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

Abstract

Background: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by inhaled granulocyte-macrophage colony stimulating factor (GM-CSF) is considered safe and effective. Evidence of benefit from GM-CSG inhalation for mild to moderate aPAP patients is limited.

Methods: In this multicenter, randomized, open-labeled clinical trial, 36 aPAP patients with mild to moderate disease severity were randomized into either the GM-CSF treatment group or control group. Inhaled GM-CSF was prescribed for 6 months, and patients received follow-up for another 18 months without treatment. Physiological features of the patients were analyzed.

Results: There were 36 patients (19 in the treatment group, 17 in the control group) included. There were no significant differences in the primary endpoints as measured by the change of alveolar arterial oxygen gradient (A-aDO2) from the baseline values to the values obtained during treatment or during the following 18-month non-treatment observation period [control group vs. treatment group: 0.51 ± 12.09 mmHg vs. -0.35 ± 13.76 mmHg, p = 0.848 (3 month); 1.85 ± 11.21 mmHg vs. 7.31 ± 8.81 mmHg, p = 0.146 (6 months); 6.05 ± 11.14 mmHg vs. 6.61 ± 10.64 mmHg, p = 0.899 (24 months)]). Percentage of diffusion capacity predicted (DLCO%) and percentage of total lung capacity predicted (TLC%), however, were significantly improved in the treatment group by the end of the study (P = 0.010 and 0.027). St. George Respiratory questionnaire (SGRQ) scores were better after 6 months treatment with GM-CSF compared to the control group, and the benefits of treatment were maintained throughout the observation period. No severe side effects were observed during the study.

Conclusion: Six months of inhaled GM-CSF treatment had no effect on the alveolar-arterial oxygen gradient in patients with mild to moderate pulmonary alveolar proteinosis. There were changes in some clinical or laboratory measures, but no clinically important changes were noted at the end of study. (Clinical Trial Registry: NCT02243228, Registered on September 17, 2014, https://www.clinicaltrials.gov/ct2/show/NCT02243228?term=NCT02243228&draw=2&rank=1 ).

Keywords: Autoimmune pulmonary alveolar proteinosis; Granulocyte-macrophage colony stimulating factor; Inhalation.

Conflict of interest statement

This work was supported partly by the North China Pharmaceutical Corporation (NCPC) and Beijing Yikang Healthcare Technology Co. Ltd. Both companies were not involved in the data analysis and interpretation. The drug was donated by NCPC.

Figures

Fig. 1

The clinical trial comprised of three sequential periods: high-dose therapy for 3 months (150 μg twice daily every other week), low-dose therapy for 3 months (150 μg once daily every other week) and observation for 18 months. Study visits during treatment were designed at 0, 3 and 6 months. Thereafter, patients were followed up with using visits at 9, 12, 18 and 24 months. Patients’ safety questionnaires were reviewed by telephone at 1. 15 and 21 months

Fig. 2

Flow diagram of the study cohort. aPAP: autoimmune pulmonary alveolar proteinosis; GM-CSF: granulocyte-macrophage colony stimulating factor

Fig. 3

No significant differences were observed between the treatment group and the control group in terms of changes in A-aDO2 and PaO2 from baseline to 3 and 6 months of treatment and over the following 18 months (a and b). [A-aDO2 levels in control group vs. treatment group: 0.51 ± 12.09 mmHg vs. -0.35 ± 13.76 mmHg, p = 0.848 (at 3 months); 1.85 ± 11.21 mmHg vs. 7.31 ± 8.81 mmHg, p = 0.146 (at 6 months); 6.05 ± 11.14 mmHg vs. 6.61 ± 10.64 mmHg, p = 0.899 (at 24 months)]. No significant differences were observed between the treatment group and the control group for the absolute value of A-aDO2 and PaO2 during both the treatment period, as well as the follow up period (c and d)

Fig. 4

There were significant differences in the DLCO% and TLC% between the treatment group compared to the control group at the end of the study (P < 0.05, respectively, a and b). However, there were no significant differences between the two groups in terms of other pulmonary function tests, including FVC and DLCO/VA, both during the 6-month treatment period and the 18-month follow-up period (c and d). [DLCO% (control group vs. treatment group): 67.12 ± 14.72 vs. 69.19 ± 19.83, p = 0.732 (at 3 months); 70.83 ± 14.62 vs. 74.91 ± 14.80, p = 0.465 (at 6 months); 64.67 ± 16.22 vs. 80.87 ± 19.40, p = 0.027 (at 24 months)]. [TLC% (control group vs. treatment group): 74.09 ± 11.37 vs. 73.12 ± 15.29, p = 0.836 (at 3 months); 74.28 ± 11.18 vs. 78.48 ± 8.88, p = 0.269 (at 6 months); 70.97 ± 10.79 vs. 79.77 ± 7.76, p = 0.010 (at 24 months)]

Fig. 5

The SGRQ score during the 24-month study period. a: total SGRQ score; b: SGRQ symptom score; c: SGRQ activity score; d: SGRQ effect score. *:P < 0.05, **: P < 0.01

Fig. 6

There was no significant difference between the treatment and control groups in terms of no disease progression rate (measured by time to rescue therapy) over the 24 month duration of the study. P > 0.05