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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04544293
Recruitment Status : Recruiting
First Posted : September 10, 2020
Last Update Posted : December 15, 2022
Sponsor:
Information provided by (Responsible Party):
Savara Inc.

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Subject 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
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF)

Drug: Placebo
Matching placebo


Outcome Measures
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Primary Outcome Measures :
  1. Change from baseline in percentage (%) predicted diffusing capacity of the lung for carbon monoxide (DLCO) to Week 24 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: From Baseline to Weeks 4 and 24 ]
    Assessment of the safety of MOL compared to placebo


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

    1. 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.
    2. 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.
  11. 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.
  12. 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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04544293


Contacts
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Contact: Raymond D Pratt, MD +1 (240) 899-7050 info@savarapharma.com
Contact: Brian T Maurer +1 (512) 774-5786 info@savarapharma.com

Locations
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Sponsors and Collaborators
Savara Inc.
Investigators
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Principal Investigator: Bruce Trapnell, MD Children's Hospital Medical Center, Cincinnati
More Information
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Responsible Party: Savara Inc.
ClinicalTrials.gov Identifier: NCT04544293    
Other Study ID Numbers: SAV006-05
2020-001263-85 ( EudraCT Number )
First Posted: September 10, 2020    Key Record Dates
Last Update Posted: December 15, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pulmonary Alveolar Proteinosis
Autoimmune Diseases
Lung Diseases
Respiratory Tract Diseases
Immune System Diseases
 Molgramostim
Sargramostim
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents