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

An Open-label, Non-controlled, Multicentre, Pilot Clinical Trial of Inhaled Molgramostim in Subjects With Antibiotic-resistant Non-tuberculosis 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.

Study Overview

• Status: Completed
• Conditions: Mycobacterium Infections, Nontuberculous
• Intervention / Treatment: Drug: Inhaled molgramostim; Drug: Antimycobacterial regimen

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital
  • Queensland
    • Chermside West, Queensland, Australia, 4032
      • The Prince Charles Hospital
    • Greenslopes, Queensland, Australia, 4120
      • Greenslopes Private Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• United Kingdom
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Inhaled molgramostim; 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation; Other Names: rh-GM-CSF; Drug: Antimycobacterial regimen; Multidrug NTM guideline-based antimycobacterial regimen
Experimental: 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	Drug: Inhaled molgramostim; 300 µg / dose molgramostim (recombinant human GM-CSF) for inhalation; Other Names: rh-GM-CSF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants 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 participants who were smear positive at Baseline.	48 weeks
Number of Participants 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 Participants 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 participants who were smear positive at Baseline.	60 weeks
Change From Baseline in Symptom Scores (Assessed Using Lower Respiratory Tract Infections - Visual Analogue Scale)	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).	Baseline to Week 48
Change From Baseline in Symptom Scores (Assessed Using Quality of Life Questionnaire - Bronchiectasis (QOL-B))	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.	Baseline to Week 48
Change From Baseline in Global Rating of Health (GRH)	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).	Baseline to Week 48
Change From Baseline in Body Weight		Baseline to Week 48
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.	Baseline to Week 48
Change From Baseline in Dyspnea Scores During a 6MWT		Baseline to Week 48
Number of Adverse Events (AEs) During the Trial Period	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.	60 weeks
Number of Serious AEs (SAEs) During the Trial Period	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).	60 weeks
Number of Adverse Drug Reactions (ADRs) During the Trial Period	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.	60 weeks
Number of Severe AEs During the Trial Period	All AEs were assessed by the investigator for severity (mild, moderate, severe) according to current regulatory standards.	60 weeks
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	Analyses for anti-GM-CSF antibodies were performed at a central laboratory.	60 weeks

Collaborators and Investigators

• Sponsor: Savara Inc.
• Investigators: Principal Investigator: Grant Waterer, Prof., Royal Perth Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): October 15, 2019
• Study Completion (Actual): January 13, 2020

Study Registration Dates

• First Submitted: January 16, 2018
• First Submitted That Met QC Criteria: January 29, 2018
• First Posted (Actual): February 5, 2018

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Infections; Communicable Diseases; Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunologic Factors; Anti-Bacterial Agents; Sargramostim; Molgramostim
• Other Study ID Numbers: SAV008-01; 2017-003374-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No