A randomized, double-blind, placebo-controlled clinical trial of once-daily inhaled molgramostim nebulizer solution in adult subjects with autoimmune pulmonary alveolar proteinosis (aPAP).

Phase 3

Withdrawn

Conditions: autoimmune PAP
pulmonary alveolar proteinosis
10003816
10024967

Registration Number: NL-OMON55020

Lead Sponsor: Parexel Nederland

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Withdrawn

Sex: Not specified

Target Recruitment: 3

Inclusion Criteria

1. 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.
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 first Screening and Baseline visits.
5. Change in % predicted DLCO of <15% points during the screening period.
6. 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.
7. Resting SpO2 >85% during 15 minutes without use of supplemental oxygen at
the Screening visits.
8. Male or female
9. 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 the screening visits,
and a negative urine pregnancy test at Baseline visit (Visit 3) and must not be
lactating.
* Post-menopausal is defined as no menses for at least 12 months without an
alternative medical cause. A high follicle stimulating hormone (FSH) level in
the postmenopausal range may be used to confirm a post-menopausal state in
women not using hormonal contraception or hormonal replacement therapy.
However, in the absence of 12 months of amenorrhea, a single FSH measurement is
insufficient.
** A female is considered of childbearing potential following menarche and
until becoming post-menopausal unless permanently sterile. Permanent
sterilization methods include hysterectomy, bilateral salpingectomy and
bilateral oophorectomy.
***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.
10. 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.
11. 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 months 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, or diagnosis of
interstitial lung disease other than aPAP.
14. 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.
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.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The primary endpoint is the change in % predicted DLCO from baseline to Week<br /><br>24. The aim of this endpoint is to demonstrate treatment effect on gas<br /><br>exchange, using a standardized lung function test that has been shown to<br /><br>predict need for rescue treatment.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>- The secondary efficacy endpoints are Saint George*s Respiratory Questionnaire<br /><br>(SGRQ) Total, SGRQ Activity, exercise capacity (EC) and change in % predicted<br /><br>DLCO from baseline to Week 48. The aim of these endpoints is to serve as<br /><br>clinically meaningful endpoints that address health status and function.</p><br>