Safety Extension Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis (IMPALA-X)

An Open-label, Non-controlled, Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis Patients

SAV006-03 is an open-label extension study for participants who had completed the IMPALA study.

At the baseline visit, eligible participants may continue or re-start treatment with 300 µg inhaled molgramostim (recombinant human Granulocyte-Macrophage Colony Stimulating Factor; GM-CSF) administered intermittently in cycles of seven days molgramostim, administered once daily, and seven days off treatment.

Participants will be treated with inhaled molgramostim for up to 36 months.

During the trial, whole lung lavage will be applied as rescue therapy.

Study Overview

• Status: Terminated
• Conditions: Autoimmune Pulmonary Alveolar Proteinosis
• Intervention / Treatment: Drug: Molgramostim

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Århus, Denmark
    • Dept. Of Respiratory Diseases & Allergy
• France
  • Rennes, France
    • CHU Rennes Hospital Pontchaillou, Service de Pneumologie
• Germany
  • Essen, Germany
    • Ruhrlandklinik Essen Westdeutsches Lungenzentrum am Universitätsklinikum Essen GmbH
  • Gauting, Germany
    • Asklepios Fachkliniken München - Gauting Klinik für Pneumologie
  • Heidelberg, Germany
    • Thoraxklinik am Universitätsklinikum Heidelberg Abteilung für Pneumologie und Beatmungsmedizin
  • Lübeck, Germany
    • Universitätsklinikum Schleswig-Holstein Zentralklinikum Lübeck Medizinische Klinik III - Pneumologie
• Greece
  • Athens, Greece
    • Attikon University Hospital 2nd Pulmonary Department Athens Medical School National and Kapodistrian University of Athens
• Israel
  • Tel Aviv, Israel
    • Rabin Medical Center Institute of Pulomonary Medicine
• Italy
  • Pavia, Italy
    • S.C. Pneumologia Fondazione IRCCS Policlinico San Matteo
• Netherlands
  • Nieuwegein, Netherlands
    • St. Antonius Hospital
• Russian Federation
  • Saint Petersburg, Russian Federation
    • Pavlov first Saint Petersburg State Medical Univerisity
• Turkey
  • Istanbul, Turkey, 34020
    • Yedikule Pulmonary Diseases and Pulmonary Surgery Training and Research Hospital
• United Kingdom
  • London, United Kingdom
    • Dept. Of Intensive Care Unit Royal Brompton Hospital London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Completer of the IMPALA trial.
• Females who have been post menopausal for >1 year, or females of child-bearing potential who are not pregnant or lactating and are using acceptable contraceptive methods.
• Males agreeing to use using acceptable contraceptive methods.
• Willing and able to provide signed informed consent.

Exclusion Criteria:

• Treatment with GM-CSF products other than molgramostim nebuliser solution within three months of Baseline.
• Treatment with any investigational medicinal product other than inhaled molgramostim within four weeks of Baseline.
• History of allergic reactions to GM-CSF.
• Connective tissue disease, inflammatory bowel disease or other autoimmune disorder requiring treatment associated with significant immunosuppression, e.g. more than 10 mg/day systemic prednisolone.
• Previous experience of severe and unexplained side effects during aerosol delivery of any kind of medicinal product.
• History of, or present, myeloproliferative disease or leukaemia.
• Apparent pre-existing concurrent pulmonary fibrosis.
• Any other serious medical condition which in the opinion of the investigator would make the subject unsuitable for the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Molgramostim nebulizer solution (300 μg); Open-label treatment with molgramostim nebulizer solution (300 μg) administered intermittently (repetitive cycles of 7 days of treatment followed by 7 days off-treatment).	Drug: Molgramostim; 300 µg inhaled molgramostim in cycles of once daily administration for 7 days, then 7 days off treatment.; Other Names: Recombinant human GM-CSF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Treatment-emergent Adverse Events (TEAEs)	The primary objective of this trial was safety assessed by adverse event (AE) reporting. Definitions and reporting procedures for AEs were done according to current regulatory standards. AEs were collected by the investigator by a non-leading question and by reporting events directly observed or spontaneously volunteered by participants. Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns. Treatment-emergent was defined as events occurring on study drug and up to 7 days after last dose of study drug.	139 weeks
Number of Serious TEAEs	Serious TEAEs were defined as any untoward medicinal occurrence or effect that at any dose: Results in death; Is life-threatening; Requires hospitalisation or prolongation of existing hospitalisation; Results in persistent or significant disability or incapacity; Is a congenital abnormality or birth defect; May jeopardise the participant or may require medical intervention to prevent one or more of the outcomes listed above (Important Medical Events).	139 weeks
Number of Treatment-emergent Adverse Drug Reactions (ADRs)	All AEs were assessed by the investigator for causality (unlikely, possible, probable, not applicable) according to current regulatory standards. AEs which had a 'possible' or 'probable' causality were classified as ADRs.	139 weeks
Number of TEAEs Leading to Treatment Discontinuation		139 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alveolar-arterial oxygen gradient	Difference in oxygen tension between lungs and blood	36 months
6-minute walk distance		36 months
St Georges Respiratory Questionnaire total score	Respiratory-specific questionnaire measuring impact on overall health, daily life, and perceived well-being. Scores range from 0 to 100, with higher scores indicating more limitations.	36 months
Frequency of whole lung lavages during the trial		36 months
Diffusion capacity of the lung for carbon monoxide		36 months
Forced expiratory volume in one second		36 months
Forced vital capacity		36 months
Arterial oxygen tension		36 months
Pulmonary alveolar proteinosis Disease Severity Score	Disease-specific score graded based on symptoms of PAP and oxygenation of blood. Scores range from 1 to 5, where 5 indicates most severe disease.	36 months
Need for oxygen supplement therapy		36 months
Number of subjects not requiring treatment for pulmonary alveolar proteinosis		36 months
Time off treatment for pulmonary alveolar proteinosis		36 months

Collaborators and Investigators

• Sponsor: Savara Inc.
• Investigators: Principal Investigator: Francesco Bonella, Prof., Interstitial and Rare Lung Disease Unit, Ruhrlandklinik University Hospital, Essen, Germany

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2018
• Primary Completion (Actual): January 14, 2021
• Study Completion (Actual): January 14, 2021

Study Registration Dates

• First Submitted: March 21, 2018
• First Submitted That Met QC Criteria: March 28, 2018
• First Posted (Actual): March 29, 2018

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Autoimmune Diseases; Pulmonary Alveolar Proteinosis; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Sargramostim; Molgramostim
• Other Study ID Numbers: SAV006-03; 2017-004078-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No