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

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.

• Inhaled molgramostim (Drug), also known as rh-GM-CSF: 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation
• Antimycobacterial regimen (Drug): Multidrug NTM guideline-based antimycobacterial regimen

Primary outcomes

• Number of Participants With Sputum Culture Conversion to Negative [48 weeks]: Sputum culture conversion is defined as at least 3 consecutive sputum samples without growth of NTM during the treatment period.

Secondary outcomes

• Number of Participants With Sputum Smear Conversion to Negative [48 weeks]: Sputum smear conversion is defined as at least three consecutive negative acid-fast bacilli (AFB) stained sputum smears on microscopy during the treatment period among participants who were smear positive at Baseline.
• Number of Participants With Durable Sputum Culture Conversion [60 weeks]: Durability is defined as sputum culture conversion at or before Week 24 and culture still negative for growth of NTM at 12-weeks follow-up.
• Number of Participants With Durable Sputum Smear Conversion [60 weeks]: Durability is defined as sputum smear conversion at or before Week 48 and AFB stained smear still negative for NTM at 12-weeks follow-up among participants who were smear positive at Baseline.
• Change From Baseline in Symptom Scores (Assessed Using Lower Respiratory Tract Infections - Visual Analogue Scale) [Baseline to Week 48]: For each of the clinical symptoms of Lower Respiratory Tract Infections (dyspnea, fatigue, cough, pain, and sputum), the participant assessed the severity using a 10 cm visual analogue scale (VAS) ranging from 0 = no symptoms to 10 = worst possible symptoms. A total LRTI score was calculated by summing up the score of each symptom (i.e., total LRTI score ranged from 0 to 50).
• Change From Baseline in Symptom Scores (Assessed Using Quality of Life Questionnaire - Bronchiectasis (QOL-B)) [Baseline to Week 48]: The QOL-B questionnaire including 37 items on 8 scales (emotional functioning, health perceptions, physical functioning, respiratory symptoms, role functioning, social functioning, treatment burden, vitality) was used to assess participant's quality of life (QoL). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardised on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and QoL. Scales contain between 3 and 9 items, thus changing 1 answer category will correspond to a change of 11.1 to 3.7 points.
• Change From Baseline in Global Rating of Health (GRH) [Baseline to Week 48]: GRH was assessed as an interviewer questionnaire, which assesses global health as "excellent, good, fair or poor". For analysis, these were scored as 1 (poor) to 4 (excellent).
• Change From Baseline in Body Weight [Baseline to Week 48]
• Change From Baseline in 6-Minute Walking Distance (6MWD) [Baseline to Week 48]: The 6-minute walk test (6MWT) was performed in accordance with the European Respiratory Society/American Thoracic Society (ERS/ATS) guideline by technicians with documented training and experience. The 6MWT was performed twice at each visit.
• Change From Baseline in Dyspnea Scores During a 6MWT [Baseline to Week 48]
• Number of Adverse Events (AEs) During the Trial Period [60 weeks]: All trial subjects were carefully monitored for the occurrence of AEs during the trial period from Baseline (Visit 2) to the 12-week Follow-up visit (Visit 15). AEs were collected by the investigator by a non-leading question and by reporting events directly observed or spontaneously volunteered by participants. Participants were also encouraged to contact the clinic in between visits if they experienced AEs or had any concerns.
• Number of Serious AEs (SAEs) During the Trial Period [60 weeks]: SAEs were defined as any untoward medicinal occurrence or effect that at any dose: * Results in death * Is life-threatening * Requires hospitalisation or prolongation of existing hospitalisation * Results in persistent or significant disability or incapacity * Is a congenital abnormality or birth defect * May jeopardise the participant or may require medical intervention to prevent one or more of the outcomes listed above (Important Medical Events).
• Number of Adverse Drug Reactions (ADRs) During the Trial Period [60 weeks]: All AEs were assessed by the investigator for causality (unlikely, possible, probable, not applicable) according to current regulatory standards. AEs which had a 'possible' or 'probable' causality were classified as ADRs.
• Number of Severe AEs During the Trial Period [60 weeks]: All AEs were assessed by the investigator for severity (mild, moderate, severe) according to current regulatory standards.
• Number of Participants Withdrawn From Treatment Due to an AE During the Trial Period [60 weeks]
• Change From Baseline in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) [Baseline to Week 48]
• Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) (% Predicted) [Baseline to Week 48]
• Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) [Baseline to Week 48]
• Number of Subjects With Development of Anti-GM-CSF Antibodies in Serum [60 weeks]: Analyses for anti-GM-CSF antibodies were performed at a central laboratory.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Number of Participants With Sputum Culture Conversion to Negative (Primary), Count of participants, Participants: Inhaled Molgramostim/Antimycobacterials 2; Inhaled Molgramostim 3
• Number of Participants With Sputum Smear Conversion to Negative (Secondary), Count of participants, Participants: Inhaled Molgramostim/Antimycobacterials 5; Inhaled Molgramostim 6
• Number of Participants With Durable Sputum Culture Conversion (Secondary), Count of participants, Participants: Inhaled Molgramostim/Antimycobacterials 1; Inhaled Molgramostim 1
• Number of Participants With Durable Sputum Smear Conversion (Secondary), Count of participants, Participants: Inhaled Molgramostim/Antimycobacterials 5; Inhaled Molgramostim 6
• Change From Baseline in Symptom Scores (Assessed Using Lower Respiratory Tract Infections - Visual Analogue Scale) (Secondary), Mean, score on a scale: Inhaled Molgramostim/Antimycobacterials 2.48 +/- 9.13; Inhaled Molgramostim 4.32 +/- 13.32
• Change From Baseline in Symptom Scores (Assessed Using Quality of Life Questionnaire - Bronchiectasis (QOL-B)) (Secondary), Mean, score on a scale: Inhaled Molgramostim/Antimycobacterials 0.00 +/- 8.33; Inhaled Molgramostim 3.12 +/- 12.12
• Change From Baseline in Global Rating of Health (GRH) (Secondary), Mean, score on a scale: Inhaled Molgramostim/Antimycobacterials -0.78 +/- 0.67; Inhaled Molgramostim -0.38 +/- 0.81
• Change From Baseline in Body Weight (Secondary), Mean, kilogram: Inhaled Molgramostim/Antimycobacterials -1.77 +/- 2.51; Inhaled Molgramostim -1.44 +/- 3.09
• Change From Baseline in 6-Minute Walking Distance (6MWD) (Secondary), Mean, meter: Inhaled Molgramostim/Antimycobacterials -17.1 +/- 62.5; Inhaled Molgramostim 12.5 +/- 56.2
• Change From Baseline in Dyspnea Scores During a 6MWT (Secondary), Mean, score on a scale: Inhaled Molgramostim/Antimycobacterials 0.79 +/- 0.92; Inhaled Molgramostim 1.43 +/- 3.01
• Number of Adverse Events (AEs) During the Trial Period (Secondary), Number, events: Inhaled Molgramostim/Antimycobacterials 199; Inhaled Molgramostim 223
• Number of Serious AEs (SAEs) During the Trial Period (Secondary), Number, events: Inhaled Molgramostim/Antimycobacterials 14; Inhaled Molgramostim 17
• Number of Adverse Drug Reactions (ADRs) During the Trial Period (Secondary), Number, events: Inhaled Molgramostim/Antimycobacterials 67; Inhaled Molgramostim 81
• Number of Severe AEs During the Trial Period (Secondary), Number, events: Inhaled Molgramostim/Antimycobacterials 5; Inhaled Molgramostim 6
• Number of Participants Withdrawn From Treatment Due to an AE During the Trial Period (Secondary), Count of participants, Participants: Inhaled Molgramostim/Antimycobacterials 3; Inhaled Molgramostim 2
• Change From Baseline in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) (Secondary), Mean, percent predicted: Inhaled Molgramostim/Antimycobacterials -4.565 +/- 8.198; Inhaled Molgramostim -3.079 +/- 7.766
• Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) (% Predicted) (Secondary), Mean, percent predicted: Inhaled Molgramostim/Antimycobacterials -1.7986 +/- 10.2133; Inhaled Molgramostim -3.4011 +/- 6.9830
• Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) (Secondary), Mean, percent predicted: Inhaled Molgramostim/Antimycobacterials -2.4575 +/- 6.6511; Inhaled Molgramostim -2.6135 +/- 7.7040
• Number of Subjects With Development of Anti-GM-CSF Antibodies in Serum (Secondary), Count of participants, Participants: Inhaled Molgramostim/Antimycobacterials 5; Inhaled Molgramostim 10

Adverse events

Time frame: Baseline to 12-week follow-up (60 weeks in total).

Serious adverse events by term

Other adverse events by term

Limitations and caveats: This was an exploratory study without hypothesis testing. Only descriptive statistics were used. The study included participants with treatment refractory NTM infection, who were severely affected by their background disease (in most cases bronchiectasis). These participants probably had an even lower potential for improvement than was assumed prior to the study. The study was further limited by the lack of a placebo control.

• Results publication: Thomson RM, Loebinger MR, Burke AJ, Morgan LC, Waterer GW, Ganslandt C. OPTIMA: An Open-Label, Noncomparative Pilot Trial of Inhaled Molgramostim in Pulmonary Nontuberculous Mycobacterial Infection. Ann Am Thorac Soc. 2024 Apr;21(4):568-576. doi: 10.1513/AnnalsATS.202306-532OC. PMID 37948736

• Study Protocol (PDF, 2018-10-04)
• Statistical Analysis Plan (PDF, 2020-02-19)

• Grant Waterer, Prof., Principal investigator, Royal Perth Hospital

NIH grants: 2017