Autologous Transplantation of Bronchial Basal Cells for Treatment of Bronchiectasis

Bronchiectasis is a disease resulted from progressive destruction of bronchi with no effective drug for its treatment. In this study, we intends to carry out a randomized, single-blinded, controlled pilot clinical trial at 1/2 phase. During the process, autologous bronchial basal cells (BBCs) will be dissected from trial tissue via bronchoscopic brushing. Then the BBCs will be expanded and detected by quality control. In the following, qualified BBCs will be injected directly into the lesion by fiberoptic bronchoscopy after airway clearance. The investigators will evaluate the safety and effectiveness of the treatment by measuring a serial of indicators, including occurrence of adverse events, pulmonary function, 6 minute walk distance (6MWD), the distance-saturation product (DSP), St. George's Respiratory Questionnaire (SGRQ), FACED scoring, bronchiectasis severity index (BSI) , and high-resolution computed tomography (HRCT) at week 4, week 12, and week 24 after cell transplantation.

Study Overview

• Status: Completed
• Conditions: Bronchiectasis
• Intervention / Treatment: Biological: Bronchial basal cells (BBCs); Procedure: Bronchoscopic airway clearance treatment （B-ACT）

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Ruijin Hospital Shanghai Jiaotong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects diagnosed as bronchiectasis.
• Subjects with a DLCO < 80% predicted value.
• Subjects with stable condition for more than 2 weeks.
• Subjects can do pulmonary function tests.
• Subjects can tolerate bronchoscopy.
• Subjects signed informed consent.

Exclusion Criteria:

• Women of childbearing age at the stage of pregnancy or lactation, or those without taking effective contraceptive measures.
• Subjects with positive serological tests for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or syphilis (HBV carriers and patients with stable chronic hepatitis B could be accepted if titers of HBV DNA < 500 IU/mL or copies < 1000 copies/mL; patients with curative hepatitis C were eligible if HCV RNA tests were negative).
• Subjects with any malignancy.
• Subjects with any of the following pulmonary diseases: active tuberculosis, pulmonary embolism, pneumothorax, multiple huge bullae, uncontrolled asthma, acute exacerbation of chronic bronchitis or extremely severe COPD.
• Subjects with other serious diseases, such as poorly controlled diabetes, myocardial infarction, unstable angina, cirrhosis, and acute glomerulonephritis.
• Subjects with leukopenia (WBC less than 4x10^9 / L) or agranulocytosis (WBC less than 1.5x10^9 / L or neutrophils less than 0.5x10^9 / L) caused by any reason.
• Subjects with severe renal impairment, serum creatinine> 1.5 times of the upper limit of normal.
• Subjects with liver disease or liver damage: ALT, AST, total bilirubin> 2 times of the upper limit of normal.
• Subjects with a history of mental illness or suicide risk, with a history of epilepsy or other central nervous system disorders.
• Subjects with severe arrhythmias (such as ventricular tachycardia, frequent superventricular tachycardia, atrial fibrillation, and atrial flutter, etc.) or cardiac degree II or above conduction abnormalities displayed via 12-lead ECG.
• Subjects with a history of alcohol or illicit drug abuse.
• Subjects accepted by any other clinical trials within 3 months before the enrollment.
• Subjects with poor compliance, difficult to complete the study.
• Any other conditions that might increase the risk of subjects or interfere with the clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cell treatment group; Patients receive both autologous BBCs transplantation and B-ACT therapy.	Biological: Bronchial basal cells (BBCs); Airway epithelial cells were collected in patients of the cell treatment group by a disposable 2-mm brush in order to obtain BBCs. The obtained tissue were washed and enzymatically digested to form a single-cell suspension, which was then cultured under R-Clone system, a patented technique of Regend Therapeutics, Ltd.. For patients in the cell treatment group, on the basis of B-ACT therapy, they were also received autologous BBCs transplantation. Cell suspension was diluted with normal saline. Fibrotic bronchoscopy was guided into the lobular or segmental airways and cells were instilled into lobes.; Other Names: P63+ lung stem/progenitor cells; Airway basal cells; Lung stem/progenitor cells; Procedure: Bronchoscopic airway clearance treatment （B-ACT）; The bronchoscopy was performed by board-certified respiratory physicians of Ruijin Hospital using a flexible fiber-optic bronchoscope. B-ACT therapy was performed on all patients in both groups according to the protocol. In brief, continuous suction was performed with the sputum aspirator from the trachea to the subsegmental during the entering of bronchoscope to remove the visible secretions from entire respiratory tract, and then operators used normal saline to collect lavage fluid (the volume various depending on the operator's judgement).
Sham Comparator: Control group; Patients only receive B-ACT therapy.	Procedure: Bronchoscopic airway clearance treatment （B-ACT）; The bronchoscopy was performed by board-certified respiratory physicians of Ruijin Hospital using a flexible fiber-optic bronchoscope. B-ACT therapy was performed on all patients in both groups according to the protocol. In brief, continuous suction was performed with the sputum aspirator from the trachea to the subsegmental during the entering of bronchoscope to remove the visible secretions from entire respiratory tract, and then operators used normal saline to collect lavage fluid (the volume various depending on the operator's judgement).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diffusing capacity of the lung for carbon monoxide (DLCO)	An indicator of pulmonary function	Week 4, 12, and 24 after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced expiratory volume measured at the first second (FEV1)	An indicator for pulmonary function test to assess airway obstruction	Week 4, 12, and 24 after treatment
Forced vital capacity (FVC)	An indicator for pulmonary function test to indicate the maximum amount of air a person can expel from the lungs after a maximum inhalation	Week 4, 12, and 24 after treatment
The ratio of forced expiratory volume in the first one second to the forced vital capacity (FEV1/FVC)	An indicator in pulmonary function test to represent the proportion of a person's vital capacity that they are able to expire in the first second of forced expiration to the full vital capacity	Week 4, 12, and 24 after treatment
Maximum Mid Expiratory Flow (MMEF)	An indicator in pulmonary function test to stand for maximal (mid-)expiratory flow and is the peak of expiratory flow as taken from the flow-volume curve and measured in liters per second	Week 4, 12, and 24 after treatment
Maximum Voluntary Ventilation (MVV)	An indicator in pulmonary function test to measure the maximum amount of air that can be inhaled and exhaled within one minute	Week 4, 12, and 24 after treatment
6 minute walk distance (6MWD) and distance saturation product (DSP)	An indicator for heart and pulmonary function	Week 4, 12, and 24 after treatment
St. George's Respiratory Questionnaire (SGRQ)	An indicator to measure health status (quality of life) in patients with diseases of airways obstruction	Week 4, 12, and 24 after treatment
FACED scoring	An assessment of severity tool, validated for people with non-cystic fibrosis bronchiectasis. F means "FEV1", A means "Age", C means "Chronic colonization", E means "Extension", D means "Dyspnoea".	Week 4, 12, and 24 after treatment
Bronchiectasis Severity Index (BSI)	A combination of clinical, radiological and microbiological features to predict morbidity and mortality.	Week 4, 12, and 24 after treatment
High resolution computed tomography (HR-CT) imaging of lung	An indicator for analysis of dilated bronchi, HR-CT images of lung will be analyzed to indicate the pulmonary structure	Week 4, 12, and 24 after treatment
Safety outcomes: adverse events	Any unexpected and unfavorable medical occurrence related to any medical intervention in the study	Through study completion, an average of 24 weeks

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Collaborators: Regend Therapeutics
• Investigators: Principal Investigator: Yun Feng, M.D., Ph.D, Ruijin Hospital

Publications and helpful links

General Publications

• Zuo W, Zhang T, Wu DZ, Guan SP, Liew AA, Yamamoto Y, Wang X, Lim SJ, Vincent M, Lessard M, Crum CP, Xian W, McKeon F. p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration. Nature. 2015 Jan 29;517(7536):616-20. doi: 10.1038/nature13903. Epub 2014 Nov 12.
• Ma Q, Ma Y, Dai X, Ren T, Fu Y, Liu W, Han Y, Wu Y, Cheng Y, Zhang T, Zuo W. Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation. Protein Cell. 2018 Mar;9(3):267-282. doi: 10.1007/s13238-018-0506-y. Epub 2018 Jan 17.

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2020
• Primary Completion (Actual): May 17, 2023
• Study Completion (Actual): May 17, 2023

Study Registration Dates

• First Submitted: August 22, 2018
• First Submitted That Met QC Criteria: August 30, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Actual): December 5, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Bronchiectasis; Bronchial basal cells; Autologous transplantation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Bronchial Diseases; Bronchiectasis
• Other Study ID Numbers: 201810

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No