthesia.
* Women who are pregnant, breastfeeding, or planning pregnancy.
* Intravenous drug users.
* Participation in or currently participating in other clinical studies involving drugs, devices, or other interventions within the month prior to enrollment.
* Other conditions deemed unsuitable for inclusion in this study by the investigators, such as anatomical unsuitability, psychiatric disorders, or psychological disorders.

Primary outcomes:
measure: Device/Surgery-Related Serious Adverse Events
timeFrame: Visit1~Visit8(Preoperative -28 days to week 12±7 days)
measure: Device/Surgery Adverse Event Rate
timeFrame: Visit1~Visit8(Preoperative -28 days to week 12±7 days)
measure: Serious Adverse Event Rate
timeFrame: Visit1~Visit8(Preoperative -28 days to week 12 ±7 days)
measure: Device Defect Rate
timeFrame: the treatment period(day0)
measure: Cough Visual Analogue Scale (VAS)
timeFrame: during the screening period, the treatment period, day 3, weeks 1, 2, 4, 8, and 12
measure: Cough frequency within 2 hours
timeFrame: during the screening period and at weeks 4 and 12
measure: Modified Cough Evaluation Tool (CET)
timeFrame: during the treatment period and at weeks 1, 2, 4, 8, and 12
measure: Leicester Cough Questionnaire (LCQ)
timeFrame: during the treatment period and at weeks 1, 2, 4, 8, and 12
measure: Tracheal Vibratory Cough Stimulation Test
timeFrame: during the screening period and at weeks 4 and 12
measure: Capsaicin Cough Stimulation Test
timeFrame: during the screening period and at weeks 4 and 12
measure: Performance evaluation of Cryotherapy Ablation Equipment
timeFrame: the treatment period(day0)
measure: Performance evaluation of Cryotherapy Ablation Catheter
timeFrame: the treatment period(day0)
Secondary outcomes:
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
state: Guangdong
Study officials:
References:
citation: Song WJ, Chang YS, Faruqi S, Kim JY, Kang MG, Kim S, Jo EJ, Kim MH, Plevkova J, Park HW, Cho SH, Morice AH. The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. Eur Respir J. 2015 May;45(5):1479-81. doi: 10.1183/09031936.00218714. Epub 2015 Feb 5. No abstract available.
citation: Lai K, Chen R, Lin J, Huang K, Shen H, Kong L, Zhou X, Luo Z, Yang L, Wen F, Zhong N. A prospective, multicenter survey on causes of chronic cough in China. Chest. 2013 Mar;143(3):613-620. doi: 10.1378/chest.12-0441.
citation: Gibson PG, Vertigan AE. Management of chronic refractory cough. BMJ. 2015 Dec 14;351:h5590. doi: 10.1136/bmj.h5590.
citation: Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB, McGarvey L; CHEST Expert Cough Panel. Anatomy and neurophysiology of cough: CHEST Guideline and Expert Panel report. Chest. 2014 Dec;146(6):1633-1648. doi: 10.1378/chest.14-1481.
citation: Nasra J, Belvisi MG. Modulation of sensory nerve function and the cough reflex: understanding disease pathogenesis. Pharmacol Ther. 2009 Dec;124(3):354-75. doi: 10.1016/j.pharmthera.2009.09.006. Epub 2009 Oct 7.
citation: Khalid S, Murdoch R, Newlands A, Smart K, Kelsall A, Holt K, Dockry R, Woodcock A, Smith JA. Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. J Allergy Clin Immunol. 2014 Jul;134(1):56-62. doi: 10.1016/j.jaci.2014.01.038. Epub 2014 Mar 22.
citation: Belvisi MG, Birrell MA, Wortley MA, Maher SA, Satia I, Badri H, Holt K, Round P, McGarvey L, Ford J, Smith JA. XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough. Am J Respir Crit Care Med. 2017 Nov 15;196(10):1255-1263. doi: 10.1164/rccm.201704-0769OC.
citation: Long L, Yao H, Tian J, Luo W, Yu X, Yi F, Chen Q, Xie J, Zhong N, Chung KF, Lai K. Heterogeneity of cough hypersensitivity mediated by TRPV1 and TRPA1 in patients with chronic refractory cough. Respir Res. 2019 Jun 6;20(1):112. doi: 10.1186/s12931-019-1077-z.
citation: Mai Y, Zhan C, Zhang S, Liu J, Liang W, Cai J, Lai K, Zhong N, Chen R. Arnold Nerve Reflex: Vagal Hypersensitivity in Chronic Cough With Various Causes. Chest. 2020 Jul;158(1):264-271. doi: 10.1016/j.chest.2019.11.041. Epub 2020 Jan 13.
citation: Niimi A, Chung KF. Airway inflammation and remodelling changes in patients with chronic cough: do they tell us about the cause of cough? Pulm Pharmacol Ther. 2004;17(6):441-6. doi: 10.1016/j.pupt.2004.09.004.
citation: Niimi A, Torrego A, Nicholson AG, Cosio BG, Oates TB, Chung KF. Nature of airway inflammation and remodeling in chronic cough. J Allergy Clin Immunol. 2005 Sep;116(3):565-70. doi: 10.1016/j.jaci.2005.07.010.
citation: Matsumoto H, Niimi A, Tabuena RP, Takemura M, Ueda T, Yamaguchi M, Matsuoka H, Jinnai M, Chin K, Mishima M. Airway wall thickening in patients with cough variant asthma and nonasthmatic chronic cough. Chest. 2007 Apr;131(4):1042-9. doi: 10.1378/chest.06-1025.
citation: Nakaji H, Niimi A, Matsuoka H, Iwata T, Cui S, Matsumoto H, Ito I, Oguma T, Otsuka K, Takeda T, Inoue H, Tajiri T, Nagasaki T, Kanemitsu Y, Chin K, Mishima M. Airway remodeling associated with cough hypersensitivity as a consequence of persistent cough: An experimental study. Respir Investig. 2016 Nov;54(6):419-427. doi: 10.1016/j.resinv.2016.06.005. Epub 2016 Jul 31.
citation: Hara J, Fujimura M, Ueda A, Myou S, Oribe Y, Ohkura N, Kita T, Yasui M, Kasahara K. Effect of pressure stress applied to the airway on cough-reflex sensitivity in Guinea pigs. Am J Respir Crit Care Med. 2008 Mar 15;177(6):585-92. doi: 10.1164/rccm.200703-457OC. Epub 2008 Jan 10.
citation: Sen RP, Walsh TE. Fiberoptic bronchoscopy for refractory cough. Chest. 1991 Jan;99(1):33-5. doi: 10.1378/chest.99.1.33.
citation: Heching M, Rosengarten D, Shitenberg D, Shtraichman O, Abdel-Rahman N, Unterman A, Kramer MR. Bronchoscopy for Chronic Unexplained Cough: Use of Biopsies and Cultures Increase Diagnostic Yield. J Bronchology Interv Pulmonol. 2020 Jan;27(1):30-35. doi: 10.1097/LBR.0000000000000629.
citation: Sheski FD, Mathur PN. Cryotherapy, electrocautery, and brachytherapy. Clin Chest Med. 1999 Mar;20(1):123-38. doi: 10.1016/s0272-5231(05)70131-3.
citation: Hvidtfeldt M, Pulga A, Hostrup M, Sanden C, Mori M, Bornesund D, Larsen KR, Erjefalt JS, Porsbjerg C. Bronchoscopic mucosal cryobiopsies as a method for studying airway disease. Clin Exp Allergy. 2019 Jan;49(1):27-34. doi: 10.1111/cea.13281. Epub 2018 Oct 12.
citation: Mathur PN, Wolf KM, Busk MF, Briete WM, Datzman M. Fiberoptic bronchoscopic cryotherapy in the management of tracheobronchial obstruction. Chest. 1996 Sep;110(3):718-23. doi: 10.1378/chest.110.3.718.
citation: Zhang L, Yin Y, Zhang J, Zhang H. Removal of foreign bodies in children's airways using flexible bronchoscopic CO2 cryotherapy. Pediatr Pulmonol. 2016 Sep;51(9):943-9. doi: 10.1002/ppul.23361. Epub 2016 Mar 11.