Efficacy and Safety of Inhaled Molgramostim (rhGM-CSF) in Autoimmune Pulmonary Alveolar Proteinosis (IMPALA)

A Randomised, Double-blind, Placebo-controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis Patients

This study evaluates inhaled molgramostim (recombinant human granulocyte macrophage-colony stimulating factor [rhGM-CSF]) in the treatment of autoimmune pulmonary alveolar proteinosis (aPAP) patients. A third of the patients will receive inhaled molgramostim once daily for 24 weeks, a third will receive inhaled molgramostim intermittently (7 days on, 7 days off) for 24 weeks and a third will receive inhaled matching placebo for 24 weeks.

Study Overview

• Status: Completed
• Conditions: Autoimmune Pulmonary Alveolar Proteinosis
• Intervention / Treatment: Drug: Molgramostim; Device: PARI eFlow nebulizer system; Drug: Placebo

Detailed Description

The trial is a phase 2, randomized, double-blind, placebo-controlled multicentre clinical trial investigating efficacy and safety of inhaled molgramostim (rhGM-CSF) in patients with aPAP.

The trial will include 2 periods; a double-blind treatment period consisting of up to 8 trial visits (Screening, Baseline, and at Weeks 4, 8,12, 16, 20 and 24 after randomisation) and a open-label follow-up period consisting of up to 5 trial visits (at Weeks 4, 12, 24, 36 and 48 post-treatment).

In the double-blind treatment period, eligible subjects will be randomised to treatment for up to 24 weeks with either: 1) inhaled molgramostim (300 µg) once daily (MOL-OD), 2) inhaled molgramostim (300 µg) and matching placebo administered intermittently (7 days on and 7 days off) (MOL-INT) or 3) inhaled placebo once daily (PBO). During the follow-up period, all participants will receive inhaled molgramostim intermittently (7 days on, 7 days off). During the trial, whole lung lavage (WLL) may be applied as rescue therapy in case of significant clinical worsening.

• Study Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital
• France
  • Rennes, France
    • CHU Rennes Hospital Pontchaillou
• Germany
  • Essen, Germany
    • Westdeutsches Lungenzentrum am Universitätsklinikum Essen
  • Gauting, Germany, 82131
    • Asklepios Fachkliniken München - Gauting
  • Heidelberg, Germany
    • Thoraxklinik am Universitatsklinikum Heidelberg
  • Lübeck, Germany, 23538
    • Universitätsklinikum Schleswig-Holstein Zentralklinikum, Lübeck Medizinische Klinik III, Pneumologie
• Greece
  • Athens, Greece
    • Attikon University Hospital
• Israel
  • Petaẖ Tiqwa, Israel
    • Rabin Medical Center
• Italy
  • Pavia, Italy
    • IRCCS Policlinico San Matteo
• Japan
  • Niigata, Japan
    • Niigata University Medical and Dental Hospital
  • Osaka, Japan
    • National Hospital Organization Kinki-Chuo
  • Sendai, Japan
    • Tohoku University Hospital
  • Toyohashi, Japan
    • Aichi Medical University Hospital
  • Yokohama, Japan
    • Kanagawa Cardiovascular and Respiratory Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 0 3080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center, Division of Pulmonary and Critical Care Medicine
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center, Division of Pulmonary and Critical Care Medicine
• Netherlands
  • Nieuwegein, Netherlands
    • St. Antonius Hospital
• Portugal
  • Lisboa, Portugal
    • Hospital de dia de Pneumologia
  • Porto, Portugal, 4200-319
    • Hospital Sao Joao
• Russian Federation
  • St. Petersburg, Russian Federation
    • City Hospital St. Petersburg
• Slovakia
  • Vyšné Hágy, Slovakia, 05984
    • II. Pulmonary Department National Institut for TB, Lung Diseases and Chest Surgery
• Spain
  • Barcelona, Spain, 08907
    • Hospital University de Bellvitge (HUB)
• Switzerland
  • Lausanne, Switzerland
    • Centre Hospitalier Universitaire Vaudois
• Turkey
  • İstanbul, Turkey, 34020
    • Yedikule Pulmonary Diseases and Pulmonary Surgery Training and Research Hospital
• United Kingdom
  • London, United Kingdom
    • Royal Brompton Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• aPAP diagnosed by computed tomography, or by biopsy, or by Broncho Alveolar Lavage (BAL), and by increased GM-CSF autoantibodies in serum.
• Stable or progressive aPAP during a minimum period of 2 months prior to the Baseline visit.
• Arterial oxygen tension (PaO2) <75 mmHg/<10 kilo Pascal (kPa) at rest, OR desaturation of >4 percentage points on the 6MWT
• An alveolar-arterial oxygen difference [(A-a)DO2] of minimum 25 mmHg/3.33 kPa
• Female or male ≥18 years of age
• Females who have been post-menopausal for >1 year or females of childbearing potential after a confirmed menstrual period using a highly efficient method of contraception (i.e. a method with <1% failure rate such as combined hormonal contraception, progesterone-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence), during and until 30 days after last dose of double-blind trial treatment. Females of childbearing potential must have a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test at dosing at Baseline (Visit 2) and must not be lactating
• Males agreeing to use condoms during and until 30 days after last dose of double-blind medication, or males having a female partner who is using adequate contraception as described above
• Willing and able to provide signed informed consent
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures specified in the protocol as judged by the investigator

Exclusion Criteria:

• Diagnosis of hereditary or secondary PAP
• WLL within 1 month of Baseline
• Treatment with GM-CSF within 3 months of Baseline
• Treatment with rituximab within 6 months of Baseline
• Treatment with plasmapheresis within 3 months of Baseline
• Treatment with any investigational medicinal product within 4 weeks of Screening
• Concomitant use of sputum modifying drugs such as carbocysteine or ambroxol
• 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
• Known active infection (viral, bacterial, fungal or mycobacterial)
• Apparent pre-existing concurrent pulmonary fibrosis
• Any other serious medical condition which in the opinion of the investigator would make the participant unsuitable for the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Double-blind molgramostim once daily; Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks	Drug: Molgramostim; 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation; Other Names: rhGM-CSF; Device: PARI eFlow nebulizer system; PARI eFlow nebulizer system
Experimental: Double-blind molgramostim intermittent; Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles)	Drug: Molgramostim; 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation; Other Names: rhGM-CSF; Device: PARI eFlow nebulizer system; PARI eFlow nebulizer system
Placebo Comparator: Double-blind placebo; Inhalation of placebo nebuliser solution once daily for 24 weeks	Device: PARI eFlow nebulizer system; PARI eFlow nebulizer system; Drug: Placebo; Placebo nebulizer solution for inhalation
Experimental: Open-label molgramostim intermittent; Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 or 48 weeks from completion of the double-blind period	Drug: Molgramostim; 300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation; Other Names: rhGM-CSF; Device: PARI eFlow nebulizer system; PARI eFlow nebulizer system

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment	Measurement of (A-a)DO2 was done by blood gas analysis. An arterial blood sample was collected in the supine position, after resting for at least 10 minutes (or longer if required to achieve stable oxygen saturation). The sample was analyzed for arterial oxygen tension (PaO2) and partial pressure of carbon dioxide (PaCO2). The calculation of (A-a)DO2 was done centrally by using a formula described in the protocol.	From baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment	The 6MWD was assessed by the use of 6-minute walking test (6MWT). The 6MWT was performed in accordance with the 2014 ATS/ERS guideline "field walking tests in chronic respiratory disease" (Holland et al. 2014) by technicians with documented training and experience. Where possible, the test was conducted with the participant breathing ambient atmospheric air. If the participant required oxygen supplementation at rest, a titration procedure was carried out as part of the 6MWT at screening in order to determine the oxygen flow rate required for the participant to complete the test. This flow rate was to be used during subsequent tests, if possible.	From baseline to 24 weeks
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment	The SGRQ is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It consists of two parts, where Part 1 covers the participants' recollection of their symptoms over the preceding period (1 month recall used in this trial, Symptoms component) and Part 2 addresses the participants' current state in terms of disturbances to their daily physical activity (Activity component) and a wide range of disturbances of psycho-social function (Impact component). A total score as well as individual component scores were calculated. Scores (total and component) range from 0 to 100, with higher scores indicating more limitations.	From baseline to 24 weeks
Number of Whole Lung Lavage During 24 Weeks of Treatment	In all versions of the protocol (no participants were recruited under version 1.0), whole lung lavage (single lung or both lungs) was applied as rescue therapy. In protocol version 2.0, the criterion for performing whole lung lavage was an increase in (A-a)DO2 by more than 10 mmHg/1.33 kilopascal compared to baseline. In protocol version 3.0 onwards, the criterion for performing whole lung lavage was clinical worsening of aPAP based on symptoms, reduced exercise capacity and/or findings of hypoxemia or desaturation according to the investigator's judgement. In protocol versions 2.0 and 3.0, participants undergoing whole lung lavage during the double-blind period were to discontinue double-blind treatment, encouraged to continue to follow the same visit schedule and, if required, receive further whole lung lavage at the investigator's discretion. In protocol version 4.0 and 5.0, participants undergoing whole lung lavage were to continue double-blind treatment.	From baseline to 24 weeks
Number of Adverse Events (AEs) During 24 Weeks of Treatment	Treatment-emergent adverse events (AEs) were assessed on or after the first dose of trial drug to 28 days after last dose. Information about AEs was collected by the investigator by a non-leading question such as "have you experienced any new health problems or worsening of existing conditions" and by reporting events directly observed or spontaneously volunteered by participants (e.g., in the Subject Diary Card, where subjects were asked to record any AEs and answer questions regarding lung toxicity and known systemic effects). Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns. All AEs were assessed by the investigator for severity (mild, moderate, severe), outcome (recovered, not recovered, recovered with sequelae, fatal, unknown) and causality (unlikely, possible, probable, not applicable) according to current regulatory standards.	From baseline to 24 weeks
Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment	SAEs are 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 anomaly or birth defect; May jeopardise the subject or may require intervention to prevent one or more of the other outcomes listed above (Important Medical Events)	From baseline to 24 weeks
Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment	All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to a medicinal product qualify as ADRs. The expression reasonable causal relationship means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility i.e. the relationship cannot be ruled out.	From baseline to 24 weeks
Number of Severe AEs During 24 Weeks of Treatment	All AEs were assessed by the investigator for severity (mild, moderate, severe) according to current regulatory standards: Mild: The AE is easily tolerated and does not interfere with daily activity.; Moderate: The AE interferes with daily activity, but the subject is still able to function. Medical intervention may be considered.; Severe: The AE is incapacitating and requires medical intervention.	From baseline to 24 weeks
Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment	Participants could be discontinued from treatment and assessments at any time, if deemed necessary by the investigator. Potential reasons for discontinuation of treatment included e.g. unacceptable AE.	From baseline to 24 weeks

Collaborators and Investigators

• Sponsor: Savara Inc.
• Investigators: Principal Investigator: Cliff Morgan, MD, Royal Brompton Hospital London

Publications and helpful links

General Publications

• Trapnell BC, Inoue Y, Bonella F, Morgan C, Jouneau S, Bendstrup E, Campo I, Papiris SA, Yamaguchi E, Cetinkaya E, Ilkovich MM, Kramer MR, Veltkamp M, Kreuter M, Baba T, Ganslandt C, Tarnow I, Waterer G, Jouhikainen T; IMPALA Trial Investigators. Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2020 Oct 22;383(17):1635-1644. doi: 10.1056/NEJMoa1913590. Epub 2020 Sep 7.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2016
• Primary Completion (Actual): April 19, 2019
• Study Completion (Actual): September 27, 2019

Study Registration Dates

• First Submitted: February 28, 2016
• First Submitted That Met QC Criteria: March 2, 2016
• First Posted (Estimate): March 8, 2016

Study Record Updates

• Last Update Posted (Actual): April 12, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

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: MOL-PAP-002; 2015-003878-33 (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: Yes
• Studies a U.S. FDA-regulated device product: Yes