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Whole Lung Lavage (WLL)/Inhaled Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) in Autoimmune Pulmonary Alveolar Proteinosis (PAP)

Information source: IRCCS Policlinico S. Matteo
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pulmonary Alveolar Proteinosis

Intervention: GM-CSF [Leukine (Sargramostim)] (Drug); WLL (Procedure)

Phase: Phase 2/Phase 3

Status: Enrolling by invitation

Sponsored by: IRCCS Policlinico S. Matteo

Official(s) and/or principal investigator(s):
Maurizio Luisetti, MD, Principal Investigator, Affiliation: Fondazione IRCCS Policlinico San Matteo

Summary

The investigators designed an experimental, randomized by parallel groups, stratified according to previous treatment, open-label study evaluating the superiority of the combination of whole lung lavage/inhaled GM-CSF versus whole lung lavage alone in patients with pulmonary alveolar proteinosis. The primary efficacy objective is the total resolution of the pulmonary involvement. PAP patients matching the enrolment criteria will enter the study. If requiring the first WLL, they will be randomized to receive WLL (1st level control group) or WLL/followed by inhaled GM-CSF, according to an acute (12 weeks) followed by maintenance (6 months) schedule (1st level treated group).

Clinical Details

Official title: Whole Lung Lavage Followed by Inhaled Sargramostim in the Treatment of Autoimmune Pulmonary Alveolar Proteinosis

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: The total resolution of the pulmonary involvement

Secondary outcome:

Avoidance of recurrence of the disease requiring multiple WLLs

Investigation of determinants of the outcome

Detailed description: Background: Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by accumulation of lipoproteinaceous material within alveolar spaces, leading to respiratory failure. Whole lung lavage (WLL) is the current therapeutic option, but it may induce complete resolution of the disorder only in 30% of patients. Based on PAP pathophysiology, a few pilot studies dealing with administration of rGM-CSF (Sargramostim) to patients either s. c. or aerosolized have been performed, with hopeful results. Objectives. We designed an experimental, randomized by parallel groups, stratified according to previous treatment, open-label study looking at evaluation the superiority of the combination WLL/inhaled GM-CSF vs WLL alone in PAP patients. The study also includes a side, observational section. The primary efficacy objective is the total resolution of the pulmonary involvement in all treated patients. The study includes some secondary efficacy objectives as well: avoidance of disease recurrence, avoidance of respiratory infections, investigation of biomarkers predicting the disease outcome, effect of treatments on underlying pathophysiology of PAP. Methods: PAP patients matching the enrollment criteria will enter the study. 1) If requiring the first WLL, they will be randomized to receive WLL (1st level control group) or WLL/ followed by inhaled GM-CSF, according to an acute (12 weeks) followed by maintenance (6 months) schedule (1st level treated group). 2) PAP patients requiring the second WLL: a) the 1st level control group subjects will be randomized to receive WLL alone (2nd level control group) or WLL/GM-CSF (2nd level treated group); b) the 1st level treated group will receive WLL/GM-CSF (1st level re-treated group). 3) PAP patients requiring the 3rd WLL will receive WLL/GM-CSF (2nd level re-treated group). 4) PAP patients not requiring additional WLL, but with persistent lung abnormalities will receive the course of inhaled GM-CSF (Residual disease treated group). At scheduled time, the PAP patients will be evaluated by questionnaire, respiratory function testing, CT-assisted lung profusion score, severity score, quality of life form, clinical chemistry. Expected results: We plan to identify the best treatment schedule for PAP patients. We will be able to identify the optimal sequence of the treatments (i. e., WLL + short-term inhaled GM-CSF or WLL + short-and long-term inhaled GM-CSF) and the optimal treatment in case of recurrence.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- First step: only autoimmune PAP subjects will be included

- Second step (eligibility for the WLL):

- presence of persistent or progressive respiratory failure (PaO2 at rest < 60 mm

Hg)

- absence of respiratory failure at rest, but evidence for exertional

- desaturation < 90% or > 5 percentage points using the modified Bruce's protocol

(5)

- careful evaluation of conditions contraindicating the WLL (see below)

- discussion with the patient about cost-effectiveness of the procedure and

signature of the standard informed consent. Points a) and b) will be evaluated over a period of 3 months, to avoid spontaneous improvement or resolution. (The former happens in 10% of cases falling in point b): in the case of fluctuation of saturation values around the threshold value, the procedure will be delayed until values are stable; the latter happened in 2/51 autoimmune PAP patients from our series, and the complete resolution occurred within the first 2 months from the diagnosis.)

- Third step (eligibility for the study): this step will be accomplished essentially by

evaluation of the presence of conditions contraindicating the GM-CSF inhalation and upon ad hoc informed consent obtained from the patient Exclusion Criteria:

- chronic lung disease associated with already existing respiratory failure (such as

pulmonary emphysema or fibrosis)

- chronic heart failure or ischemic heart disease

- active pulmonary embolism

- progressive cancer

- other severe metabolic conditions

- secondary PAP

- previously experience of severe and unexplained side-effects during aerosol delivery

of any kinds of agents

Locations and Contacts

Fondazione IRCCS Policlinico San Matteo, Pavia, PV 27100, Italy
Additional Information

Related publications:

Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003 Dec 25;349(26):2527-39. Review.

Starting date: July 2009
Last updated: July 27, 2009

Page last updated: August 23, 2015

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