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

Sponsor

IRCCS Policlinico S. Matteo (Other)

Overall Status

Unknown status

CT.gov ID

NCT00901511

Collaborator

Agenzia Italiana del Farmaco (Other)

Enrollment

Location

Arms

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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).

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Alveolar Proteinosis	Drug: GM-CSF [Leukine (Sargramostim)] Procedure: WLL	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

18 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 2009

Anticipated Primary Completion Date :

Jul 1, 2012

Anticipated Study Completion Date :

Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: WLL/GM-CSF Whole lung lavage followed by inhaled GM-CSF	Drug: GM-CSF [Leukine (Sargramostim)] Acute treatment: the PAP subjects will receive inhaled rGM-CSF (Sargramostim, Leukine) at the dose of 250 mcg/24 hours. The acute treatment will be accomplished in 12 weeks, for 7 consecutive days every second week (thus, 6 weeks on and 6 weeks off). For those PAP patients receiving the GM-CSF for the first time (1st and 2nd level treated groups), the treatment will be performed by 1 week run-in, after discharge from the ICU, in the Respiratory Disease Department (during this period PAP patients usually receive e.v. corticosteroids, and oral antibiotics). After the run-in period, the patient is discharged and inhalation treatment will continue at home. Maintenance treatment: 17 weeks after the WLL (4 weeks after the completion of the acute treatment), the PAP patient will start the maintenance treatment. He/she will receive inhaled GM-CSF at the dose of 250 mcg/daily for 2 consecutive days every 14 days (2 days on and 12 days off) for a period of 6 month Other Names: Leukine (Sargramostim) Procedure: WLL Whole lung lavage
Active Comparator: WLL alone	Procedure: WLL Whole lung lavage

Arm

Intervention/Treatment

Experimental: WLL/GM-CSF

Whole lung lavage followed by inhaled GM-CSF

Drug: GM-CSF [Leukine (Sargramostim)]

Acute treatment: the PAP subjects will receive inhaled rGM-CSF (Sargramostim, Leukine) at the dose of 250 mcg/24 hours. The acute treatment will be accomplished in 12 weeks, for 7 consecutive days every second week (thus, 6 weeks on and 6 weeks off). For those PAP patients receiving the GM-CSF for the first time (1st and 2nd level treated groups), the treatment will be performed by 1 week run-in, after discharge from the ICU, in the Respiratory Disease Department (during this period PAP patients usually receive e.v. corticosteroids, and oral antibiotics). After the run-in period, the patient is discharged and inhalation treatment will continue at home. Maintenance treatment: 17 weeks after the WLL (4 weeks after the completion of the acute treatment), the PAP patient will start the maintenance treatment. He/she will receive inhaled GM-CSF at the dose of 250 mcg/daily for 2 consecutive days every 14 days (2 days on and 12 days off) for a period of 6 month

Other Names:

Leukine (Sargramostim)

Procedure: WLL

Whole lung lavage

Active Comparator: WLL alone

Procedure: WLL

Whole lung lavage

Outcome Measures

Primary Outcome Measures

The total resolution of the pulmonary involvement [36 months]

Secondary Outcome Measures

Avoidance of recurrence of the disease requiring multiple WLLs [36 months]
Investigation of determinants of the outcome [36 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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