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

This study is enrolling participants by invitation only.
Sponsor:
Collaborator:
Agenzia Italiana del Farmaco
Information provided by:
IRCCS Policlinico S. Matteo
ClinicalTrials.gov Identifier:
NCT00901511
First received: May 11, 2009
Last updated: July 27, 2009
Last verified: July 2009
  Purpose

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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Whole Lung Lavage Followed by Inhaled Sargramostim in the Treatment of Autoimmune Pulmonary Alveolar Proteinosis

Resource links provided by NLM:


Further study details as provided by IRCCS Policlinico S. Matteo:

Primary Outcome Measures:
  • The total resolution of the pulmonary involvement [ Time Frame: 36 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Avoidance of recurrence of the disease requiring multiple WLLs [ Time Frame: 36 months ] [ Designated as safety issue: No ]
  • Investigation of determinants of the outcome [ Time Frame: 36 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 18
Study Start Date: July 2009
Estimated Study Completion Date: July 2013
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Leukine (Sargramostim)
Procedure: WLL
Whole lung lavage
Active Comparator: WLL alone Procedure: WLL
Whole lung lavage

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00901511

Locations
Italy
Fondazione IRCCS Policlinico San Matteo
Pavia, PV, Italy, 27100
Sponsors and Collaborators
IRCCS Policlinico S. Matteo
Agenzia Italiana del Farmaco
Investigators
Principal Investigator: Maurizio Luisetti, MD Fondazione IRCCS Policlinico San Matteo
  More Information

Publications:
Responsible Party: Maurizio Luisetti,MD, Fondazione IRCCS Policlinico San Matteo - Pavia-Italy
ClinicalTrials.gov Identifier: NCT00901511     History of Changes
Other Study ID Numbers: FARM7MCPK4, Codice Interno 19900508, EudraCT 2008-007086-23
Study First Received: May 11, 2009
Last Updated: July 27, 2009
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by IRCCS Policlinico S. Matteo:
Whole lung lavage
Pulmonary surfactant
GM-CSF
Autoantibodies anti GM-CSF

Additional relevant MeSH terms:
Pulmonary Alveolar Proteinosis
Lung Diseases
Respiratory Tract Diseases
Pulmonary Surfactants
Respiratory System Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 27, 2014