Inhalation of Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) for Autoimmune Pulmonary Alveolar Proteinosis (PAP)

A Prospective Study of Inhaling Granulocyte-macrophage Colony Stimulating Factor in Adult Patients With Mild-to-moderate Autoimmune Pulmonary Alveolar Proteinosis in China: a Randomized Open-label Study

The purpose of the study is to evaluate if inhaled granulocyte-macrophage colony stimulating factor delay the increase in alveolar-arterial oxygen difference, compared to no treatment, for adult patients with mild-to-moderate autoimmune pulmonary alveolar proteinosis in China over a two-year period.

Study Overview

• Status: Unknown
• Conditions: Autoimmune Pulmonary Alveolar Proteinosis
• Intervention / Treatment: Drug: GM-CSF

Detailed Description

Autoimmune pulmonary alveolar proteinosis (PAP, previously known as idiopathic PAP) is a rare interstitial lung disease elicited by the formation of autoantibodies which neutralize the activity of granulocyte-macrophage colony-stimulating factor (GM-CSF) which decreases macrophage clearance of surfactant.

Currently, the standard treatment strategy for PAP is whole lung lavage (WLL)，which is invasive and has limitations. Inhaled GM-CSF therapy became a new option for PAP patients not only because of its effectiveness and safety, but it is convenient way for patients who are reluctant to do operation as well. We are planning to prospectively evaluate if inhaled granulocyte-macrophage colony stimulating factor would delay the increase in alveolar-arterial oxygen difference (A-aDO2, which is the most sensitive factor in evaluating APAP5), compared to placebo, for patients with mild-to-moderate autoimmune pulmonary alveolar over a two-year period.

A total of 42 subjects with APAP who meet the inclusion criteria will be enrolled at Peking Union Medical College Hospital and Nanjing Drum Tower Hospital. After observe APAP patients for 3 months to rule out patients who resolved spontaneously, the participants will undergo randomization (by random number table)and stratified into two different groups by their DSS. Then they will be treated by GM-CSF (using nebulizer, 150ug bid) every other week or no treatment for 6 months, and will be followed on an outpatient basis at 2 weeks, and 1, 3, 6, 9, 12, 15, 18, 21 and 24 months after initiation of therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100730
      • Recruiting
      • Peking Union Medical College Hospital
      • Contact: Kai-Feng Xu, M.D.; Phone Number: 86 10-69155039; Email: kaifeng.xu@gmail.com
      • Contact: Xin-Lun Tian, M.D.; Phone Number: 86 10-69155039; Email: xinlun_t@sina.com
      • Principal Investigator: Xin-Lun Tian, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Accessible population:

Adult patients with mild-to-moderate autoimmune pulmonary alveolar and without spontaneous remission will be enrolled at Peking Union Medical College Hospital and Nanjing Drum Tower Hospital.

Inclusion Criteria:

• Adult autoimmune PAP subjects will be included: 1) a positive PAS stain from BALF or lung biopsy; 2) high level of serum anti-GM-CSF antibody (>2.39ug/ml, the cut-off point in our hospital); 3) age above 18 years old; 4) exclude hereditary and secondary PAP.
• Able to give written informed consent and comply with the requirements of the study.
• Patients are not eligible for the whole lung lavage (WLL), decided by clinicians.
• Eligibility for GM-CSF inhalation: 1) Disease severity score (DSS) is 1-3; 2) No treatment with GM-CSF therapy or WLLin the 3 months prior to enrollment. Definition of DSS2: 1, no symptom and PaO2>=70mmHg；2, PaO2>=70mmHg with symptoms；3, PaO2>=60 and <70mmHg; 4, PaO2>=50 and <60mmHg; 5, PaO2<50mmHg.

Exclusion Criteria:

• Patients will be observed for 3 months and all APAP patients who resolved spontaneously will be excluded from our study.
• PAP resulting from another condition (e.g. occupational exposure to silica, underlying HIV, respiratory infections, myeloproliferative disorder or leukaemia);
• A normal or low-titre serum anti-GM-CSF antibody (≤2.39ug/ml);
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies；
• Chronic lung disease associated with already existing respiratory failure (such as pulmonary emphysema or fibrosis);
• Other serious medical conditions which, in the opinion of the investigator, would make the patient unsuitable for the study.
• Pregnancy.

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: GM-CSF, nebulizer; After the patients were randomly divided into two groups, they will be treated by GM-CSF (using nebulizer, 150ug bid) every other week for 6 months.	Drug: GM-CSF; Other Names: HUABEI JIMUXIN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
A-aDO2 difference	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to relapse	The definition of relapse were as follow: 1) newly requirement for whole lung lavage (WLL); or 2) PAP associated death; or 3) a reduction in PaO2 of more than 10mmHg, or an increase in DA-aO2 of more than 10mmHg; or 4) a worsen chest HRCT.	up to 2 years
FEV1 difference		2 years
6 minutes walking distance difference		2 years
Severe adverse event		2 years

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Collaborators: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Investigators: Principal Investigator: Kai-Feng Xu, M.D., Peking Union Medical College Hosptial

Publications and helpful links

General Publications

• Tian X, Yang Y, Chen L, Sui X, Xu W, Li X, Guo X, Liu L, Situ Y, Wang J, Zhao Y, Meng S, Song W, Xiao Y, Xu KF. Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a six month phase II randomized study with 24 months of follow-up. Orphanet J Rare Dis. 2020 Jul 2;15(1):174. doi: 10.1186/s13023-020-01450-4.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Anticipated): August 1, 2017
• Study Completion (Anticipated): August 1, 2017

Study Registration Dates

• First Submitted: September 14, 2014
• First Submitted That Met QC Criteria: September 16, 2014
• First Posted (Estimate): September 17, 2014

Study Record Updates

• Last Update Posted (Estimate): September 17, 2014
• Last Update Submitted That Met QC Criteria: September 16, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: granulocyte-macrophage colony stimulating factor(GM-CSF); Autoimmune pulmonary alveolar proteinosis (PAP)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Autoimmune Diseases; Pulmonary Alveolar Proteinosis
• Other Study ID Numbers: XT 01