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

NCT02702180 | Completed Phase 2 Results DMC FDA Drug FDA Device

• 2 other identifiers: MOL-PAP-0022015-003878-33
• Study Type: interventional
• Target: 139
• Locations: 18 countries
• Sites: 30

Brief Summary

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.

Conditions

Autoimmune Pulmonary Alveolar Proteinosis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment

  From baseline to 24 weeks

• Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment

  From baseline to 24 weeks

• Number of Whole Lung Lavage During 24 Weeks of Treatment

  From baseline to 24 weeks

• Number of Adverse Events (AEs) During 24 Weeks of Treatment

  From baseline to 24 weeks

• Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment

  From baseline to 24 weeks

Study Arms (4)

Double-blind molgramostim once daily

EXPERIMENTAL

Inhalation of molgramostim nebuliser solution 300 mcg once daily for 24 weeks

Drug: Molgramostim; Device: PARI eFlow nebulizer system

Double-blind molgramostim intermittent

EXPERIMENTAL

Inhalation of molgramostim nebuliser solution 300 mcg for 7 days and placebo nebuliser solution for 7 days for 24 weeks (12 cycles)

Drug: Molgramostim; Device: PARI eFlow nebulizer system

Double-blind placebo

PLACEBO COMPARATOR

Inhalation of placebo nebuliser solution once daily for 24 weeks

Drug: Placebo; Device: PARI eFlow nebulizer system

Open-label molgramostim intermittent

EXPERIMENTAL

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; Device: PARI eFlow nebulizer system

Interventions

Molgramostim DRUG

300 mcg molgramostim (rhGM-CSF) nebulizer solution for inhalation

Also known as: rhGM-CSF

Double-blind molgramostim intermittent; Double-blind molgramostim once daily; Open-label molgramostim intermittent

Placebo DRUG

Placebo nebulizer solution for inhalation

Double-blind placebo

PARI eFlow nebulizer system DEVICE

PARI eFlow nebulizer system

Double-blind molgramostim intermittent; Double-blind molgramostim once daily; Double-blind placebo; Open-label molgramostim intermittent

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Savara Inc.: lead

Study Sites (30)

UCLA

Los Angeles, California, 90095, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Royal Prince Alfred Hospital

Sydney, New South Wales, 2050, Australia

Location

Aarhus University Hospital

Aarhus, Denmark

Location

CHU Rennes Hospital Pontchaillou

Rennes, France

Location

Westdeutsches Lungenzentrum am Universitätsklinikum Essen

Essen, Germany

Location

Asklepios Fachkliniken München - Gauting

Gauting, 82131, Germany

Location

Thoraxklinik am Universitätsklinikum Heidelberg

Heidelberg, Germany

Location

Universitätsklinikum Schleswig-Holstein Zentralklinikum, Lübeck Medizinische Klinik III, Pneumologie

Lübeck, 23538, Germany

Location

Attikon University Hospital

Athens, Greece

Location

Rabin Medical Center

Petah Tikva, Israel

Location

IRCCS Policlinico San Matteo

Pavia, Italy

Location

Niigata University Medical and Dental Hospital

Niigata, Japan

Location

National Hospital Organization Kinki-Chuo

Osaka, Japan

Location

Tohoku University Hospital

Sendai, Japan

Location

Aichi Medical University Hospital

Toyohashi, Japan

Location

Kanagawa Cardiovascular and Respiratory Center

Yokohama, Japan

Location

St. Antonius Hospital

Nieuwegein, Netherlands

Location

Hospital de dia de Pneumologia

Lisbon, Portugal

Location

Hospital Sao Joao

Porto, 4200-319, Portugal

Location

City Hospital St. Petersburg

Saint Petersburg, Russia

Location

II. Pulmonary Department National Institut for TB, Lung Diseases and Chest Surgery

Vyšné Hágy, 05984, Slovakia

Location

Seoul National University Hospital

Seoul, 0 3080, South Korea

Location

Asan Medical Center, Division of Pulmonary and Critical Care Medicine

Seoul, 05505, South Korea

Location

Samsung Medical Center, Division of Pulmonary and Critical Care Medicine

Seoul, 135-710, South Korea

Location

Hospital University de Bellvitge (HUB)

Barcelona, 08907, Spain

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, Switzerland

Location

Yedikule Pulmonary Diseases and Pulmonary Surgery Training and Research Hospital

Istanbul, 34020, Turkey (Türkiye)

Location

Royal Brompton Hospital

London, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 32897035 BACKGROUND

MeSH Terms

Conditions

Pulmonary Alveolar Proteinosis, Acquired

Interventions

molgramostim; regramostim

Results Point of Contact

• Title: Raymond D. Pratt, MD, PACP - Chief Medical Officer
• Organization: Savara Inc

ray.pratt@savarapharma.com

+1 512 784 8757

Study Officials

• Cliff Morgan, MD

  Royal Brompton Hospital, London

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2016
• First Posted: March 8, 2016
• Study Start: March 21, 2016
• Primary Completion: April 19, 2019
• Study Completion: September 27, 2019
• Last Updated: April 12, 2023
• Results First Posted: April 15, 2022

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1); FR (1); JP (5); PT (2); DK (1); US (3); DE (4); IT (1); NL (1); KR (3); GB (1); AU (1); RU (1); CH (1); ES (1); GR (1); SL (1); TU (1)