IMPALA-2: Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)

• Sponsor: Savara Inc. (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04544293
• Collaborator: (none)
• Enrollment: 160
• Locations: 54
• Arms: 2
• Anticipated Duration (Months): 48.7
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

160 subjects with autoimmune pulmonary alveolar proteinosis (aPAP) will be randomized to receive once daily treatment with inhaled molgramostim or placebo for 48 weeks. Subjects completing the 48 week placebo-controlled period will receive open-label treatment with once daily inhaled molgramostim for 48 weeks.

Condition or Disease	Intervention/Treatment	Phase
Autoimmune Pulmonary Alveolar Proteinosis	Drug: Molgramostim; Drug: Placebo	Phase 3

Detailed Description

This is an interventional, randomized, double-blind, 2-arm, parallel groups, placebo-controlled, multi-center, phase 3 trial in adult subjects who are diagnosed with aPAP.

An aPAP diagnosis should be confirmed by an anti-GM-CSF auto-antibody test result, and history of PAP based on either high resolution computed tomography, lung biopsy, or bronchoalveolar lavage cytology, should be available.

The trial consists of a 6-week screening period, a 48-week randomized, double-blind treatment period, a 48-week open-label treatment period, and a conditional 4-week safety follow-up period. The maximum treatment duration will be 97 weeks and the maximum trial duration will be 108 weeks. During the trial, whole lung lavage will be allowed as rescue treatment in case of worsening of aPAP.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subject will be randomized 1:1 to treatment with inhaled molgramostim or placeboSubject will be randomized 1:1 to treatment with inhaled molgramostim or placebo
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Clinical Trial of Once-daily Inhaled Molgramostim Nebulizer Solution in Adult Subjects With Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
• Actual Study Start Date: May 10, 2021
• Anticipated Primary Completion Date: Jun 1, 2024
• Anticipated Study Completion Date: Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Molgramostim Double-blind treatment with molgramostim nebulizer solution 300 µg once daily for 48 weeks, followed by open-label treatment with molgramostim nebulizer solution 300 µg once daily for 48 weeks	Drug: Molgramostim; Molgramostim 300 µg nebulizer solution; Other Names: Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF)
Placebo Comparator: Placebo Double-blind treatment with placebo nebulizer solution once daily for 48 weeks, followed by open-label treatment with molgramostim nebulizer solution 300 µg once daily for 48 weeks	Drug: Molgramostim; Molgramostim 300 µg nebulizer solution; Other Names: Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) ; Drug: Placebo; Matching placebo

Outcome Measures

Primary Outcome Measures

1. Change from baseline in percentage (%) predicted diffusing capacity of the lung for carbon monoxide (DLCO) to Week 24 [From Baseline to Week 24]

   As a measure of pulmonary gas exchange, a standardized lung function test, DLCO, will be conducted. The single-breath DLCO test will be performed in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for DLCO testing.

Secondary Outcome Measures

1. Change from baseline in percentage (%) predicted DLCO to Week 48 [From Baseline to Week 48]

   As a measure of pulmonary gas exchange, a standardized lung function test, DLCO, will be conducted. The single-breath DLCO test will be performed in accordance with ATS/ERS guidelines for DLCO testing.

2. Change from baseline in St. Georges Respiratory Questionnaire (SGRQ) Total score to Week 24 [From Baseline to Week 24]

   The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good).

3. Change from baseline in SGRQ Activity component score to Week 24 [Week 24]

   The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good).

4. Change from baseline in exercise capacity (EC), expressed as peak metabolic equivalents (METs) to Week 24 [From Baseline to Week 24]

   As a functional measure of exertional limitations related to dyspnea, EC will be assessed by an exercise treadmill test. EC will be expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved will be used to calculate peak METs.

5. Change from baseline in SGRQ Total score to Week 48 [Week 48]

   The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good).

6. Change from baseline in SGRQ Activity from baseline to Week 48 [From Baseline to Week 48]

   The SGRQ includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. The subjects will be asked to grade their current health on a 5-point scale (very poor, poor, fair, good, or very good).

7. Change from baseline in EC, expressed as peak METs to Week 48 [From Baseline to Week 48]

   As a functional measure of exertional limitations related to dyspnea, EC will be assessed by an exercise treadmill test. EC will be expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved will be used to calculate peak METs.

8. Change from baseline in alveolar-arterial oxygen difference (A-aDO2) to Week 24 (Specifically for Japan and South Korea) [From Baseline to Week 24]

   A-aDO2 will be used as an additional measure of gas exchange.

9. Number of subjects with serious and non-serious adverse events [From screening (6-week) until Follow-up visit (Week 100)]

   Assessment of the safety of MOL compared to placebo

10. Number of subjects with positive treatment-boosted anti Granulocyte macrophage colony stimulating factor (GM-CSF) antibody titers during 24 weeks' treatment and during 48 weeks' treatment [From screening (6-week) until Follow-up visit (Week 100)]

    Assessment of the safety of MOL compared to placebo

11. Changes in Forced vital capacity (FVC) [From Baseline to Weeks 24 and 48]

    Assessment of the safety of MOL compared to placebo

12. Changes in Forced expiratory volume in one second (FEV1) [From Baseline to Weeks 24 and 48]

    Assessment of the safety of MOL compared to placebo

13. Change in QT interval corrected by Fridericia (QTcF) [From Baseline to Weeks 4 and 24]

    Assessment of the safety of MOL compared to placebo

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject must be ≥18 years of age, at the time of signing the informed consent (≥20 in Japan).

2. A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.

3. History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest.

4. DLCO 70% predicted or lower at the screening and baseline visits.

5. Change in % predicted DLCO of <15% points during the screening period.

6. Demonstrated functional impairment in the treadmill exercise test (defined as a peak MET ≤8).

7. Willing and able to come off supplemental oxygen use prior to and during the treadmill exercise test, the DLCO assessment, and the arterial blood gas sampling.

8. Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at the screening visits.

9. Male or female

10. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

11. Male subjects: Males agreeing to use condoms during and until 30 days after last dose of trial treatment, or males having a female partner who is using adequate contraception as described below.

12. Female subjects: 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, vasectomized partner, sexual abstinence*), during and until 30 days after last dose of trial treatment. Females of childbearing potential must have a negative serum pregnancy test at the screening visits, and a negative urine pregnancy test at Baseline visit (Visit 3) and must not be lactating.

13. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

14. 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:

1. Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant production.

2. WLL performed within 3 months prior to baseline.

3. Requirement for WLL at screening or baseline.

4. GM-CSF treatment within 6 months prior to baseline.

5. Treatment with rituximab within 6 months prior to baseline.

6. Treatment with plasmapheresis within 6 weeks prior to baseline.

7. Treatment with any investigational medicinal product within 5 half-lives or 3 months (whichever is longer) prior to baseline.

8. Previously randomized in this trial.

9. History of allergic reactions to GM-CSF or any of the excipients in the nebulizer solution.

10. Inflammatory or autoimmune disease of a severity that necessitates significant (e.g. more than 10 mg/day systemic prednisolone) immunosuppression.

11. Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product.

12. History of, or present, myeloproliferative disease or leukemia.

13. Apparent pre-existing concurrent pulmonary fibrosis.

14. Acute or unstable cardiac or pulmonary disease that may be aggravated by exercise.

15. Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect the efficacy evaluation in the trial.

16. Physical disability or other condition that precludes safe and adequate exercise testing.

17. Any other serious medical condition which in the opinion of the Investigator would make the subject unsuitable for the trial.

18. Pregnant, planning to become pregnant during the trial, or breastfeeding woman. For France only: including as further defined by French Health Code L-1121-5.

19. For France only: Any subject considered to be "vulnerable" on account of, e.g., mental or physical disability, socio-economic situation, or subjects deprived of their liberty. For France only: including as further defined by French Health Code L1121-8-1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Of Arkansas For Medical Services	Little Rock	Arkansas	United States	72205
2	UCLA David Geffen School of Medicine	Los Angeles	California	United States	90095
3	National Jewish Health	Denver	Colorado	United States	80206
4	Yale University	New Haven	Connecticut	United States	06520
5	University of Florida Health	Gainesville	Florida	United States	32610
6	Emory University	Atlanta	Georgia	United States	30322
7	Loyola University	Maywood	Illinois	United States	60153
8	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
9	Washington University in St. Louis	Saint Louis	Missouri	United States	63110
10	Duke University Medical Center	Durham	North Carolina	United States	27710
11	Wake Med Health & Hospital	Raleigh	North Carolina	United States	27610
12	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
13	Cleveland Clinic	Cleveland	Ohio	United States	44195
14	University of Pennsylvania Perelman School of Medicine - Pulmonology	Philadelphia	Pennsylvania	United States	19104
15	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
16	UT Southwestern Medical Center	Dallas	Texas	United States	75390
17	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
18	Westmead Hospital	Westmead	New South Wales	Australia	2145
19	Hôpital Erasme	Bruxelles	Région De Bruxelles-Capitale	Belgium	1070
20	UZ Leuven - Campus Gasthuisberg - Pneumologie	Leuven	Vlaams Brabant	Belgium	3000
21	University of Calgary	Calgary	Alberta	Canada	T2N 4N1
22	University Institute of Cardiology and Respirology of Quebec	Québec		Canada	G1V 4G5
23	Hôpital Louis Pradel	Bron	Auvergne-Rhône-Alpes	France	69500
24	CHU Pontchaillou	Rennes	Bretagne	France	35033
25	Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg	Germany	69126
26	Klinik Donaustauf	Donaustauf	Bayern	Germany	93093
27	Asklepios Fachkliniken Muenchen-Gauting	Muenchen-Gauting	Bayern	Germany	82131
28	Ruhrlandklinik Westdeutsches Lungenzentrum	Essen	Nordrhein-Westfalen	Germany	45239
29	Attikon University Hospital	Athens		Greece	12462
30	St. Vincent's University Hospital	Dublin		Ireland	DO4 T6F4
31	Fondazione IRCCS Policlinico San Matteo	Pavia	Lombardia	Italy	27100
32	Hokkaido University Hospital	Sapporo	Hokkaidô	Japan	060-8648
33	Kanagawa Cardiovascular and Respiratory Center	Yokohama	Kanagawa	Japan	236-0051
34	Tohoku University Hospital - Respiratory Tract Medicine	Sendai	Miyagi	Japan	980-8574
35	National Hospital Organization Kinki-Chuo Chest medical Center	Sakai	Osaka	Japan	591-8555
36	Kyorin University Hospital	Mitaka	Tokyo	Japan	181-8611
37	Chiba University Hospital - Respiratory Medicine	Chiba		Japan	260-8677
38	Kumamoto University Hospital	Kumamoto		Japan	860-8556
39	Aichi Medical University Hospital	Nagakute		Japan	480-1195
40	Saitama Red Cross Hospital	Saitama		Japan	330-8553
41	Seoul National University Hospital	Seoul		Korea, Republic of	03080
42	Severance Hospital - Yonsei University Health System - Pulmonary	Seoul		Korea, Republic of	03722
43	Asan Medical Center	Seoul		Korea, Republic of	05505
44	Samsung Medical Center	Seoul		Korea, Republic of	06351
45	St Antonius Hospital	Nieuwegein	Utrecht	Netherlands	3435CM
46	Instytut Gruzlicy i Chorob Pluc	Warszawa	Mazowieckie	Poland	01-138
47	Hospital Pulido Valente	Lisboa		Portugal	1769-001
48	Hospital São João	Porto		Portugal	4200-319
49	Institutul de Pneumoftiziologie "Marius Nasta"	Bucuresti		Romania	050159
50	Hospital Universitario de Bellvitge	Barcelona	Cataluña	Spain	08907
51	Ege University Hospital - Department of Pulmonology	Bornova	Izmir	Turkey	35100
52	Health Sciences University Gulhane Training and Research Hospital	Ankara		Turkey	6010
53	Yedikule Chest Disease and Surgery Training and Research Hospital	Istanbul		Turkey	34020
54	Royal Brompton and Harefield NHS Foundation Trust	London		United Kingdom	SW3 6NP

Sponsors and Collaborators

• Savara Inc.

Investigators

• Principal Investigator: Bruce Trapnell, Prof, Children's Hospital Medical Center, Cincinnati

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Savara Inc.
• ClinicalTrials.gov Identifier: NCT04544293
• Other Study ID Numbers: SAV006-05; 2020-001263-85
• First Posted: Sep 10, 2020
• Last Update Posted: Jun 21, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Pulmonary Alveolar Proteinosis; Autoimmune Diseases; Molgramostim; Sargramostim

Study Results

No Results Posted as of Jun 21, 2022