A Study on Radiation-induced Pulmonary Fibrosis Treated With Clinical Grade Umbilical Cord Mesenchymal Stem Cells

Phase I Study of Radiation-induced Pulmonary Fibrosis Treated With Clinical Grade Umbilical Cord Mesenchymal Stem Cells

Radiation therapy is one of the main means for treating malignant tumor, during which radioactive lung injury is inevitable. Currently there is nearly no effective clinical treatment for late post-radiotherapy pulmonary fibrosis. This study intends to carry out an open, single-center, non-randomized phase I clinical trial. During the treatment, the local lesions will be fully lavaged, and then clinical grade umbilical cord mesenchymal stem cells (MSCs) will be injected directly into the lesion by fiberoptic bronchoscopy. After six-month observation, the investigators will initially evaluate the safety and effectiveness of the treatment by measuring two key indicators-the CT density histogram and the patients' self-evaluation, and one secondary indicator-the changes of TGF-β1 contents, both before and after the treatment. Meanwhile, the investigators will make a preliminary discuss about the possible immunomodulatory effects of the umbilical cord MSCs.

Study Overview

• Status: Completed
• Conditions: Post-radiotherapy Pulmonary Fibrosis
• Intervention / Treatment: Biological: clinical grade umbilical cord mesenchymal stem cells

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Chongqing
    • Chongqing, Chongqing, China, 400038
      • First Affiliated Hospital of the Third Military University, PLA (Southwest Hospital)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, 18-70 years old.
2. Subjects with a clear history of malignancy.
3. Subjects with a clear history of chest radiation therapy at least 3 months earlier.
4. Subjects diagnosed as chronic phase of radiation-induced pneumonitis or radiation-induced pulmonary fibrosis stage (see Annex 3 for diagnosis).
5. Subjects signed informed consent.

Exclusion Criteria:

1. Women of childbearing age at the stage of pregnancy or lactation, or those without taking effective contraceptive measures.
2. Subjects with syphilis or HIV positive antibody.
3. Subjects with infection aggravated within the past month.
4. Subjects suffering from any of the following pulmonary diseases: active tuberculosis, pulmonary embolism, pneumothorax, multiple huge bullae, uncontrolled asthma, severe pneumonia, acute exacerbation of chronic bronchitis, AECOPD, severe and / or extremely severe COPD, etc..
5. Subjects suffering from other serious diseases, such as myocardial infarction, unstable angina, cirrhosis, and acute glomerulonephritis.
6. Subjects with progression-free survival (PFS) less than 0.5 years or Karnofsky performance scores less than 60 points.
7. Subjects with leukopenia (WBC less than 4x109 / L) or agranulocytosis (WBC less than 1.5x109 / L or neutrophils less than 0.5x109 / L) caused by any reason.
8. Subjects with severe renal impairment, serum creatinine> 1.5 times the upper limit of normal.
9. Subjects with liver disease or liver damage: ALT, AST, total bilirubin> 2 times the upper limit of normal
10. Subjects with a history of mental illness or suicide risk, with a history of epilepsy or other central nervous system disorders.
11. 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.
12. Subjects with a history of alcohol or illicit drug abuse.
13. Subjects accepted by any other clinical trials within 3 months before the enrollment
14. Subjects with poor compliance, difficult to complete the study.
15. 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: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: treatment group; Patients will receive 10^6 (1 million) /Kg/person cells of clinical grade umbilical cord mesenchymal stem cells (MSCs) injected via fiberoptic bronchoscopy after fully lavage of the localized lesions	Biological: clinical grade umbilical cord mesenchymal stem cells; 10^6 (1 million) /Kg/person cells of clinical grade umbilical cord MSCs will be injected after fully lavage of the localized lesions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite indicators, including quantitative analysis of CT density histograms, self-evaluation and changes of TGF-β1 content	Different proportions will be assigned to the three indicators. The overall curative effect can be judged with scores ranging from 0 to100. Specific proportions are as follows: full scores of 50 points for image changes, 25 for self-efficacy evaluation and 25 for TGF-β1 content changes. The image changes can be classified into four levels: significant control, improved, stable, and progressive; the self-efficacy evaluation can also be classified into four levels: effective, improved, stable and invalid; the changes of TGF-β1 content will be classified into three levels: improved, stable, and progressive. The four levels will be scored on the ratio of 5:4:3:1, the three levels will be scored on the ratio of 5:3:1.	6 months
Safety Evaluation	Clinical adverse events evaluated as definitely/ probably/possibly concerned with stem cell therapy in this trial and abnormal results of laboratory tests or other special examinations will be observed and recorded in detail.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Indicator 1: change in blood gas analysis		3-6 months
Clinical Indicator 2: change in pulmonary function analysis		3-6 months
Clinical Indicator 3: 6-minute walk test distance		3-6 months
Clinical Indicator 4: change in MRC chronic dyspnea scale		3-6 months
Clinical Indicator 5: change in St. George's Respiratory Questionnaire (SGRQ) scale		3-6 months
Immunological Indicator in serum 1: T lymphocyte counts in peripheral blood	Cellular immunological indicator: T lymphocyte counts in peripheral blood measured in serum	3-6 months
Immunological Indicator in serum 2: response level of CD4+ T lymphocyte subsets (such as Th1 / Th2)	Cellular immunological indicator: response level of CD4+ T lymphocyte subsets (such as Th1 / Th2) measured in serum	3-6 months
Immunological Indicator in serum 3: concent of immunoglobulin	Humoral immunological indicator: concent of immunoglobulin measured in serum	3-6 months
Immunological Indicator in serum 4: expression levels of various cytokines (IL-1, IL-3, IL-6, IL-8, TNF-α, GM-CSF, etc)	Humoral immunological indicator: expression levels of various cytokines in serum (IL-1, IL-3, IL-6, IL-8, TNF-α, GM-CSF, etc) measured in serum	3-6 months
Immunological Indicator in serum 5: subtype analysis and phagocytic activity analysis of macrophage	Macrophage-related polarization indicator: subtype analysis and phagocytic activity of macrophage measured in serum	3-6 months
Immunological Indicator in serum 6: expression levels of IL-12, IL-10	Macrophage- related polarization indicators: expression levels of IL-12, IL-10 measured in serum	3-6 months
Immunological Indicator in lavage fluid 1: T lymphocyte counts in peripheral blood	Cellular immunological indicator: T lymphocyte counts in peripheral blood measured in lavage fluid	6 months
Immunological Indicator in lavage fluid 2: response level of CD4+ T lymphocyte subsets (such as Th1 / Th2)	Cellular immunological indicator: response level of CD4+ T lymphocyte subsets (such as Th1 / Th2) measured in lavage fluid	6 months
Immunological Indicator in lavage fluid 3: concent of immunoglobulin	Humoral immunological indicator: concent of immunoglobulin measured in lavage fluid	6 months
Immunological Indicator in lavage fluid 4: expression levels of various cytokines (IL-1, IL-3, IL-6, IL-8, TNF-α, GM-CSF, etc)	Humoral immunological indicator: expression levels of various cytokines (IL-1, IL-3, IL-6, IL-8, TNF-α, GM-CSF, etc) measured in lavage fluid	6 months
Immunological Indicator in lavage fluid 5: subtype analysis and phagocytic activity analysis of macrophage	Macrophage-related polarization indicator: subtype analysis and phagocytic activity of macrophage measured in lavage fluid	6 months
Immunological Indicator in lavage fluid 6: expression levels of IL-12, IL-10	Macrophage-related polarization indicators: expression levels of IL-12, IL-10 measured in lavage fluid	6 months
Inflammatory Indicators: measured by routine blood test including C-reactive protein (CRP)		3 months
Fibrosis Indicators in serum 1: content of transforming growth factor -α/β (TGF-α/TGF-β)	Content of transforming growth factor α/β (TGF-α/TGF-β) measured in serum	3-6 months
Fibrosis Indicators in serum 2: content of hydroxyproline	Content of hydroxyproline measured in serum	3-6 months
Fibrosis Indicators in serum 3: content of matrix metalloproteinase 1/7(MMP1/MMP7)	Content of matrix metalloproteinase 1/7(MMP1/MMP7) measured in serum	3-6 months
Fibrosis Indicators in lavage fluid 1: content of transforming growth factor -α/β (TGF-α/TGF-β)	Content of transforming growth factor -α/β (TGF-α/TGF-β) measured in lavage fluid	6 months
Fibrosis Indicators in lavage fluid 2: content of hydroxyproline	Content of hydroxyproline measured in lavage fluid measured in lavage fluid	6 months
Fibrosis Indicators in lavage fluid 3: content of matrix metalloproteinase 1/7(MMP1/MMP7)	Content of matrix metalloproteinase 1/7(MMP1/MMP7) measured in lavage fluid	6 months

Collaborators and Investigators

• Sponsor: Jianwu Dai
• Collaborators: Southwest Hospital, China
• Investigators: Study Chair: Wei Xiong, M.D, First Affiliated Hospital of the Third Military University, PLA (Southwest Hospital); Study Director: Xiaotian Dai, M.M, First Affiliated Hospital of the Third Military University, PLA (Southwest Hospital)

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: October 20, 2014
• First Submitted That Met QC Criteria: October 26, 2014
• First Posted (Estimate): October 28, 2014

Study Record Updates

• Last Update Posted (Actual): July 24, 2019
• Last Update Submitted That Met QC Criteria: July 23, 2019
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: MSCs; radiation-induced pulmonary fibrosis
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis
• Other Study ID Numbers: CAS-XDA001-SH/IGDB