Clinical trial NCT02702180: Efficacy and Safety of Inhaled Molgramostim (rhGM-CSF) in Autoimmune Pulmonary Alveolar Proteinosis
Official title: A Randomised, Double-blind, Placebo-controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autoimmune Pulmonary Alveolar Proteinosis
Lead sponsor: Savara Inc.
Sponsor class: INDUSTRY
First posted: 2016-03-08
Enrollment: 139
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Absolute Change From Baseline of Alveolar-arterial Oxygen Concentration (A-a(DO2)) After 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
Secondary outcomes:
measure: Change From Baseline in 6-minute Walking Distance (6MWD) After 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
measure: Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score After 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
measure: Number of Whole Lung Lavage During 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
measure: Number of Adverse Events (AEs) During 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
measure: Number of Serious Adverse Events (SAEs) During 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
measure: Number of Adverse Drug Reactions (ADRs) During 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
measure: Number of Severe AEs During 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
measure: Number of Participants With at Least 1 AE Leading to Treatment Discontinuation During 24 Weeks of Treatment
timeFrame: From baseline to 24 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Rennes
country: France
facility: CHU Rennes Hospital Pontchaillou
city: Essen
country: Germany
facility: Westdeutsches Lungenzentrum am Universitätsklinikum Essen
city: Gauting
country: Germany
facility: Asklepios Fachkliniken München - Gauting
city: Heidelberg
country: Germany
facility: Thoraxklinik am Universitätsklinikum Heidelberg
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Zentralklinikum, Lübeck Medizinische Klinik III, Pneumologie
city: Athens
country: Greece
facility: Attikon University Hospital
city: Petaẖ Tiqwa
country: Israel
facility: Rabin Medical Center
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo
city: Niigata
country: Japan
facility: Niigata University Medical and Dental Hospital
city: Osaka
country: Japan
facility: National Hospital Organization Kinki-Chuo
city: Sendai
country: Japan
facility: Tohoku University Hospital
city: Toyohashi
country: Japan
facility: Aichi Medical University Hospital
city: Yokohama
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center, Division of Pulmonary and Critical Care Medicine
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center, Division of Pulmonary and Critical Care Medicine
city: Nieuwegein
country: Netherlands
facility: St. Antonius Hospital
city: Lisboa
country: Portugal
facility: Hospital de dia de Pneumologia
city: Porto
country: Portugal
facility: Hospital Sao Joao
city: St. Petersburg
country: Russian Federation
facility: City Hospital St. Petersburg
city: Vyšné Hágy
country: Slovakia
facility: II. Pulmonary Department National Institut for TB, Lung Diseases and Chest Surgery
city: Barcelona
country: Spain
facility: Hospital University de Bellvitge (HUB)
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: İstanbul
country: Turkey
facility: Yedikule Pulmonary Diseases and Pulmonary Surgery Training and Research Hospital
city: London
country: United Kingdom
facility: Royal Brompton Hospital
Study officials:
affiliation: Royal Brompton Hospital, London
name: Cliff Morgan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.