Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.
The Impala study aimed to determine whether the inhalation of GM-CSF (molgramostim) vs matched placebo could change in a statistical significant manner the alveolar–arterial difference in oxygen concentration (A-aDo2) at week 24.The study was designed as a double blind placebo controlled three group trial. Inhaled GM-CSF was administered either continuously or intermittently.
138 patients were assigned to receive placebo and either the continuous schedule or/and the intermittent one. Patients were recruited on the basis of a chest CT, the results of either lung biopsy or cytologic analysis of bronchoalveolar lavage fluid, and a positive serum test for GM-CSF autoantibodies. Furthermore, were required to have an A-aDo2 of 25 mm Hg or more, a Pao2 of less than 75 mm Hg at rest while breathing ambient air or a decrease in oxygen saturation of more than 4 percentage points during the 6-minute walk test, and unremitting or progressive aPAP as indicated by improvement in the vital capacity of less than 5% or improvement in the DLco of less than 10% within 2 months before enrollment.
For the primary end point the change from baseline in the A-aDo2 at week 24 improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (−12.8 mm Hg vs. −6.6 mm Hg).The mean change from baseline in the percent of predicted DLco at week 24, was greater in the continuous-molgramostim group than in the placebo group (12.0 vs. 4.2 percentage points). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George’s Respiratory Questionnaire total score at week 24 (−12.4 points vs. −5.1 points. For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The time from baseline to the first use of whole-lung lavage therapy was not significantly different between patients receiving continuous molgramostim and those receiving placebo.
During the open-label treatment-extension period, for which there was no control group, improvements in the A-aDo2, DLco, SGRQ total score, and distance covered on the 6-minute walk test were observed among patients who had received continuous molgramostim, intermittent molgramostim, or placebo during the blinded intervention period. In conclusion the above study showed some beneficial effects which are mainly attributed to measurements related to pulmonary gas transfer. However no statistical significant differences were observed in exercise capacity and in the need of whole lung lavage. The continuous schedule was superior to the intermittent one.
The study gave us a positive but small message. We need to know whether these effects are confirmed in a long term basis and to better define both the dosing scheme and the time dependent schedule.