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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03421743

Acronym

OPTIMA

Enrollment

Registered

2018-02-05

Start date

2018-03-01

Completion date

2020-01-13

Last updated

2024-07-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Mycobacterium Infections, Nontuberculous

Brief summary

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.

Detailed description

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.

Interventions

DRUGInhaled molgramostim

300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation

DRUGAntimycobacterial regimen

Multidrug NTM guideline-based antimycobacterial regimen

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Open-label, non-controlled, multicenter, pilot clinical trial

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.

Countries

Australia, United Kingdom

Participant flow

Recruitment details

This was a multicenter study conducted in a total of 5 sites in Australia and the UK. First participant was enrolled on 1 March 2018 and last participant completed the study on 13 January 2020.

Pre-assignment details

Adults with chronic pulmonary NTM infection and a positive sputum culture at Screening were recruited into 2 groups: 1. On multidrug NTM guideline-based antimycobacterial regimen ongoing for ≥6 months prior to Baseline. 2. Had stopped multidrug NTM regimen ≥28 days prior to Screening (lack of response/intolerance)/never started such treatment.

Participants by arm

Arm	Count
Inhaled Molgramostim/Antimycobacterials Inhaled molgramostim administered in 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 Inhaled molgramostim: 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation	14
Inhaled Molgramostim Inhaled molgramostim administered in participants who remain sputum culture positive but have stopped a multidrug 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 Inhaled molgramostim: 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation	18
Total	32

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	1
Overall Study	Lack of Efficacy	1	0
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Inhaled Molgramostim/Antimycobacterials	Inhaled Molgramostim	Total
Age at NTM diagnosis	60.9 years STANDARD_DEVIATION 9.7	60.1 years STANDARD_DEVIATION 11.7	60.4 years STANDARD_DEVIATION 10.7
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	10 Participants	6 Participants	16 Participants
Age, Categorical Between 18 and 65 years	4 Participants	12 Participants	16 Participants
Age, Continuous	67.4 years STANDARD_DEVIATION 9.9	66.0 years STANDARD_DEVIATION 9	66.6 years STANDARD_DEVIATION 9.3
Baseline 6-Minute Walking Distance (6MWD)	431.0 meters STANDARD_DEVIATION 89.6	440.8 meters STANDARD_DEVIATION 107.1	436.5 meters STANDARD_DEVIATION 98.4
Baseline Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)	71.005 percent predicted STANDARD_DEVIATION 23.076	73.166 percent predicted STANDARD_DEVIATION 17.338	72.221 percent predicted STANDARD_DEVIATION 19.926
Baseline dyspnea scores	2.08 score on a scale STANDARD_DEVIATION 2.48	2.47 score on a scale STANDARD_DEVIATION 2.06	2.30 score on a scale STANDARD_DEVIATION 2.22
Baseline Forced Expiratory Volume in 1 Second (FEV1)	72.2231 percent predicted STANDARD_DEVIATION 19.101	69.7239 percent predicted STANDARD_DEVIATION 24.2097	70.8173 percent predicted STANDARD_DEVIATION 21.8175
Baseline Forced Vital Capacity (FVC)	77.1785 percent predicted STANDARD_DEVIATION 18.6934	82.7931 percent predicted STANDARD_DEVIATION 22.054	80.3367 percent predicted STANDARD_DEVIATION 20.5249
Baseline Global Rating of Health (GRH) scores	2.64 score on a scale STANDARD_DEVIATION 0.84	2.78 score on a scale STANDARD_DEVIATION 0.65	2.72 score on a scale STANDARD_DEVIATION 0.73
Baseline Lower Respiratory Tract Infections - Visual Analogue Scale (LRTI-VAS) Scores	19.71 score on a scale STANDARD_DEVIATION 9.74	14.87 score on a scale STANDARD_DEVIATION 9.29	16.99 score on a scale STANDARD_DEVIATION 9.65
Baseline Quality of Life Questionnaire - Bronchiectasis (QOL-B) scale scores Emotional functioning	83.97 score on a scale STANDARD_DEVIATION 15.76	80.09 score on a scale STANDARD_DEVIATION 13.14	81.72 score on a scale STANDARD_DEVIATION 14.18
Baseline Quality of Life Questionnaire - Bronchiectasis (QOL-B) scale scores Health perceptions	42.31 score on a scale STANDARD_DEVIATION 24.41	52.31 score on a scale STANDARD_DEVIATION 20.17	48.12 score on a scale STANDARD_DEVIATION 22.23
Baseline Quality of Life Questionnaire - Bronchiectasis (QOL-B) scale scores Physical functioning	58.46 score on a scale STANDARD_DEVIATION 29.71	61.11 score on a scale STANDARD_DEVIATION 28.21	60.00 score on a scale STANDARD_DEVIATION 28.39
Baseline Quality of Life Questionnaire - Bronchiectasis (QOL-B) scale scores Respiratory symptoms	60.01 score on a scale STANDARD_DEVIATION 21.7	66.41 score on a scale STANDARD_DEVIATION 12.75	63.72 score on a scale STANDARD_DEVIATION 17.05
Baseline Quality of Life Questionnaire - Bronchiectasis (QOL-B) scale scores Role functioning	62.05 score on a scale STANDARD_DEVIATION 32.93	74.07 score on a scale STANDARD_DEVIATION 23.97	69.03 score on a scale STANDARD_DEVIATION 28.21
Baseline Quality of Life Questionnaire - Bronchiectasis (QOL-B) scale scores Social functioning	59.83 score on a scale STANDARD_DEVIATION 27.49	56.94 score on a scale STANDARD_DEVIATION 26.97	58.15 score on a scale STANDARD_DEVIATION 26.77
Baseline Quality of Life Questionnaire - Bronchiectasis (QOL-B) scale scores Treatment burden	65.28 score on a scale STANDARD_DEVIATION 17.25	73.61 score on a scale STANDARD_DEVIATION 20.52	69.44 score on a scale STANDARD_DEVIATION 18.81
Baseline Quality of Life Questionnaire - Bronchiectasis (QOL-B) scale scores Vitality	41.03 score on a scale STANDARD_DEVIATION 23.3	55.56 score on a scale STANDARD_DEVIATION 19.8	49.46 score on a scale STANDARD_DEVIATION 22.19
Body weight	52.24 kilogram STANDARD_DEVIATION 8.84	66.50 kilogram STANDARD_DEVIATION 14.4	60.26 kilogram STANDARD_DEVIATION 14.07
NTM type Mycobacterium abscessus	3 Participants	6 Participants	9 Participants
NTM type Mycobacterium avium complex	11 Participants	13 Participants	24 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	2 Participants	2 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	14 Participants	16 Participants	30 Participants
Region of Enrollment Australia	12 participants	18 participants	30 participants
Region of Enrollment United Kingdom	2 participants	0 participants	2 participants
Sex: Female, Male Female	12 Participants	10 Participants	22 Participants
Sex: Female, Male Male	2 Participants	8 Participants	10 Participants
Smoking status Current	0 Participants	1 Participants	1 Participants
Smoking status Never	11 Participants	9 Participants	20 Participants
Smoking status Previous	3 Participants	8 Participants	11 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	2 / 14	1 / 18
other Total, other adverse events	14 / 14	18 / 18
serious Total, serious adverse events	8 / 14	6 / 18

Outcome results

Primary

Number of Participants With Sputum Culture Conversion to Negative

Sputum culture conversion is defined as at least 3 consecutive sputum samples without growth of NTM during the treatment period.

Time frame: 48 weeks

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Inhaled Molgramostim/Antimycobacterials	Number of Participants With Sputum Culture Conversion to Negative	2 Participants
Inhaled Molgramostim	Number of Participants With Sputum Culture Conversion to Negative	3 Participants

Secondary

Change From Baseline in 6-Minute Walking Distance (6MWD)

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.