Pilot Trial of Inhaled Molgramostim in Non-tuberculous Mycobacterial (NTM) Infection

The trial is an open-label, non-controlled, multicenter, pilot clinical trial of inhaled molgramostim (recombinant human granulocyte-macrophage colony stimulating factor; rhGM-CSF) in subjects with persistent pulmonary non-tuberculous mycobacterial (NTM) infection. Participants will be treated for 24-weeks with inhaled molgramostim and followed up for 12-weeks after end of treatment. The primary aim of the trial is to investigate the efficacy of inhaled molgramostim on NTM sputum culture conversion to negative.

The study will comprise a Screening Visit, a Baseline Visit, a 24-week treatment period and a 12-week follow-up period. 30 adult participants with a history of chronic NTM infection with at least 2 positive cultures in the prior 2 years, of which at least one is within the last 6 months prior to Screening, will be considered for enrollment. Participants should provide a positive NTM sputum culture at Screening to be eligible.

Two subgroups of participants will be recruited:

* Group 1: Participants who remain sputum culture positive while currently on a multidrug NTM guideline based antimycobacterial regimen, which has been ongoing for at least 6 months prior to the Baseline Visit.
* Group 2: Participants who remain sputum culture positive but have either stopped a multidrug NTM guideline based antimycobacterial regimen at least 28 days prior to Screening due to lack of response or intolerance, or never started such treatment.

The treatment period will consist of 14 trial visits (Screening \[within 10 weeks of Baseline\], Baseline, and every 4 weeks to Week 48 \[visits at Weeks 28, 36 and 44 included telephone contact, others included clinic visits\]) and a Follow-up visit 12 weeks after the end of treatment.

At the Baseline visit, eligible participants will start treatment with molgramostim nebulizer solution, 300 μg, administered by inhalation using an eFlow Nebulizer System. At each visit, sputum samples will be collected for staining and microscopy, and microbiological culture. In addition, clinical assessments including body weight, patient reported outcomes, and diffusion capacity of the lung for carbon monoxide (DLCO) will be conducted at each clinic visit. Spirometry will be assessed at Baseline, and at Weeks 12, 24, 32, 40 and 48. A 6-minute walk test (6-MWT) will be conducted at Baseline, at Weeks 12, 24, 48 and at the 12-week Follow-up visit. Safety laboratory samples will be collected at Screening, Baseline and at Weeks 4, 12, 24, 32, 40, 48 and at the 12-week Follow-up visit. Anti-GM-CSF antibodies will be assessed at Baseline, at Week 4, 12, 24, 32, 48, and at the 12-week Follow-up visit.

Eligibility Criteria:
Inclusion Criteria:

1. History of chronic pulmonary infection with MAC or M. abscessus (defined as at least 2 documented positive sputum cultures in the prior 2 years, of which at least one was obtained in the 6 months prior to Screening).
2. Subject fulfills one of the following criteria:

   * Subjects who remain sputum culture positive while currently on a multidrug NTM guideline based antimycobacterial regimen, which has been ongoing for at least 6 months prior to the Baseline Visit
   * Subjects who remain sputum culture positive but have either stopped a multidrug NTM guideline based antimycobacterial regimen at least 28 days prior to Screening due to lack of response or intolerance, or never started such treatment.
3. Ability to produce at least 2 mL of sputum or be willing to undergo an induction that produces at least 2 mL of sputum for clinical evaluation.
4. Female or male ≥18 years of age.
5. Females who have been post-menopausal for more than 1 year or females of childbearing potential after a confirmed menstrual period using a highly efficient method of contraception (i.e. a method with less than 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 thirty (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 dosing at Baseline (Visit 2) and must not be lactating.
6. Males agreeing to use condoms during and until thirty (30) days after last dose of medication, or males having a female partner who is using adequate contraception as described above.
7. Willing and able to provide signed informed consent.
8. 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. Subjects diagnosed with cystic fibrosis.
2. Prior therapy with inhaled or systemic GM-CSF.
3. Subjects with hemoptysis of ≥60 mL in a 24 hour period within 4 weeks prior to Screening.
4. Concurrent disease with a life expectancy of less than 6 months.
5. History of, or present, myeloproliferative disease, leukemia or other hematological malignancy.
6. Active pulmonary malignancy (primary or metastatic); or any malignancy requiring chemotherapy or radiation therapy within one year prior to Screening or anticipated during the study period.
7. Active allergic bronchopulmonary mycosis or connective tissue disease, inflammatory bowel disease or other autoimmune disorder requiring therapy associated with significant immunosuppression, such as systemic corticosteroids at a dose equivalent of 10 mg/day or more of prednisolone, within 3 months prior to Screening or anticipated during the study period.
8. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening.
9. HIV infection or other disease associated with significant immunodeficiency.
10. History of lung transplantation.
11. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior to Screening.
12. Treatment with any investigational medicinal product within 3 months of Screening.
13. Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product
14. Any other serious medical condition which in the opinion of the investigator would make the subject unsuitable for the trial.