Study of Human Bone Marrow Mesenchymal Stem Cells in aPAP

Study Overview
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Brief Summary
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The purpose of this open-label phase IIa clinical trial study is to evaluate the safety and preliminary efficacy of hBMMSC intravenous treatment in patients with aPAP.

Detailed Description
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Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease for which there is no specific drug treatment. Currently, the standard treatment strategy for PAP is whole-lung lavage (WLL), which is invasive and has limited therapeutic efficacy. The purpose of this study is to evaluate the safety and preliminary efficacy of hBMMSC intravenous treatment in patients with aPAP. The clinical trial intends to involve 10 participants. The trial is expected to last approximately 2 years.

Official Title
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An Open-label Phase IIa Study to Evaluate the Safety and Preliminary Efficacy of hBMMSC Injection in the Treatment of aPAP

Conditions
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Autoimmune Pulmonary Alveolar Proteinosis

Intervention / Treatment
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* Drug: human Bone Marrow Mesenchymal Stem Cell (hBMMSC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18 years or older Patients diagnosed with aPAP by both CT and biopsy (TBLB, TBCB, or surgical lung biopsy) or bronchoalveolar perfusion (BAL) as well as GM-CSF autoantibodies in serum positive No remission was demonstrated by CT, pulmonary function test results,or blood gas analysis at least 2 times (at least 3 months apart) before enrollment At rest PaO2≤70 mmHg Fertile participants must receive effective medical contraception (for both male and female participants, up to one year after the last study dosing) Voluntary signed informed consent Exclusion Criteria: Diagnosed with hereditary PAP, secondary PAP, or another type of PAP Received whole lung lavage（WLL） therapy within 6 months before enrollment Received previous GM-CSF therapy within 6 months before enrollment Received other clinical trial treatment within 3 months before enrollment Participated in other stem cell studies within 1 year before enrollment Inflammatory disease or autoimmune disorder requiring treatment associated with significant immunosuppression (e.g. more than 10 mg/day systemic prednisolone) Active infection (viral, bacterial, fungal or mycobacterial), which may affect the assessment of efficacy in the trial History of malignant tumors Known allergic reactions to any of the ingredients in the study drug Participants who, in the opinion of the investigator, would aggravate any other serious pre-existing medical condition are not suitable for this trial Women who are known to be pregnant, breastfeeding, have a positive pregnancy test (which will be detected during the screening process), or plan to become pregnant during the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: hBMMSC<br>1.0×10^6/kg hBMMSC (participant's body weight) single dose 2.0×10^6/kg hBMMSC (participant's body weight) single dose 2.0×10^6/kg hBMMSC (participant's body weight) administered twice | Drug: human Bone Marrow Mesenchymal Stem Cell (hBMMSC)<br>* Group 1: 1.0×10^6 cells/kg (participant's body weight) single dose (n=3) Group 2: 2.0×10^6 cells/kg (participant's body weight) single dose (n=3) Group 3: 2.0×10^6 cells/kg (participant's body weight) administered twice (n=4)<br>* Other names: hBMMSC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alveolar-arterial difference in oxygen tension (A-aDO2) | The changes of alveolar-arterial difference in oxygen tension (A-aDO2) relative to baseline were assessed in the hBMMSC treated group after 24 weeks of treatment. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Number of participants with serious and non-serious adverse events | 48 weeks | 
| Difference in pulmonary function | Pulmonary function tests include diffusing capacity of the lung for carbon monoxide(DLCO),forced vital capacity(FVC), forced expiratory volume in one second(FEV1).Change from Baseline in the DLCO、FVC、 FEV1 as measured | 4 weeks, 12 weeks, 24 weeks, 48 weeks | 
| Alveolar-arterial oxygen difference (A-aDO2) | Change from Baseline in the A-aDO2 as measured | 48 weeks | 
| Difference in 6-minute walk distance (6MWD) | Change from Baseline in the 6MWD as measured | 4 weeks, 12 weeks, 24 weeks, 48 weeks | 
| Percutaneous arterial oxygen saturation (SpO2) | Change from Baseline in the SpO2 as measured | 4 weeks, 12 weeks, 24 weeks, 48 weeks | 
| Difference in modified Medical Research Council（mMRC） | Change from Baseline in the mMRC as tested | 4 weeks, 12 weeks, 24 weeks, 48 weeks | 
| Difference in St. George's Respiratory Questionnaire（SGRQ） | Change from Baseline in the SGRQ as tested | 4 weeks, 12 weeks, 24 weeks, 48 weeks | 
| Imaging（Chest CT score ） | Parenchymal lung density determined by quantitative computed tomography (CT) densitometry. Change from Baseline (Day 0) in the parenchymal densitometry as measured at 24 and 48 weeks | 24 weeks, 48 weeks | 
| Difference in Disease severity score (DSS) | Change from Baseline in the DSS score | 24 weeks, 48 weeks | 
| Difference in arterial partial pressure of oxygen (PaO2) | Change from Baseline in the PaO2 as measured | 24 weeks, 48 weeks | 
| Difference in Krebs Von den Lungen-6（KL-6） | Change from Baseline in the KL-6 as measured | 2 weeks，4 weeks, 12 weeks, 24 weeks | 
| Difference in carcinoembryonic antigen（CEA） | Change from Baseline in the CEA as measured | 2 weeks，4 weeks, 12 weeks, 24 weeks | 
| Difference in lactate dehydrogenase (LDH) | Change from Baseline in the LDH as measured | 2 weeks，4 weeks, 12 weeks, 24 weeks | 
| Number of Rescue whole lung lavage (WLL) in 108 weeks | Criteria for performing WLL were based on symptoms, decreased exercise capacity, and/or worsening of clinical symptoms of aPAP as judged by the investigator that the participant developed hypoxemia or decreased oxygen saturation | 108 weeks |