Phase I/IIa Clinical Trial of Human Umbilical Cord Mesenchymal Stem Cell Injection in the Treatment of Idiopathic Pulmonary Fibrosis (IPF)
Study Details
Study Description
Brief Summary
Main purpose
-To explore the safety and tolerance of human umbilical cord mesenchymal stem cells in the treatment of idiopathic pulmonary fibrosis (IPF).
Secondary purpose
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To explore the preliminary efficacy of human umbilical cord mesenchymal stem cells in the treatment of idiopathic pulmonary fibrosis (IPF), and to recommend the appropriate dose of cell therapy for subsequent clinical studies.
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To explore the immunogenicity of human umbilical cord mesenchymal stem cell injection in the treatment of idiopathic pulmonary fibrosis (IPF).
This study adopts a clinical research design of multi center, single dose and increasing dose.
18 qualified IPF subjects will be included in this study.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Dose escalation Four different doses were set, and three subjects in each dose plan received human umbilical cord mesenchymal stem cell injection successively. Each subject received a single dose of 6.0*10^6, 3.0*10^7, 6.0*10^7, and 9.0*10^7 cells / person. |
Drug: Human umbilical cord mesenchymal stem cell injection
Different doses of human umbilical cord mesenchymal stem cell injection were infused to the focus of patients with idiopathic pulmonary fibrosis through bronchoscope, and the tolerance of subjects to different doses of human umbilical cord mesenchymal stem cell injection was observed, and the curative effect was preliminarily observed.
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Outcome Measures
Primary Outcome Measures
- Tolerance of patients with idiopathic fibrosis to human umbilical cord mesenchymal stem cell injection [From the first administration to 4 weeks after administration]
Incidence and severity of adverse events according to CTCAE5.0
- Dose exploration of patients with idiopathic fibrosis to human umbilical cord mesenchymal stem cell injection [From the first administration to 4 weeks after administration]
The maximum tolerable dose (MTD) of a single administration depends on whether dose limiting toxicity (DLT) occurs within 4 weeks after the first administration, for example (1) Hematological toxicity of grade 3 and above caused by the treatment of human umbilical cord mesenchymal stem cell injection, （2） There are grade 3 and above non hematological toxic reactions caused by the treatment of human umbilical cord mesenchymal stem cell injection, except for the following cases, (3) Any other toxicity related to cell therapy that is higher than the baseline level is judged as clinically significant and / or unacceptable by the investigator and the sponsor, (4) There are acute exacerbations and serious adverse events (SAE) of IPF related to the treatment of human umbilical cord mesenchymal stem cell injection (which may be related, likely to be related and definitely related)
Secondary Outcome Measures
- Preliminary efficacy evaluation [The 4th, 12th, 24th and 48th week after administration]
Changes from baseline in St. George's respiratory questionnaire SGRQ, dyspnea score, cough score and 6-minute walk test (grade and distance)in the treatment of idiopathic pulmonary fibrosis (IPF), and to recommend the appropriate dose of cell therapy for subsequent clinical studies
- Preliminary efficacy evaluation [The 4th, 12th, 24th and 48th week after administration]
Changes in lung function (FVC, DLCO sb) compared with baseline
Other Outcome Measures
- Preliminary efficacy evaluation [The 4th, 12th, 24th and 48th week after administration]
Changes in abnormal values of routine safety tests (blood routine, urine routine, blood biochemistry, 12 lead ECG, etc.) compared with baseline
- Preliminary efficacy evaluation [The 12th, 24th and 48th week after administration]
Changes in chest HRCT scores from baseline
- Preliminary efficacy evaluation [The 12th, 24th and 48th week after administration]
Changes of lung tumor markers from baseline
- Preliminary efficacy evaluation [Within 48 weeks after administration]
Frequency and severity of acute exacerbations of IPF
- Immunogenicity of human umbilical cord mesenchymal stem cells [The 1st and 4th weeks after administration]
Changes of specific immunoglobulin G (IgG) from baseline
- Immunogenicity of human umbilical cord mesenchymal stem cells [The 1st and 4th weeks after administration]
Cytokines (TNF- α、 IFN- γ、 Changes of IL-2, IL-4, IL-5 and IL-6) from baseline
Eligibility Criteria
Criteria
Inclusion Criteria:
- (1) Age 50~75 years old (including the threshold), regardless of gender;
(2) IPF was diagnosed according to the diagnostic guidelines for idiopathic pulmonary fibrosis jointly issued by the American Thoracic Society (ATS), the European Respiratory Society (ERs), the Japanese Respiratory Society (JRS) and the Latin American Thoracic Association (ALAT) in 2018;
(3) Subjects with typical imaging manifestations of IPF (honeycomb, stretch bronchiectasis or bronchiectasis (mainly in ground glass shadow and fine mesh shadow) on HRCT within 12 months before screening;
(4) Within 3 months before administration, the researcher determined that the disease was stable. The pulmonary carbon monoxide diffusion volume (DLCO) was 30% - 79% of the predicted value (corrected by HB value), or FVC was 50% - 80% of the predicted value;
(5) Blood biochemical examination should meet the following standards: alanine aminotransferase (ALT) ≤ 1.5uln, aspartate aminotransferase (AST) ≤ 1.5uln, total bilirubin (TBIL) ≤ 1.5uln, direct bilirubin (DBIL) ≤ 1.5uln, blood creatinine (CR) ≤ 1.5uln;
(6) Expected survival ≥ 12 months;
(7) Subjects who have good compliance, can understand and cooperate with the completion of pulmonary function examination, are willing to take drugs according to the requirements of the protocol and receive follow-up examination on time;
(8) Subjects who voluntarily participated in the trial, understood and signed the informed consent form.
Exclusion Criteria:
- (1) Have previously received stem cell therapy, or are intolerant to cell therapy, or have taken drugs that may cause or aggravate pulmonary fibrosis (such as amiodarone, bleomycin or methotrexate);
(2) Suffering from interstitial lung disease (ILD) other than IPF, including but not limited to: any other type of interstitial pneumonia; Lung disease related to exposure to fibroblasts or other environmental toxins or drugs; Other types of occupational lung disease; Granulomatous pulmonary disease; Pulmonary vascular disease; Systemic diseases, including vasculitis, infectious diseases (i.e. tuberculosis) and connective tissue diseases;
(3) Those who need oxygen therapy at present (oxygen therapy time 15h/d);
(4) Those who used or planned to use nidanib during the study 1 month before screening;
(5) Subjects with a history of mechanical ventilation or complicated with infectious pneumonia and asthma within 1 month before screening;
(6) Patients with malignant tumors within 5 years before screening;
(7) Those who have been hospitalized for 3 times or more due to acute exacerbation of IPF or other respiratory diseases within 1 year before screening;
(8) There is evidence that the subjects currently have digestive, urinary, cardiovascular, cerebrovascular, hematological, nervous, mental and metabolic diseases that may affect safety, such as type 2 diabetes with poor blood glucose control (fasting blood glucose ≥ 10.0mmol/l or HbA1c ≥ 8.0%), hypertension with poor blood pressure control (≥ 160/100mmhg), etc;
(9) Have a history of psychotropic drug abuse and drug abuse;
(10) People with known history of immune system (such as thymus disease and systemic lupus erythematosus);
(11) Patients with positive serum Virology (HBsAg, HCV antibody, HIV antibody, Treponema pallidum antibody), including hepatitis B virus carriers, patients with stable hepatitis B after drug treatment (DNA titer ≤ 500iu/ml or copy number < 1000copies/ml) and cured patients with hepatitis C (HCV RNA test negative) can be enrolled after being judged to be qualified by the researcher;
(12) People who are allergic to human albumin, narcotic drugs or their ingredients;
(13) Subjects who participated in any other clinical trials within the first 3 months of screening;
(14) Subjects who cannot tolerate bronchoscopy (including but not limited to the following conditions: active massive hemoptysis; severe hypertension and arrhythmia; myocardial infarction or history of unstable angina pectoris within 4-6 weeks before screening; severe cardiopulmonary dysfunction; uncorrectable bleeding tendency (platelet count < 60 × 109/l), such as severe coagulation dysfunction, uremia and severe pulmonary hypertension; Severe superior vena cava obstruction syndrome; Suspected aortic aneurysm; Multiple pulmonary bullae; General condition (extreme failure);
(15) The researchers judged that the risk of general anesthesia / local anesthesia was higher;
(16) Human chorionic gonadotrophin in pregnancy or lactation, or screening β （ β- HCG) positive, or unable and unwilling to take effective non drug contraceptives during the study period and 6 months after the end of the study;
(17) Other circumstances that the researcher believes are not suitable for entering this test.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Shanghai Sixth People's Hospital | Shanghai | Shanghai | China | 200233 |
Sponsors and Collaborators
- Shanghai Life Science & Technology
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J, Yerkovich ST, Khalil D, Atkinson KM, Hopkins PM. A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014 Oct;19(7):1013-8. doi: 10.1111/resp.12343. Epub 2014 Jul 9.
- Glassberg MK, Minkiewicz J, Toonkel RL, Simonet ES, Rubio GA, DiFede D, Shafazand S, Khan A, Pujol MV, LaRussa VF, Lancaster LH, Rosen GD, Fishman J, Mageto YN, Mendizabal A, Hare JM. Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial. Chest. 2017 May;151(5):971-981. doi: 10.1016/j.chest.2016.10.061. Epub 2016 Nov 24.
- Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011 May 14;9:12. doi: 10.1186/1478-811X-9-12.
- Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, Boyd R, Trounson A. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol. 2009 Jul;175(1):303-13. doi: 10.2353/ajpath.2009.080629. Epub 2009 Jun 4.
- Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011 Mar 15;183(6):788-824. doi: 10.1164/rccm.2009-040GL.
- Tzouvelekis A, Paspaliaris V, Koliakos G, Ntolios P, Bouros E, Oikonomou A, Zissimopoulos A, Boussios N, Dardzinski B, Gritzalis D, Antoniadis A, Froudarakis M, Kolios G, Bouros D. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013 Jul 15;11:171. doi: 10.1186/1479-5876-11-171.
- SHLF-MSC-101