Pilot Trial of Inhaled Molgramostim in Nontuberculous Mycobacterial (NTM) Infection

Study Overview
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Brief Summary
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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 Nontuberculous Mycobacterial (NTM) infection. Subject will be treated for 24-weeks with inhaled molgramostim and will be 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.

Detailed Description
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The study will comprise a Screening Visit, Baseline Visit, a 24-week treatment period and a 12-week follow up period. The Screening Visit (Visit 1) will be conducted up to 10 weeks prior to the Baseline Visit (Visit 2) to determine eligibility. Adult subjects with a history of chronic Nontuberculous Mycobacterial (NTM) infection with at least 2 positive cultures in the prior two years, of which at least one is within the last 6 months prior to Screening, will be considered for enrollment. Subjects should provide a positive NTM sputum culture at Screening to be eligible. Two subgroups of subjects will be recruited: Group 1: 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. Group 2: 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. The study will include 30 subjects.

Official Title
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An Open-label, Non-controlled, Multicentre, Pilot Clinical Trial of Inhaled Molgramostim in Subjects With Antibiotic-resistant Non-tuberculosis Mycobacterial (NTM) Infection

Conditions
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Mycobacterium Infections, Nontuberculous

Intervention / Treatment
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* Drug: Inhaled molgramostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). 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. 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. Female or male ≥18 years of age. 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. 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. Willing and able to provide signed informed consent. 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: Subjects diagnosed with cystic fibrosis. Prior therapy with inhaled or systemic GM-CSF. Subjects with hemoptysis of ≥60 mL in a 24 hour period within 4 weeks prior to Screening. Concurrent disease with a life expectancy of less than 6 months. History of, or present, myeloproliferative disease, leukemia or other hematological malignancy. 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. 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. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to Screening. HIV infection or other disease associated with significant immunodeficiency. History of lung transplantation. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior to Screening. Treatment with any investigational medicinal product within 3 months of Screening. Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product Any other serious medical condition which in the opinion of the investigator would make the subject unsuitable for the trial. -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, non-controlled, multicenter, pilot clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled molgramostim/antimycobacterials<br>Inhaled molgramostim administered in subjects who remain sputum culture positive while currently on a multidrug Nontuberculous Mycobacterial (NTM) guideline based antimycobacterial regimen, which has been ongoing for at least 6 months prior to the Baseline Visit | Drug: Inhaled molgramostim<br>* 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation<br>* Other names: rh-GM-CSF;|
| Experimental: Inhaled molgramostim<br>Inhaled molgramostim administered in subjects who remain sputum culture positive but have stopped a multidrug Nontuberculous Mycobacterial (NTM) guideline based antimycobacterial regimen at least 28 days prior to Screening due to lack of response or intolerance, or who never started such treatment | Drug: Inhaled molgramostim<br>* 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation<br>* Other names: rh-GM-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with sputum culture conversion to negative | Sputum culture conversion is defined as at least three consecutive sputum samples without growth of Nontuberculous Mycobacteria (NTM) during the treatment period. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with sputum smear conversion to negative | 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 subjects who were smear positive at Baseline. | 48 weeks | 
| Number of subjects with durable sputum culture conversion | 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. | 60 weeks | 
| Number of subjects with durable sputum smear conversion | 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 subjects who were smear positive at Baseline. | 60 weeks | 
| Change in semi-quantitative grade of number of NTM on microscopy of AFB stained sputum smears |  | 60 weeks | 
| Change in semi-quantitative grade of sputum cultures |  | 60 weeks | 
| Change in symptom scores (assessed using Lower Respiratory Tract Infections - Visual Analogue Scale (LRTI-VAS) |  | 60 weeks | 
| Change in Quality of Life scores (assessed using Quality of Life Questionnaire - Bronchiectasis (QOL-B)) |  | 60 weeks | 
| Change in Global Rating of Health (GRH) |  | 60 weeks | 
| Change in body weight |  | 60 weeks | 
| Change in 6-minute walk distance (6MWD) |  | 60 weeks | 
| Change in oxygen desaturation during a 6-minute walk test (6MWT) |  | 60 weeks | 
| Change in Borg CR10 scores for dyspnea during a 6MWT |  | 60 weeks | 
| Number of adverse events (AEs) during the trial period |  | 60 weeks | 
| Number of serious AEs (SAEs) during the trial period |  | 60 weeks | 
| Number of adverse drug reactions (ADRs) during the trial period |  | 60 weeks | 
| Number of severe AEs during the trial period |  | 60 weeks | 
| Number of AEs leading to treatment discontinuation during the trial period |  | 60 weeks | 
| Change in white blood cell counts (WBC) in blood |  | 60 weeks | 
| Change in white cell differential counts in blood |  | 60 weeks | 
| Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) |  | 48 weeks | 
| Change in forced expiratory volume in 1 second (FEV1) (% predicted) |  | 48 weeks | 
| Change in forced vital capacity (FVC) (% predicted) |  | 48 weeks | 
| Number of subjects with development of anti-molgramostim antibodies in serum |  | 60 weeks |