Randomized, Double-Blind, Placebo-Controlled Trial of Inhaled Molgramostim in Adults with Autoimmune Pulmonary Alveolar Proteinosis

Trial ID: 2024-511052-41-00
Protocol: SAV00605
Sponsor: Savara ApS

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Diseases & Conditions

Alveolar proteinosis

Objectives

The primary objective of this clinical trial is to investigate the **efficacy** of molgramostim compared to placebo in adult subjects with **autoimmune pulmonary alveolar proteinosis** (aPAP). This objective is clinically relevant as it aims to determine the therapeutic potential of molgramostim in improving the condition of patients suffering from aPAP, a rare lung disease characterized by the accumulation of surfactant in the alveoli, leading to impaired gas exchange and respiratory distress.

Secondary objectives include:

Investigating the **safety** of molgramostim compared to placebo. This is crucial for assessing the risk-benefit profile of the treatment, ensuring that any therapeutic benefits are not outweighed by adverse effects.

Participants

The clinical trial investigating the efficacy of molgramostim compared to placebo in patients with **Autoimmune Pulmonary Alveolar Proteinosis** includes a total of 118 participants. The study population comprises both male and female subjects, aged 18 years and older, with specific age criteria for participants in Japan set at 20 years and above. Participants were selected based on their ability to provide informed consent and comply with the trial's requirements, including scheduled visits and procedures. The trial population includes individuals with a confirmed diagnosis of autoimmune PAP, as evidenced by a serum anti-GM-CSF autoantibody test and a history of PAP confirmed through lung biopsy, bronchoalveolar lavage cytology, or high-resolution computed tomography of the chest. Participants are required to have a DLCO of 70% predicted or lower and demonstrate a change in % predicted DLCO of less than 15% during the screening period. Lifestyle considerations include the ability to discontinue supplemental oxygen use during specific assessments and maintaining a resting SpO2 greater than 85% without supplemental oxygen. The trial includes both male and female participants, with contraceptive use required in accordance with local regulations. The study also involves a vulnerable population, ensuring additional ethical considerations are in place.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of once-daily inhaled **molgramostim** nebulizer solution in adult subjects diagnosed with **autoimmune pulmonary alveolar proteinosis** (aPAP). The trial aims to compare the effects of molgramostim against a placebo over a period of 96 weeks. Participants will be randomly assigned to receive either the active treatment or placebo, ensuring that neither the participants nor the investigators are aware of the group assignments, thus maintaining the double-blind nature of the study.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, ability to provide informed consent, and a confirmed diagnosis of aPAP. The primary endpoint is the change in the percentage of predicted DLCO from baseline to Week 24, with secondary endpoints including changes in DLCO and SGRQ scores at Weeks 24 and 48. Participants will undergo regular follow-up visits to monitor their health status, adherence to the treatment regimen, and any adverse events. These visits will include assessments such as DLCO tests, treadmill exercise tests, and arterial blood gas sampling.

The expected duration of participant involvement is approximately 96 weeks, with the trial estimated to conclude by December 31, 2026. Participants may be withdrawn from the study early if they experience significant adverse effects, are unable to comply with the study protocol, or if the investigator deems it necessary for their safety. The end-of-study visit will involve a final assessment to evaluate the overall impact of the treatment and to ensure the well-being of the participants as they exit the trial.

Treatment

The clinical trial involves the administration of **Molgradex**, an experimental medication formulated as a **solution for inhalation**. The active substance in Molgradex is **molgramostim**, which is provided by Serendex Pharmaceuticals A/S. The medication is administered via **inhalation use**. The dosing regimen for Molgradex is a maximum daily dose of 300 micrograms, with a total maximum dose of 201,600 micrograms over a treatment period of 96 days. The trial aims to evaluate the efficacy of Molgradex in adult subjects diagnosed with autoimmune pulmonary alveolar proteinosis (aPAP).

In addition to the experimental treatment, the study includes a **placebo nebulizer solution** as a comparator. The placebo is designed to mimic the pharmaceutical form of the active treatment but does not contain the active substance, molgramostim. The placebo is administered in the same manner as Molgradex, via inhalation, to maintain the double-blind nature of the trial. This ensures that neither the participants nor the investigators are aware of which treatment is being administered, thereby reducing bias and allowing for a more accurate assessment of Molgradex's efficacy.

Efficacy

The efficacy of molgramostim in the treatment of **autoimmune pulmonary alveolar proteinosis (aPAP)** will be assessed through a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the change in the percentage of predicted diffusing capacity of the lung for carbon monoxide (DLCO) from baseline to Week 24. Secondary endpoints include changes in the percentage of predicted DLCO from baseline to Week 48, changes in the St. George's Respiratory Questionnaire (SGRQ) Total and Activity scores from baseline to Weeks 24 and 48, and changes in exercise capacity (EC), expressed as peak metabolic equivalents (METs), from baseline to Weeks 24 and 48.

Measurements will be collected at specified timepoints, including baseline, Week 24, and Week 48, using validated scales and tests. The DLCO will be assessed through pulmonary function tests, while the SGRQ scores will be obtained through patient-reported outcomes. Exercise capacity will be measured using standardized exercise tests to determine peak METs. Data collection and analysis will adhere to the trial protocol to ensure the reliability and validity of the efficacy assessments.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subject must be ≥18 years of age, at the time of signing the informed consent. Specific for Japan; Subject must be ≥20 years of age, at the time of signing the informed consent.
A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.
History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest.
DLCO 70% predicted or lower at the first screening and Baseline visits
Change in % predicted DLCO of <15% points during the screening period.
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.
Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at the Screening visits.
Male or female
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a. 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. b. 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 Screening (Visit 1) and a negative urine pregnancy test at baseline (Visit 3) and must not be lactating. *Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the trial treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
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.
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.

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Exclusion Criteria

Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant production.
Inflammatory or autoimmune disease of a severity that necessitates significant (e.g. more than 10 mg/day systemic prednisolone) immunosuppression.
Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product.
History of, or present, myeloproliferative disease or leukemia.
Apparent pre-existing concurrent pulmonary fibrosis, or diagnosis of interstitial lung disease other than aPAP.
Acute or unstable cardiac or pulmonary disease that may be aggravated by exercise or confound assessment of the primary endpoint: including presence of pulmonary edema, or diagnosis of chronic obstructive pulmonary disease (COPD), pulmonary vasculitis, or pulmonary hypertension.
Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect the efficacy evaluation in the trial.
Physical disability or other condition that precludes safe and adequate exercise testing.
Any other serious medical condition which in the opinion of the Investigator would make the subject unsuitable for the trial
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.
WLL performed within 3 months prior to baseline.
Requirement for WLL at screening or baseline.
GM-CSF treatment within 6 months prior to baseline.
Treatment with rituximab within 6 months prior to baseline.
Treatment with plasmapheresis within 6 weeks months prior to baseline.
Treatment with any investigational medicinal product within 5 half- lives or 3 months (whichever is longer) prior to baseline.
Previously randomized in this trial.
History of allergic reactions to GM-CSF or any of the excipients in the nebulizer solution.
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, including as further defined by French Health Code articles L1121-6, L1121-8, and L1121-8-1.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	19 May 2021	1
France	Not Recruiting	19 May 2021	8
Germany	Not Recruiting	19 May 2021	7
Ireland	Not Recruiting	19 May 2021	1
Italy	Not Recruiting	19 May 2021	9
Poland	Not Recruiting	19 May 2021	3
Portugal	Not Recruiting	19 May 2021	1
Romania	Not Recruiting	19 May 2021	2
Spain	Not Recruiting	19 May 2021	2