A Study of hBMMSC Injection in Patients With aPAP

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 efficacy and safety of hBMMSC intravenous treatment in patients with aPAP. The clinical trial intends to involve 10 participants. The trial is expected to last approximately 3 years.

• The human Bone Marrow Mesenchymal Stem Cell (hBMMSC) injection (Drug): The hBMMSC injection will be administered by intravenous infusion at a dose of 2.0 × 10⁶ cells/kg per administration. A total of 2 doses will be administered, with a 2-week interval between doses.
• Lactated Ringer's Injection (crystalloid) (Drug): Lactated Ringer's Injection will be used as the comparator and administered by intravenous infusion at a volume of 2 mL/kg per administration. A total of 2 doses will be administered, with a 2-week interval between doses.

Primary outcomes

• Alveolar-arterial difference in oxygen tension (A-aDO2) [24 weeks]: The between-group difference in the change from baseline in the alveolar-arterial oxygen tension gradient (\[A-a\]DO₂) at Week 24, comparing the hBMMSC injection group with the placebo group.

Secondary outcomes

• Diffusing capacity of the lungs for carbon monoxide (DLCO, % predicted) [24 weeks/48 weeks]: The between-group differences in the efficacy of hBMMSC injection versus placebo on the diffusing capacity of the lungs for carbon monoxide (DLCO, % predicted) at Weeks 24 and 48 after treatment
• PaO₂ [24 weeks/48 weeks]: The between-group differences in PaO₂ at Weeks 24 and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• Oxygenation index [24 weeks/48 weeks]: The between-group differences in oxygenation indexat Weeks 24 and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• Oxygen therapy requirements [24 weeks/48 weeks]: The between-group difference in oxygen therapy requirements at Weeks 24 and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• Disease severity score (DSS) [24 weeks/48 weeks]: The between-group differences in disease severity score (DSS) at Weeks 24 and 48 after treatment, comparing the hBMMSC injection group with the placebo group.Disease Severity Score (DSS) is a scoring system used to evaluate disease severity based on predefined clinical signs, symptoms, or pathological changes. a higher DSS indicates more severe disease, whereas a lower DSS indicates milder disease, with 0 typically representing no detectable disease.
• 6-minute walk test (6MWT) [12/24/48 weeks]: The between-group differences in the 6-minute walk test (6MWT) results at Weeks 12, 24, and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• Cardiopulmonary exercise testing (CPET) [12/24/48 weeks]: The between-group differences in the cardiopulmonary exercise testing (CPET) results at Weeks 12, 24, and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• Forced vital capacity (FVC) [4/24/48 weeks]: The between-group differences in forced vital capacity (FVC) at Weeks 4, 24, and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• Forced expiratory volume in 1 second (FEV₁) [4/24/48 weeks]: The between-group differences in forced expiratory volume in 1 second (FEV₁) at Weeks 4, 24, and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• Pulmonary lesions assessed by imaging [24/48 weeks]: The between-group difference in changes in pulmonary lesions assessed by imaging at Weeks 24 and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• Proportion of patients whose disease progressed to requiring whole-lung lavage (WLL) during the study period and the interval to WLL [96 weeks]: The between-group difference in the proportion of patients whose disease progressed to requiring whole-lung lavage (WLL) during the study period and the interval to WLL, comparing the hBMMSC injection group with the placebo group
• Medical Research Council (mMRC) dyspnea scores [4/12/24 weeks]: The between-group differences in modified Medical Research Council (mMRC) dyspnea scores at Weeks 4, 12, 24, and 48 after treatment, comparing the hBMMSC injection group with the placebo group. Modified Medical Research Council (mMRC) Dyspnea Scale is a questionnaire used to assess the severity of breathlessness and its impact on daily activities, particularly in patients with chronic obstructive pulmonary disease (COPD). The score ranges from 0 to 4, with Grade 0 indicating breathlessness only during strenuous exercise and Grade 4 indicating severe breathlessness that limits leaving the house or dressing. A higher mMRC score indicates more severe dyspnea and greater activity limitation
• St. George's Respiratory Questionnaire (SGRQ) scores [4/12/24/48 weeks]: The between-group differences in St. George's Respiratory Questionnaire (SGRQ) scores at Weeks 4, 12, 24, and 48 after treatment, comparing the hBMMSC injection group with the placebo group. The St. George's Respiratory Questionnaire (SGRQ) is a disease-specific questionnaire used to assess health-related quality of life in patients with respiratory diseases. The total score ranges from 0 to 100, where higher scores represent worse respiratory health status and greater impairment of quality of life.
• The safety of hBMMSC injection [24/48 weeks]: The safety of hBMMSC injection compared with placebo during Weeks 24 and 48, as assessed by the incidence of adverse events (AEs), serious adverse events (SAEs), adverse drug reactions (ADRs), important adverse events, and discontinuations due to AEs.
• The proportion of patients with an improvement from baseline in [A-a]DO₂ [24/48 weeks]: The proportion of patients with an improvement from baseline in \[A-a\]DO₂ at Weeks 24 and 48 after treatment
• The proportion of patients with an improvement from baseline in DLCO [24/48 weeks]: The proportion of patients with an improvement from baseline in DLCO at Weeks 24 and 48 after treatment
• The incidence of AEs and SAEs [48 weeks]: The incidence of AEs and SAEs through Week 48 after treatment
• The proportion of patients with improvements from baseline in PaO₂ [24/48 weeks]: The proportion of patients with improvements from baseline in PaO₂ at Weeks 24 and 48 after treatment
• The proportion of patients with improvements from baseline in oxygenation index [24/48 weeks]: The proportion of patients with improvements from baseline in oxygenation index at Weeks 24 and 48 after treatment
• The proportion of patients with improvements from baseline in disease severity score (DSS) [24/48 weeks]: The proportion of patients with improvements from baseline in disease severity score (DSS) at Weeks 24 and 48 after treatment
• The proportion of patients with improvement in pulmonary lesions [24/48 weeks]: The proportion of patients with improvement in pulmonary lesions as assessed by imaging at Weeks 24 and 48 after treatment
• The between-group differences in peripheral capillary oxygen saturation (SpO₂) [4/12/24/48 weeks]: The between-group differences in peripheral capillary oxygen saturation (SpO₂) at Weeks 4, 12, 24, and 48 after treatment, comparing the hBMMSC injection group with the placebo group
• The proportion of patients with improvements in the 6-minute walk test (6MWT) [12/24/48 weeks]: The proportion of patients with improvements in the 6-minute walk test (6MWT) results at Weeks 12, 24, and 48 after treatment
• The proportion of patients with improvements in the cardiopulmonary exercise testing (CPET) [12/24/48 weeks]: The proportion of patients with improvements in the cardiopulmonary exercise testing (CPET) results at Weeks 12, 24, and 48 after treatment
• The change in serum anti-GM-CSF antibody levels [24/48 weeks]: The between-group difference in the change from baseline in serum anti-GM-CSF antibody levels at Weeks 24 and 48 after treatment
• The changes in body weight in the hBMMSC injection group compared to the placebo group [4/12/24/48 weeks]
• The changes in height in the hBMMSC injection group compared with the placebo group [4/12/24/48 weeks]
• The changes in blood pressure in the hBMMSC injection group compared with the placebo group [4/12/24/48 weeks]
• The changes in pulse rate in the hBMMSC injection group compared with the placebo group [4/12/24/48 weeks]
• The changes in body temperature in the hBMMSC injection group compared with the placebo group [4/12/24/48 weeks]
• The changes in complete blood count in the hBMMSC injection group compared with the placebo group [4/12/24/48 weeks]
• The changes in urinalysis in the hBMMSC injection group compared with the placebo group [4/12/24/48 weeks]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Male or female participants aged ≥18 years;
2. Patients with pulmonary alveolar proteinosis (PAP) confirmed by imaging, bronchoalveolar lavage (BAL) cytology, or lung biopsy, including transbronchial lung biopsy (TBLB), transbronchial cryobiopsy (TBCB), or surgical lung biopsy, and who are positive for serum anti-GM-CSF antibodies;
3. At rest and while breathing room air, arterial partial pressure of oxygen (PaO₂) >50 mmHg, and either PaO₂ ≤70 mmHg or an oxygenation index corrected for the fraction of inspired oxygen (PaO₂/FiO₂ ratio) ≤333 mmHg; or, in participants with symptoms such as cough, sputum production, and exertional dyspnea, PaO₂ <75 mmHg or a PaO₂/FiO₂ ratio ≤357 mmHg;
4. At least two assessments, performed at an interval of ≥2 months, indicating no significant spontaneous improvement of the disease, defined as an improvement in \[A-a\]DO₂ of <10 mmHg and an improvement in DLCO % predicted of <10%. If only one of these criteria is met, the investigator shall determine, based on the participant's symptoms, oxygen therapy requirements, imaging findings, and previous treatments, whether the disease is in a stable, non-remitting or progressive state, and shall document the basis for this determination;
5. Participants of childbearing potential must use effective medically accepted contraceptive methods, regardless of sex, until 1 year after the last study treatment administration;
6. Voluntary provision of written informed consent.

Exclusion Criteria:

1. Patients diagnosed with hereditary, secondary, or other types of PAP;
2. Patients who received whole-lung lavage (WLL) or granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy within 3 months prior to screening;
3. Patients who received treatment as part of another clinical study within 3 months prior to screening;
4. Patients who participated in another clinical study involving stem cell therapy within 1 year prior to screening;
5. Patients with inflammatory or autoimmune diseases requiring concomitant treatment with immunosuppressive agents, such as prednisolone >10 mg/day;
6. Patients with a history of infection requiring systemic antibiotics, antifungal agents, or antiviral agents; active infections (viral, bacterial, fungal, or mycobacterial); or other diseases that may interfere with the assessment of efficacy in the study;
7. History of malignancy;
8. Known hypersensitivity or allergic reaction to any component of the investigational product;
9. Participants who, in the investigator's judgment, are unsuitable for participation in the study, or who have any condition that, in the investigator's opinion, may increase the participant's risk or interfere with the conduct or assessment of the clinical trial;
10. Female participants who are pregnant or breastfeeding, female participants planning to become pregnant, or male or female participants who intend to have children within 3 months after completion of the study.